Podcasts about th17

#56. Ting som nevnes i denne episoden: aktivering av T- og B-celler. Effektorceller versus hukommelsesceller. Th1 vs Th2 vs Th17 vs. follikulære T-hjelpeceller. CD40 og CD40 ligand (CD40L). Antistoffproduserende celler (plasmablaster og plasmaceller). Opsonisering. Antistoffavhengig cellemediert cytotoksisitet (ADCC). Komplementmediert cytotoksisitet (CDC).Tredje sesong er muliggjort gjennom et stipend fra Norsk revmatologisk forening. Hosted on Acast. See acast.com/privacy for more information.

Trample Damage joins us once again in the present to follow up on our initial review and take an in depth look at all the pieces of TH17, and how they add up to the current endgame experience. You can find all Trample's Content through this link, and you can support him in game with code "trample" for all Supercell game purchases. You can also support this podcast by using either code "coolrick" or code "spencer" or just by sharing our episodes with your clan and friends. Here's a fun random YT Channel link as thanks to a friendTimestamps:(00:00) Intro(02:20) Firespitters(10:47) Giga Bomb and Inferno Artillery(15:58) 3rd Merges(23:54) Throwers(27:56) Minion Prince(33:55) Yeti Bombs(41:44) MGT, Furnace, Sneezy(44:56) QoL Changes(52:05) Final Grades(1:00:54) Listener Questions and Shoutouts

6 months ago Trample Damage and Cool Rick got a peek at TH17 in Helsinki during the World Finals week. This is our initial reactions to what we saw. Next episode Trample will return for a mid lifecycle TH17 review to discuss what we got right, what we got wrong, and what we want for the rest of this year. Timestamps:(00:00) Intro and Initial Reactions(04:53) Defense(21:39) Overall Difficulty and Offense(44:42) Give me a Grade for Th17

A proteína STING atua como moduladora da atividade das células do grupo TH17, que são essenciais na defesa do organismo contra bactérias e fungos, mas quando trabalham em excesso provocam inflamações descontroladas

Send us a textShort Summary: How diet shapes the gut microbiome and impacts health, with microbiologist Dr. Peter Turnbaugh breaking down the complex science.About the guest: Peter Turnbaugh, PhD is a professor of microbiology and immunology at the University of California, San Francisco, where he leads a lab studying the gut microbiome's role in nutrition and drug response.Note: Podcast episodes are fully available to paid subscribers on the M&M Substack and everyone on YouTube. Partial versions are available elsewhere. Full transcript and other information on Substack.Episode Summary: Nick talks to Peter Turnbaugh discuss the pitfalls of oversimplified diet labels in research, Turnbaugh's studies comparing plant-based and animal-based diets in humans, and how these shifts rapidly alter gut microbes and short-chain fatty acid profiles. Key Takeaways:The term “high-fat diet” in research is often misleading, as it can include high carbs and vary widely, complicating study comparisons.In a 2014 study, switching humans to a plant-based (high-fiber) or animal-based (ketogenic, no-fiber) diet changed their gut microbiome within one day, showing its remarkable adaptability.Ketogenic diets reduce Bifidobacterium in the gut, which may lower inflammation-linked immune cells (Th17), potentially aiding conditions like multiple sclerosis.Short-chain fatty acids (e.g., butyrate) don't just come from fiber; they persist even on zero-fiber ketogenic diets, hinting at alternative microbial pathways.Gut microbes can activate or deactivate drugs, like antibiotics or digoxin, suggesting microbiomes may explain why drugs work differently across individuals.Ketone bodies like BHB alone can mimic some ketogenic diet effects on the microbiome and immunity, simplifying research and hinting at therapeutic potential.Related episode:M&M #203: Metagenomics, Microbiome Transmission, Gut Microbiome in Health & Disease | Nicola Segata*Not medical advice.Support the showAll episodes, show notes, transcripts, etc. at the M&M Substack Affiliates: Lumen device to optimize your metabolism for weight loss or athletic performance. Use code MIND for 10% off. Readwise: Organize and share what you read. Athletic Greens: Comprehensive & convenient daily nutrition. Free 1-year supply of vitamin D with purchase. KetoCitra—Ketone body BHB + potassium, calcium & magnesium, formulated with kidney health in mind. Use code MIND20 for 20% off any subscription. MASA Chips—delicious tortilla chips made from organic corn and grass-fed beef tallow. No seed oils or artificial ingredients. Use code MIND for 20% off. For all the ways you can support my efforts

Grab a beverage and join Kat, Darth Yoda and CallMeTee as we review TH17 and the February update and discuss the ore economy in Clash of Clans!

The first TH17 update brings us the Multi Gear Tower, Troop Launcher, Minion Prince Metal Pants, and loads of QoL changes.Use code "corrupt" to support our guest with any in game purchases and⁠ check out his content on youtube.Timestamps:(00:00) Intro(01:43) Multi Gear Tower(07:49) Troop Launcher(16:49) New Troop and Spell Levels(24:40) Defense Levels and Supercharging(31:13) Metal Pants(36:03) Snake Bracelet and Rethinking Equipment(42:03) The Alchemist(46:37) Quality of Life and Misc(1:02:13) Listener Questions

RedThorn's own swashbuckling coleader - King Redbeard - joins Kat to talk about TH17, the Blood & Legends tournament and what is going on with Clash of Clans these days!?

www.twitch.tv/crystal2joinhttp://discord.gg/buG3ETtZZr

Kat, $C-Note$ and Ace sat down to celebrate the ClashMas Season and give their thoughts on TH17 so far.

Controllable Heroes event, Clashmas cosmetics, and what we want from the future of TH17. Links: ⁠Minion Prince fanart contest⁠ ⁠Into the Clash-iverse Spotify episode 1⁠ (its also on Apple) Timestamps: (00:00) Intro (01:53) Controllable Heroes (07:10) Treasure Chests (12:21) Clashmas Cosmetics (21:31) Talkin TH17 (28:57) Hero Hall and Future of Heroes (36:03) Next Update Requests (43:20) Listener Questions (54:14) Shoutouts and Goodbye

Introducing the Teagle! CallMeTee and Darth Yoda from Sons of Guns join Kat to review TH16, the TH17 update. Plus a discussion about Hard Mode and Yoda tells us how he really feels about Legends League.

An autoimmune disease is a condition in which the immune system attacks its own tissues. It is typically characterized by low regulatory T-cells and high Th17 and Th2 cells. T-reg cells prevent autoimmune diseases by supporting an appropriate immune response. There are natural ways to support your immune system so that it operates at an optimal level. Poor gut health and gut inflammation can block the function of vitamin D3. Without enough vitamin D, T-reg cells do not work properly. The majority of the population is vitamin D-resistant. To support the immune system, you need 8,000 to 10,000 IU of vitamin D daily, but even more to overcome resistance. Poor gut health, inflammation, and low vitamin D are a perfect storm for developing an autoimmune condition. B. infantis and L. reuteri are vital for your immune system, but many people don't have them because these probiotics are very sensitive to antibiotics. These two important microbes help prevent autoimmune diseases, greatly affect T-reg cells, and suppress inflammatory immune cells. L. reuteri helps increase oxytocin, one of the most potent anti-stress hormones. High cortisol levels mean high stress, which suppresses the immune system. The best way to consume l. reuteri is to cultivate it in a dairy product. If you're low in selenium, you will have higher amounts of inflammatory immune cells. Selenium helps lower Th17, Th2 cells, and auto-antibodies involved in autoimmune disorders. Prolonged fasting can improve your immune system by increasing T-reg cells and creating new stem cells. L. reuteri strain https://www.amazon.com/BioGaia-Osfort... Super Gut book link: https://amzn.to/4dIxTy2 Yogurt Recipe: https://www.culturedfoodlife.com/reci... **I am finding that using only ONE TBS of prebiotic fiber in the recipe makes a better-quality product. How to Make It: https://drdavisinfinitehealth.com/201...https://www.culturedfoodlife.com/l-re... MICROBIOME MASTER CLASS WEBSITE: https://innercircle.drdavisinfinitehe... Yogurt Maker—https://lvnta.com/lv_lrJY1A8ZLtxmwUpYdX Yogurt Jars—https://lvnta.com/lv_qB2B90JNh0hQjaMoXk Yogurt Containers—https://lvnta.com/lv_SFt3wnanoNkBHrf0Rs

Kat sat down with Duck from the Good Guys to discuss the aftermath of th16 and what he hopes to see from TH17. Plus... the great Mutant Possum reveal!!

Today, we're going to take a look at the underlying cause of autoimmune disease. Your immune system has two parts: the innate immune system that you're born with and the acquired immune system that's created through a series of infections. Over time, the acquired immune system becomes stronger and offers protection against infection. The innate immune system is not the problem when it comes to autoimmune diseases. Autoimmune disorders typically involve problems with the T-regulatory cells or T-cells. Also called suppressor T-cells, these cells are the peacemakers of the immune system and stop the immune reaction when the job is done. Prednisone, the synthetic version of cortisol, is commonly used as a treatment for autoimmune diseases. Both prednisone and vitamin D have reduce inflammation, but Vitamin D empowers and enhances the immune system. Prednisone suppresses the innate and the acquired immune systems. Vitamin D shifts the immune system to increase the T-cells. Inflammatory TH1 and TH17 cells are usually too high when someone has an autoimmune disease. Vitamin D suppresses both of these cells, reducing inflammation. Prednisone raises your blood glucose levels while vitamin D does not. Vitamin D enhances the cells that makes insulin and helps to regulate your blood sugars. Prednisone can break down your bone, leading to osteoporosis. Vitamin D helps you absorb calcium and supports bone remineralization. The thymus gland makes T-cells. As we age, the thymus gland deteriorates and our immune systems decline. Vitamin D slows down this process, but you need larger, therapeutic doses. Vitamin D does not work without the cofactors magnesium, vitamin K2, and zinc. Dr. Coimbra of Brazil created a protocol that involves increasing vitamin D to penetrate any resistance. This lowers the parathyroid hormone which means that vitamin D levels have significantly increased. DATA: https://www.coimbraprotocol.com/gener... https://ajcn.nutrition.org/article/S0... http://www.vitamindprotocol.com/vitam...

Discussing the big pieces from Stuart's AMA, TH17 speculation, and going over our wishlists for Clash of Clans in 2025. Links: Stuart's Full AMA Hit Rates for TH12-TH16 through the years Index of all Clash of Clans Podcasts Timestamps: (00:00) Intro (03:57) AMA TH17 Features (Hero, Merging, Army Changes) (16:03) AMA Equipment Future (New Levels? Torch) (22:14) AMA General Game Stuff (Legends, Hard Mode, Live Service (37:11) Our Top 5 Wishlists for Clash of Clans (50:01) Listener Questions (59:15) Superfluous Nonsense

Um grupo de pesquisadores franceses descobriu que a presença de um subtipo do linfócito Th17, uma das células que compõem nosso sistema de defesa, pode contribuir em alguns casos ao desenvolvimento de certos tipos de tumores, como os do intestino, fígado ou pâncreas. Taíssa Stivanin, da RFI em ParisO estudo foi realizado durante quatro anos por especialistas do CNRS (Centro Nacional de Pesquisa Científica da França), do Inserm (Instituto de Pesquisas Médicas da França), da universidade Claude-Bernard Lyon 1 e do Centro de Pesquisa Oncológica de Lyon.Os cientistas franceses identificaram um dos mecanismos do processo inflamatório presente em algumas doenças crônicas que levaria ao surgimento de certos cânceres, disse à RFI Brasil o imunologista francês Julien Marie, que participou da pesquisa, publicada no final de julho na revista científica Nature Immunology.Para entender como os pesquisadores chegaram a essa conclusão, é necessário compreender o papel dos glóbulos vermelhos ou brancos, os linfócitos, em nosso organismo. “Os glóbulos vermelhos são responsáveis pelo transporte do oxigênio no sangue e os brancos combatem os agentes infecciosos e as células defeituosas”, explicou o cientista francês.Os glóbulos brancos são divididos em dois grandes grupos, formados pelos linfócitos B, que produzem os anticorpos, e os linfócitos T. A função deles é destruir células defeituosas ou que foram contaminadas por um vírus ou uma bactéria, por exemplo. Para isso, libera moléculas como as citocinas, que vão criar a inflamação e favorecer a cicatrização e a cura.O problema é que esse processo às vezes pode sofrer alterações e gerar doenças ou agravar infecções – um exemplo é a forma grave da Covid-19. A equipe francesa descobriu que o linfócito Th17, presente na Doença de Crohn, uma patologia crônica intestinal, poderia atuar no aparecimento de células cancerígenas.Muitos tumores, lembra Julien Marie, surgem a partir de uma inflamação crônica. Quando ela atinge uma parte específica do intestino, como é o caso dos pacientes que têm Crohn, as células vão se modificar e se tornar cancerígenas exatamente na porção inflamada. “No nosso estudo, tentamos entender quais eram as células do sistema imunológico na origem dessa inflamação que vai gerar o câncer. São etapas extremamente precoces do desenvolvimento da doença”.Esse mecanismo localizado ajudou a equipe a “cercar” a área onde ocorre todas as modificações celulares. Os cientistas então constataram que um subtipo dos linfócitos Th17 estava na origem de alguns tumores. “Hoje temos técnicas que permitem analisar uma célula de cada vez. Percebemos que as células Th17 tinham oito subtipos, e um deles podia desencadear o câncer através da inflamação criada por ela mesma”, explica.Citocina bloqueia aparecimento do câncerO estudo analisou os linfócitos invitro, no laboratório, as células das biópsias de pacientes que tinham a Doença de Crohn. Eles têm, em geral, quase seis vezes mais chances de desenvolver um câncer colorretal que um indivíduo normal, explicou o cientista francês, e entender o porquê era um dos objetivos da equipe.Durante o estudo, os pesquisadores conseguiram provar que o linfócito Th17 estava presente nos pacientes que desenvolveram os tumores. “No nosso artigo científico caracterizamos os linfócitos que geram o câncer, fazemos uma descrição deles e definimos um certo número de marcadores que propomos para defini-los", explicou. "Fomos ainda mais longe, porque toda a questão por trás da nossa pesquisa era saber se podíamos bloquear o aparecimento do câncer”, acrescenta.Foi justamente essa uma das grandes descobertas da pesquisa. “O desenvolvimento das células cancerígenas pode ser bloqueado pela presença de uma citocina, TGF–β (TGFBETA)”. Se o nível dessa citocina diminui no intestino, por exemplo, favorecerá o aparecimento do câncer, reitera Julien Marie.A descoberta pode ajudar no desenvolvimento de novas terapias contra o câncer e também na prevenção, através da utilização dos marcadores propostos no estudo. Eles são preditivos do risco de desenvolvimento da doença e permitirão um diagnóstico precoce ou até mesmo antecipar o risco do paciente antes de o câncer aparecer.Para Julien Marie, o estudo também é importante porque quebra um paradigma: o nosso sistema imunológico, criado para proteger o organismo, às vezes pode ser nocivo. De cada três cânceres, lembra, um se desenvolve a partir de uma inflamação crônica – um mecanismo que ainda continua sendo, em parte, um mistério para a Ciência.

Community Manager Frame is in the hot seat, answering questions about the state of the game, the future, bugs, the gold pass fiasco and loads more in this special extra long episode. Timestamps: (00:00) - All about Frame (06:07) - Future of cosmetics and pricing (10:47) - Will treasure chests be monetized? (13:43) - What will 2025 bring? (17:29) - How hard will TH17 be? (19:26) - Engaging (or not) with Reddit (23:42) - Gold Pass switcheroo (29:43) - Has there been a shift to focus more on revenue? (35:30) - Tencent influence (39:03) - Increase in bugs & glitches (43:06) - Customer support issues (46:05) - Future of eSports (51:22) - BB and/or CC content coming? (54:07) - Unlimited Heroes Event (57:15) - Return of merch (59:14) - Supercell Make (1:00:35) - Mashup Madness (1:02:50) - Haaland (1:04:19) - Building & troop cosmetics (1:06:51) - Clan notices (1:09:01) - Legendary equipment coming? (1:10:26) - Planning for more decorations (1:13:46) - Expanding Hard Mode to legends or CWL (1:14:34) - Win Trading in Legends League (1:16:28) - Monthly discord chats with the CMs (1:20:24) - Frame being awesome

Your immune system is so much more than just fighting off the occasional cold. It is deeply connected to EVERYTHING in your body and can be a primary root cause of many common (but not normal) health issues! From chronic fatigue, IBS, and painful periods to stubborn weight loss resistance, skin issues, and more the immune system plays a role! In this episode, we're diving deep into how your immune system works, what happens when TH1, TH2, and TH17 cells go into overdrive, and the signs that your immune system might be out of balance. If you're dealing with autoimmune conditions, chronic inflammation, or mysterious symptoms that just won't go away, this episode is for you. I'll be breaking down how to spot the signs, understand your body's signals, and most importantly, what you can do to support and rebalance your system based on your unique symptoms and health history. If you need help getting to the root cause of your health issues or symptoms click here to apply for coaching!

BUFFALO, NY- August 16, 2024 – A new #review was #published as the #cover paper of Aging (listed by MEDLINE/PubMed as "Aging (Albany NY)" and "Aging-US" by Web of Science), Volume 16, Issue 15, entitled, “Types of cell death and their relations to host immunological pathways”. Various immune pathways in the host, such as TH1, TH2, TH3, TH9, TH17, TH22, TH1-like, and THαβ, have been identified. While TH2 and TH9 responses primarily target multicellular parasites, host immune pathways against viruses, intracellular microorganisms (like bacteria, protozoa, and fungi), and extracellular microorganisms utilize programmed cell death mechanisms to initiate immune responses and effectively eliminate pathogens. In their review, researchers Kuo-Cheng Lu, Kuo-Wang Tsai, Yu-Kuen Wang, and Wan-Chung Hu from Taipei Tzu Chi Hospital, Fu Jen Catholic University, Taoyuan Armed Forces General Hospital, Tri-Service General Hospital and Ming Chuan University, reviewed these cell death pathways associated with the host immunological pathways. "These relationships can help us understand the host defense mechanisms against invading pathogens and provide new insights for developing better therapeutic strategies against infections or autoimmune disorders.” DOI - https://doi.org/10.18632/aging.206035 Corresponding authors - Wan-Chung Hu - Wanchung.Hu09@tzuchi.com.tw Video short - https://www.youtube.com/watch?v=oPaevm0vpR8 Sign up for free Altmetric alerts about this article - https://aging.altmetric.com/details/email_updates?id=10.18632%2Faging.206035 Subscribe for free publication alerts from Aging - https://www.aging-us.com/subscribe-to-toc-alerts Keywords - aging, apoptosis, autophagy, ferroptosis, necroptosis, NETosis, pyroptosis About Aging-US The mission of the journal is to understand the mechanisms surrounding aging and age-related diseases, including cancer as the main cause of death in the modern aged population. The journal aims to promote 1) treatment of age-related diseases by slowing down aging, 2) validation of anti-aging drugs by treating age-related diseases, and 3) prevention of cancer by inhibiting aging. (Cancer and COVID-19 are age-related diseases.) Please visit our website at https://www.Aging-US.com​​ and connect with us: Facebook - https://www.facebook.com/AgingUS/ X - https://twitter.com/AgingJrnl Instagram - https://www.instagram.com/agingjrnl/ YouTube - https://www.youtube.com/@AgingJournal LinkedIn - https://www.linkedin.com/company/aging/ Pinterest - https://www.pinterest.com/AgingUS/ Spotify - https://open.spotify.com/show/1X4HQQgegjReaf6Mozn6Mc MEDIA@IMPACTJOURNALS.COM

John Alcorn, PhD is a scientist at UPMC Children's Hospital of Pittsburgh and an associate professor in the University of Pittsburgh School of Medicine. The Alcorn lab is focused on T cell immunity, host defense, epithelial cell biology, and lung physiology. A primary lab focus is on Influenza infection and the host defense mechanisms of T helper 17 cells. His lab has recently shown that the TH17 effector cytokines IL-17 and IL-22 are required for host defense against a variety of extracellular pathogens.

What we think TH17 might bring us, as well as talking about the future of Heroes. Links: Frame's AMA Godly's Defense Concepts Timestamps: (00:00) Intro and last thoughts on Haaland event (05:55) MORE event (11:43) Frame's AMA (14:35) TH17 Predictions (38:03) Future of Heroes (47:08) Listener Questions and Outro, stick around --- Send in a voice message: https://podcasters.spotify.com/pod/show/reddit-talks-clash/message

Kat welcomes Itzu for a frank discussion on hero equipment, TH16 and what he wants to see at TH17.

In this episode of Derms and Conditions, our host, James Q. Del Rosso, DO, interviews April Armstrong, MD, MPH, a professor and Chief of Dermatology at UCLA, about the development of tapinarof, a novel nonsteroidal topical treatment for psoriasis.  They begin by discussing Dr Armstrong's history of professional interest in psoriasis. The conversation then moves to focus solely on tapinarof, a topical cream that works by modulating the aryl hydrocarbon receptor (AhR).  Dr Armstrong explains the unique mechanism of action of tapinarof and its effects on Th17 cytokines, antioxidant activity, and skin barrier function. She also discusses the efficacy demonstrated in clinical trials, with nearly 40% of patients achieving PASI 75 after 12 weeks, as well as the remittive effect in maintaining clear or almost clear skin.  They address the safety profile of tapinarof, including the occurrence of folliculitis and contact irritation, and provide tips for its use in clinical practice. Dr Armstrong also emphasizes its versatility and potential as a combination therapy with systemic medications. All in all, the episode provides listeners with an expansive understanding of tapinarof as an effective and well-tolerated nonsteroidal treatment for plaque psoriasis.

Autoimmune progesterone dermatitis - Sirolimus for KP rubra - Spironolactone does not cause cancer - Dupi -> Th17/23 issues - Berdazimer for molluscum - Want to donate to the cause? Do so here! http://www.uofuhealth.org/dermasphere Check out our video content on YouTube: https://www.youtube.com/@dermaspherepodcast and VuMedi!: https://www.vumedi.com/channel/dermasphere/ The University of Utah's Dermatology ECHO: ⁠https://physicians.utah.edu/echo/dermatology-primarycare - ⁠ Connect with us! - Web: ⁠https://dermaspherepodcast.com/⁠ - Twitter: @DermaspherePC - Instagram: dermaspherepodcast - Facebook: https://www.facebook.com/DermaspherePodcast/ - Check out Luke and Michelle's other podcast, SkinCast! ⁠https://healthcare.utah.edu/dermatology/skincast/⁠ Luke and Michelle report no significant conflicts of interest… BUT check out our friends at: - ⁠Kikoxp.com ⁠(a social platform for doctors to share knowledge) - ⁠https://www.levelex.com/games/top-derm⁠ (A free dermatology game to learn more dermatology!)

