Podcasts about hla b

Je reçois aujourd'hui Lucie qui a 33 ans et souffre de spondylarthrite ankylosante. Malgré un frère atteint de spondylarthrite et la présence du gêne HLA B 27, Lucie va être confronté à une très longue errance médicale et sera enfin diagnostiqué lorsque la maladie aura malheureusement pris de l'ampleur.Ce que j'ai trouvé fou dans le témoignage de Lucie, ce sont les aller-retour de l'activité de la maladie sur ses IRM. Parfois, l'activité inflammatoire était bien visible et parfois non. Cela pose vraiment question autour de la difficulté de poser un diagnostic, mais surtout de ne pas évincer une spondylarthrite lorsque l'IRM revient négative.Il est primordial pour moi de donner la parole à des personnes ayant vécu ce genre de parcours afin que toutes les nuances de cette maladie puissent être connues du plus grand nombre et que les errances diminuent enfin.Je vous laisse découvrir son parcours et vous souhaite une très belle écoute.Vous pouvez suivre le podcast sur son compte Instagram : Un mot sur mes mauxMontage : Yasmine FleurotMixage : SebMusique Oak StudioHébergé par Ausha. Visitez ausha.co/politique-de-confidentialite pour plus d'informations.

Découvrez en 10 minutes avec Dr Didier POIVRET, rhumatologue, l'essentiel à savoir concernant la goutte en MG. ✅ Comment traiter une crise de goute en 2024 ? ✅ Quand et comment introduire un traitement de fond hypouricémiant par Allopurinol ? ✅ Chez qui demander le typage HLA B 508 ? ✅ Quand adresser le malade au rhumatologue ou néphrologue ? ✅ Que sait-on de nouveau sur la goutte en 2024 que vous devriez connaître en MG ? Les RÉPONSES du CAS CLINIQUE (COMMENTÉES EN VIDEO par Dr POIVRET ), cliquez-ici

Drs Michael S. Saag and Rajesh Gandhi discuss HIV and Antiretroviral Therapy Guidelines. When to begin treatment, which treatment to choose, and how to treat the whole person, not just the HIV. Relevant disclosures can be found with the episode show notes on Medscape (https://www.medscape.com/viewarticle/986509). The topics and discussions are planned, produced, and reviewed independently of advertisers. This podcast is intended only for US healthcare professionals. Resources HIV Infection and AIDS https://emedicine.medscape.com/article/211316-overview Zidovudine (Rx) https://reference.medscape.com/drug/retrovir-zdv-zidovudine-342639 ddI and d4T Plus Protease Inhibitors https://pubmed.ncbi.nlm.nih.gov/11364012/ HIV-Protease Inhibitors https://pubmed.ncbi.nlm.nih.gov/9562584/ Initiation of Antiretroviral Therapy in Early Asymptomatic HIV Infection https://pubmed.ncbi.nlm.nih.gov/26192873/ Early Symptomatic HIV Infection https://reference.medscape.com/article/211873-overview IAS-USA https://www.iasusa.org/ Antiretroviral Drugs for Treatment and Prevention of HIV Infection in Adults: 2022 Recommendations of the International Antiviral Society-USA Panel https://pubmed.ncbi.nlm.nih.gov/36454551/ Integrase Strand Transfer Inhibitors Are Effective Anti-HIV Drugs https://pubmed.ncbi.nlm.nih.gov/33572956/ Dolutegravir (Rx) https://reference.medscape.com/drug/tivicay-tivicay-pd-dolutegravir-999861 Bictegravir/Emtricitabine/Tenofovir Alafenamide (Biktarvy) https://www.medscape.com/viewarticle/941921_4 Dolutegravir/Lamivudine as a First-Line Regimen in a Test-and-Treat Setting for Newly Diagnosed People Living With HIV https://pubmed.ncbi.nlm.nih.gov/34115650/ Tenofovir DF (Rx) https://reference.medscape.com/drug/viread-tenofovir-df-342633 Tenofovir AF (Rx) https://reference.medscape.com/drug/vemlidy-tenofovir-af-1000007 Abacavir (Rx) https://reference.medscape.com/drug/ziagen-abacavir-342600 HLA B 5701 Testing https://www.ncbi.nlm.nih.gov/books/NBK560797/ Dolutegravir/Rilpivirine (Rx) https://reference.medscape.com/drug/juluca-dolutegravir-rilpivirine-1000216 Efficacy and Safety of Dolutegravir-Rilpivirine for Maintenance of Virological Suppression in Adults With HIV-1: 100-Week Data From the Randomised, Open-Label, Phase 3 SWORD-1 and SWORD-2 Studies https://pubmed.ncbi.nlm.nih.gov/31307948/ Non-Nucleoside Reverse Transcriptase Inhibitor (NNRTI) https://clinicalinfo.hiv.gov/en/glossary/non-nucleoside-reverse-transcriptase-inhibitor-nnrti Cabotegravir/Rilpivirine: The Last FDA-Approved Drug to Treat HIV https://pubmed.ncbi.nlm.nih.gov/35596583/ Anticipating and Managing Drug Interactions: Pharmacokinetics of Long-Acting HIV Treatment and Prevention Formulations https://www.medscape.com/viewarticle/986504 Mpox Vaccination Basics https://www.cdc.gov/poxvirus/mpox/vaccines/index.html COVID-19 Treatment Guidelines https://www.covid19treatmentguidelines.nih.gov/therapies/antivirals-including-antibody-products/summary-recommendations/ Mpox in People With Advanced HIV Infection: A Global Case Series https://pubmed.ncbi.nlm.nih.gov/36828001/ Information for Healthcare Providers: Tecovirimat (TPOXX) for Treatment of Mpox https://www.cdc.gov/poxvirus/mpox/clinicians/obtaining-tecovirimat.html HIV and Opioid Use Disorder: Screening Tools, Chronic Pain Management, and Access to Care in the Outpatient Setting https://www.medscape.com/viewarticle/986506