BUFFALO, NY- February 13, 2024 – A new #research paper was #published in Aging (listed by MEDLINE/PubMed as "Aging (Albany NY)" and "Aging-US" by Web of Science) Volume 16, Issue 2, entitled, “IL-17 promotes IL-18 production via the MEK/ERK/miR-4492 axis in osteoarthritis synovial fibroblasts.” The concept of osteoarthritis (OA) as a low-grade inflammatory joint disorder has been widely accepted. Many inflammatory mediators are implicated in the pathogenesis of OA. Interleukin (IL)-18 is a pleiotropic cytokine with versatile cellular functions that are pathogenetically important in immune responses, as well as autoimmune, inflammatory, and infectious diseases. IL-17, a proinflammatory cytokine mainly secreted by Th17 cells, is upregulated in OA patients. However, the role of IL-17 in OA progression is unclear. In this new study, researchers Kun-Tsan Lee, Chih-Yang Lin, Shan-Chi Liu, Xiu-Yuan He, Chun-Hao Tsai, Chih-Yuan Ko, Yuan-Hsin Tsai, Chia-Chia Chao, Po-Chun Chen, and Chih-Hsin Tang from National Chung-Hsing University, Taichung Veterans General Hospital, Shin-Kong Wu Ho-Su Memorial Hospital, Mackay Medical College, China Medical University, Show-Chwan Memorial Hospital, Fu-Jen Catholic University, National Taiwan Normal University, Asia University, and China Medical University Hsinchu Hospital used synovial tissues collected from healthy donors and OA patients to detect the expression level of IL-18 by immunohistochemistry stain. “Elucidation of the molecular mechanisms and main factors involved in OA pathogenesis may help with the development of novel therapeutic targets that relieve OA pain or prevent the disease from progressing.” The OA synovial fibroblasts (OASFs) were incubated with recombinant IL-17 and subjected to Western blot, qPCR, and ELISA to examine IL-18 expression level. The chemical inhibitors and siRNAs which targeted signal pathways were used to investigate signal pathways involved in IL-17-induced IL-18 expression. The microRNAs which participated IL-18 expression were surveyed with online databases miRWalk and miRDB, followed by validation with qPCR. This study revealed significantly higher levels of IL-18 expression in synovial tissue from OA patients compared with healthy controls, as well as increased IL-18 expression in OASFs from rats with severe OA. In vitro findings indicated that IL-17 dose-dependently promoted IL-18 production in OASFs. Molecular investigations revealed that the MEK/ERK/miR-4492 axis stimulated IL-18 production when OASFs were treated with IL-17. “This study provides novel insights into the role of IL-17 in the pathogenesis of OA, which may help to inform OA treatment in the future.” DOI - https://doi.org/10.18632/aging.205462 Corresponding authors - Po-Chun Chen - pcchen@ntnu.edu.tw, and Chih-Hsin Tang - chtang@mail.cmu.edu.tw Subscribe for free publication alerts from Aging - https://www.aging-us.com/subscribe-to-toc-alerts About Aging-US Launched in 2009, Aging-US publishes papers of general interest and biological significance in all fields of aging research and age-related diseases, including cancer—and now, with a special focus on COVID-19 vulnerability as an age-dependent syndrome. Topics in Aging-US go beyond traditional gerontology, including, but not limited to, cellular and molecular biology, human age-related diseases, pathology in model organisms, signal transduction pathways (e.g., p53, sirtuins, and PI-3K/AKT/mTOR, among others), and approaches to modulating these signaling pathways. Please visit our website at https://www.Aging-US.com​​ and connect with us: Facebook - https://www.facebook.com/AgingUS/ X - https://twitter.com/AgingJrnl Instagram - https://www.instagram.com/agingjrnl/ YouTube - https://www.youtube.com/@AgingJournal LinkedIn - https://www.linkedin.com/company/aging/ Pinterest - https://www.pinterest.com/AgingUS/ Spotify - https://open.spotify.com/show/1X4HQQgegjReaf6Mozn6Mc Media Contact 18009220957 MEDIA@IMPACTJOURNALS.COM

In this episode, hosts Jordan Briggs and Marcus White are joined by the insightful Dr. Stewart Gillespie to unravel the mysteries of the immune system. Dr. Gillespie provides valuable insights into the innate and acquired immune systems, shedding light on crucial concepts such as Th1, Th2, Th9, and Th17. Explore the complexities of immunology as the conversation delves into practical tools and hacks to fortify your immunity in the face of modern health challenges. Dr. Gillespie shares actionable tips to empower your immune system and enhance overall well-being.

Question: How to Find the Root Cause of Autoimmunity? Short Answer: Autoimmune conditions are likely driven by deficiencies of vitamins A and D, which contribute to post-infectious autoimmunity by compromising the rhythmic rise and fall of myeloid-derived suppressor cells (MDSCs), and to autoimmunity regardless of infections through impaired suppression of Th17 helper T cells. More broadly, infections and tissue damage are the most likely drivers of autoimmunity onset. However, energy metabolism governs everything through the second law of thermodynamics, which holds that energy must be used to prevent everything from randomly mixing, and this includes randomly mixing the immune defense against pathogens with immune attacks on the host. In this example, we discuss how a respiratory chain disorder would compromise absorption and distribution of zinc and compromise the oxidation of NADH to NAD+, and how both of these would interact with a genetic impairment in acetaldehyde dehydrogenase to prevent the activation of vitamin A to retinoic acid. Autoimmunity thus results as one of many symptoms of vitamin A deficiency driven not by lack of vitamin A, but rather by impaired activation of vitamin A, secondary to impaired energy metabolism.  This is a clip from a live Q&A session open to CMJ Masterpass members. In addition to this episode, you can access two other free samples using this link: https://chrismasterjohnphd.substack.com/p/questions-on-nac-biofilms-vitamin In that batch of free episodes you will also find the answer to this question: Can NAC hurt your gut health? Why Would Vitamin C Cause Joint Pain, Muscle Pain, and Brain Fog? If you want to become a Masterpass member so you can participate in the next live Q&A, or so you can have access to the complete recording and transcript of each Q&A session, you can save 10% off the subscription price for as long as you remain a member by using this link to sign up: https://chrismasterjohnphd.substack.com/qanda Learn more about the Masterpass here: https://chrismasterjohnphd.substack.com/about This snippet is from the May 13, 2023 AMA. The full recording and transcript is reserved for Masterpass members. Here is a preview of what's included: GLA to lower hydroxyhaemopyrrolin-2-one? When would I use the StrateGene and Genova Methylation Panel for nutritional testing? Energy metabolism as a root cause of gut issues? Nutrition for skin healing? Nutrition for hypnic jerks? Suggestions for snoring or sleep apnea? Nutrition to protect against restaurant meals? What is the cause of crusty eyes in the morning? What causes brain fog? How much oxalate should one eat each day? Should I be concerned about low alkaline phosphatase? What nutrients give tall children to short parents? Energy metabolism impairment mimicking Wilson's disease. Can taking digestive enzymes reduce our own production? Rapid-fire response to non-winners from the question contest. Here's a link to the full AMA: https://chrismasterjohnphd.substack.com/p/recording-and-transcript-of-the-may  Access the show notes, transcript, and comments here.  

What's the deal with Armra and why is every health influencer talking about it? Is there solid research to back up its extraordinary claims? How does colostrum compare to serum bovine immunoglobulins in terms of sourcing, tolerance and efficacy? Tune in to hear us unpack this buzzworthy new product and whether it is worth the hefty price tag.    In this episode, we discuss the benefits of colostrum and immunoglobulins and whether Armra is all it's cracked up to be. Whenever we look at a buzzworthy new product, we want to understand the active compound and its mechanism of action, and whether the actual proprietary compound has been tested in clinical trials. Learn how Armra stacks up and why we ultimately prefer serum immunoglobulins (such as our GI Immune Builder) over dairy based colostrum.     Also in this episode: What is colostrum?Breast Milk: Nature's Perfect Food  Addressing Leaky GutGI Lining Support What's up with Armra?Technical Paper on Armra Clinical Trial on Armra (Results Pending) Serum Bovine Immuglobulins vs. ColostrumGI Immune Builder Serum-derived bovine immunoglobulin/protein isolate: postulated mechanism of action for management of enteropathy Bovine immunoglobulin/protein isolate binds pro-inflammatory bacterial compounds and prevents immune activation in an intestinal co-culture model Bovine immunoglobulin protein isolates for the nutritional management of enteropathy Dietary requirement for serum-derived bovine immunoglobulins in the clinical management of patients with enteropathy Serum-derived bovine immunoglobulin/protein isolate in the alleviation of chemotherapy-induced mucositis Attenuation of colitis by serum-derived bovine immunoglobulin/protein isolate in a defined microbiota mouse model Oral serum-derived bovine immunoglobulin/protein isolate has immunomodulatory effects on the colon of mice that spontaneously develop colitis Evaluation of serum-derived bovine immunoglobulin protein isolate in subjects with diarrhea-predominant irritable bowel syndrome Potential mechanisms of effects of serum-derived bovine immunoglobulin/ protein isolate therapy in patients with diarrhea-predominant irritable bowel syndrome Impact of serum-derived bovine immunoglobulin/ protein isolate therapy on irritable bowel syndrome and inflammatory bowel disease: a survey of patient perspective Management of inflammatory bowel disease with oral serum-derived bovine immunoglobulin Evaluation of oral serum-derived bovine immunoglobulins in HIV-infected patients with chronic idiopathic diarrhea N-acetyl glucosamine Collagen-induced arthritis: severity and immune response attenuation using multivalent N-acetyl glucosamine N-acetylglucosamine inhibits T-helper 1 (Th1)/ T-helper 17 (Th17) cell responses and treats experimental autoimmune encephalomyelitis N-acetylglucosamine: production and applications.  A pilot study of N-acetyl glucosamine, a nutritional substrate for glycosaminoglycan synthesis, in paediatric chronic inflammatory bowel disease N-acetylglucosamine for treatment of inflammatory bowel disease Naturally Nourished Episode 347 Functional Approaches to Lyme Disease Ultimate Medicine Cabinet Bundle   This episode is sponsored by: Noble Origins, an animal-based organs focused company serving up Nose-To-Tail Protein With Organs, Collagen, & Colostrum. Our Noble Organs Complex is a powdered blend of high-quality beef organs from New Zealand-sourced grass-fed Beef liver, heart, kidney, pancreas, and spleen. Bring Nose-to-tail nutrition to the masses that need it most: Americans. We do this through a delicious once-a-day shake that the whole family can love. Check it out here and use code ALIMILLERRD to get a free bag of Noble Organs Complex at checkout.

Today we speak with an expert on sugar and things meant to replace it. The stakes are high. Very high. Sugar consumption in the population is astronomical and so is the use of sugar replacements. Knowing the impacts of both could help experts provide dietary guidance and help consumers make decisions. Dr. Robert Lustig is Professor Emeritus of Pediatrics in the Division of Endocrinology at the University of California, San Francisco. He specializes on the regulation of energy balance by the central nervous system; body weight regulation, appetite, metabolism, and is very well known for his work on sugar and their substitutes and on policies aimed at improving the diet of the population. A YouTube video on the effects of consuming sugar called “Sugar: The Bitter Truth,” has now been viewed 24 million times. Interview Summary   URL for “The Bitter Truth video (https://youtu.be/dBnniua6-oM)   Let's start out with this - so the big hope is that sugar replacements, artificial sweeteners, non-nutritive sweeteners, all known as different things, replace sugar and that people can enjoy sweet taste without the calories. But, of course, the picture is way more complicated. Being an endocrinologist, you are in a good position to explain what happens when the sweeteners enter the body. I'd like to get to that in just a moment, but let's lead off with another question. Why is it so important for people to consume less sugar?   First, let's talk about what sugar is. The food industry tells you that sugar is just empty calories. I wish that were true. If that were true, then you could basically spend your discretionary calories on sugar with no problem. But it's not true. There are two molecules in dietary sugar: the sucrose or the high fructose corn syrup or honey maple syrup agave. They are all basically the same. One molecule of something called glucose, one molecule of something called fructose. Glucose is the energy of life. Glucose is metabolizable by every cell on the planet. Glucose is so important that if you don't consume it, your body makes it. The liver will take fats and turn it into glucose. It will take amino acids and turn it into glucose process called gluconeogenesis. Glucose actually makes your cells work better. It makes your mitochondria function better, the mitochondria being the little energy burning factories inside each of your cells. Glucose, for lack of a better word, we can call good. Fructose, on the other hand, it is completely different, is metabolized completely differently inside the body and inside the liver. What fructose does is it inhibits mitochondrial function. It actually inhibits three separate enzymes necessary for mitochondria to do their job. So, fructose inhibits energy generation. Now, the food industry will tell you fructose is four calories per gram. Fructose is ready energy. That is why they put high fructose corn syrup in the sports drinks, for example. Well, turns out, that fructose may be ready energy for a bomb calorimeter, but it is not ready energy for your mitochondria. You don't burn in a bomb calorimeter (a laboratory instrument), you burn via your mitochondria. It turns out, mitochondria are actually poisoned by fructose. So in fact, fructose is a chronic, dose-dependent mitochondrial toxin and this is why we have to eat less of it. But the problem is the food industry keeps putting it in anyway despite the fact that it is killing us.   How much more of it are people consuming than what you might suggest?   The American Heart Association years ago came up with a upper limit per day of about 25 grams, which would be about six teaspoons per day. I was actually part of that group that came up with that and I stick to it because that's what the data show. We are currently consuming 94 grams. We are consuming almost quadruple the amount that is the upper limit. Now, the notion that something could have empty calories but still be bad for you is not a crazy one. We have two things in our diet that we know are calories but are clearly toxic to us. One is alcohol. Alcohol, seven calories per gram, but alcohol is a poison. And then also trans fats. Trans fats are nine calories per gram, but trans fats are a poison. So just because something has calories doesn't have anything to do with its metabolic impact.   Where are people getting all the sugar from? I'm assuming it's not from their sugar bowl.   Exactly. It is not the sugar they add. It is the sugar the food industry adds. Now, where is it? Well, the obvious source is soft drinks. That's number one by far and away. I mean soft drinks are basically, you know, the devil incarnate. Several municipalities have actually figured that out, and it's one of the reasons we have soda taxes because it's actually directed at the problem. A lot of it is in other things that we identify as sweet: candy, cakes, ice cream. A lot of it is in other things like breakfast, cereal, yogurt, even cured meats. It is in a whole host of other things. When you add it all up, 65% of the sugar you consume is in ultra-processed foods. It is not in regular food. It is not in sugar you added to your own food. It is in ultra-processed foods. An ultra-processed food is the vehicle by which the payload, that is that fructose, is doing its damage.   Thanks for that background. We're really here to talk about the artificial sweeteners but it is irresistible talking to you about sugar in general because you described the whole picture in such a compelling way. So thank you for that. So, onto the artificial sweeteners. What are the main ones in the food supply?   Well, there are a whole bunch. The most common ones that the food industry uses the most, obviously aspartame, which is Equal. And also sucralose, which is Splenda. But there are others now out on the market: Neotame, there's Acesulfame-K, there's monk fruit, there's Stevia, and all the Steviol glycoside derivatives. There's now Allulose, and there's Tagatose. There's a whole host of different sweeteners that are considered "non-nutritive” meaning they don't have calories.   These things show up in ways that people don't necessarily recognize. I mean Diet Coke, Diet Pepsi, those sort of things, it's obvious they're artificially sweetened. But these things are showing up in a lot of places, aren't they?   Indeed. The food industry now understands that sugar is a problem and people have been calling for less sugar but what they're not calling for is less sweet. And so the industry has a job. It has to deal with that dichotomy.   I know understanding their impacts is complicated by the fact that there are a lot of these things and they're all chemically different from one another. I'm imagining they have different metabolic effects. What happens when these things get into the body?   Right, and that is the issue. It has nothing to do with calories. People think calories are the issue. This has nothing to do with calories. That's one of the reasons, Kelly, that I'm committed to one concept: kill the calorie. Kill the calorie as a unit of measure. It was never appropriate. It was actually subterfuge, and it was actually promoted and promulgated by the food industry because if it is about calories, they can assuage their culpability for what they've done to our food supply. This has nothing to do with calories. This has to do with metabolic health.   Now, the World Economic Forum just published a white paper called the, "True Purpose of Nutrition," and it comes down to two words: metabolic health. That is what is going on inside the cell and that's where the artificial sweeteners do their damage, inside the cell. That's what we have to talk about. There are several places in the body where artificial sweeteners can do damage that have absolutely nothing to do with calories. The first, you put something sweet on your tongue. Message goes tongue to brain, "Sugar's coming." Brain sends a message to the pancreas, "Sugar's coming, release the insulin." Then the sugar never comes because it was a diet sweetener. What does the pancreas do? It turns out it releases the insulin anyway even though it had no calories, even though it wasn't sugar, just because of the sweet taste. So this is known as the cephalic phase of insulin secretion. That insulin is driving energy storage into fat, number one, and it's also driving cell proliferation in your coronary arteries, cell proliferation in your breast tissue, in other words, cardiovascular disease and cancer and ultimately leading to burnout of your pancreas, and now you've got diabetes too. Even though these artificial sweeteners have no calories, they still generate an insulin response, which is still problematic from a metabolic standpoint.   So because of the sweet taste and the body's response to that, I'm assuming what you're saying would be true to all of sweeteners?   Exactly. All of them do that. The next step is the artificial sweetener goes down your gullet, goes into your intestine, and the intestine has these bacteria in it called the microbiome. Most people have now heard of that. Different bacteria lead to different effects in the intestine. But think of your intestine - I mean it's a sewer. It has a whole lot of S-H-you-know-what in there. The goal of the intestine is to keep the S-H-you-know-what IN the lumen of the intestine and not allow it into the bloodstream. It uses three barriers. It has a physical barrier called the mucin layer. It has a biochemical barrier known as tight junctions or zonulins. It also has an immunological barrier called Th17 cells. Those three barriers have to work right to keep the junk out of your bloodstream because if the junk gets into your bloodstream, you now have systemic inflammation, which drives insulin resistance and drives chronic metabolic disease as well. So keeping your intestine in tiptop shape is really important. Well, it turns out those diet sweeteners alter the microbiome. Some of those bacteria like those sweeteners and utilize them to make toxic byproducts, which damage the mucin layer, damage that biochemical tight junction barrier and allow for things to seep through. This is a process called leaky gut. For reasons that are still unclear, sugar tends to deplete those Th17 cells, rendering the immunologic barrier devoid of function. The sum total of which means all the you-know-what in your intestine ends up in your bloodstream, goes to your liver, generates insulin resistance, and you are off to the chronic metabolic disease races as well, from diet sweeteners having nothing to do with calories.   What an amazing picture your painting of these things.   We've got one more mechanism. At the fat cell, now this I really don't understand and it's early data but seems to be consistent. Turns out adipocytes, fat cells, have receptors for diet sweeteners. Don't ask me why. I don't know why. But it turns out, diet sweeteners can act like insulin right at the fat cell to increase energy deposition into the fat cell. Growing those fat cells all by themselves, due to the diet sweetener rather than due to insulin. Now how dumb is that? As a result, there are a lot of different ways diet sweeteners might end up causing problems as well, having nothing to do with calories, having nothing to do with fructose. There was a paper that came out in the European Journal of Clinical Nutrition. It was a meta-analysis of sugar and also of diet sweeteners in terms of diabetes and heart disease. What I can say in one sentence to sum up what this paper showed is that the toxicity of one Coca-Cola equals the toxicity of two diet Coca-Colas. Half as bad. That doesn't mean good. It means half as bad.   Boy, I mean, any one of the three major pathways to harm would be of concern. If you add them all together, it is a pretty striking picture, isn't it? I imagine, even if somebody knew about this, they might say, well, you know, I'm willing to accept those risks. I mean, even though you are making them sound substantial, but I'm willing to accept those risks if these products help me control my weight. Do they?   Well, they don't. That's part of the problem. There is not one study, not one study in the entire world's literature, that shows that switching from sugared beverages to diet beverages actually controls weight. The reason is because even though the diet sweeteners don't release as much insulin now, when you drink the diet sweetener, the pancreas releases it later. That's actually been shown in several studies now. You get a delayed insulin response, so that the 24-hour insulin burden is the same whether you consume the sugar or the diet sweetener.   Let's talk about safety for a minute. What about sort of the typical toxicology concerns that people have had for years about these substances, irrespective of what they're doing to the pancreas and to the other, the microbiome, et cetera? What about the just kind of pure safety of them?   Right, so the one that has generated the most heat, not too much light, unfortunately, is aspartame, NutraSweet. It turns out that aspartame has a very long and checkered history. Did you know that aspartame was made by Searle, G.D. Searle? And, do you know who the CEO of G.D. Searle was at the time that aspartame was approved by the FDA?   I do not.   His name was Donald Rumsfeld.   An interesting character in history.   Indeed, wouldn't you think? It turns out that G.D. Searle actually buried most of the toxicology of aspartame in order to get it approved. It is a long complicated and involved story, which we don't have time for. I'm not even privy to most of the details on that. The bottom line was it ultimately did get approved despite the fact that there was a significant amount of concern about toxicology of this compound. Those questions still remain today. That is one. Another one that is a big issue is sucralose. Sucralose is also called Splenda. Sucralose is a chlorinated poly-fructose and it's extremely sweet, no question about that. It seems to have some GI side effects that a lot of people don't like. It also has now been associated with cancer. And most recently, the one that's gotten the most attention and almost assuredly, Kelly, the reason you called me is the paper that came out about three weeks ago in science about erythritol. So erythritol is a sugar alcohol, and now the meta-analysis of erythritol consumption suggests that it may in fact contribute to heart disease. Now, is that true? Meta-analysis are complicated. People think meta-analysis are the piece de resistance, the highest bar of medical information and analysis. I have four words for meta-analysis: garbage in, garbage out. Meta-analyses are only as good as the studies that they base the data on. If those studies were done by the food industry, which almost all of these are, because that's who stands to benefit from them. These are almost never NIH studies. These are almost always food industry studies, as you know, the odds are 7.61 times more likely to find in favor of the compound of interest. So all of these are, shall we say, biased. All of these are tainted, and meta-analyses are basically a conglomeration of tainted studies. So what do you expect the result to be?   Thanks for that background. I'm imagining also regarding toxicology and safety, that some of the newer sweeteners like Splenda for example, sucralose, there hasn't been enough years of use to pick up long-term chronic effects.   Well certainly, if you're using cardiovascular or cancer events, you're absolutely right. A lot of these events, you know, take a long time to manifest themselves. Sometimes, a generation or even two generations for that matter, especially for heart disease and cancer. The 15-year-old is drinking 10 diet sodas. When do you expect the heart attack to show up? You know, it's complicated.   So we use biomarkers to try to answer these questions, but then the biomarker has to actually be a good proxy for those events and often they're not. Let me give you an example, LDL. Everybody thought LDL was the bad guy. Turns out triglycerides are the way worse guy. LDL has a hazard risk ratio for heart disease of 1.3. Triglycerides have a hazard risk ratio of 1.8. Triglycerides are 50% more important in determining heart disease than LDL is, but we use LDL as the biomarker because it's more stable. So you have to use the right biomarker and you have to interpret it properly and it actually has to mean something and it has to change relatively acutely. All of which are problematic for all of these biomarkers. It's hard. It's hard to do these kinds of analyses. Having said that, my group, a scientific advisory team that I convened to help an offshore ultra-processed food company improve the health of their products. We've published this just last month in Frontiers in Nutrition. The company is called Kuwaiti Danish Dairy Company, or KDD. The title of the paper is, "The Metabolic Matrix: Re-Engineering Ultra-processed Foods to Protect the Liver, Feed the Gut, and Support the Brain." We did a deep dive on diet sweeteners. We looked at all of these diet sweeteners and their proxies, all the biomarkers. The one that actually popped out that looked to be the most beneficial, at least acutely, is a new one that we're actually kind of interested in and is picking up speed and it's called allulose. Allulose currently is 12 times the cost of sugar, but that's coming down. It turns out allulose lowers LDL and raises HDL. So it may have a better cardiovascular profile, but again, all the caveats that we mentioned before.   That's very interesting. So given your interest in pediatrics, what about children using these sweeteners?   I am totally against children using sugar because they get fatty liver disease and Type 2 diabetes, and I am totally against them using diet sweeteners because, number one, we don't know what they're going to do. Number two, they don't actually lead to weight loss. That data we do have. So as far as I'm concerned, we really only have one option and that is de-sweeten our lives. We have to de-sweeten the food.   Perfect lead in to the next question I was going to ask. So do you think it is possible for people to become accustomed to less sweetness? I mean, let's say the food industry is required to gradually reduce sugar and sweetness from the sweeteners. What do you think would happen?   Absolutely. It is not only possible, it is eminently doable. And I know why and we have the data for why that is. So there is a very smart lady, neuroscientist at the University of Michigan by the name of Monica Dus, who has done all this work in fruit flies of all places. She has shown the desensitization of the tongue to sugar has to do with changes in receptors and changes in specific substrates in the taste buds of the tongue. When you stop the sugar availability, it takes three weeks for those receptors to increase and repopulate, and for those problematic substrates to go away. You can actually retrain your tongue in three weeks to be much more sensitive to the sugar that is in the food naturally. After a three-week abstinence period or a reduction or a weaning period, a blueberry will taste like a sugar bomb in your mouth. So we know this can happen and we actually have proven this for salt previously. The UK, as you know Kelly, back in 2003, the Blair government convened all the food industry concerns in Great Britain. So Marks & Spencer, and Weight Rose, and Tesco, et cetera, all around the big table, didn't let media in, and basically said to every single food industry concerned in Great Britain, "Look, we have a hypertension and stroke problem and it's because of the salt content of the food and we are going to play referee here in the government. And each of you is going to reduce the salt content of your food by 10% per year over a three-year period so that you'll reduce your salt by 30% at the end of this and everyone's going to play together, so that there's no competitive disadvantage and most importantly, we're not going to tell anybody." That's what they did. Sure enough, in 2011, a paper appeared in Burge Medical Journal, demonstrating a 40% reduction in hypertension and stroke because of the public health effort that the Blair government made in terms of reducing the amount of salt in processed food. We can do the same with sugar today.   The salt example is a good one because I think many people have sort of experienced this in their day-to-day lives, even in the United States, where industry hasn't done exactly what's happening in Britain. People have tried to reduce salt in their diet, add less salt, and buy products with less salt. And then sometimes they'll go back and consume something that they had before and find it extremely salty, even unpleasantly salty. It's interesting to hear on the sugar front that that same experience might be possible and that there's a biological reason for it. It is not just that you psychologically get accustomed to different levels of sugar, in this case, but there's a biological change occurring that might help keep that going.   Absolutely. You can change people's behavior by changing their biochemistry. This is how I got into this field by using a drug that suppressed insulin and getting kids who were 400 pounds due to their brain tumor to actually lose weight and start exercising because we got their insulin down. You can fix the biochemistry and the behavior will follow suit. The food industry could do that and we wouldn't even notice.   So I'm guessing I know the answer to this question before I even ask it, but let's go ahead. Would you suggest the food industry be mandated to make gradual reductions in sugar, just like you mentioned with salt in the UK?   Absolutely, I'm working toward that. The only thing that I say is we should not tell anybody.   So it would be sort of a stealth move then. You would not necessarily have to make a big deal of it to the public, because they might assume there's going to be a change in the desirability and the pleasure of the products when that's not necessarily the case.   As soon as you do something to their food, someone's going to scream, "Nanny state!" This is not nanny state. Ultimately, this is a public health problem. We have to deal with it with a public health solution. You know, that means changing things. If the amount of sugar in our food supply went down, say by 3% every six months down, so that we were able to cut our sugar consumption by 25%, which would be the same basically as what a tax would do. We would save so many billions of dollars in healthcare costs, and we would increase productivity so much. We actually published a paper, a microsimulation analysis in BMJ years ago where we quantified the savings to government, to insurers, to the public. If we actually got sugar down and, you know, actually listened to what the USDA told us, it would be amazing. There is data, there's a pathway forward, there's precedent for doing it. I absolutely think that is where we need to go.   Rob, you're making me feel very smart at the moment, because I figured this was going to be a podcast filled with information and helpful bits of knowledge and it sure was. I'm really grateful that you were able to join us and the topic couldn't be more important. Thank you again for being with us.     Bio   Robert H. Lustig, M.D., M.S.L. is Emeritus Professor of Pediatrics in the Division of Endocrinology, and Member of the Institute for Health Policy Studies at UCSF. Dr. Lustig is a neuroendocrinologist, with expertise in metabolism, obesity, and nutrition. He is one of the leaders of the current “anti-sugar” movement that is changing the food industry. He has dedicated his retirement from clinical medicine to help to fix the food supply any way he can, to reduce human suffering and to salvage the environment. Dr. Lustig graduated from MIT in 1976, and received his M.D. from Cornell University Medical College in 1980. He also received his Masters of Studies in Law (MSL) degree at University of California, Hastings College of the Law in 2013. He is the author of the popular books Fat Chance (2012), The Hacking of the American Mind (2017), and Metabolical: The Lure and the Lies of Processed Food, Nutrition, and Modern Medicine (2021). He is the Chief Science Officer of the non-profit Eat REAL, he is on the Advisory Boards of the UC Davis Innovation Institute for Food and Health, the Center for Humane Technology, Simplex Health, Levels Health, and ReadOut Health, and he is the Chief Medical Officer of BioLumen Technologies, Foogal, Perfact, and Kalin Health.  

In pursuit of mechanisms and evidence-based approaches, gut health has been revealed as a critical cornerstone of neurological health. In this episode, we're going into detail on what the gut layers are. I hope this video will help someone else who's trying to understand how the gut works for purposes of biohacking with functional medicine, nutrition, supplements, etc. For any intervention, is there evidence of a relationship, and is there data that it worked in other humans? We talk about: what the gut mucus is made out of elements of the gut barrier - the many ways the body keeps microbes and partially digested food away kinds of intestinal epithelial cells (Goblet cells, Paneth cells, M cells, etc.) and their functions types of gut associated lymphoid tissue (GALT) and their distinctions - lamina propria, Peyer's patches, lymph nodes the enteric nervous system and enteroendocrine cells different types of CD4+ T cells: Th1, Th2, Th17, and Treg, what they respond to, and their major outputs the mechanism of nutrient absorption the mechanism of leaky gut (paracellular transport through tight junctions) Here's the video: https://youtu.be/sIn_VxH6zDA Transcript of the video, for those who are pressed for time: https://www.brainforest.org/post/leaky-gut-anatomy I hope this helps someone understand their gut a little better on the path to health. Stay tuned for our next podcast on the relationship between leaky gut and aging. Share this resource with others who are studying gut anatomy on the path to health!

Vijay Kuchroo is the Samuel L. Wasserstrom Professor of Neurology at Harvard Medical School, Senior Scientist at Brigham and Women's Hospital, and Co-Director of the Center for Infection and Immunity, at the Brigham Research Institutes, Boston. He is also an associate member of the Broad Institute, and a participant in a Klarman Cell Observatory project that focuses on T cell differentiation. He is the founding Director of the Evergrande Center for Immunologic Diseases at Harvard Medical School and Brigham and Women's Hospital. His major research interests include autoimmune diseases—particularly the role of co-stimulation—the genetic basis of experimental autoimmune encephalomyelitis and multiple sclerosis, as well as cell surface molecules and regulatory factors that regulate the induction of T cell tolerance and dysfunction. His laboratory bred several transgenic mice that serve as animal models for human multiple sclerosis. The Kuchroo laboratory was also the first to describe the TIM family of genes, and identified Tim-3 as an inhibitory receptor expressed on T cells, which is now being exploited for cancer immunotherapy. He was first to describe the development of highly pathogenic Th17 cells, which have been shown to induce multiple different autoimmune diseases in humans. Kuchroo is the lead author on a paper describing the development of Th17, which is one of the most cited papers in the field of Immunology.Kuchroo came to the United States in 1985, as a Fogarty International Fellow at The National Institutes of Health, Bethesda, MD for one year, before joining the department of pathology at Harvard Medical School, as a research fellow. Later, he joined the Center for Neurologic Diseases at Brigham and Women's Hospital as a junior faculty member in 1992.He obtained his degree in Veterinary Medicine from the College of Veterinary Medicine, Hisar, India. Subsequently, he specialized in pathology at the University of Queensland, Brisbane Australia, where he obtained a Ph.D. in 1985. He received the Fred Z. Eager Research Prize and medal for his Ph.D. research work at the University of Queensland. Based on his contributions, he was awarded the Javits Neuroscience Award by the National Institutes of Health in 2002 and the Ranbaxy prize in Medical Research from the Ranbaxy Science Foundation in 2011. He was named Distinguished Eberly Lecturer in 2014, and obtained a Nobel Laureate Peter Doherty Lecture/Prize in 2014.Kuchroo has 25 patents and has founded 5 different biotech companies including CoStim Pharmaceuticals and Tempero Pharmaceuticals. He also serves on the scientific advisory boards and works in advisory capacity to a number of internationally recognized pharmaceutical companies including: Biocon, Syngene, Pfizer, Novartis and Glaxo-Smith-Klein (GSK).Alix Ventures, by way of BIOS Community, is providing this content for general information purposes only. Reference to any specific product or entity does not constitute an endorsement nor recommendation by Alix Ventures, BIOS Community, or its affiliates. The views & opinions expressed by guests are their own & their appearance on the program does not imply an endorsement of them nor any entity they represent. Views & opinions expressed by Alix Ventures employees are those of the employees & do not necessarily reflect the view of Alix Ventures, BIOS Community, affiliates, nor its content sponsors.Thank you for listening!BIOS (@BIOS_Community) unites a community of Life Science innovators dedicated to driving patient impact. Alix Ventures (@AlixVentures) is a San Francisco based venture capital firm supporting early stage Life Science startups engineering biology to create radical advances in human health.Music: Danger Storm by Kevin MacLeod (link & license)

Sinus problems are rampant. Americans spend over $1 Billion annually to treat sinus problems with over-the-counter medications, which is crazy. It's not just common in the chronic illness world and in the autoimmune world, and ESPECIALLY in the mold world, it's common in everyone. Sinus inflammation is interesting. I have had really great success healing my own sinuses. I'm not recommending that everyone (or anyone) do what I did, but what I REALLY DID was I spent several years intensely studying deep immunology and the Ear, Nose, and Throat and Allergy literature, read 100s of studies, and used things like high dose supplements and essential oils to have really good success with nasal polyps and chronic sinusitis. I haven't had sinus issues for over 3 years. Here is a video of what I did to get rid of nasal polyps, it's crazy.  When I talk about sinuses, I'm also talking about ENT areas - ear infections, tonsils, sore throats, pharyngitis, which includes things like Strep and PANDAS, but most of my success was with the nose. The whole ENT region is a hotbed of infections and pathogens, and is right across the wall from the brain, and things like antibodies, histamine, chemical toxins, inflammatory cytokines, and mycotoxins from mold can ride the "olfactory elevator" (as Dr. Jill Crista calls it) right up to the brain - right to deep, midline areas like the frontal cortex (brain fog, etc), pituitary (hormones), amygdala (anxiety, fear, etc), hypothalamus (temp, dysautonomia, etc), neurological dysfunctions and more.  Sinus inflammation drives many immune mechanisms, including Th2 and eosinophilic inflammation, mast cell activation and histamine, and Th17 inflammation, which is tissue-damaging autoimmune inflammation and will drive autoimmune progression. THAT IS THE MOST IMPORTANT PIECE OF THE PUZZLE!  One thing that can drive this immune activation are chronic biofilms including Strep, Staph (MARCoNS), and Mold/Yeast that are incredibly persistent and antibiotic resistant. Biofilm colonies, like in the gut, grow on sinuses, adenoids, tonsils (that's why they remove them!) and ENT surfaces - and when they adhere to a surface they are over 1000x harder to kill, and they are highly persistent and antibiotic resistant. THIS IS THE OTHER MOST IMPORTANT PIECE! In this episode I talk about 4 levels of supporting sinus inflammation naturally:1 - Breathe Clean Air!!!! Allergies are obviously an issue....You can't be living in mold....I talk about air purifiers, mold candles, HVAC filters, and more.2 - Fix your Gut and Balance your Immune System - I talk about using things like probiotics, herbal killers, SCFA, vitamins D and A, glutathione, perilla, quercetin, luteolin, etc to support barrier integrity, mast cell activation, Th2 dominance.3 - Break Biofilms and Kill Infections - Nasal Spray, Neti Pot, Nebulizer, Gargle - I talk about using essential oils, iodine, hydrogen peroxide, silver, propolis, aqualaurin, biocidin, etc to break up biofilms and help kill pathogens. 4 - Maintain - I talk about the importance of breathing clean air, doing regular nasal rinses, and more to maintain. This is not medical advice, but many people have seen their ENT with very little answer besides antihistamines, antibiotics, or steroids, so these are just some of the things that people are doing out there, and hopefully it can help you solve YOUR puzzle!I also mention this, my favorite newsletter and started by an amazing ENT surgeon:www.sinusitiswellness.com

Welcome to Season 5 of Living Well with MS, where we are pleased to welcome holistic health practitioner and expert Magic Barclay as our guest!  Keep reading for the key episode takeaways and Magic's bio. Make sure you sign up to our newsletter to hear our latest tips and news about living a full and happy life with MS. And if you're new to Overcoming MS, visit our introductory page to find out more about how we support people with MS. Bio: Magic Barclay is the lead practitioner and founder of ‘Wholistic Natural Health Australia', a holistic health practice. She also is a host of the podcast “A Magical Life: Health, Wealth and Weight Loss”. Magic's life changed when she faced multiple life-threatening conditions and at the same time, found herself divorced and raising her two children alone. She decided to find the root cause of her health issues and that set her on a path of life-changing learning that affected her whole family. Magic is a Master Practitioner in immune health, mould toxicity recovery and Psycho-Neuro-Endocrine-Immunology (the study of the interaction between psychological processes and the nervous and immune systems of the human body) of trauma. She tells us that she is a “mum of two amazing humans and two gorgeous furbabies, a grower of organic food for her family and a passionate native gardener”. Magic's mission is to help people heal naturally, reconnect to the environment and reach their own potential. She mainly works with women aged 45-65 who feel unheard or misled by mainstream medicine and anyone who wants to bring their health back to basics. Selected Key Takeaways: The purpose of functional medicine Functional medicine involves looking at the systems of the body. It looks at what each system does and how it works with the other systems. We often say, "no system works alone." We particularly look at the root cause because if you don't look at that, then other issues keep arising. Belief in yourself is a powerful part of healing If people don't believe in themselves, they're not going to get well. We see a lot of people just given diagnosis after diagnosis, label after label, and they start believing that's who they are. Magic believes that this is a really awful way to live because you're a person, you are not the label that was given to you by your doctor. You are still a person. So, what they do in functional medicine is uncover: Who is that person? And who do [they] want to be? Reduce stress by acknowledging the stressor isn't forever If you find yourself around people that increase your stress, don't be around them or decide to be around them for five or 10 minutes. Give yourself a time cap and tell yourself after 10 minutes “I'm out of this situation and I'll be okay”. If you find you are stressed by work, a doctor's appointment or driving, either take yourself out of the situation, find an alternative, or give yourself a time limit so that you know internally it's not forever. And don't sit there thinking, “I'm so stressed,” as your body hears that and guess what? It replies, "Really? This is a low level of stress, you want to be stressed? I'll raise the bar." Related Links: Magic's Wholistic Natural Health Find out more about PNEI and Dr. Gabor Maté https://drgabormate.com/ Make natural laundry detergent from horse chestnuts/ conkers/ buckeyes https://wastelandrebel.com/make-laundry-detergent-out-of-chestnuts/ Parkinson's protein from gut to brain https://www.nih.gov/news-events/nih-research-matters/tracking-spread-parkinsons-proteins-gut-brain The Blood Brain Barrier in MS https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8395058/ Th1 and Th17 response in MS https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5491887/ Don't miss out: Subscribe to this podcast and never miss an episode. You can catch any episode of Living Well with MS here or on your favourite podcast listening app. If you like Living Well with MS, please leave a 5-star review on Apple Podcasts or wherever you tune into the show. Feel free to share your comments and suggestions for future guests and episode topics by emailing podcast@overcomingms.org. Make sure you also sign up to our newsletter to hear our latest tips and news about living a full and happy life with MS. If you enjoy this podcast and want to support the ongoing work of Overcoming MS, you can leave a donation here.

Dr. Vijay Kuchroo is the Samuel L. Wasserstrom Professor of Neurology at Harvard Medical School. His major research interests include the role of co-stimulation in autoimmune diseases, as well as cell surface molecules and regulatory factors that regulate the induction of T cell tolerance and dysfunction. He talks about the conditions necessary to differentiate Th17 cells and their role in autoimmunity. He also discusses his group's discovery of Tim-3, an inhibitor receptor on T cells which is now being exploited for cancer immunotherapy.

There has been a steady rise in autoimmune disease throughout industrialised societies over the last 30 years. Almost 4.5% of the world's population is affected by one of more than 80 different autoimmune diseases.To add to these already alarming statistics, recent studies have revealed that the incidence of autoimmune diseases worldwide is increasing at a rate of 19% per year.While we know that numerous predisposing genetic risk factors have been identified, these only account for a fraction of the overall incidence of autoimmune diseases.There are studies pointing to a strong influence of environmental and lifestyle factors, but translating this into a meaningful therapeutic model is a challenge, especially under the current, prevailing medical paradigm.Nevertheless, there are those who have pioneered this field of research and, through their personal and professional endeavours, have made it all but impossible to ignore how profound an impact diet, lifestyle and mindset can have when faced with seemingly intractable conditions.Dr Terry Wahls is a clinical professor of medicine at the University of Iowa. In 2000, she was diagnosed with relapsing remitting multiple sclerosis and from that point, began to steadily decline. Because of her academic medical training, Terry began a research journey that eventually led her to investigate these under-explored factors and from this she developed a treatment plan that would help restore her health. Today, Dr Terry Wahls is a teacher and mentor to millions of people around the world who are seeking more effective ways to treat multiple sclerosis and other progressive health problems.Her story is truly inspirational and we are so fortunate to have Terry share this on the IMH Patient Journeys podcast. References:Jamka M, et.al. The Effect of the Paleolithic Diet vs. Healthy Diets on Glucose and Insulin Homeostasis. J Clin Med. 2020;9(2):296. Challa HJ, Bandlamudi M, Uppaluri KR. Paleolithic Diet. [Updated 2022 May 2]. Abbott RD, et.al. Efficacy of the Autoimmune Protocol Diet as Part of a Multi-disciplinary, Supported Lifestyle Intervention for Hashimoto's Thyroiditis. Cureus. 2019;11(4)Gauree G. et.al. Efficacy of the Autoimmune Protocol Diet for Inflammatory Bowel Disease, Inflammatory Bowel Diseases, Volume 23, Issue 11, 1 November 2017, Pages 2054–2060Cecilio LA, et.al. The prevalence of HLA DQ2 and DQ8 in patients with celiac disease, in family and in general population. Arq Bras Cir Dig. 2015 Jul-Sep;28(3):183-5.Mangalam, Ashutosh et.al. (2009). HLA-DQ8 (DQB1*0302)-restricted Th17 cells exacerbate experimental autoimmune encephalomyelitis in HLA-DR3-transgenic mice. Journal of immunology.Santoro L, et.al. Looking for celiac disease in Italian women with endometriosis: a case control study. Biomed Res Int. 2014;2014 Małgorzata Królik, et.al. Possible effect of the HLA-DQ2/DQ8 polymorphism on autoimmune parameters and lymphocyte subpopulation in recurrent pregnancy losses, Journal of Reproductive Immunology, Volume 149, 2022,Garcia J, et.al. Social isolation and connectedness as determinants of well-being: Global evidence mapping focused on LGBTQ youth. Glob Public Health. 2020 Apr;15(4):497-519. doi: 10.1080/17441692.2019.1682028. Epub 2019 Oct 28. Rothman, Emily F.et.al. "The Prevalence of Sexual Assault Against People Who Identify as Gay, Lesbian, or Bisexual in the United States: A Systematic Review". Trauma, Violence, & Abuse. 12 (2): 55–66. Brenton JN, et al. Phase II study of ketogenic diets in relapsing multiple sclerosis: safety, tolerability and potential clinical benefits. J Neurol Neurosurg Psychiatry. 2022;93(6):637-644.

Recently a review article from 2020 caught my eye; Reconsidering the Role of Melatonin in Rheumatoid Arthritis. Sleep is a major issue for RA, and many patients and clinicians are turning to melatonin to aid with sleep issues, are we causing more harm than good? Melatonin has been known:  as a powerful antioxidant and anti-inflammatory properties to help with regulating T cell responses, T helper (Th)1, Th17, and regulatory T cells (Tregs). to help modulate the circadian rhythm and enhance sleep On the flip side, there is evidence from animal studies showing there are receptors for melatonin on synovial macrophages which promote the release of some Th-1-type proinflammatory cytokines. It has also been pointed out that the higher blood concentrations of melatonin in arthritic patients, especially in the early morning, might explain the morning stiffness and joint swelling experienced by patients - but does that mean that melatonin should be completely avoided? So far most of that evidence is coming from animal studies but are they translating with similar outcomes in human RCT? Let's dive into 2  human trials to see how melatonin impacts your RA clients. Save the Date! Dr. Alison Danby, ND will be running a 1-day Autoimmune 101 Workshop for clinicians on Friday, October 21, 2022. Registration opens September 21st. Join our mailing list to make sure you are in the know to grab those Early Bird Savings.  References: https://confident-clinician-club.s3.ca-central-1.amazonaws.com/The+Expert+Clinician/Autoimmune+101/TCC+Podcast/RA+%26+Melatonin+2007++(1).pdf https://confident-clinician-club.s3.ca-central-1.amazonaws.com/The+Expert+Clinician/Autoimmune+101/TCC+Podcast/RA+and+melatonin+-+2020+RCT+(1).pdf

At Cornell University in Ithaca, NY, Mandy joins Immune to discuss her career and her research on understanding how Th17 cells develop and are influenced to be ‘good' or ‘bad' in their function. Hosts: Vincent Racaniello, Cynthia Leifer, Steph Langel, and Brianne Barker Guest: Mandy McGeachy Subscribe (free): Apple Podcasts, Google Podcasts. RSS, email Become a patron of Immune! Links for this episode Th17 cytokines in health and disease (Immunity) Time stamps by Jolene. Thanks! Music by Steve Neal. Immune logo image by Blausen Medical Send your immunology questions and comments to immune@microbe.tv

There are many health benefits associated with good quality sea salt, and it's something I recommend to my patients and personally add to my food regularly.At the same time, we know that too much salt can be problematic. Research shows that excessive salt consumption can increase Th17 cells and inhibit Tregs (the opposite of what we want to happen - check out last week's bonus episode for a quick summary).So, should everyone with Graves' disease and Hashimoto's avoid salt?Today I'm sharing the research around salt intake and autoimmunity and how you can safely consume salt as a part of your diet.In this episode, you'll learn:Why I regularly use and recommend sea saltWhat studies show about the correlation between a high-salt diet and autoimmunityMy recommendations for daily salt consumptionAs always, I hope you found this episode valuable, and I look forward to catching you in the next episode!To learn more, visit the show notes at https://savemythyroid.com/podcast/can-salt-trigger-thyroid-autoimmunity/.

Ok so let's talk about gut health. Gut health and detox are pretty much the two most important topics, and toxins affect gut health....but good gut health is necessary for proper detoxification.....I think gut health wins. At least for this next podcast series :) Gut health is foundational to health, inflammation, and aging. It's so crucial, but so few people seem to have it mastered IF they are still experiencing symptoms, and I mean ANY symptoms - joint pain, fatigue, anxiety, depression, bipolar, metabolic, certainly autoimmune flares, not just digestive symptoms. I'm going to go deeper into some specific topics in the next few episodes, but this one is an overview, and I made a list of the 10 most important things for gut health. The first 3 are symptoms, the next 4 are mechanisms, and the last 3 are infections, and understanding these 10 things will give you a pretty good grasp on understanding gut health and digestion overall!Diarrhea - I talk about IBS, IBD, low microbiome and good bacteria/probiotics, glutamine, mast cells, and hydrogen SIBO....Constipation - I talk dysbiosis/methane, and a LOT about vagal motor outflow and vagus nerve activity that controls motility as well as HCL, bile, enzymes....Bloating - When I hear bloating I think small intestine and fermentation. Dysbiosis is often at the root, which includes proper digestion (HCL and bile), and I touch on SIBO/SIFO, avoiding FODMAPs foods....Digestion - This is critical!! Chewing your food, being in parasympathetic mode, then proper stomach acid - it can be too high (mast cells) or too low (more common), pancreatic digestive enzymes, bile from the gallbladder (steatocrit), and of course VAGUS BABY!Dysbiosis - The 10 lbs of bacteria in your gut can become imbalanced. Low good bacteria, general microbiome imbalances…..and LPS!!!!!Leaky Gut - Everyone can have some intestinal permeability, is yours pathological, and if so what kind is it - paracellular or transcellular? Food Sensitivities - IgG testing, and how food sensitivities can drive autoimmune reactivity, general inflammatory tone, and initiate T cell mediated tissue damageSIBO - Bloating! Fermentation of fibers, starches, sugars, FODMAPs ...why you need HCL, bile, vagus outflow……Why I think SIBO testing is dumb….Candida - OMG….the single biggest thing I see. Antibiotics, sugar, stress, birth control, mold exposure, can drive a Th17 inflammatory response (autoimmune), can also drive Th2 (and both will decrease Th1)......and why I love urinary organic acids testing for fungal issues.Parasites - this I am going to do a whole episode on because it's crazy, it's quite frankly pretty controversial in the autoimmune world, is it better to have or to not have them??? The answer is IT DEPENDS. But I do talk about someone who was diagnosed with Ulcerative Colitis and it actually seemed to be a parasitic infection, pretty interesting story :)Share this with someone, subscribe, leave a rating and review, and follow me elsewhere!

T-helper 17 (Th17) cells and regulatory T cells (Tregs) play a role in developing autoimmune conditions like Graves' disease and Hashimoto's.Today I'm sharing everything you need to know about these cells since you'll hear me refer to them a lot in future podcast episodes.In this episode, you'll learn:Where Th17 and Treg cells originateThe role of Th17 and Treg cellsHow Th17 and Treg cells are connected to autoimmune conditionsNutrients, supplements, and natural agents that have been shown to increase regulatory T cells and decrease Th17 cellsTune in for next week's Q&A episode, where I'll discuss something many people commonly use in their homes that can increase Th17 cells.I hope you found this episode valuable, and I look forward to catching you in the next episode!To learn more, visit the show notes at https://savemythyroid.com/podcast/what-are-th17-and-treg-cells/.

Oleic acid, a key to activating the brain's ‘fountain of youth'   Baylor College of Medicine, March 22, 2022   Many people dread experiencing the cognitive and mood declines that often accompany reaching an advanced age, including memory disorders such as Alzheimer's disease and mood conditions like depression. While searching for new ways to prevent or treat these and other related conditions, a team at Baylor College of Medicine and the Jan and Dan Duncan Neurological Research Institute (Duncan NRI) at Texas Children's Hospital identified a missing piece of the puzzle of how memory and mood are sustained and regulated in the brain. Their study, published in the Proceedings of the National Academy of Sciences, reveals that oleic acid produced in the brain is an essential regulator of the process that enables learning and memory and supports proper mood regulation. The finding has paved the path to discovering potential new therapeutic strategies to counteract cognitive and mood decline in patients with neurological disorders.   (NEXT)   Chemical found in leafy greens shown to slow growth of COVID-19 and common cold viruses   Johns Hopkins University School of Medicine, March 23, 2022   Researchers at Johns Hopkins Children's Center report evidence from lab experiments that a chemical derived from a compound found abundantly in broccoli and other cruciferous plants may offer a potentially new and potent weapon against the viruses that cause COVID-19 and the common cold. In a study described March 18 in the journal Communications Biology, the scientists showed that sulforaphane, a plant-derived chemical, known as a phytochemical, already found to have anti-cancer effects, can inhibit the replication of SARS-CoV-2, the coronavirus that causes COVID-19, and another human coronavirus in cells and mice. Sulforaphane's natural precursor is particularly abundant in broccoli, cabbage, kale and Brussels sprouts. First identified as a "chemopreventive" compound by a team of Johns Hopkins scientists decades ago, natural sulforaphane is derived from common food sources, such as broccoli seeds, sprouts and mature plants, as well as infusions of sprouts or seeds for drinking. Previous studies, including those at Johns Hopkins Medicine, have shown sulforaphane to have cancer and infection-prevention properties by way of interfering with certain cellular processes.   (NEXT)   New clues about how a high-salt diet contributes to cardiometabolic diseases found deep in the brain   Medical College of Georgia and Georgia State University, March 22, 2022    Deep in the brain a group of large neurons produce a hormone which prompts our bodies to hold onto more fluid and increase blood pressure. Scientists say these neurons play a critical role in enabling our bodies to maintain healthy homeostasis by using this skill set to efficiently eliminate the excessive salt we consume in an unhealthy meal. But scientists at the Medical College of Georgia and Georgia State University also say that the chronic high-salt diet most Americans consume can turn this system against us, resulting in hyperactivity of these neurons, continuing production of this hormone vasopressin, constriction of blood vessels and increasing our risk for common cardiometabolic diseases like high blood pressure and heart disease. They are finding that salt loading increases the firing of vasopressin-producing neurons, increases constriction of blood vessels and decreases local blood flow. More typically when neurons become active, blood flow to them increases, in a process called neurovascular coupling. This helps ensure working neurons have the adequate oxygen and nutrients needed to sustain increased activity.   (NEXT)   Vitamin D may keep low-grade prostate cancer from becoming aggressive   University of South Carolina, March 22, 2022   In cases of low-grade prostate cancer, many urologists do not treat the disease, but instead do what's called "active surveillance. The cure—meaning surgery or radiation—is probably worse than the disease, so they wait a year and then do another biopsy to see where the patient stands. However, knowing that they have even low-grade prostate cancer can cause patients and their families excessive anxiety, which prompts some of the men to undergo an elective prostatectomy, despite the risk of complications such as infection, urinary incontinence and erectile dysfunction.   (NEXT)   How sugar promotes inflammation   University of Wurzburg (Germany), March 22, 2022   People who consume sugar and other carbohydrates in excess over a long period of time have an increased risk of developing an autoimmune disease. In affected patients, the immune system attacks the body's own tissue and the consequences are, for example, chronic inflammatory bowel diseases such as Crohn's disease and ulcerative colitis, type 1 diabetes and chronic inflammation of the thyroid gland. The underlying molecular mechanisms that promote autoimmune diseases are multilayered and complex. Now, scientists at the Julius Maximilians University of Würzburg (JMU) have succeeded in deciphering new details of these processes. Their work support the notion that excessive consumption of glucose directly promotes the pathogenic functions of certain cells of the immune system and that, conversely, that a calorie-reduced diet can have a beneficial effect on immune diseases. In their study, the scientists focused on a group of cells of the immune system that have not been known for very long: T helper cells of type 17, also called Th17 lymphocytes, which play an important role in regulating (auto-) inflammatory processes.

Youtube Video: Mold Toxicity and Mycotoxin IllnessYoutube Video: Research Review - Neural Antibodies in Patients with Symptoms and Histories of Mold/Chemical ExposuresYoutube Video: Research Review - Mycotoxins Induce NeurotoxicityI say this all the time, but mold toxicity is crazy. Indoor molds such as Aspergillus, Penicillium, and Stachybotrys produce mycotoxins, which are also crazy. Mold and mycotoxins can both disrupt the immune system in a myriad of different ways, which is why they are associated with autoimmunity in many ways.In this podcast, I didn't want to just read stats or research, I wanted to talk about the mechanisms by which molds and mycotoxins can affect the immune system, which are varied and complex. The research is out there on mold, but it can be hard to find because mold toxicity goes by several names - Sick Building Syndrome, Dampness and Mold Hypersensitivity Syndrome, Chronic Inflammatory Response Syndrome, Mixed Mold Mycotoxicosis, Hypersensitivity Pneumonitis to name a few - and there are many different molds, and many mycotoxins. When you work with patients and you are aware of these mechanisms, mold is an incredibly common problem. It never ceases to amaze me how many people I see whose symptoms or disease timeline correlate with a prolonged exposure to water damage, a damp or moldy environment, or a history of repeated mold exposures!Mold is ubiquitous, so your body tries really hard immunologically to tolerate it, and sometimes it tolerates it for a looong time - until one day it stops tolerating it. Mycotoxins from mold can remain indefinitely in tissues, and many have an affinity for the brain, where they disrupt mitochondrial ATP production. Some molds and mycotoxins suppress the immune system, some activate the immune system, some suppress innate immune function and increase adaptive, some do the opposite. Some people have several mycotoxins present at once, doing several different things, along with other pathogens and toxins accumulating faster due to the effects of mold. You can see how mold exposure and toxicity can quickly become quite complex immunologically! Molds and mycotoxins can cause leaky gut, leaky sinus, leaky lung, leaky brain, they can deplete glutathione, impact the microbiome, increase pathogen burdens like EBV and CMV, disrupt Th1/Th2 balance, and turn on vicious cycles of inflammation (NFkB, iNOS, NO-ONOO, Th17) - - all of which are underlying mechanisms of autoimmunity. When you hear all these various mechanisms, you begin to understand why molds and mycotoxins can contribute to autoimmunity, cancer, chronic infection, and even death, not to mention the most common symptoms of fatigue, anxiety, depression, brain fog, ENT symptoms, pituitary/thryoid/adrenal/reproductive imbalances, headaches, insomnia. There are a lot of mechanisms, and there are a lot of other variables, including genetics, history, exposure, and everything else in your bucket, but MOLD AND MYCOTOXINS are one of the scariest things on the planet!

Multiple Sclerosis News Today's multimedia associate, Price Wooldridge, reads a news article about how pro-inflammatory T helper 17 (Th17) immune cells directly interact with myelin-producing cells, promoting their damage and death. Price also reads “The Painful Tooth: My Weekend of Agony”, a column by John Connor. =================================== Treatment for Relapsing MS Progression | MAYZENT® (siponimod) Read about MAYZENT, a once daily pill that can significantly slow down disability progression in people with relapsing MS. See full prescribing & safety info. https://www.mayzent.com/?utm_source=changeinrms&utm_medium=vanityurl&utm_campaign=novartis_mayzent_2020&utm_content=soundcloud ===================================== Are you interested in learning more about multiple sclerosis? If so, please visit: https://multiplesclerosisnewstoday.com/ ===================================== To join in on conversations regarding multiple sclerosis, please visit: https://multiplesclerosisnewstoday.com/forums/

Why You Should Listen: In this episode, you will learn about the numerous contributors to conditions associated with brain inflammation. About My Guest: My guest for this episode is Dr. Kenneth Bock. As a leader in integrative medicine, Kenneth Bock, MD has accumulated over 35 years of experience diagnosing the root cause of chronic illnesses and restoring balance to his patients' immune systems. He founded Bock Integrative Medicine in response to the increasing need for board-certified medical providers who take a unique “whole body” approach to diagnosing and treating chronic illness. Dr. Bock is a well-respected integrative medicine doctor and autism expert who focuses on the treatment of autism and co-occurring conditions, PANS/PANDAS, Infection-Triggered Autoimmune Brain Inflammation, tick-borne illnesses, and adult conditions such as Chronic Fatigue Syndrome, Fibromyalgia, and heart disease. He integrates alternative modalities with conventional medicine into a comprehensive integrative medicine practice. His natural curiosity and expertise in working with medical problems that have been difficult to diagnose and treat make him sought after by patients throughout the world as an expert at tackling complex medical problems. Key Takeaways: How often do psychiatric conditions find themselves rooted in underlying biological factors such as infections and environmental toxicants? What is Infection-Triggered Autoimmune Brain Inflammation (ITABI)? What is Mood Dysregulation Spectrum and the symptoms that may present? What are some of the common nutrient deficiencies observed? How can immune tolerance be improved? Is it the bug or the host response that makes the disease? What are the common infections seen in ITABI? What tools can be helpful in quenching the fire of inflammation? What role do Th1, Th2, Th17, and Treg cells play? How can intestinal barrier function be improved? What role does the vagus nerve play in healing? How are the underlying triggers for PANS or ITABI identified? Can CBD be helpful for neuroinflammation? Is IVIG a helpful tool in children with ITABI? Which Lyme-associated microbe is the hardest to treat? Does mold exposure in water-damaged building play a role? What is the role of evaluating and supporting mitochondrial function in ITABI recovery?   Connect With My Guest: https://BrainInflamed.com https://BockIntegrative.com Related Resources: https://BockNutritionals.com Interview Date: September 29, 2021 Transcript: To review a transcript of this show, visit http://BetterHealthGuy.com/Episode153 Additional Information: To learn more, visit http://BetterHealthGuy.com. Disclaimer: The content of this show is for informational purposes only and is not intended to diagnose, treat, or cure any illness or medical condition. Nothing in today's discussion is meant to serve as medical advice or as information to facilitate self-treatment. As always, please discuss any potential health-related decisions with your own personal medical authority.

T cells are a part of your immune system, which has many many important parts of course. T cells are particularly important in autoimmunity because the T CELLS ARE WHAT DO THE DAMAGE!!!In my last episode about Hashimoto's I talked about antibody levels and described how will antibodies "flag" something as bad so that immune cells can come destroy it, but antibodies have no destructive properties. The progression and destruction of autoimmune disease is determined by the level of T cell activity! T cells destroy the gut in autoimmunity. T cells destroy the joints in autoimmunity. T cells destroy the thyroid. T cells destroy the myelin of your nerves. THEY ARE IMPORTANT!!What type(s) are there? What do they do? How do I know if mine are working properly?This episode goes through all of that information! I go through the 4 most important polarizations of T cells: Th1 (fights intracellular infections)Th2 (produces mucus and expels allergens and parasites)Th17 (causes tissue-damaging inflammation)Regulatory T cells (Tregs), which are the peacemakers that dampen inflammationAutoimmunity ALWAYS has an imbalance of too much Th17 activity and not enough Treg activity, but what about Th1/Th2? Eventually MOST autoimmune patients will present with decreased Th1 and increased Th2, and in this episode I go through some of the details of how this happens, how the patient presents and how this needs to be handled clinically to get it under control!

New research connects imbalanced gut probiotics and induction of Grave's disease. How does this happen and what can you do to prevent it or treat it?

In Episode #65, Dr. Jill Interviews Dr. Lauren Tessier on Mold and Mycotoxins and how to test and treat for this common cause of autoimmunity. Learn more about immune dysfunction including TH17 dominance and it's link to autoimmunity.

En el segundo capítulo sobre sistema inmunitario, trato la respuesta inmune que nuestro cuerpo realiza contra bacterias, hongos y/o protozoos y como esto se podría relacionar por ejemplo con dolores articulares. https://regenerauniversity.com/master-psiconeuroinmunologia-clinica/

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.09.23.310466v1?rss=1 Authors: Xu, J., Zhang, P., Huang, Y., Bekris, L., Lathia, J., Chiang, C.-W., Li, L., Pieper, A. A., Leverenz, J. B., Cummings, J., Cheng, F. Abstract: Systematic identification of molecular networks in disease relevant immune cells of the nervous system is critical for elucidating the underlying pathophysiology of Alzheimer's disease (AD). Two key immune cell types, disease-associated microglia (DAM) and disease-associated astrocytes (DAA), are biologically involved in AD pathobiology. Therefore, uncovering molecular determinants of DAM and DAA will enhance our understanding of AD biology, potentially identifying novel therapeutic targets for AD treatment. Here, we present an integrative, network-based methodology to uncover conserved molecular networks between DAM and DAA. Specifically, we leverage single-cell and single-nucleus RNA sequencing data from both AD transgenic mouse models and AD patient brains, drug-target networks, metabolite-enzyme associations, and the human protein-protein interactome, along with large-scale patient data validation from the MarketScan Medicare Supplemental Database. We find that common and unique molecular network regulators between DAM (i.e, PAK1, MAPK14, and SYK) and DAA (i.e., NFKB1, FOS, and JUN) are significantly enriched by multiple neuro-inflammatory pathways and well-known genetic variants (i.e., BIN1) from genome-wide association studies. Further network analysis reveal shared immune pathways between DAM and DAA, including Fc gamma R-mediated phagocytosis, Th17 cell differentiation, and chemokine signaling. Furthermore, integrative metabolite-enzyme network analyses imply that fatty acids (i.e., elaidic acid) and amino acids (i.e., glutamate, serine, and phenylalanine) may trigger molecular alterations between DAM and DAA. Finally, we prioritize repurposed drug candidates for potential treatment of AD by agents that specifically reverse dysregulated gene expression of DAM or DAA, including an antithrombotic anticoagulant triflusal, a beta2-adrenergic receptor agonist salbutamol, and the steroid medications (fluticasone and mometasone). Individuals taking fluticasone (an approved anti-inflammatory and inhaled corticosteroid) displayed a significantly decreased incidence of AD (hazard ratio (HR) = 0.858, 95% confidence interval [CI] 0.829-0.888, P < 0.0001) in retrospective case-control validation. Furthermore, propensity score matching cohort studies also confirmed an association of mometasone with reduced incidence of AD in comparison to fluticasone (HR =0.921, 95% CI 0.862-0.984, P < 0.0001). Copy rights belong to original authors. Visit the link for more info

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.09.18.304071v1?rss=1 Authors: Narasimhan, R. L., Throm, A. A., Koshy, J. J., Saldanha, K. M. R., Chandranpillai, H., Lal, R. D., Kumravat, M., Kumar K M, A., Batra, A., Zhong, F., Liu, J. Abstract: Inflammatory bowel disease (IBD) is a complex, chronic inflammatory disease of the gastrointestinal tract with subtypes Crohn's disease (CD) and ulcerative colitis (UC). While evidence indicates IBD is characterized by alterations in the composition and abundance of the intestinal microbiome, the challenge remains to specify bacterial species and their metabolites associated with IBD pathogenesis. By the integration of microbiome multi-omics data and computational methods, we provide analyses and methods for the first time to identify microbiome species and their metabolites that are associated with the human intestine mucosal immune response in patients with CD and UC at a systems level. First, we identified seven gut bacterial species and seventeen metabolites that are significantly associated with Th17 cellular differentiation and immunity in patients with active CD by comparing with those obtained in inactive CD and non-IBD controls. The seven species are Ruminococcus gnavus, Escherichia coli, Lachnospiraceae bacterium, Clostridium hathewayi, Bacteroides faecis, Bacteroides vulgatus, and Akkermansia muciniphila, and a few associated metabolites include the secondary bile acid lithocholate and three short-chain fatty acids (SCFAs): propionate, butyrate, and caproate. We next systematically characterized potential mechanistic relationships between the Th17-involved metabolites and bacterial species and further performed differential abundance analysis for both microbiome species and their metabolites in CD and UC relative to non-IBD controls with their metagenomic and metabolomic data. Based on the deconvolution of immune cell compositions from host intestinal bulk RNA-seq, we investigated changes in immune cell composition and abundance in CD and UC in comparison to non-IBD controls. Finally, we further extended our species and metabolite associations with immune cells from Th17 and Th2 cells to B cells, plasma B cells, CD4+ T cells, and CD8+ T cells. While a set of associations of immune cells with bacterial species and metabolites was supported by published evidence, the new findings in this work will help to furthering our understanding of immune responses and pathogenesis in IBD. Copy rights belong to original authors. Visit the link for more info

In this monolog, Tanu briefly discusses the recent study from Ang et al. about the effect of ketogenic diet on gut microbiota and Th17 cells. There are three diets discussed in the episode based on fat to carb ratio: the standard or baseline diet (35:50), high fat diet (75:10), and ketogenic diet (90:0). Check out our memes on Facebook (@antibuddies) and Twitter (@antibuddiesP). Join us on our monthly journal club at our Youtube channel: https://www.youtube.com/channel/UCxyrHotyyY3sSwcp1zigeCw Send us your queries/questions/suggestions at antibuddies1@gmail.com.   Source: https://www.sciencedirect.com/science/article/abs/pii/S0092867420304906

Unsere neue Folge ist da ! Viel Spaß mit unserem Journal Club, Verbrennungen, Lokalanästhestikaintoxikation und Hyponatriämie. Dazu unsere, zugegeben, etwas kontroverse Diskussion zur HWS-Orthese. Wir freuen uns auf euer Feedback! Kommentare Vermischtes Rethink Salt Kleinewietfeld M, Manzel A, Titze J, et al. Sodium chloride drives autoimmune disease by the induction of pathogenic TH17 cells. Nature. 2013;496(7446):518-522. doi:10.1038/nature11868 Diagnosing and Treating Systemic […] Der Beitrag Podcast August 2020 – Folge 19 erschien zuerst auf pin-up-docs - don't panic.

On today's episode we discuss: — Epidemiology: A sharp peak in rates of intestinal obstruction (IO) during the lockdown period in Kerela, India (referred to as "lockdown belly") leads authors to propose four common risk factors, 75% are modifiable with diet and physical activity. These include: 60 years of age or older, prior abdominal surgery, strict adherence to lockdown restrictions, and poor quality diet. — Understanding the Pathology: A cross sectional study from Columbia University that analyzed kidney biopsies of SARS-CoV-2 infected patients (n=17), revealed a spectrum of glomerular and tubular injuries, acute kidney injury (88%), and lack of SARS-CoV-2 detection in kidney cells as evidence against direct viral injury as a pathophysiologic mechanism of disease. Authors conclude that the principle nephrogenicity of SARS-CoV-2 likely results from ischemic damage and a dysregulated immune response. '— Transmission and Prevention: A group of psychologists found that habit reversal training (HRT) was an effective method of treating repetitive behavior problems, such as face touching, and therefore may be an effective strategy for decreasing transmission of SARS-CoV-2. The principles of HRT are centered on mindfulness and behavior modification, and authors include a practical guide to implementing these practices. — Management: italian authors describe how the anti-coagulant Defibrotide may be the “drug of choice” for treating the hypercoagulable state associated with severe COVID-19 disease because of its profibrinolytic, antithrombotic, and anti-inflammatory effects. These would theoretically protect from the growing evidence implicating the role of endothelial damage and a hyperinflammatory state in SARS-CoV-2 infection. '— Transmission and Prevention:describes the effect of T cell imbalance, specifically between Treg and Th17, on uncontrolled systemic inflammation in severe COVID-19 cases in pregnancy found that: - Treg cells decreased and Th17 cells increased, with a consequent decrease in the Treg/Th17 cell ratio. - Treg cells dysregulation in COVID-19 was shown trigger hyperinflammation and tissue damage. - Increased Th17 is associated with fetal allograft rejection at the feto-maternal interface. - COVID-19 infection puts pregnant persons at higher risk for pregnancy complications. --- Support this podcast: https://anchor.fm/covid19lst/support

Dr Carolyn Lam: Welcome to Circulation on the Run, your weekly podcast summary and backstage pass to the journal and its editors. I'm Dr Carolyn Lam, associate editor from the National Heart Center and Duke National University of Singapore. Dr Greg Hundley: And I'm Dr Greg Hundley, associate editor, Director of the Pauley Heart Center from VCU Health in Richmond, Virginia. Dr Carolyn Lam: Our feature paper today discusses trans-ethnic genome-wide association studies and the insights in the genetic architecture and heritability of long QT syndrome, a massive study that we will be digging into, but only after we talk a little bit about the other papers in this week's issue. And I'm going to start, Greg. Are you ready with your coffee? Dr Greg Hundley: I am. Dr Carolyn Lam: The first original paper really represents seminal work, showing that the endothelium can directly regulate obesity and insulin resistance. Now, as obesity develops, there is a decline in adipose tissue vascularity, which seems counterintuitive, and an increase in fibrosis. So authors, led by Dr Chen from the Irell and Manella Graduate School of Biological Sciences in the City of Hope, speculated that the reduction in vascularity in this adipose tissue might have an adverse effect on adipose tissue function. Now, these authors previously identified Argonaute-1, or AG01, a key component of microRNA-induced silencing complex, as a crucial regulator in hypoxia-induced angiogenesis. So in the current study, they aim to determine the AG01-mediated endothelial cell transcriptome, the functional importance of AG01-regulated endothelial function in vivo, and the relevance to adipose tissue function and obesity. A new mouse model with genetic deletion of AG01 in the endothelium was useful to investigate the importance of endothelial regulation of adipose tissue function. The findings were that in mice fed high fat, high sucrose diet, the suppression of endothelial AG01 promoted adipose tissue browning, and led to an anti-obesity phenotype. Endothelial cell AG01 thrombospondin-1 pathway was induced in the endothelium from human donors with insulin resistance. In total, this study suggests a novel mechanism, by which endothelial cells through AG01 thrombospondin-1 pathway controls vascularization and function of adipose tissues, insulin sensitivity, and whole-body metabolic state. Dr Greg Hundley: Interesting, Carolyn. So tell me about this clinically. Where do we take this from here? Dr Carolyn Lam: I thought you would ask. So endothelial dysfunction, per se, can cause metabolic dysregulation, rendering targeting dysfunctional endothelium, a potential therapeutic strategy to counteract obesity, and metabolic disorders. So this study really opens a door to that. Dr Greg Hundley: Very nice. Well, I've got another basic science paper, and it evaluates single-cell RNA sequencing to dissect the immunological network of autoimmune myocarditis. And it comes from Dr Jiangping Song from the State Key Laboratory of Cardiovascular Disease of Fuwai Hospital, and the National Center for Cardiovascular Disease, Chinese Academy of Medical Sciences, and Peking Union Medical College. So Carolyn, the study aimed to investigate the immunological network during the transition from myocarditis to cardiomyopathy, and to identify the genes contributing to the inflammatory response to myocarditis. So mice were treated with myosin heavy chain alpha-peptides to generate an experimental autoimmune myocarditis model. The investigators performed single-cell RNA sequencing analysis of CD45 plus cells extracted from mouse hearts during different experimental autoimmune myocarditis phases, including normal control, acute inflammation, subacute inflammation, and then in the myopathy phase. Also, human heart tissues were collected from surgically removed hearts of patients who had undergone heart transplantation. Dr Carolyn Lam: So what did they find, Greg? Dr Greg Hundley: Well, Carolyn, a comparison of the single-cell RNA sequencing data from different experimental autoimmune myocarditis phases suggested that some cell clusters, such as macrophage cluster 2 and Th17 cells, were associated with the inflammatory response in the experimental autoimmune myocarditis model. The HIF1A expression level correlated with the extent of the inflammatory response, and PX-478, a HIF1A inhibitor, alleviated the inflammation during the different experimental autoimmune myocarditis phases. Immunohistochemical staining revealed that HIF1A expression was upregulated in autoimmune myocarditis from the tissue samples from the explanted hearts. Thus, the HIF1A inhibitor alleviated inflammatory cell infiltration, and that may serve as a potential therapeutic target in clinical practice. Dr Carolyn Lam: Wow. That is some serious clinical implications. Well, my next paper is really the first systematic echocardiographic evaluation of consecutive patients requiring hospitalization due to COVID-19, and it comes from Dr Topilsky and colleagues from Tel Aviv Medical Center. Dr Greg Hundley: So Carolyn, what did they find in this series? Dr Carolyn Lam: So among a hundred consecutive patients diagnosed with COVID-19 infection who underwent complete echocardiographic evaluation, within 24 hours of admission, only 32% had a normal echocardiogram at baseline. The most frequent abnormality was right ventricular dilatation or dysfunction. Among patients developing clinical deterioration during follow-up, which were 20% of these hospitalized patients, repeated echocardiograms showed further deterioration of the right ventricular parameters, probably related to increased pulmonary resistance. Five of these patients had deep vein thrombosis. Dr Greg Hundley: Carolyn, my next study comes from Dr Stephen Fremes, and it's a modeling study out of the University of Toronto. It modeled TAVR versus SAVR valve durability to determine the effects on life expectancy across a broad range of age. Dr Carolyn Lam: Interesting. And what were the results? Dr Greg Hundley: Well, based on their simulation models, the durability of TAVR valves must be 70% shorter than that of surgically replaced valves to result in reduced life expectancy in patients with similar demographics to recent trials. However, in younger patients, the threshold for TAVR valve durability was substantially higher. In younger patients, life expectancy was reduced when TAVR durability was 30%, 40% and 50% shorter than surgical valves in 40, 50 or 60-year-old patients, respectively. So Carolyn, these findings suggest that durability concerns should not influence the initial treatment decision regarding TAVR versus SAVR in older low-risk patients, based on current evidence supporting TAVR valve durability. However, in younger low-risk patients, valve durability must be weighed against other patient factors, such as life expectancy. Dr Carolyn Lam: Thanks Greg, for that summary. Well, let me tell you about other papers in this issue. There are a pair of letters to the editor by Dr Opotowsky, and a response by Dr Goldberg regarding the paper results of the Fontan Udenafil Exercise Longitudinal, or FUEL trial. There's a research letter by Dr Strik, Validating QT-Interval Measurement Using the Apple Watch ECG to Enable Remote Monitoring During the COVID-19 Pandemic. There are two On My Mind papers, the first, Telemedicine and Forgotten America by Dr Julien, and the second, The COVID-19 Pandemic: Ethical and Scientific Imperatives for "Natural" Experiments by Dr Lewis. Dr Greg Hundley: Very nice. Well, Carolyn, I've got a research letter evaluating the effect of evolocumab on atherogenic lipoproteins during the peri and early post-infarction period. It's a placebo-controlled randomized trial from Dr Gary Gerstenblith. Sarah Cuddy also worked through a tough case of cardiac amyloid when a fat biopsy was negative, but imaging studies of the heart suggested cardiac amyloid. Carolyn, I've also got an On My Mind piece, and it's entitled, Can Old Ally Defeat a New Enemy? And it's by Dr Paul Gurbel, and he discusses the use of inhaled aspirin to treat patients with COVID-19. And then finally, Carolyn, I have a prospective piece from Dr Robert Lefkowitz who discusses β-arrestin-biased angiotensin II receptor agonists for treatment of COVID-19. Well, Carolyn, what a great issue, and let's get onto that feature discussion. Dr Carolyn Lam: Yay. Let's go, Greg. Dr Greg Hundley: Well, listeners. Now we're turning to our feature discussion, and we are very fortunate to have Professor Connie Bezzina from Amsterdam University Medical Center to talk to us about her paper related to long QT syndrome. Welcome, Connie. And I was wondering, before we get started in discussing your paper, could you tell us a little bit about the background in this area? And then, what was the hypothesis that you wanted to address? Prof Connie Bezzina: So over the last 20 to 30 years, we've learned a lot about the genetic underpinnings of inherited cardiac disorders associated with sudden cardiac arrest. And basically, we've learned a lot about mutations in specific genes that co-segregate with these disorders within families. However, two outstanding features have remained unresolved. Essentially, the first unresolved issue is the fact that we observe, oftentimes, a low disease penetrance and variable disease expression within families, which means that not everybody within a family that carries a familial mutation is affected by the disorder. But two, so among those that are affected, some are affected more severely than others. So some people would have only the ECG abnormality, whereas other people, for instance, would have the ECG abnormality and arrhythmic events. And you could also have individuals, indeed, who don't even manifest any disease manifestations. This is one of the outstanding challenges. The other outstanding challenge is the fact that, despite extensive genetic testing of the known genes in some probands and some families, they remain genetically lucid, in that we don't find a likely genetic defect in a minority of families. And of course, that hinders genetic testing and implementation of genetic testing in such families. Dr Greg Hundley: What was the question you were going to answer with your study? And tell us a little bit about your study design and your study population. Prof Connie Bezzina: Yeah, so essentially, we figured that assigning these disorders to one large genetic defect might be an oversimplification of biological phenomenon. So we hypothesized that even in these Mendelian disorders, the inheritance of additional genetic factors alongside the familial mutation could contribute to risk. Of course, there will be other factors such as environmental factors, which we did not tackle in the study. The central hypothesis of the study was that common genetic variation, which is present in the germ population, could modulate the effect of the familial genetic defect of the Mendelian mutation. So in order to do this, we assembled a large consortium of investigators from multiple centers in Europe, in North America and Japan, worldwide, to bring together about 1700 probands with the long QT syndrome. So we tested this hypothesis in the long QT syndrome because we figured, among the rare inherited rhythm disorders, it's one of the more common disorders. Also, because each individual center has too few patients. To do this locally, we put this group of investigators together to come up with 1700 probands. The study design was a genome-wide association study with a case-control design, where we tested the association of millions of SNPs littered across the genome with susceptibility for the disorder. So this led us to identify three single-nucleotide polymorphisms that are associated with susceptibility for the long QT syndrome. What we immediately saw is that, actually, these three SNPs, perhaps not surprisingly at all, had been previously associated with the extent of the QT interval, with QT interval in the general population. This is not surprising, of course, because repolarization is a central part of physiological mechanism in the long QT syndrome. So this basically indicated overlap between genetic control of the QT interval in the germ population and susceptibility to the long QT syndrome. So the fact that the three SNPs that we identified as long QT syndrome susceptibility SNPs had been associated with QT interval duration in the germ population, we felt that that was pointing to assure genetic underpinnings between these two phenotypes. So we went on to investigate that by looking at the correlation between the odds ratio for long QT syndrome susceptibility and the effect that these SNPs have on QT interval in the germ population. And in fact, we found a very high correlation between those. So essentially, this pointed to sure genetic factors between QT interval in the germ population and long QT syndrome susceptibility. Of course, we wanted to look for disease variability. The next thing we wanted to do was whether these SNPs could actually explain disease variability. Now, this was perhaps the most disappointing part of the study, because when we constructed a polygenic risk score based on SNPs that impact on the QT in the germ population, we found no relation to QT interval among patients, and also no relation to life-threatening arrhythmic events among the patients. We think that this is because our patients... or probrands. They're primarily probands, so they are all more sick. So we didn't have enough variability in our patient set to identify an association with disease variability. And in fact, this is at variance with previous studies that tested individual SNPs, and even our own studies with smaller polygenic risk scores that did find an association between a polygenic risk score based on QT SNPs and QT prolongation and events among patients. So we think that this is certainly something to study further in the future, in larger patient sets where we not only have the probands, but also their relatives, their mutation-carrying relatives, which will give us a bigger variability to actually test this hypothesis. So we think that looking at probands actually was a very good design to find susceptibility variance but was not maybe a good design to find SNPs or polygenic risk scores to test their effect on disease variability. Dr Greg Hundley: It sounds like you've found certain gene low PSI that indicate a predilection for prolongation of the QT interval, but not necessarily are those gene low PSI consistent with who's going to experience an adverse cardiovascular event as a result of their genetic constitution. Is that a fair statement? Prof Connie Bezzina: Well, I think that the setting, because we had probands, they were the most sick people in their families. I think to have stronger conclusions on that, we need to test the polygenic risk scores in families where there are people who are differentially affected. Dr Greg Hundley: I see. I- Prof Connie Bezzina: We had too-narrow of a variability in a probands-only design, as opposed to a study where we would have probands who are severely affected and mutation-carrying relatives who are less severely affected. Dr Greg Hundley: Very nice. So that puts that clearly into context. This was a massive effort. You have quite a list of investigators, and you mentioned you had to gather so many sites. How would you conduct that next study? Would you need another large collection of individuals and many sites to take that on? Prof Connie Bezzina: Yes. I'm a geneticist, and geneticists always want larger, larger numbers, and I'm also one of those. So I'm interested in explaining as much as possible into individual variability. And I think to do that properly, I think we should go preferably for a similar design where we will approach the same centers. And hopefully, we can organize the next study, which will have these probands and their relatives. Dr Greg Hundley: Now, just quickly, for us working in the clinic, how should we approach genetic testing in patients with long QT? Prof Connie Bezzina: At the moment, I think our findings don't have an immediate impact. I think our findings tell us about the genetic architecture of the disorder. And actually, one thing I haven't gone into yet is the fact that what we also found is that patients who do not have mutations in the no-long QT genes, which were called mutation-negative, which are about 20% of all long QT syndrome probands, actually have a higher burden of these common variants that prolong the QT interval. So we think, actually, that mutation-negative long QT syndrome probands will not have a Mendelian large effect variant but will have perhaps a higher burden of these QT-prolonging alleles. Therefore, I think this has direct implications for clinical genetics of these patients, because if you have a proband in whom you don't find a mutation in the known genes, you could think that maybe it is not monogenic, which has implications because you don't have a single genetic defect to test on that family. One would need to keep follow-up of more family members until we understand more about the genetics of those individuals. Dr Greg Hundley: So Connie, this has been just a wonderful discussion. Any additional studies examining the genetic architecture of individuals that we need to think about for the future? Prof Connie Bezzina: Sure. So for long QT syndrome in particular, as additional SNPs that modulate the QT interval in the germ population are identified, it will be very important to incorporate these into larger polygenic risk scores, and see whether we could have a better discriminative capacity of such polygenic risk scores in discriminating between severely affected and less severely affected people, or who is more at risk for an arrhythmic event. Outside of long QT syndrome, I think there's a lot of work to be done with respect to the likely complex inheritance of many of these disorders that we previously considered to be Mendelian. So for instance, ongoing work in our group concerns Brugada syndrome, where we're seeing the same kind of thing, and hypertrophic cardiomyopathy, where we're seeing the same kind of inheritance. Dr Greg Hundley: Well listeners, on behalf of both Carolyn and myself, we look forward to catching you on the run next week. Take care. This program is copyright the American Heart Association 2020.

As a research fellow in clinical medicine, Sharee Basdeo focuses primarily on tuberculosis (TB), which has co-evolved with the human immune system for thousands of years. By tuning in, you'll discover: How the three general responses to TB exposure differ, and why it's been difficult to determine why only some people develop active TB disease after exposure   What is problematic about drug therapies and the vaccine for TB What Basdeo believes is the next step in TB-related research There are roughly three categories of responses to TB: a person can be exposed to TB but mount no immune response and show no signs of having been exposed, a person can be exposed and their immune system can mount an effective response which contains the TB infection and puts it in a dormant state, or a person can be exposed and develop active TB disease.  So, what determines which course of action will occur? This is a question that has yet to be answered, and one that many people are actively researching. Basdeo discusses this topic, along with many other fascinating subjects, including how those who harbor latent TB can develop active TB as they age, innate immunity, what happens when the wrong drug or wrong dose of drug is taken for TB, how the lung and gut microbiome might be related to the immune response for TB, the mutagenesis of TB and why it is difficult to kill TB, how TB finds ways to tune down the immune response to allow itself to exist undetected, and the importance of Th17 cells. Visit https://www.tcd.ie/research/profiles/?profile=sbasdeo to learn more about Basdeo's work. Available on Apple Podcasts: apple.co/2Os0myK

Dr. Corry's Bio: David B. Corry is Professor of Pathology & Immunology and Medicine; Vice Chair for Immunology, Department of Pathology & Immunology at Baylor College of Medicine in Houston, Texas.  Dr. Corry further holds the Fulbright Endowed Chair in Pathology.  He received his M.D. degree from the University of Texas Southwestern Medical School and after residency training in Internal Medicine at Duke University Medical Center, he completed his clinical training in Pulmonary and Critical Care Medicine at the University of California at San Francisco.  In 1992, he joined the immunology laboratory of Dr. Richard Locksley to study mechanisms of T cell differentiation and immune injury.  He then joined the faculty at San Francisco General Hospital as Adjunct Assistant Professor and in 1999 joined the faculty at Baylor College of Medicine.  The primary objectives of Dr. Corry's research are to discover the fundamental immune and environmental causes of chronic human inflammatory diseases to improve the diagnosis, prognosis, and therapy of these often profoundly disabling conditions.  Dr. Corry's laboratory discovered the seminal importance of the of the IL-4/IL-13 signaling pathway in asthma; the fundamental role that environmental and endogenous proteinases play in the pathogenesis of TH2-dependent allergic inflammation; the fibrinogen-Toll like receptor 4 interaction in the control of antifungal immunity and allergic inflammation; and the fungal infectious basis of allergic airway disease of humans, including chronic rhinosinusitis and asthma.  In collaboration with Dr. Farrah Kheradmand, the Corry laboratory discovered the critical role that matrix metalloproteinases play in orchestrating allergic inflammation; first demonstrated the autoimmune TH1/TH17 basis of human emphysema; the critical roles that peroxisome proliferator activated receptor gamma (PPAR-g) and osteopontin play in emphysema; and that the primary disease-causing factor in tobacco smoke-related emphysema is nanoparticulate carbon black.  Dr. Corry's laboratory further pioneered the study of microRNAs (miRs) in pulmonary disease and discovered the pro-inflammatory role of let-7 miRs in experimental asthma and the critical role that miR-22 and histone deacetylase 4 (HDAC4) play in organizing pathologic TH17 responses in experimental emphysema.  Most recently, Dr. Corry's laboratory has discovered that low-grade fungal sepsis due to the yeast Candida albicans produces a durable cerebritis with features resembling Alzheimer's Disease.  Current research in the Corry laboratory is directed at translating these discoveries into improved diagnostic and therapeutic strategies for human allergic, smoking-related, and degenerative central nervous system diseases. Dr. David Corry is a physician and professor at Baylor College of Medicine who joins the show to discuss allergies, fungal infections, immunology, and so much more. In this episode, you will discover: What the most common reason is for death in people who suffer from asthma How a fungal infection could actually be the underlying cause of your allergic reaction to allergens in the environment Where in the body mycobiomes can be found, and what type of conditions they have been linked to Ever since the early days of his training as a physician, Dr. David Corry gravitated toward a strong clinical interest in diseases of the lungs, and discovered one of the major problems facing pulmonologists today: textbook and even the most advanced treatments don't always work on some of the most common illnesses, including chronic sinusitis and asthma. Further, the more severe the disease, the less likely it is that treatment will work. This sparked Dr. Corry's interest and compelled him to examine what is really going on with these conditions and how diagnoses and treatments for them might be improved. Dr. Corry's clinic focuses on treating advanced, potentially life-threatening inflammatory airway diseases, as well as chronic obstructive pulmonary disease (COPD) or emphysema that are complicated by sensitization to pollens or molds, which in turn leads to a particular pattern of inflammation called eosinophilic bronchitis. By using techniques that have been developed over the course of ten years' worth of research using mouse models, Dr. Corry and his team have been targeting the core problem that underlies these different conditions.  What might that problem be? This question leads him to explain one of the most important discoveries uncovered through his research, which is that in addition to continual exposure to an allergen such as pollen or cedar or mold, there is a factor that drives these allergies: airway mycosis, or the growth of mold in the airway. Dr. Corry explains what is really meant by the broad term “allergies” and the many different forms it can take in different people, how airway mycosis not only worsens but can also cause the symptoms of allergies, and how he treats his patients having been equipped with this knowledge. He also discusses the difficulty in prescribing antifungal medication, the presence of mycobiomes in the human body, and some of the most common sources of mold growth that you might not think of (and what to do about them).  He shares the specifics of the research he and his team are currently conducting, which aims to determine why only a small percentage of people develop serious disorders related to airway mycosis. He explains his two-fold hypothesis and when they expect to have sufficient data on the matter.  Tune in for all the details and visit https://www.bcm.edu/people-search/david-corry-19841 to learn more.

Talk to a Dr. Berg Keto Consultant today and get the help you need on your journey (free consultation). Call 1-540-299-1557 with your questions about Keto, Intermittent Fasting or the use of Dr. Berg products. Consultants are available Monday through Friday from 8:30 am to 9 pm EST. Saturday & Sunday 9 am to 5 pm EST. USA Only. Take Dr. Berg's Free Keto Mini-Course! Today we're going to talk about autoimmune conditions and what causes autoimmune conditions? An autoimmune condition is a situation where your body has created immune cells that are attacking itself. This creates inflammation, and the inflammation creates a lot of collateral damage. It's all of the free radicals that end up actually destroying the tissue. The immune cells that are attacking itself are called autoantibodies. You can have these autoantibodies to pretty much any tissue in the body. What autoimmune conditions boil down to is one cell called the Th17 cell becoming overactive. Excessive amounts of this cell are responsible for autoimmune conditions. In your immune system, you have a lot of different T cells. The T stands for thymus. Typically T helper cells do things like recruiting help to fight infection and generating weaponry. It's the main controller in the battle against infections. One of the functions of these cells is to maintain the intestinal barrier. This is the barrier that helps keep out viruses and pathogens. If there's a break in the wall and harmful bacteria get in, they can invade the inside of the body, causing an immune attack. Now, your body is going to start creating antibodies against these cells. If those cells are pathogens, this is a good thing. But, what if those cells are your own cells? This, of course, wouldn't be good. Another function of Th17 cells is making sure that the body doesn't destroy its own tissue. This cell could help prevent autoimmune conditions. The Th17 cells also work with the T regulatory cells, which have an even greater function of preventing autoimmune diseases. It may also help suppress autoimmune diseases and hyperinflammatory conditions. T regulatory cells also calm down infections. Dr. Eric Berg DC Bio: Dr. Berg, 51 years of age is a chiropractor who specializes in weight loss through nutritional & natural methods. His private practice is located in Alexandria, Virginia. His clients include senior officials in the U.S. government & the Justice Department, ambassadors, medical doctors, high-level executives of prominent corporations, scientists, engineers, professors, and other clients from all walks of life. He is the author of The 7 Principles of Fat Burning. FACEBOOK: fb.me/DrEricBerg?utm_source=Podcast&utm_medium=Anchor TWITTER: http://twitter.com/DrBergDC?utm_source=Podcast&utm_medium=Post&utm_campaign=Daily%20Post YOUTUBE: http://www.youtube.com/user/drericberg123?utm_source=Podcast&utm_medium=Anchor DR. BERG'S SHOP: https://shop.drberg.com/?utm_source=Podcast&utm_medium=Anchor MESSENGER: https://www.messenger.com/t/drericberg?utm_source=Podcast&utm_medium=Anchor DR. BERG'S VIDEO BLOG: https://www.drberg.com/blog?utm_source=Podcast&utm_medium=Anchor

There is a new exciting paper on the connection between eradicating the intestinal parasite Blasctocystis hominis and improving Hashimoto’s disease. I previously reported this infection connection in a case study which revealed an individual with Hashimoto’s disease getting better after eradicating Blastocystis hominis. Case studies aren’t the strongest scientific proof of a particular therapy but now we have and excellent paper with three research groups including a much-needed control group. This paper is entitled, “Improving Hashimoto’s thyroiditis by eradicating Blastocystis hominis: Relation to IL-17” published in the journal Therapeutic Advances in Endocrinology and Metabolism by El-Zawawy et al. The author’s begin by pointing out a very important fact that Hashimoto’s thyroiditis was once thought to be a TH1-mediated disease but once TH17 cells were discovered it became clear that it is a TH17-mediated disease. TH17 cells drive autoimmunity through production of the cytokine IL-17. Blastocystis hominis is the most common intestinal parasite in humans and most individuals never get any symptoms. This parasite is opportunistic however so if your gut or immune system becomes compromised, it can multiply and cause gut symptoms such as constipation and diarrhea, joint pain, drive autoimmunity and a host of other health problems. Blastocystis hominis has a prevalence of 1.6% to 16% in developed countries and up to 60% in developing countries. You can get this parasite from contaminated food or water. How was this study done on Hashimoto's Thyroiditis and Blastocystis hominis? 60 patients aged 19-57 with 19 females and 1 male in each group. Group 1: 20 patients recently diagnosed with Hashimoto’s thyroiditis without Blastocystis hominis infection. Group 2: 20 patients recently diagnosed with Hashimoto’s thyroiditis with confirmed Blastocystis hominis infection. Group 3: 20 healthy subjects without Hashimoto’s thyroiditis and not infected with Blastocystis hominis infection. All subjects in group 1 and 2 had a history of fatigue. 9 patients in group 1 and 7 patients in group 2 had a history of constipation. 6 patients in group 2 had a history of diarrhea. Interestingly, all subjects in group 2 who were infected with Blastocystis hominis had significantly higher blood pressure than the other 2 non-infected groups. The following tests were done on all subjects: Free T4 Free T3 TSH Anti TPO antibodies IL-17 Stool analysis CBC (complete blood count) ALT and AST (liver enzymes) Albumin Bilirubin Cholesterol Triglycerides BUN (blood urea nitrogen) Creatinine Group 2 which was infected with Blastocystis hominis was treated with the medication Nanazoxid for 3 days to eradicate the parasite and then retested 6 weeks later. What were the study results? TSH levels were higher in groups 1 and 2 compared to the healthy group 3 as expected. Free T4 was lower in group 1 compared to group 3 however group 2 did not have lower levels than group 3. Free T3 was significantly lower in group 2 compared to group 3. Free T3 levels in group 1 were not significantly different than the control group. TPO antibodies were the same between group 1 and group 2. Group 1 and group 2 had significantly higher levels of IL-17 compared to the healthy control group. However, group 2 had significantly higher levels of IL-17 compared to group 1 because group 2 was infected with Blastocystis hominis. They also found that high levels of IL-17 correlated with higher levels of anti-TPO antibodies and lower levels of Free T3. What happened to the patients treated for Blastocysis hominis? 10 patients in group 2 reported improvement in fatigue and 5 patients had improved constipation. Diarrhea completely resolved in all 6 patients. Blood pressure in group 2 which was significantly higher before treatment did not change after treatment.

Medien berichten von Ausnahmezuständen, leeren Supermärkten und Katastrophenszenarien. Doch wie gefährlich ist dieser Virus tatsächlich? Können wir uns vor einer Infektion schützen? In dieser Episode gehen wir der Sache physiologisch und immunologisch auf den Grund, sprechen über effektive Wege das Immunsystem zu stärken und beantworten Fragen aus unserer Community.  Online-Akademie:  -35% Rabattcode Darm-Regeneration: "CORONA"  Wenn Du uns auch eine Frage stellen möchtest, schreibe uns auf: support@evolve-health.de Mehr Informationen findest du unter:  www.evolve-health.de   Quellen:  Mahallawi, Waleed et.al. (2018); MERS-CoV infection in humans is associated with a pro-inflammatory Th1 and Th17 cytokine profile; 104. 8-13. 10.1016/j.cyto.2018.01.025. Duvall MG et.al. (2016), DHA- and EPA-derived resolvins, protectins, and maresins in airway inflammation; Eur J Pharmacol. 2016 Aug 15;785:144-155 Roxas M1, Jurenka J. (2007), Colds and influenza: a review of diagnosis and conventional, botanical, and nutritional considerations. Altern Med Rev.2007 Mar;12(1):25-48 https://www.who.int/news-room/fact-sheets/detail/cardiovascular-diseases-(cvds) https://www.sozialministerium.at/Informationen-zum-Coronavirus/Neuartiges-Coronavirus-(2019-nCov).html https://link.springer.com/article/10.1007/s001290050569

Esse é o episódio especial de Natal do Microbiando! Prometemos encher suas festas de fim de ano de vírus, bactérias, fungos, protozoários e todo tipo de criatura microscópica que você possa imaginar! Pra deixar a ceia de natal mais saborosa, nós vamos discutir um pouco o problema do uso de antimicrobianos na criação de aves de abate, como frango, chester, peru, que são comidas muito tradicionais e encontradas nas ceias de natal, com o artigo “O efeito benéfico de bactérias derivadas de Perus, Lactobacillus salivarius e Lactobacillus ingluviei sobre Salmonella Heidelberg multirresistente em filhotes de peru” E como além de comer, a gente gosta de beber também, nós vamos descobrir os benefícios do vinho e da uva passas (quer dizer, do resveratrol) em controlar a inflamação com o artigo "Resveratrol modula a microbiota intestinal e previne o desenvolvimento de Colite através da indução de Células T Reguladoras e supressão de Células TH17" Veremos também os Pestivirus, vírus de renas que vem causando várias doenças nesses animais e levando-os a forma de quase zumbi. É disso que vamos falar nos artigos “Pestivirus infection in reindeer (Rangifer tarandus)" Acesse a transcrição desse episódio! Você pode ouvir os episódios do Microbiando através do iTunes, Spotify, Google Podcast, TuneIn e outros aplicativos de podcast Apoiadores do A Ciência Explica Leandro LoboGabriel SiqueiraMasashi C. InoueCelia Campos Tobaldini-MansbachEduarda Moura Obrigado por nos apoiarem através do financiamento coletivo! Apoie você também e ganhe recompensas, como canecas, bottons, adesivos e livros exclusivos. Não pode ajudar financeiramente? Siga nossas redes sociais e compartilhe nossas matérias com seus amigos!

Elisabetta Volpe,Santa Lucia Rome, Italy, speaks on "Th17 in multiple sclerosis". This movie is part of "Flow cytometry: from basic principles to advanced application" Course, 8-10 May 2019, ICGEB Trieste, Italy.

This week, we discuss immunology with special guest, Diana Contreras. We cover some of the basics of immunology - discussing innate and adaptive/acquired immunity and the cells associated with both. Diana teaches us about the main cells in the adaptive immune system, B and T cells. Then, we dive into Diana's science background - discussing how she ended up studying immunology as a PhD student at Vanderbilt. We also discuss her current work studying metabolic differences between two different types of T cells (Th2 and Th17) with Dr. Jeff Rathmell.

John Alcorn, PhD is a scientist at UPMC Children's Hospital of Pittsburgh and an associate professor in the University of Pittsburgh School of Medicine. The Alcorn lab is focused on T cell immunity, host defense, epithelial cell biology, and lung physiology. A primary lab focus is on Influenza infection and the host defense mechanisms of T helper 17 cells. His lab has recently shown that the TH17 effector cytokines IL-17 and IL-22 are required for host defense against a variety of extracellular pathogens. 

Dan Littman discusses the opposing roles of Th17 cells. They protect mucosal surfaces from infection with bacteria and fungi, but they can also cause autoimmune inflammation.

Dan Littman discusses the opposing roles of Th17 cells. They protect mucosal surfaces from infection with bacteria and fungi, but they can also cause autoimmune inflammation.

How can we keep our immune systems in fighting shape? What happens when our immune systems are responding well or are missing key genes? is there targeted gene therapies that can be used to help save lives of those most at risk from infection?  How does our body hunt down and stop Listeria in it's tracks? Plus undercooked wild game or pork can lead to parasitic infections, but how does the body fight back?References: E Mamcarz et al. Lentiviral gene therapy with low dose busulfan for infants with X-SCID. The New England Journal of Medicine, April 17, 2019; DOI: 10.1056/NEJMoa1815408 Kazuhito Sai, Cameron Parsons, John S. House, Sophia Kathariou, Jun Ninomiya-Tsuji. Necroptosis mediators RIPK3 and MLKL suppress intracellular Listeria replication independently of host cell killing. The Journal of Cell Biology, 2019; jcb.201810014 DOI: 10.1083/jcb.201810014 Nicola Steel, Aduragbemi A. Faniyi, Sayema Rahman, Stefanie Swietlik, Beata I. Czajkowska, Bethany T. Chan, Alexander Hardgrave, Anthony Steel, Tim D. Sparwasser, Mushref B. Assas, Richard K. Grencis, Mark A. Travis, John J. Worthington. TGFβ-activation by dendritic cells drives Th17 induction and intestinal contractility and augments the expulsion of the parasite Trichinella spiralis in mice. PLOS Pathogens, 2019; 15 (4): e1007657 DOI: 10.1371/journal.ppat.1007657

Apparently chewing stimulates the production of Th17 cells in the mouth, which could help fight disease in some parts of the body.

Apparently chewing stimulates the production of Th17 cells in the mouth, which could help fight disease in some parts of the body.

Good dental hygiene is crucial in the fight against gum disease, which can lead to a common condition called periodontitis. It comes about when changes to the bacteria in the mouth cause a reaction called inflammation in areas around the teeth, potentially destroying tissue and bone and causing tooth loss. But quite why an altered microbiome causes this inflammation isn't known, so there are no targeted treatments, and surgery is the main option for severe cases. But now scientists have spotted that periodontitis patients have higher numbers of immune cells called TH17 cells in their mouths,... Like this podcast? Please help us by supporting the Naked Scientists

Good dental hygiene is crucial in the fight against gum disease, which can lead to a common condition called periodontitis. It comes about when changes to the bacteria in the mouth cause a reaction called inflammation in areas around the teeth, potentially destroying tissue and bone and causing tooth loss. But quite why an altered microbiome causes this inflammation isn't known, so there are no targeted treatments, and surgery is the main option for severe cases. But now scientists have spotted that periodontitis patients have higher numbers of immune cells called TH17 cells in their mouths,... Like this podcast? Please help us by supporting the Naked Scientists

O episódio de número 4 do Podcast Microbiando chegou para trazer as novidades da Microbiologia e Imunologia para vocês. E nele debatemos como uma população de células T, chamadas de gama delta, regulam a termogênese. Esse artigo foi publicado na revista Nature Immunology neste em 2018 e foi desenvolvido por um grupo da Universidade de Harvard nos EUA, em colaboração com a Universidade de Negev em Israel e com Trinity College na Irlanda e se chama “γδ T cells producing interleukin-17A regulate adipose regulatory T cell homeostasis and thermogenesis”, algo em português como "Células T gama delta produtoras de IL-17A regulam a homeostase de células T reguladoras do tecido adiposo e a termogênese". No quadro Microlitros de Notícias: uma breve pipetada de novidades da Microbiologia e Imunologia temos algumas informações importantes sobre a Raiva; uma reportagem falando sobre o estado de dormência de algumas bactérias e a implicação em determinadas doenças; e também falaremos sobre o sistema CRISPR/Cas descoberto em alguns microrganismos e seu potencial como ferramenta de edição genética. E na Filogênia da Ciência, iremos trazer as descobertas da microbiologista Rebecca Lancefield.   Tópicos comentados nesse episódio Imunologia Células T Termogênese Tecido adiposo Gordura branca Gordura marrom Homeostase Vírus da Raiva Estado de dormência bacteriana Sistema CRISPR/Cas Rebecca Lancefield   Referências desse episódio Kohlgruber A. C. et al., γδ T cells producing IL-17A regulate adipose regulatory T cell homeostase and thermogenesis. Nat Immunol. 2018, 19:464-474. Chehimi M, Vidal H, Eljaafari A. Pathogenic Role of IL-17-Producing Immune Cells in Obesity, and Related Inflammatory Diseases. J Clin Med. 2017, 14;6(7): E68. Liang L, Hur J, Kang JY, Rhee CK, Kim YK, Lee SY. Effect of the anti-IL-17 antibody on allergic inflammation in an obesity-related asthma model. Korean J Intern Med. 2018, 19. Chen Y, Tian J, Tian X, Tang X, Rui K, Tong J, Lu L, Xu H, Wang S. Adipose tissue dendritic cells enhances inflammation by prompting the generation of Th17 cells. PLoS One. 2014, 9(3):e92450. Christine R. Fisher, Daniel G. Streicker e Matthias J. Schnell. (2018). The spread and evolution of rabies virus: conquering new frontiers. Nature Reviews MS (2018). Ministério da Saúde. Brasil tem segundo caso de pacientes que sobreviveram ao vírus da raiva humana. Protocolo para Tratamento de Raiva Humana no Brasil. 2009. Laboissiere, Paula. Pará tem 12 casos notificados de raiva humana. 2018. STUART, J. e JAY, L. Dormancy contributes to the maintenance of microbial diversity. PNAS, Novembro de 2009. BRADLEY, P. et al. The Bacterial Cytoplasm Has Glass-like Properties and Is Fluidized by Metabolic Activity. Cell, Novembro de 2013. MARTIN, G. e STEFAN, K. Mycobacterium tuberculosis: Success through dormancy. FEMS Microbiology Reviews, Maio de 2012. KOZARVOK, E. Bacterial invasion of vascular cell types: vascular infectology and atherogenesis. Future Cardiology, Janeiro de 2012. Rossi, Ciro C. ; Araujo-Alves, Amanda V. CRISPR, o sistema imune adaptativo bacteriano. Microbiologia In Foco, Soc Bras de Microbiologia, p. 15 - 18, 01 nov. 2016. Live Science. What Is CRISPR? Broad Institute. QUESTIONS AND ANSWERS ABOUT CRISPR Antonio Regalado. De Quem é a Maior Descoberta da Biotecnologia do Século? Gaudelli N. M., Komor A. C., Rees H. A., Packer M. S., Badran A. H., Bryson D. I., et al. (2017). Programmable base editing of A∙T to G∙C in genomic DNA without DNA cleavage. Nature 551, 464–471. Cox, D. B. T., Gootenberg, J. S., Abudayyeh, O. O., Franklin, B., Kellner, M. J., Joung, J., et al. (2017). RNA editing with CRISPR-Cas13. Science358, 1019–1027. Encyclopedia.com. Lancefield, Rebecca Craighill (1895-1981) Encyclopaedia Britannica. Rebecca Lancefield.   Sobre o Podcast Microbiando A ideia do Microbiando é discutir artigos científicos de ponta em tod...

In our latest podcast, we speak with special guest, Dr. Vijay Kuchroo, covering cancer research, innate lymphoid cells, and the integration of immune cells into multiple systems. Topics The Kuchroo Laboratory Immune Checkpoints Innate Lymphoid Cells Sean Parker and Cancer Immunotherapy Immuno-Oncology Research Tools Keywords: Dr. Vijay Kuchroo, Harvard, Tregs, Th17, ILC, innate lymphoid cells, tumor cells, immune checkpoints, TIGIT, PD-1, cancer, GWAS, synapses  

Chewing stimulates the production of Th17 cells in the mouth, which can protect the body against disease.

Hosts: Vincent Racaniello, Dickson Despommier, and Daniel Griffin The TWiP triumvirate solve the case of the Thai Woman with Facial Swelling, and explain how Th17 T cells protect against the intracellular parasite Trypanosoma cruzi. Become a patron of TWiP. Links for this episode: Th17 cells protect against Trypanosoma cruzi (PLoS Path) Plasticity of helper CD4+ cells (Science) Image credit Letters read on TWiP 120 This episode is sponsored by CuriosityStream, a subscription streaming service that offers over 1,400 documentaries and non­fiction series from the world's best filmmakers. Get unlimited access starting at just $2.99 a month, and for our audience, the first two months are completely free if you sign up at curiositystream.com/microbe and use the promo code MICROBE. Case Study for TWiP 120 A 48 yo man from Mali comes to hospital ER in Washington Heights in NY with profuse watery diarrhea. Born in Mali, came to US at 18, working in US as long haul truck driver for 30 y, frequently visits Mali, recently to attend his father’s funeral. Got symptoms one week after return (was there for 3 weeks). 3 liters diarrhea/day. No past med/surg history, not seen doctor in long time. No allergies. Unknown what father died of, Mother in Mali is ok. No medications. Some alcohol, marijuana use. Does report that has exposure to professional female sex workers, no condoms. Temp of 39 C, bp down 80/40, heart over 110, rapid breathing high 20s, cachectic. Wasted. Fungating lesion perianally. Undergoes HIV testing, clade B. T cells

Allen opens the show with a fantastic Burt Reynolds story. Then, the guys discuss the virtues of taking big risks as an aspiring artist, Walt Disney had some big ones, a marathon edit session on the newest WSF short film, and then they wrap it all up with a preview of the Fall television season and some thoughts on Stranger Things.

[intro music]   Hello, and welcome to Episode Forty-Three of Multiple Sclerosis Discovery, the podcast of the MS Discovery Forum. I’m your host, Dan Keller.   This week’s podcast features an interview with Dr. May Han, who discusses issues related to following patients with clinically isolated syndrome. But first, here are some new items on the MS Discovery Forum.   We recently posted an article on a surprisingly strong association between a certain gene variant and non-response to interferon beta in people with RRMS. The study is a meta-analysis of three independent cohorts in Italy, France, and the U.S., and it comes from the labs of Philip De Jager and Filippo Boneschi. You’ll find this article by clicking first on News & Future Directions and then on New Findings.   This past week we published the latest in our series of data visualizations. This month’s visualization is a series of word clouds illustrating how key terms in the MS clinical-trial literature have changed between 1993 and 2014. To find this visualization, first click on Research Resources, then on Data Visualizations, and then on Word Cloud.   According to our curated list of the latest scientific articles related to MS, 30 such articles were published last week. To see last week’s list, go to msdiscovery.org and click on Papers. We selected one of those papers as an Editors’ Pick. It’s study of the association between depressive symptoms and walking ability in people with RRMS.   Are you attending the annual meeting of the Consortium of Multiple Sclerosis Centers in Indianapolis this week? If so, please come visit us at the Accelerated Cure Project’s booth. We’ll be demonstrating some of our latest data visualizations along with other features of the MS Discovery Forum. You’ll find the booth in the hallway close to the main entrance to the exhibit hall, and we look forward to meeting you.   [transition music]   Now to the interview. Dr. May Han is an assistant professor in Neurology and Neurological Sciences at Stanford University. I spoke with her about following patients with clinically isolated syndrome, as well as her approach to patients with MS across the course of their disease. But first, she addressed some unmet needs in MS.   Interviewer – Dan Keller Dr. Han, you told me that we’re good at the diagnosis of MS in general, but still there’s a vast area that we don’t know about. What are some of those unmet needs?   Interviewee – May Han So it’s been over 150 years since Charcot first described multiple sclerosis, and I have to say that we have come a long way in understanding and treating this disease. But as you have mentioned, there are still areas where we have no idea, there are gaps in our understanding of this disease. One of these areas that is clinically very relevant and is very challenging is in the day and age where we have a dozen disease-modifying therapies for MS patients, and yet we don’t have a good way, a scientific way of selecting the most effective therapy for a particular patient is what I find quite challenging in the clinics.   MSDF What gives you clues or how do you approach this essentially algorithm of deciding where to begin and how to move on to other medications if the first one’s not working well?   Dr. Han Currently, of course, we follow the guidelines. So for any relapsing-remitting patients, our logic is to go for the safest medication that we think are going to be most effective, which means we go with the first-line therapies. So we have the convention ABC drugs such as beta-interferon family of therapies and glatiramer acetate, plus the newer oral medications such as Tecfidera and fingolimod or Gilenya that we use for the first-line therapy; not a whole lot of science in choosing these medications for a particular patient, but what we would do is initially we would educate the patient about these disease-modifying therapies and then select the medication together with the patient to see what would be most appropriate and the patient could be most compliant for a particular medication.   To give you an example, certain patients have aversion to needles, in which case we go with the oral medications. We also have in mind what the preference of the patient, such as whether they could be able to follow it through for years on end with a particular medication. Ideally, we would like to have zero relapses or MRI activity when a patient is on a disease-modifying therapy, but as we all know none of these medications are 100% foolproof, and they can still have some degree of MRI activity or infrequent relapses on this medication. However, if a patient is clearly not responding to a therapy either in terms of not being compliant, being intolerant to the mode of administration, or if they’re having worsening disease activity, we would decide to go on to stronger medications or second-line of therapy.   MSDF Do you initially discuss a plan of action, a stepwise pattern of medication prescribing, or do you wait until something needs to be changed to bring it up with patients?   Dr. Han That is a very good question. I’m sure it varies among clinicians, but, however, I would like to paint the picture to the patient the best that I can. So, let’s say for example, if a patient who is a newly-diagnosed MS patient who has very few MRI lesions, I would discuss with them what the most appropriate medication could be. We would decide a medication and we would also give them an outline of what the followup plan would be and when we would be deciding to switch to a different therapy, and if so, which medications would be most likely appropriate for them, and also how we would monitor them. So by doing this, it gives the patient a better picture of their path and what to watch out for, and in my experience we have a better outcome with these patients.   MSDF Do you find that once you achieve success in limiting relapses and lesions that the medication is fairly stable for a long time, or do you have to have an armamentarium that you keep moving through?   Dr. Han So my model if a patient is responding to a medication, unless they have other side effects or reasons to switch, I would like to get the most mileage out of the medication as much as I can for a particular patient. However, if a patient, for example, has JC virus positivity, in which case even if they’re responding to Tysabri really well, there is a cutoff time point where we have to sit down and consider whether this patient should be switched onto a different medication to prevent the development of opportunistic brain inflammation such as PML, in which case what the next medication would be. And so we would sit down and talk the pros and cons; this conversation was started even before the patient was started on medication, but that would be the checkpoint.   MSDF I suppose another aspect is do medications start to fail patients even after a long period of stability, or do they usually continue to be stable if the medication is working for some period of time?   Dr. Han This is also a very pertinent question. MS patients, as we know, is very heterogeneous. Some of the patients, if they are stable on a medication, they would continue to do well on a medication for several years up to decades. However, some patients would have an initial improvement or stabilization of their disease, however in the later stages they would have worsening disease. And it is really unclear whether because their disease per se is getting worse or whether their body is rejecting the medication secondary to the immune response. And that is also one area that we should do research on to better understand this condition.   MSDF When you say reject the medication, are you actually referring to an immune rejection such as with, say, interferon; I would think it would be less likely they would actually mount an immune response to a small molecule. Am I clear on that or not?   Dr. Han I think we have quite a lot of information in terms of beta interferon therapies, because we clearly know that patients do tend to develop antibodies against beta interferon, especially the therapy. However, even that we don’t really know if all those antibodies are attacking the drug or whether they are just there. So just by finding the antibody alone is not enough to say that the patient is not responding to it; I think we need to use it hand-in-hand with the clinical response as well as the MRI activity.   Getting to the second part of your question whether there’ll be less intolerance or rejection to the therapy if it were small molecules, but I don’t think we understand at the cellular or molecular level. For small molecules there could be receptor down-regulation, there could be availability or cellular sequestration, or even the prodrug being converted to an active drug, or how the breakdown process occurs. So when a patient does not respond anymore to a medication, we just know that the clinical response is worse, and we don’t really know whether it is because the disease activity has worsened or other aspects, pharmacodynamic or kinetic aspects of the system has changed in such a way that they no longer respond. So, again, we do need to do more research to have a better understanding.   MSDF You have called it MS comes in many different flavors. Have you found that any medications are particularly good for different constellations of symptoms, or is everything about equal no matter how they present?   Dr. Han Very good question as well. I think in the experimental models people know that MS, or central system autoimmunity, can have a bias towards one type of inflammation as opposed to the other. For example, some would say that certain medications are better to treat Th1 as opposed to the Th17 type of inflammation, however in human beings there’s no clear-cut Th1 MS or Th17 MS. I don’t think people have done enough studies to clearly decipher the immune profiles of patients. So the answer is we don’t know.   MSDF Finally, let’s talk about the need for biomarkers especially very early in the disease when someone’s presenting with CIS which may or may not become MS. Where does that stand and how acute is the need?   Dr. Han The need is there, especially if you look at it from a patient who just had an initial attack. If you tell them that we don’t really know whether this is a one-time thing or whether you’re going to develop MS, and we’ll have to wait and see for three-plus years. So for these three years, the patient’s life is very much consumed by the “is it going to be MS” kind of question. And it does affect their physical-mental wellbeing as well as their quality of life.   I think we’ve come a long way with the advancement of the MRI studies in such a way that if a patient has MRI lesions together with the first-time attack, we could almost clearly say that this is going to blossom into MS. However, for patients who are radiographically clean and who just had one episode, it would be very, very helpful to have some kind of blood biomarkers to predict whether this could be a single event or whether it could be a central nervous system inflammatory disorder.   MSDF You picked three years as a period of waiting, watching. Are they out of the woods after that, or how late can it blossom into full MS?   Dr. Han It’s always a bell-shaped curve. There are patients who would declare themselves sooner than three years, there are also patients who would take several years before they have the second attack. I have one patient who had an initial attack of optic neuritis and nine years later she had the second attack. During that period, she had had MRI scans for three years which were clean. So, I guess, one is never completely out of the woods, but at the same time it is also not prudent to perform unnecessary tests on a patient.   So I think we have to focus on what is the safety net and pick a period of time, but at the same time it is very important to educate a patient to symptoms to watch out for, how to get help, and to work very closely with the primary care physician or a neurologist so in case the symptoms show up they will not be ignored or delayed to receiving treatment.   MSDF Is there anything we’ve missed or is important to add? I’m sure it’s a gigantic field, but is there anything glaring that should be added?   Dr. Han I would like to encourage people in the field to also focus on the secondary-progressive stage of MS. We know that relapsing-remitting MS patients with or without therapy eventually would end up having secondary-progressive MS, so it’ll be really important to decipher whether during the secondary-progressive stage there is no inflammation but only the early neurodegeneration, or how the immune system and the central nervous system interact and how we can change it, or at least modulate it, to either delay or to prevent neurodegeneration. The third area that I think is very important is to try to understand the regenerative aspects of the central nervous system.   As I have given you the example, if we have two patients who have had similar lesion burden or even lesions that are approximately the same in similar areas, a patient can be severely devastated, neurologically devastated, whereas the other may have minimal neurologic deficits. And we would always say that it depends on the brain reserve, or neural reserve, but we don’t quite know what it is. Is it the stem cells, is it the nervous system being more resistant to insult and how the immune system interacts with it? And I think this is also a big area that we should focus on, of course, to prevent further damage, but also once the damage is done to limit the damage and perhaps to regenerate it. And I think that people always have within themselves the ability to heal.   MSDF Good, thank you.   Dr. Han Thank you.   [transition music]   Thank you for listening to Episode Forty-Three of Multiple Sclerosis Discovery. This podcast was produced by the MS Discovery Forum, MSDF, the premier source of independent news and information on MS research. MSDF’s executive editor is Robert Finn. Msdiscovery.org is part of the non-profit Accelerated Cure Project for Multiple Sclerosis. Robert McBurney is our President and CEO, and Hollie Schmidt is vice president of scientific operations.   Msdiscovery.org aims to focus attention on what is known and not yet known about the causes of MS and related conditions, their pathological mechanisms, and potential ways to intervene. By communicating this information in a way that builds bridges among different disciplines, we hope to open new routes toward significant clinical advances.   We’re interested in your opinions. Please join the discussion on one of our online forums or send comments, criticisms, and suggestions to editor@msdiscovery.org.    [outro music]

[intro music]   Hello, and welcome to Episode Forty-Two of Multiple Sclerosis Discovery, the podcast of the MS Discovery Forum. I’m your host, Dan Keller.   This week’s podcast features an interview with Dr. Lawrence Steinman, who discusses a surprising result involving amyloid, a molecule typically associated with destruction in Alzheimer’s disease, in an animal model of MS.   Our Drug-Development Pipeline includes continually updated information on 44 investigational agents for MS. During the past week we added 1 new trial and 16 other pieces of information. The drugs with important additions are dimethyl fumarate, daclizumab, glatiramer acetate, and natalizumab. To find information on all 44 compounds, visit msdiscovery.org and click first on Research Resources and then on Drug-Development Pipeline.   According to our curated list of the latest scientific articles related to MS, 50 such articles were published last week. To see last week’s list, go to msdiscovery.org and click on Papers. We selected one of those papers as an Editors’ Pick. It’s a meta-analysis of epidemiological studies of neuromyelitis optica, also called NMO or Devic’s disease. The conclusion of the meta-analysis is that there’s a high level of heterogeneity among the 9 studies that met the inclusion criteria. The prevalence of NMO in the studies ranged from 0.51 per hundred thousand in Cuba to 4.4 per hundred thousand in southern Denmark.   Will you be attending the annual meeting of the Consortium of Multiple Sclerosis Centers in Indianapolis next week? If so, please come visit us at the Accelerated Cure Project’s booth. We’ll be demonstrating some of our latest data visualizations along with other features of the MS Discovery Forum. You’ll find the booth in the hallway close to the main entrance to the exhibit hall, and we look forward to meeting you.   [transition music]   Now to the interview. I spoke with Dr. Lawrence Steinman, professor of neurology and neurological sciences, pediatrics, and genetics at Stanford University, who has a new twist on amyloid, this time in MS.   Interviewer – Dan Keller Dr. Steinman, you have proposed that amyloid can be a protective molecule as well as what’s commonly viewed as a destructive molecule. How did you come upon this?   Interviewee – Lawrence Steinman We came about it serendipitously or by accident. I had a graduate student and I thought I would give that student some low-hanging fruit, and the low-hanging fruit was to take the conventional animal model that we use for multiple sclerosis called experimental autoimmune encephalomyelitis – EAE. And when she put in these long peptides from an infamous protein named amyloid beta – A-beta – she put it into the animals with EAE at the time they were paralyzed, and I thought well, these are molecules that cause even more inflammation in the central nervous system, so they should make the disease worse, or perhaps they’ll have no effect and then we’ll have to think of another project for her PhD. So the student, Jacqueline Grant, came back and said, “Well, I gave the A-beta peptides and the animals are all better, they’re walking around.” And I first reacted, no, you must have confused the cages, let’s do it again. And when we did it again there was the same result, so then we were off to the races.   There was a second reason besides the low-hanging fruit description. May Han, my colleague, and I had reported the proteomics of MS lesions; so we took well-defined MS lesions, May cut frozen sections and then removed the lesion area with a laser tool, and then we trypsinized, fragmented the proteins, and used a modern technique, mass spectroscopy, to get the proteome, a list of all the proteins in the lesions. So amyloid proteins such as amyloid precursor protein and cal protein are found in the lesions themselves, so I thought that that was a second opportunity, a second foundation for doing these experiments in EAE; let’s see what happens when we augment, if you will, a naturally occurring protein found in the lesion to see perhaps what it’s doing. But, again, my bias, based on the dominant theory in Alzheimer’s disease is that amyloid was going to cause harm in MS as well as Alzheimer’s.   MSDF In these experiments, the amyloid was injected IV so it seems to circulate, but does it get to the brain in these mouse EAE models?   Dr. Steinman Actually, it does not get to the brain. We’ve actually put it into the brain directly to see if it would spread throughout the brain, and in our hands the molecules we’re working with do not spread. Most of these experiments showing a prion-like spread of amyloid is done in animals that are overexpressing the amyloid proteins in the brain so that they’re sort of tilting the balance to enhance spread if it’s going to occur, but we don’t get these amyloid molecules into the brain when we inject them intravenously, nor do we spread them around when we injected them directly into the brain.   MSDF So if you’re injecting them peripherally, do you think that there is some direct effect, or do you think they’re acting through lymphocytes or other circulating cells?   Dr. Steinman Well, we now know that there are at least two mechanisms. One is that when we are injecting them peripherally, these amyloid-like molecules, they go to sites of inflammation and this could include sites of inflammation within the brain. But remember, they’re on the vascular side of the lesion. And they act in a way like molecular sponges. The amyloid molecule is very sticky; in fact, when you try to work with some of the amyloid molecules, they’re like bricks, they stick to the walls of test tubes, and more importantly, they stick to each other and form these long, brick-like fibrils.   So what they’re doing when we put them into the circulation is they’re sopping up many of the inflammatory mediators that appear in the circulation during inflammatory diseases, including inflammatory diseases of the brain. These inflammatory mediators include the complement proteins and some of the famous apolipoproteins that we’ve heard about in reference to Alzheimer’s, we’ve heard the most about apolipoprotein E. So these amyloid molecules, when they’re in the circulation, actually stick and take away, precipitate away these inflammatory mediators. So I call it a molecular sponge.   There’s another set of mechanisms that we’re learning about that we’re able to use these amyloid proteins to do a couple of things to lymphocytes. One, it sets up a type 1 interferon response in lymphocytes. So the amyloid fibrils are a known trigger for the production of type 1 interferon, and type 1 interferon is actually beneficial for neuroinflammation; we have approved drugs. It’s doing another thing that we’re on the verge of publishing, but I’ll sort of give the headline without too many details; it’s setting up a type of lymphocyte that has a more regulatory function. So these are all rather unexpected roles for amyloid proteins.   MSDF And you have done adoptive transfer of some of these lymphocytes and find similar effects?   Dr. Steinman Yes. And the adoptive transfer experiments are very interesting. When we set up the system to produce a lot of type 1 interferon after we give an amyloid fibril, if the type of disease is what’s called the Th17 disease, the increased beta interferon actually worsens that, and if we create a disease that is called T-helper 1 – Th1 – then the type 1 interferon is beneficial. So we’ve engineered some amyloid structures so that they trigger less type 1 interferon, and when they trigger less type 1 interferon, then they work in both the Th1 and Th17 models. We published on that in the Journal of Experimental Medicine. But, again, even here with the type 1 interferon, the effect is nuanced and we can engineer these amyloid structures to be really beneficial and to take away the harm.   I wanted to say one thing, that clinicians and working scientists generally understand amyloid very well. Amyloid-beta that’s well known. Other amyloid proteins that people are, of course, familiar with are tau, prion protein, alpha-synuclein. But an amyloid structure is a general description of a protein that forms beta sheet, so the beta strand structure allows through hydrogen bonds the formation of what you should think of as a venetian blind, these monotonously parallel sheets that actually intercalate dyes, like Congo red or thioflavin T, so that when you shine polarized light on them they refract it in a polarized way. So we can make these structures, if you will, they’re organized nano particulars, to be more or less water-soluble, to be greater or lesser inducers of type 1 interferon. So there’s a whole armamentarium of very interesting amyloid structures that we can engineer to provide benefit in different situations.   Now what does this all mean for the Alzheimer’s hypothesis? And we’re doing an audio interview, so I’m sort of smiling wryly. I don’t want to get into that because we haven’t done the experiment in the amyloid-beta overproducing transgenic mice that have served as the model system to test whether various amyloid-lowering procedures will provide benefit, we just haven’t done that. And we’ve tried our particular approach in a number of other conditions ranging from stroke to EAE, as I said, to experimental heart attacks. And in the systems that we’ve studied, we see benefit.   MSDF But as a further proof of concept of what you have found in the protective effect of amyloid, you’ve looked at amyloid precursor protein knockout mice. Is that right?   Dr. Steinman Yes. Well, that’s a whole interesting story, and thanks for reminding me. So in a series of experiments that we have done and others have done, we first noticed that amyloid precursor protein knockout mice, they had worse EAE. Another person in Australia, Colin Masters, who’s actually one of the leaders in the field of Alzheimer’s research, looked at experimental head trauma, and in the amyloid precursor protein knockout mouse, they had a worse condition after head trauma that was alleviated by giving amyloid precursor protein in its soluble form. And then other people have shown that experimental encephalomyelitis is worse in prion knockout animals and in tau knockout animals.   We had been working with a protein called alpha-B crystallin, which is also an amyloid-forming protein, and we noticed that EAE was worse in the absence of alpha-B crystallin. So there’s a long series of experiments that loss of function, loss of the parent protein of these amyloid-producing molecules, leads to worsened inflammation, whether it’s EAE, head trauma, or somebody else did it in experimental heart attack. And we also did it in experimental stroke, so under a variety of conditions.   So this makes the argument even stronger, suggesting that amyloid structures when augmented can provide benefit and reduce inflammation, and when absent can actually exacerbate inflammation; so gain of function better, loss of function worse. So you have to look at the amyloid molecule as something that is not always harmful and pathologic. Whether it is the main culprit in Alzheimer’s, whether Alzheimer’s is an example of neuroinflammation, I leave it to people in that field because I really don’t want to take them on headlong at this point in time when we have all these fascinating results elsewhere. But I let the listeners draw their own conclusion based on the published work that I’m talking about, not only from my own lab but from other investigators all over the world.   One might want to think a little bit differently the next time one thinks about the deleterious effects of amyloid in Alzheimer’s, but I’m not going to be the one that takes on that massive scientific opinion, we’ll just have to see how it works out. I hope everyone’s been right over all these years because we certainly need some answers in that field. And if they are right, then we’ll have to integrate the kinds of things that we’re understanding about the role of amyloid proteins in other types of inflammatory conditions with a positive result in Alzheimer’s when it’s taken into the clinic. If it turns out that the experiments do not succeed in Alzheimer’s, then it will be easier to reconcile these different outcomes. But I think we’ll have to be patient; science doesn’t move as fast as some of us would like to have it move.   MSDF What was the time course of seeing a result by injecting the amyloid in your EAE models?   Dr. Steinman It’s very fast. When you inject the amyloid, it’s within 48 hours. If you stop giving the amyloid – we like to give it every day – if you stop giving it for a few days, the inflammation recurs, and that suggests that these amyloid structures are acting like a pharmaceutical. It’s not one of these situations that you sometimes see in science; you give the molecule once or twice and the disease goes away forever. This seems to be suppressing ongoing inflammation while it circulates, and when you take it away the effect is gone and the disease recurs, so that’s very interesting.   MSDF The effect seems to be too quick for remyelination to be occurring as the answer, but when you give it chronically do you see remyelination?   Dr. Steinman So far, we haven’t looked for long enough periods of time or with sensitive enough techniques. Your question triggers an experiment and we should really take a look at that. I would imagine that if you can abrogate inflammation that you’ll allow for remyelination if there’s anything left in the oligodendrocyte precursor to remyelinate itself, or if you need a little augmentation, it would be good to do a stem cell type of therapy under the protection of this kind of antiinflammatory approach.   MSDF Are you planning any early human trials?   Dr. Steinman Ha! I chuckle because this is a tough one to bring into the clinic. I’ve been funded by people who first scolded me for saying don’t take this too fast into the clinic, because I like to translate results. In this one, we’ll have to be more cautious than we might for other types of therapies.   MSDF Is there anything important to add?   Dr. Steinman I thought the questions were very comprehensive. And as you can see from where our matters stand now, there’s a lot of positive leads to pursue. And I think we’ll have to be cautious about translating in the fields of multiple sclerosis or stroke because of the infamy of the molecule I’m working with, but we’ll get there. Thank you.   MSDF Thank you.   [transition music]   Thank you for listening to Episode Forty-two of Multiple Sclerosis Discovery. This podcast was produced by the MS Discovery Forum, MSDF, the premier source of independent news and information on MS research. MSDF’s executive editor is Robert Finn. Msdiscovery.org is part of the non-profit Accelerated Cure Project for Multiple Sclerosis. Robert McBurney is our President and CEO, and Hollie Schmidt is vice president of scientific operations.   Msdiscovery.org aims to focus attention on what is known and not yet known about the causes of MS and related conditions, their pathological mechanisms, and potential ways to intervene. By communicating this information in a way that builds bridges among different disciplines, we hope to open new routes toward significant clinical advances.   We’re interested in your opinions. Please join the discussion on one of our online forums or send comments, criticisms, and suggestions to editor@msdiscovery.org.    [outro music]

[intro music]   Host – Dan Keller Hello, and welcome to Episode Thirty-Seven of Multiple Sclerosis Discovery, the podcast of the MS Discovery Forum. I’m your host, Dan Keller.   This week’s podcast features an interview with Jeanne Loring, who works with human induced pluripotent stem cells in a mouse model of MS. But to begin, we’d like to tell you about one of the most useful features of the MS Discovery Forum.   Each week somewhere between 30 and 110 papers related to multiple sclerosis are published in the scientific literature. At MSDF, we endeavor to list them all, publishing links to a curated set of each week’s new papers every Friday at msdiscovery.org/papers.   The first step in curating this list is an automated PubMed query that pulls all papers containing the terms multiple sclerosis, myelin, optic neuritis, acute disseminated encephalomyelitis, neuromyelitis optica, transverse myelitis, experimental autoimmune encephalomyelitis, cuprizone, neurodegeneration, microglia, and several related terms. This query returns many false positives. MSDF editors read all the titles and most of the abstracts and make judgments about which papers are directly relevant to MS or related disorders. Last week, for example, the query returned 139 papers and, in our judgment, only 58 of them – 42% – were truly MS-related. Some weeks the proportion is even lower than that.   The query terms neurodegeneration, myelin, and microglia are responsible for most of the false positives. Neurodegeneration, in particular, returns many references related to other neurodegenerative disorders, such as Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, stroke, and hypoxia, to name a few. Editorial judgments on which articles are relevant are often subjective, and we frequently struggle with those decisions. It’s easy to decide relevance when an article actually mentions multiple sclerosis. It’s harder when it mentions only myelin or only Th17 cells. If you think we’ve missed an important MS-related article—or if you think we’ve included an irrelevant article—I hope you’ll let us know by emailing us at editor@msdiscovery.org. And we’re open to suggestions on how to adjust our PubMed query to decrease false positives and false negatives.   Once we’ve chosen which of the articles to include in the week’s list, we select between two and four of them as Editors’ Picks. Those are the week’s articles that seem to us to be the most important or interesting or intriguing. Once again, we invite readers to take issue with our choices. We’d love to hear about important articles that we have not designated Editors’ Picks or, on the contrary, Editors’ Picks that don’t deserve the honor.   [transition music]   Now to the interview. Dr. Jeanne Loring is Professor of Developmental Neurobiology and Director of the Center for Regenerative Medicine at the Scripps Research Institute in San Diego. She and her collaborators have been testing human neural precursor cells derived from embryonic stem cells in a mouse model of MS. The cells are injected into the spinal cords of immunocompetent mice with a model of MS induced by a neurotropic hepatitis virus. The cells are rejected within a week, but in that time they suppress the immune system and induce remyelination.   Interviewer – Dan Keller In terms of how you came upon your most recent finding about human pluripotent stem cells in the mouse model of MS, could you give me a little bit of the back story?   Interviewee – Jeanne Loring Oh yeah, sure. It was really interesting. So Tom Lane and I set out to try to develop a stem cell therapy for MS using human cells. So as a control experiment, we took human pluripotent stem cells, in this case embryonic stem cells, and turned them into neural precursors; differentiated them just a little bit. And then we transplanted them into Tom’s mouse model of MS. These mice were not immunosuppressed, and so we expected the cells to be rejected. And this was just our first experiment. But the results were not what we expected. After the cells were rejected, the mice started getting better, and their clinical scores improved. And then after several months, these mice were almost indistinguishable from normal mice.   The first thing we thought was that we’d gotten the cages mixed up, and we were looking at something different. But we’ve repeated the experiment now more than a hundred times, and about 75% of the time we get the same result. So what this tells us is that these cells that we put into the animals are having some effect during the seven days that they exist in the animals that leads to both immunosuppression and remyelination and a clinical improvement which is quite remarkable.   MSDF When you say 75% of the time, does that mean you get almost no effect 25 % of the time? Or does it mean that 75% or the mice? Because that would say whether you’re making your stem cells right or not.   Dr. Loring It’s 75% of the mice.   MSDF How do you explain it at this point, or where do you go from here to find a way to explain it?   Dr. Loring So once we’d realized that we had a phenomenon that was repeatable, we realized that there was something special about these cells. And we tested other cell types, like the pluripotent stem cells that they were derived from, and human fibroblasts, and discovered that neither one of those was effective. And since then we’ve also tried other ways of making neural precursor cells, and those cells aren’t effective either. So it’s something extremely special about the cells that we used in these experiments, which is very lucky when you think about it.   So we’ve now, both Tom and I – even though we’re not in the same place – we’ve set out to try to find out what it is about these cells that gives them these properties. Our first sort of cut on this – our hypothesis – is that the cells are secreting something that has a lasting effect. Our sort of big picture idea is that there are probably more than one protein or glycoprotein being secreted. And together they suppress the immune system so they act on the inflammatory response so that they increase the number of regulatory T cells that are produced and decrease the other T cell types. And they induce remyelination.   So Tom is now working on trying to identify what factors these cells make that are inducing the T regulatory cells. And on my side, we’re trying to identify what it is that makes them remyelinate.   MSDF When you make these cells, how do you know you got a good batch? Can you characterize them? Are there biomarkers, and you can say, “We did it right this time?”   Dr. Loring Yes. In fact, that turns out to be really important because we did it wrong a few times. And we have a gene expression signature. It’s essentially diagnostic assay for this particular cell type. We’ve boiled it down to a set of qRT-PCR markers. And, because we have collaborators in Australia, we had to be able to transfer this quality control assay to them. So far it seems like those markers, I think it’s a group of 10 or 12 markers, seem to be predictive of the cells’ working in the animals.   MSDF And just to clarify, that’s real time quantitative polymerase chain reaction? How are you going about characterizing what they’re doing? I mean, are you doing cytokine measurements or you’re looking at cells that get produced in the mice?   Dr. Loring Tom is really handling the cells that get produced in the mouse. He’s doing the T cell analysis. What we’re doing, we developed an in vitro cell culture method to look for the effect of these cells on maturing oligodendroglia in culture. And we found that something secreted by these cells which shows up in their culture medium actually induces maturation of oligos – of OPCs – in vitro. I guess that’s another result that we didn’t expect to be quite so clear. So that shows that there’s something that is secreted by the cells. I mean, that’s the most likely idea. And on Tom’s side, he’s shown that the conditioned medium from the cells induces T-reg generation. And on our side, we’ve shown that conditioned medium from the cells induces oligo maturation.   So now we’re trying to figure out what it is in that conditioned medium because now we think we can do a cell-free therapy for MS if we can identify what the factors are. It would be much simpler for us to do even a protein therapy for MS than it is to do a cell therapy. So both sides are taking sort of a candidate gene approach in which we’re identifying the proteins that are most highly specifically expressed in the cells that work in the mice. We have a list of those proteins, and we’ve sort of snatched a few candidates out of that group, and we’re testing to see whether each one of those proteins in purified form has the same effect as the conditioned medium.   The other approach, which is more tedious but more likely to actually tell us what’s going on is for us to fractionate the medium into different sized proteins and then test each one of those fractions. We’re in the process of doing that right now.   MSDF But it sounds like these cells are pluripotent. Not pluripotent in the normal sense of a stem cell leading to different lineages, but they have a couple of effects. One is the immunomodulatory, the other is regenerating oligodendrocytes. Do you think it really requires the gamish of proteins? If you fractionate them, will you possibly lose the signal? And that’s a big matrix to put back together again.   Dr. Loring Yes, it is. And obviously, if we get no signal from our fractions, we’ll put our fractions back together again and try to find out whether – there are only three fractions, really, right now. So we’ll try different combinations of these fractions to try to find out if we can reproduce the effect. The effect is quite robust. We essentially get no maturation in medium conditioned by other cell types, but we get very strong maturation when we use conditioned medium from this particular neural precursor cell.   MSDF If you only have three fractions now, is it because you just have chosen not to fractionate it even more until you know what’s going on?   Dr. Loring Yes, we’re trying to hone in on it. So we don’t want too many different things to look at right away. I’m hoping that we find that only one of those fractions works, and that we can discover everything is within that fraction, but I really can’t predict what’s going to happen.   MSDF It sounds like the approach would be to put everything in except one each time as opposed to keep adding back. You’ve got to find the one critical one missing that makes the thing not work.   Dr. Loring Yes, and eventually we will do that with specific antibodies, but right now that is, since we don’t really have our candidates narrowed down enough, that isn’t a viable approach. But you’re absolutely right. We want to find out if that’s missing, whatever the things that are that are missing. And I’m hoping it’s not so complex that it’s five or six or seven proteins, because that’ll make it much harder for us.   MSDF How do characterize the condition of the mice?   Dr. Loring So that’s Tom’s area of expertise. It’s essentially an observation of the mice over time. We have a movie which I can show you, but I can’t actually do it in a recording. It’s quite obvious when the mice – they’re blind scored so the person who looks at the mice and sees how well they’re walking around doesn’t know whether they’re controls or experimentals. If you just see the movies that are selected at particular times after the cells have been transplanted, it’s quite dramatic. They have a much better clinical score. Essentially, they’re almost normal after six months.   MSDF And how are you sure that the cells you injected into the spinal cord are gone, that they’ve been rejected completely?   Dr. Loring That’s a good question. We used a method for live imaging of cells in which we use luciferase to label the cells. And then we used an instrument which allows us to image the cells in mice – in living mice – over time. So we did this in individual mice and saw that they disappeared over time. And after eight days we couldn’t detect them anymore. That doesn’t mean there isn’t one or two left because the resolution isn’t that high. We will go back eventually and look through sections of the spinal cords and see whether we can detect any. The other thing we can do is (skip 13:37) a human-specific markers. So we can just take a section of the spinal cord and find out if there’s any human cells in it at all, or any human genes in it at all. But we haven’t done that yet.   MSDF Do the cells have to be gone? Have you tried injecting a second time?   Dr. Loring No, we haven’t. We don’t know. We really don’t know. It would be very interesting if it reversed the effects. Then we’d really have a problem to solve.   MSDF What else is there important to add or that we’ve missed that’s important to this kind of research?   Dr. Loring So our dream is that we will identify a group of proteins and the concentration of those proteins necessary to have these two effects in this mouse model. And then we will do some biological engineering. We’ll be putting the cells into these little spheres and matrix that allows slow release of these proteins or controlled release of these proteins. And then, instead of putting cells in, we’ll put these beads in. And I don’t know whether that would end up being the final product or not, but there are lots of ways to deliver proteins, and this one I find rather attractive because it doesn’t require pumps or syringes. And I think that’s certainly the direction we’re going to try to go in. And so Tom Lane and I have just gotten an NIH grant for five years of funding, which seems like a very long time to me. So in five years we will have discovered the best way to deliver these things. We’ll discover what they are and the best way to deliver them. Tom has put conditioned medium into the mice, and it also works.   MSDF Because I was going to ask, had you encapsulated the cells just to see that the supernatant does it without cell contact?   Dr. Loring It turns out that the conditioned medium itself, you inject that into spinal cord, it’s not as dramatic an effect, but you have a clear clinical improvement.   MSDF Have you tried injecting it either IV or intraperitoneally?   Dr. Loring Yes. Well, we didn’t inject the conditioned medium. We did try injecting the cells, and they pretty much stayed where we injected them. These cells, unlike mesenchymal stem cells, they aren’t very migratory. So they don’t really have the receptors that cause them to move to areas of inflammation like CXCR4, for example; they don’t express that on their surfaces. So that does not seem to be a good delivery method for these cells. They don’t go anywhere.   MSDF I was also thinking that if something they secrete is important, whether it circulates. Maybe they’re not making enough concentration if you inject them outside of the central nervous system, but it seems like you’re going to be faced with a little cumbersome problem in a clinical situation years and years ahead from now if you have to keep injecting proteins into the spinal cord as opposed to more peripheral.   Dr. Loring I agree. And the solution to that is generally to look for peripheral effects and then try to suppress those when you do a therapy like this. That’s a long time, and we could certainly imagine how we would do it. But we need to know what those proteins are before we can decide on whether we expect them to have effects peripherally or not. But I agree with you; delivering them intravenously would be far easier.   MSDF I know you have a lot of work ahead of you now with this, but is there another animal model of MS – or even another mouse model of MS – where you can see if it works even in a mouse model different from this one?   Dr. Loring Yes, we’re actively pursuing that with our collaborators in Australia. And it’s interesting because they’ve gotten some positive preliminary results using the EAE model, but the approach to the EAE model I’ve realized is quite different. Generally, what people do is they provide the therapy at the time that the pathology is developing, and they try to prevent it, which is a really different idea than what we had using the mice that are already paralyzed. So they have found that if you can deliver the cells at least close to the spinal cord, then you can see some effects. The problem is that in Australia, and this is one of those technical things we had not anticipated, they don’t have permission to inject cells into the spinal cord. So they have to go through their animal rights people or their animal protection groups and try to get permission to do so. So with Craig Walsh at UC Irvine we have started doing parallel experiments with the EAE model. I’m not necessarily sure that it’s going to have similar effects. I mean, I really don’t know.   MSDF Can you describe how these mice in your experiments were made to have MS?   Dr. Loring Yes, they were given a virus, a neurotropic virus, which kills off the oligodendroglia. They become demyelinated, and there is a secondary inflammatory response. So the mice are actually paralyzed in their hind quarters at least by the time we put the cells in. They have to be fed by hand. So this is not a trivial thing to do. But we’re trying to reproduce the effects during the progressive form of MS, for example, or during an attack of MS. So we’re trying to repair the mice or cure the mice that are in a condition which would be similar to the worst case scenario for people with MS.   MSDF Do you think this may also have effects not only on the myelin, but also on damaged neurons?   Dr. Loring We don’t know, because the mice haven’t really had enough time to get a lot of neuronal damage, but that’s a very good question. We don’t know yet.   MSDF I appreciate it. Thank you.   Dr. Loring You’re welcome. It was a pleasure.   [transition music]   Thank you for listening to Episode Thirty-Seven of Multiple Sclerosis Discovery. This podcast was produced by the MS Discovery Forum, MSDF, the premier source of independent news and information on MS research. MSDF’s executive editor is Robert Finn. Msdiscovery.org is part of the non-profit Accelerated Cure Project for Multiple Sclerosis. Robert McBurney is our President and CEO, and Hollie Schmidt is vice president of scientific operations.   Msdiscovery.org aims to focus attention on what is known and not yet known about the causes of MS and related conditions, their pathological mechanisms, and potential ways to intervene. By communicating this information in a way that builds bridges among different disciplines, we hope to open new routes toward significant clinical advances.   We’re interested in your opinions. Please join the discussion on one of our online forums or send comments, criticisms, and suggestions to editor@msdiscovery.org.   [outro music]

Hosts: Vincent Racaniello, Alan Dove, Rich Condit, and Kathy Spindler Vincent, Alan, Rich and Kathy discuss how interleukin 10 modulation of Th17 helper cells contribute to alphavirus pathogenesis. Links for this episode IL10 modulation of Th17 cells during alphavirus pathogenesis (PNAS) Th17 cells involved in influenza mediated gut injury (J Exp Med) Helper T cells 2014-15 flu season (CDC) Key facts about flu & flu vaccine (CDC) Does the flu vaccine work? (Turbid plaque) Effectiveness of flu vaccine (virology blog) Image credit Letters read on TWiV 316 Weekly Science Picks Alan - It came from the pondRich - WanderersKathy - The Sense of Style by Steven PinkerVincent - Life in Our Phage World Listener Pick of the Week Fernando - Reality based? Send your virology questions and comments (email or mp3 file) to twiv@twiv.tv

Interstitial lung diseases (ILD) are severe chronic lung diseases characterized by an increased deposition of extracellular matrix in the lung interstitial space, leading to a thickening of the alveolar walls and impairment of the gas exchange. One of the most common entities in this category is idiopathic pulmonary fibrosis (IPF) with a mean survival time of 2 to 3 years from diagnosis. Until now, there is no curative therapy available and the symptomatic anti- inflammatory treatment and oxygen supplementation cannot prevent the development of the end stage pulmonary fibrosis. The chemokine receptor CCR2 is important for leukocyte recruitment to inflamed tissues through interaction with CCL2 (MCP-1). The blockade of the CCR2/CCL2 pathway attenuated the development of pulmonary fibrosis in mouse models. However, CCR2+ T-lymphocytes acquired regulatory functions in experimental arthritis during the course of disease. Therefore, it is unknown whether CCR2+ T cells are involved in the pathogenesis of IPF or, on the contrary, represent an unsuccessful effort of the immune system to limit the disease. Observations in paediatric patients with different forms of ILDs suggested a role for CCR2+ T cells in pulmonary fibrosis. To characterize these T cells, flow cytometric studies were performed using the bleomycin mouse model of pulmonary fibrosis. The kinetic of CCR2+ T cells in BALF, lung tissue, and spleen following intratracheal administration of bleomycin (BLM) was assessed at time points between day 3 and day 21. To determine, if the constellation of naïve, central memory and effector memory T cells changes after BLM treatment, and to which of these subtypes CCR2+ T cells belong to, the cells were additionally stained for CD62L and CD44. For further characterization of CCR2+ T cells, chemokine receptor co-expression with CCR2 was investigated at the time point of the maximal presence of CCR2+ T cells. Total T cell numbers increased in BAL and lung tissue but not in spleen. Percentages of CD62LlowCD44hi effector memory T cells increased in lung tissue in the early phase of BLM induced fibrosis, while the CD62LhiCD44low naïve T cell population decreased. The percentage of CCR2+ T cells increased following BLM treatment with a maximum on day 12. The majority of CCR2+CD4+ T cells showed a Tem phenotype. CCR3, CCR4, CCR6, CXCR4, and CXCR5 expressing cells increased within the pulmonary CD4+ T cell population following bleomycin treatment. Among CD8+ T cells from treated mice, CCR5, CCR6, and CXCR5 positive cells were increased. CCR7 was highly co-expressed with CCR2 in saline and bleomycin treated mice, whereas co-expression of CCR3, CCR4, CCR6 and CXCR5 increased significantly in treated mice. The results indicate an activation of pulmonary T cell populations following bleomycin treatment. CCR2+CD4+ T cells probably take part on this T cell response as they exhibit an effector memory phenotype and increase following BLM treatment. In contrast, the stable percentages of the different T cell subtypes in spleens gave no hint for a systemic T cell reaction. The pattern of chemokine receptor expression argues against a Th1 polarization and towards a Th2, Th17 or TFH polarization of CCR2+ T cells.

[intro music]   Host – Dan Keller  Hello, and welcome to Episode Five of Multiple Sclerosis Discovery, the Podcast of the MS Discovery Forum. I’m your host, Dan Keller.    This week’s Podcast features an interview with Dr. Anne Cross, who reflects on the past year in MS research. But to begin, here’s a brief summary of some of the topics we’ve been covering on the MS Discovery Forum at msdiscovery.org.    Researchers have discovered that multiple sclerosis may have something in common with colon cancer; the Wnt pathway. It’s a genetic pathway important in development, stem cell maintenance, and cell differentiation. In colon cancer, the mutation of a mediator gene called APC causes the Wnt pathway to become overactive, leading to tumor formation. Now, researchers have discovered that a loss of function mutation of APC in the brain also leads to an overactive Wnt pathway, ultimately freezing oligodendrocyte progenitor cells in their undifferentiated state.    Next, what disease-modifying therapies should women start or stop before pregnancy? In our latest news synthesis, we discuss the difficulties many women with MS have in deciding when to stop DMT before trying to conceive. Since it can take months, and even years, for a woman to conceive, it’s important that she spend the least amount of time off medication as possible to reduce the chance of relapse. Some drugs may be worth taking during pregnancy anyway, but it’s up to the neurologist to do a risk-benefit analysis for each patient. Nevertheless, many women opt to go off of DMT altogether to reduce the risk of adverse effects on the fetus.   Finally, we would like to direct your attention to funding opportunities on the MSDF webpage. Under the Professional Resources tab at msdiscovery.org, you can find a listing of various organizations offering funding for research grants, fellowship grants, and more. Currently, there are several opportunities offered from ECTRIMS with deadlines this winter. There are also several deadlines for funding from the National MS Society coming up in August.    Now for the interview.   Interviewer – Bob Finn This is Bob Finn. I’m here with Dr. Anne Cross of the Washington University in St. Louis. Dr. Cross will later today be giving a talk at the American Academy of Neurology meeting on what the year has been like in MS research. And, so, let me ask you briefly, what has the year been like? Has it been a good year, a bad year, an exciting year, a boring year?   Interviewee – Anne Cross  I think it’s been a pretty good year. There have been some mainly good things, a couple of bad things, some rather interesting and unexpected things, too. I guess some of the good things involve genetics research papers that have come out identifying genes that are associated with risk of developing MS. That’s been kind of exciting. Actually, there were 48 new genes that were identified and published this year by the International MS Genetics Consortium, which is a very large group of international researchers that have amassed probably close to 30,000 genetic samples from MS patients over the years that they’ve been in existence, which is about 10 years, plus close to double that of controls. And all these MS patient samples are from patients who were well characterized and submitted by, generally, MS specialists.    And that group did a study using something called the Immunochip, which is a genotyping array that was actually developed by a group of investigators who work on autoimmune disorders, so that array is very much weighted towards beings with immunologic function. So not too unexpectedly, all 48 of the newest identified genes all relate in some way to the immune system or are very closely linked to genes of immune function. But prior to that, the same group – the International MS Genetics Consortium – had identified about 50, a little over 50 genes that are associated with MS risk, and most of them were also related to genes of immune function. So I think together, all of this data certainly implicates the immune system, which we already knew, but I think things are certainly solidifying around that with the newest data.   MSDF  Let me ask you, if they’re using techniques that are specific for immunological genes, are they missing other genes?   Dr. Cross  They very well could be. The original studies that this group did which were published, the biggest study was published in the summer of 2011, did not do it in that fashion, though, they just did a genome-wide association study, and most of the genes that they identified were related to the immune system directly or indirectly. So, yes, I’m sure that some are being missed that aren’t related to the genes that are on this Immunochip microarray, but they’re trying to hone down a bit.    And some of the other things that were discovered were that, well, they identified 5 allelic variants; the particular allelic variant was over 50% of the time associated with risk of MS. And they also identified in this latest search – well, the strongest association was with a gene that has immune function called Vcl-10 – they actually in this latest search rediscovered the same 50 or so that they had discovered before, so they were actually mostly in this Immunochip microarray.   MSDF  So, aside from the genome-wide association studies, what else has been interesting in MS research this year?   Dr. Cross  Well, I think some of the clinical trials that have been published in the past year, and also that are just ongoing and aren’t published yet, have been interesting. This past week, Dr. Rhonda Voskuhl, who’s from UCLA, spoke and presented for the first time ever recent data from a study of estriol, which is a pregnancy hormone that was added to glatiramer acetate in women with relapsing-remitting MS, and that was compared to placebo pills added to glatiramer acetate. And the results were pretty positive, especially in the first year when there was an almost 50% reduction in relapse rate in the group that received estriol plus glatiramer. And, you know, that’s, of course, based upon longstanding data that we’ve known, that women with MS who have relapsing disease have a much decreased relapse rate during pregnancy. And then Dr. Voskuhl had done a good bit of work with estriol, in particular, which is a fairly safe pregnancy estrogen hormone compared to some of the others, but it’s not available in the United States right now.    MSDF  You mentioned that there were some disappoints.   Dr. Cross  At least for me, and probably for a lot of MS patients, the biggest disappointment was the failure of the FDA to approve a drug called alemtuzumab, which is a humanized monoclonal antibody against an antigen that’s on pretty much all the mononuclear cells of the immune system. And the US FDA failed to approve it, although, I believe, 32 countries and counting have approved it at this point, including Canada and Mexico and all of the countries of Western Europe, Australia, Brazil.   MSDF  Have there been any interesting developments on the remyelination front?   Dr. Cross  Yes, yes, yes. In fact, I hope to speak about that today. There are studies in early-phase trials right now of anti-LINGO-1, which is a humanized monoclonal antibody against a molecule called LINGO-1, which is found only in the central nervous system – at least that’s what the data says so far – and it’s expressed by oligodendroglial cells, or the cells that make central nervous system myelin. And, for whatever reason, it’s involved in inhibiting remyelination in the central nervous system. So the monoclonal antibody that inhibits it then enhances remyelination. And in mouse models it looked very good, and it also led to less injury to axons, or nerve fibers, so it had more than just a remyelinating effect. And it’s now in phase II studies in relapsing-remitting MS and optic neuritis patients. At least the relapsing-remitting MS study is fully enrolled, and so we’ll be looking forward to those results.   So another potential remyelinating agent is a little bit behind anti-LINGO-1. It’s called recombinant human IgM22, and it was developed from a natural IgM antibody that was discovered at Mayo Clinic that binds to a surface antigen on oligodendrocytes – the cells that make central nervous system myelin – and it enhances myelination in mouse models of demyelination, and, in fact, in some studies, just a single dose of that led to longstanding remyelination in the mouse model. So that’s in dose-finding studies in human beings at the present time, and hopefully will move forward from there.   Other exciting things, at least to me, are studies of stem cells that can be differentiated into different types of cells. And, at this point, you can actually take human skin cells or human fibroblasts and revert them back to stem cells; they’re called induced pluripotent stem cells. So you can actually take a person’s skin and do that, and then you can differentiate it forward into whatever cell type you want, really, these days; I mean, you can differentiate them into neurons. And in MS, we’re very interested in differentiating them into oligodendrocyte precursor cells – cells that form the cells that make central nervous system myelin.    And a study that I plan to talk about this afternoon took such cells and made them into human oligodendrocyte precursor cells and put them into the central nervous systems of mice who had a genetic mutation in myelin basic proteins, so they are essentially unmyelinated. And these mice die very soon after being born, much earlier than normal, and they put these human cells in. They had to immunosuppress the mice so that they’d accept the human cells. But these cells actually made myelin, and it was functional myelin at least from the standpoint of wrapping around fairly normal-looking nerve fibers, axons, from the mice, and forming compact, normal-appearing myelin. So that particular group, they’re from New York State and they’re affiliated with several other medical centers, and they plan to get this into humans pretty soon. Their first project, however, is going to involve fetal stem cells first, because that was easier to get approved and moved forward on, and so I believe they’re already funded to do a three-center – all in New York State – stem cell study injecting such cells into the central nervous system of people with secondary progressive MS.    MSDF  Now some patients aren’t waiting for the studies, I understand, but what is your point-of-view about that?   Dr. Cross  It depends on where they’re going and what they’re doing. I personally think there’s some shoddy research, some charlatans you might call them, out there who are taking the money and presenting false hopes to patients that I certainly disagree with. And I have one particular patient I know who went to another country and had stem cell therapy done in what she described as a very dirty environment. And luckily nothing bad happened to her from this experience, but nothing good happened either. I’m hoping that she’ll be able to get into some of these well-done, scientifically valid, protocol-driven studies that seem to have some promise.    MSDF  Any other interesting areas of MS research in the past year?   Dr. Cross  I think the unexpected finding that I plan to talk about is an association of salt – sodium in particular, the sodium component of sodium chloride – in the development of a particular type of pathogenic T-cell that at least is related to the mouse model of MS called experimental autoimmune encephalomyelitis. These are Th17 cells and they’ve been shown to, at least in some models, cause the EAE model for MS. And it was found that if you increase the salt intake of mice that had been induced to develop this model and compared them to mice who weren’t getting extra salt in their diet, that the mice who got extra salt got disease earlier; they had a more severe course, they didn’t recover as well, and they had histologically when you looked at their central nervous systems, more cells infiltrating and just more damaging. So that was kind of interesting and quite unexpected, I would say.    Two different groups of investigators sort of came up with that at the same time; I’m sure they were speaking to each other about it, that the studies came out right together. It certainly would be a modifiable environmental thing if it proves to be true, and perhaps even a little bit simple. And there is actually a scientific reason behind why this might occur. Well, there’s a response in the body by something called p38 MAP kinase in response to, like, many different stresses, but including among them osmotic stress which increased salt could cause. And that pathway that p38 MAP kinase is involved in eventually can lead to the induction of a particular kinase that is key to the development of Th17 cells. So it sort of all, you know, fits together.    There are certainly some things that don’t fit with that. I think that certain areas of the world, for example, have very high salt intake and yet have low MS rates, but it may be that there’s this environmental factor. There probably are many different environmental factors that’s going together with a genetic predisposition, and those together are probably leading, perhaps, to MS. In any event, this will have to be proven by other groups, but if the association is true, it would certainly be modifiable.     MSDF  So looking ahead into the next year of MS research, what are you particularly looking forward to seeing?   Dr. Cross  I’d like to see more data come out on some of the other oral agents; there are a couple that are in the pipeline that are being looked at that perhaps have other mechanisms of actions from what we have now. I’d like to see other studies funded for estriol so that perhaps it could come to the United States and be an adjunctive therapy probably for women with MS and probably pretty safe. I’m really hopeful – I’m not sure if it’ll be in the next year – that we’ll see some good data coming out from these scientifically valid stem cells projects to help people with progressive MS, and help people who have longstanding disability to recover some function; those are the people that really, really need help in the MS world right now.   MSDF  Well, Dr. Cross, thank you very much.   Dr. Cross  Thank you.   [transition music]   Thank you for listening to Episode Five of Multiple Sclerosis Discovery. This Podcast was produced by the MS Discovery Forum, MSDF, the premier source of independent news and information on MS research. MSDF’s executive editor is Robert Finn. Msdiscovery.org is part of the nonprofit Accelerated Cure Project for Multiple Sclerosis. Robert McBurney is our President and CEO, and Hollie Schmidt is Vice President of Scientific Operations.    Msdiscovery.org aims to focus attention on what is known and not yet known about the causes of MS and related conditions, their pathological mechanisms, and potential ways to intervene. By communicating this information in a way that builds bridges among different disciplines, we hope to open new routes toward significant clinical advances.   We’re interested in your opinions. Please join the discussion on one of our online forums or send comments, criticisms, and suggestions to editor@msdiscovery.org.   [outro music]   

Das Immunsystem von Säugern wird durch Pathogene, Allergene oder ebenso durch körpereigene Autoantigene stimuliert. Diese Stimulation resultiert in einer Differenzierung von CD4-positiven T-Zellen, die je nach eingeleiteter Immunantwort ihre entzündungsfördernden oder hemmenden Effektorfunktionen ausüben können. Basierend auf den funktionellen Eigenschaften und einem spezifischen Transkriptionsfaktorprofil sowie Zytokinsekretionsprofil lassen sich diese reaktiven Effektorzellen in Th1-, Th2-, Th17- und Treg-Subtypen unterscheiden. Vereinzelt scheinen einige der Subtypen dennoch in der Lage, Eigenschaften von entgegengesetzt polarisierten Zellsubtypen annehmen zu können, was von einem wissenschaftlichem Interesse ist und für zukünftige Therapiemethoden genutzt werden könnte. Aus diesem Grund wurde für eine Untersuchung der Plastizität von CD4-positiven Effektorzellen ein adoptives Zelltransfer-Mausmodell in Kombination mit einer Infektion der Empfängertiere durch den gastrointestinalen Wurmparasiten Nippostrongylus brasiliensis entwickelt. Das Infektionsmodell erlaubte durch die Induktion einer starken Typ-2- Immunantwort durch den Parasiten zu untersuchen, ob in vitro polarisierte oder ex vivo isolierte Th1-, Th17- sowie Treg-Zellen in einen entgegengesetzten, IL-4 produzierenden Th2-Phänotyp in vivo differenzieren können. Sowohl Th1-, als auch Th17-Zellen konnten neben dem Verlust ihrer charakteristischen IFN-γ bzw. IL-17A Zytokinsekretion IL-4 exprimieren und somit in den Th2-Subtyp konvertiert werden. Im Gegensatz dazu wiesen in vitro hergestellte und ex vivo isolierte Treg-Zellen diese Flexibilität nicht auf und behielten weitgehend ihr spezifisches Transkriptionsfaktorprofil bei. Diese neuen Erkenntnisse zur Plastizität von CD4-positiven Effektorzellen könnten darüber hinaus die inverse Korrelation von Helmintheninfektionen und ihrem vermittelnden Schutz vor autoimmunen und allergischen Erkrankungen erklären. Aus therapeutischer Sicht erscheint eine Verschiebung von unkontrollierten und autoreaktiven Th1- und Th17-Immunantworten in Autoimmunerkrankungen durch eine Helmintheninfektion hin zu einer protektiven Th2-Antwort sinnvoll. Um dies weiterführend zu überprüfen und zu klären, ob eine Th-Repolarisierung ein zugrunde liegender Mechanismus ist, wurde versucht zwei verschiedene autoimmune Mausmodelle durch eine Infektion mit dem Helminthen zu modulieren und den Ausbruch der Erkrankung zu verhindern. Es konnte jedoch lediglich eine transiente Verbesserung des Krankheitsverlaufs in einem Colitis-Mausmodell, aber nicht in einem Mausmodell ähnlich der Multiplen Sklerose durch den Helminthen N. brasiliensis beobachtet werden.

Thu, 4 Oct 2012 12:00:00 +0100 https://edoc.ub.uni-muenchen.de/15074/ https://edoc.ub.uni-muenchen.de/15074/1/Hinnerwisch_Carmen.pdf Hinnerwisch, Carmen ddc:610, ddc:

Vincent, Michael, and Ivo review the requirement for segmented, filamentous bacteria for the induction of a specific type of helper T cell in the gut. Links for this episode: Induction of Th17 cells by segmented filamentous bacteria (Cell) Segmented filamentous bacteria take the stage (Nature) Genome of segmented filamentous bacteria reveals auxotrophy (Cell) Segmented filamentous bacteria and diabetes protection (PNAS) Send your microbiology questions and comments (email or mp3 file) to twim@twiv.tv , 

Chronic granulomatous disease (CGD) is the most common inherited disorder of phagocytic functions, caused by genetic defects in the leukocyte nicotinamide dinucleotide phosphate (NADPH) oxidase. Consequently, CGD phagocytes are impaired in destroying phagocytosed microorganisms, rendering the patients susceptible to bacterial and fungal infections. Besides this immunodeficiency, CGD patients suffer from various autoinflammatory symptoms, such as granuloma formation in the skin or urinary tract and Crohn-like colitis. Owing to improved antimicrobial treatment strategies, the majority of CGD patients reaches adulthood, yet the autoinflammatory manifestations become more prominent by lack of causative treatment options. The underlying pathomechanisms driving hyperinflammatory reactions in CGD are poorly understood, but recent studies implicate reduced neutrophil apoptosis and efferocytosis, dysbalanced innate immune receptors, altered T-cell surface redox levels, induction of Th17 cells, the enzyme indolamine-2,3-dioxygenase (IDO), impaired Nrf2 activity, and inflammasome activation. Here we discuss immunological mechanisms of hyperinflammation and their potential therapeutic implications in CGD.

Osteopontin represents a multifunctional molecule playing a pivotal role in chronic inflammatory and autoimmune diseases. Its expression is increased in inflammatory bowel disease (IBD). The aim of our study was to analyze the association of osteopontin (OPN/SPP1) gene variants in a large cohort of IBD patients. Genomic DNA from 2819 Caucasian individuals (n = 841 patients with Crohn's disease (CD), n = 473 patients with ulcerative colitis (UC), and n = 1505 healthy unrelated controls) was analyzed for nine OPN SNPs (rs2728127, rs2853744, rs11730582, rs11739060, rs28357094, rs4754 = p.Asp80Asp, rs1126616 = p.Ala236Ala, rs1126772 and rs9138). Considering the important role of osteopontin in Th17-mediated diseases, we performed analysis for epistasis with IBD-associated IL23R variants and analyzed serum levels of the Th17 cytokine IL-22. For four OPN SNPs (rs4754, rs1126616, rs1126772 and rs9138), we observed significantly different distributions between male and female CD patients. rs4754 was protective in male CD patients (p = 0.0004, OR = 0.69). None of the other investigated OPN SNPs was associated with CD or UC susceptibility. However, several OPN haplotypes showed significant associations with CD susceptibility. The strongest association was found for a haplotype consisting of the 8 OPN SNPs rs2728127-rs2853744-rs11730582-rs11439060-rs28357094-rs112661-rs1126772-rs9138 (omnibus p-value = 2.07×10⁻⁸). Overall, the mean IL-22 secretion in the combined group of OPN minor allele carriers with CD was significantly lower than that of CD patients with OPN wildtype alleles (p = 3.66×10⁻⁵). There was evidence for weak epistasis between the OPN SNP rs28357094 with the IL23R SNP rs10489629 (p = 4.18×10⁻²) and between OPN SNP rs1126616 and IL23R SNP rs2201841 (p = 4.18×10⁻²) but none of these associations remained significant after Bonferroni correction. Our study identified OPN haplotypes as modifiers of CD susceptibility, while the combined effects of certain OPN variants may modulate IL-22 secretion.

Fri, 1 Jan 2010 12:00:00 +0100 https://epub.ub.uni-muenchen.de/18367/1/oa_18367.pdf Skapenko, A.; Schulze-Koops, Hendrik; Leipe, Jan; Schramm, M. ddc:6

Learn about a microRNA that confers robustness on the pathways regulating fly development (start 0:50), the cytokine interleukin-1 which acts as a key player in the production of Th17 cells (start 10:23) and using stem cell therapy to treat heart disease (start 15:22).

Background and aims: Interleukin 26 (IL-26), a novel IL-10-like cytokine without a murine homologue, is expressed in T helper 1 (Th1) and Th17 cells. Currently, its function in human disease is completely unknown. The aim of this study was to analyse its role in intestinal inflammation.Methods: Expression studies were performed by reverse transcription-PCR (RT-PCR), quantitative PCR, western blot and immunohistochemistry. Signal transduction was analysed by western blot experiments and ELISA. Cell proliferation was measured by MTS (3-(4,5-dimethylthiazol-2-yl)-5-(carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium) assay. IL-26 serum levels were determined by an immunoluminometric assay (ILMA).Results: All examined intestinal epithelial cell (IEC) lines express both IL-26 receptor subunits IL-20R1 and IL-10R2. IL-26 activates extracellular signal-related kinase (ERK)-1/2 and stress-activated protein kinase/c-Jun N-terminal kinase (SAPK/JNK) mitogen-activated protein (MAP) kinases, Akt and signal transducers and activators of transcription (STAT) 1/3. IL-26 stimulation increases the mRNA expression of proinflammatory cytokines but decreases cell proliferation. In inflamed colonic lesions of patients with Crohn's disease, an elevated IL-26 mRNA expression was found that correlated highly with the IL-8 and IL-22 expression. Immunohistochemical analysis demonstrated IL-26 protein expression in colonic T cells including Th17 cells expressing the orphan nuclear receptor RORtextgreekgt, with an increased number of colonic IL-26-expressing cells in active Crohn's disease.Conclusion: Intestinal cells express the functional IL-26 receptor complex. IL-26 modulates IEC proliferation and proinflammatory gene expression and its expression is upregulated in active Crohn's disease, indicating a role for this cytokine system in the innate host cell response during intestinal inflammation. For the first time, IL-26 expression is demonstrated in colonic RORtextgreekgt-expressing Th17 cells in situ, supporting a role for this cell type in the pathogenesis of Crohn's disease.

Traditionally, Crohn's disease has been associated with a Th1 cytokine profile, while Th2 cytokines are modulators of ulcerative colitis. This concept has been challenged by the description of tolerising regulatory T cells (Treg) and by proinflammatory Th17 cells, a novel T cell population characterised by the master transcription factor RORtextgreekgt, the surface markers IL23R and CCR6, and by production of the proinflammatory cytokines IL17A, IL17F, IL21, IL22 and IL26, and the chemokine CCL20. Th17 cells differentiate under the influence of IL1textgreekb, IL6, IL21 and IL23. Recent studies indicate that TGFtextgreekb is essential not only for the development of murine Th17 cells but also for differentiation of human Th17 cells. TGFtextgreekb reciprocally regulates the differentiation of inflammatory Th17 cells and suppressive Treg subsets, with the concomitant presence of proinflammatory cytokines favouring Th17 cell differentiation. Several studies demonstrated an important role of Th17 cells in intestinal inflammation, particularly in Crohn's disease. Genome-wide association studies indicate that IL23R and five additional genes involved in Th17 differentiation (IL12B, JAK2, STAT3, CCR6 and TNFSF15) are associated with susceptibility to Crohn's disease and partly also to ulcerative colitis. Taken together, both Th1 and Th17 cells are important mediators of inflammation in Crohn's disease, although activities previously ascribed to IL12 may be mediated by IL23. Anti-IL12/IL23p40 antibody therapy, which targets both Th1 and Th17 cells, is effective in Crohn's disease. However, the complex relationship between Th1 and Th17 cells has not been completely analysed. This will be of great importance to delineate the specific contributions of these cells to Crohn's disease and other autoimmune diseases.