Allopurinol hypersensitivity syndrome (AHS) affects approximately 1 in 1,000 patients prescribed allopurinol, with reported mortality rates between 20% and 25%. The risk of AHS is nearly 100 times higher in carriers of the HLA-B*58:01 allele than in noncarriers. Populations with a high allele frequency include Han Chinese (6%-8%), Korean (12%), and Thai (6%-8%) people.In this episode, Drs. Wid Yaseen and Jonathan Zipursky discuss their paper published in CMAJ, titled "Five things to know about…allopurinol hypersensitivity syndrome". Dr. Jonathan Zipursky is a general internist, clinical pharmacologist, and clinician scientist at Sunnybrook Health Sciences Centre. Dr. Yaseen is a second-year internal medicine resident physician at the University of Toronto. They argue that the syndrome's frequency is often underestimated and emphasize the importance of genetic testing in susceptible populations.Next, Dr. David Juurlink broadens the discussion beyond allopurinol to describe other common medications whose effectiveness and safety are significantly influenced by genetic predispositions. Dr. Juurlnk is a staff internist and head of division of clinical pharmacology and toxicology at Sunnybrook Health Sciences Centre in Toronto. He is also a medical toxicologist at the Ontario Poison Centre.  He explores the need for expanded genetic testing to protect patients and ensure proper dosing.Join us as we explore medical solutions that address the urgent need to change healthcare. Reach out to us about this or any episode you hear. Or tell us about something you'd like to hear on the leading Canadian medical podcast.You can find Blair and Mojola on Twitter @BlairBigham and @DrmojolaomoleCMAJTwitter (in English): @CMAJ Twitter (en français): @JAMC FacebookInstagram: @CMAJ.ca The CMAJ Podcast is produced by PodCraft Productions

Martin improves ankylosing spondylitis, fibromyalgia, IBS, psoriasis, weight loss, and muscle gain on the carnivore diet. Read Martin's story here: https://carnivore.diet/martin-improves-ankylosying-spondylitis-psoriasis-carnivore-diet Timestamps: 00:00 Trailer 00:49 Introduction 02:47 Exercising way out of poor eating habits 03:31 Psoriasis 05:41 Playing Whack-A-Mole with medications 06:36 Sudden spasm 07:42 HLA B 27 marker testing positive 09:04 Immune suppressants and side effects 10:45 Autoimmune disease and diet 12:46 Ankylosing spondylitis 14:30 Psoriasis working itself from the skin into the joints. 16:31 Food, stress, other triggers 18:16 Going vegan 20:57 Starting the carnivore diet 22:17 Waking up without pain 24:16 Playing first hockey game 26:15 Going back to life 28:18 Psoriasis almost completely gone 30:07 Working out and fatigue 31:36 Carnivore diet and social situations 32:39 Physicians' complete lack of curiosity 34:22 Is carnivore bullet-proof? 35:42 When wheels come off 37:03 Trying carnivore diet out of desperation 38:07 Adding fruit back in the diet 40:38 Recovering from pineapple 42:34 Getting nervous before interview 43:59 How long it takes for autoimmune issues to resolve on carnivore diet 46:13 Looking and feeling amazing 48:51 Improved recovering on carnivore diet 50:12 No replacement for displacement 52:50 Alcohol on the carnivore diet 53:52 Gut testing See open positions at Revero: https://jobs.lever.co/Revero/ Join Carnivore Diet for a free 30 day trial: https://carnivore.diet/join/ Book a Carnivore Coach: https://carnivore.diet/book-a-coach/ Carnivore Shirts: https://merch.carnivore.diet Subscribe to our Newsletter: https://carnivore.diet/subscribe/ . ‪#revero #shawnbaker #Carnivorediet #MeatHeals #HealthCreation   #humanfood #AnimalBased #ZeroCarb #DietCoach  #FatAdapted #Carnivore #sugarfree  ‪

For more information on this topic or to schedule a consultation please visit us at http://WhatIsHashimotos.com What causes Hashimoto's? I don't feel like maybe I've put out a succinct enough explanation of this. Just based on like, thinking back to some of the presentations I've made and, and, and I wanted to do this to either update or clarify that question for people Hashimoto's patients come into us. And back in the day before we knew a whole lot about Hashimoto's and how to determine if the person even had it the numbers were all over the place. Nobody knew what the ranges were. A lot of people still don't know what the ranges are. They're still all over the, I mean, I've talked to somebody in Alabama the other day where the range of zero to a hundred the Mayo clinic is now agreeing that the range is zero to nine. I, in my city, there was a hospital zero to nine. There's another hospital, zero to 34, and there's another hospital to zero to 24. So there was a lot of confusion on that. And, and, and those types of things made it really challenging. So we went a lot on symptoms. And one of the things we started to recognize was if mom had a thyroid problem and the grandma had a thyroid problem and their sister had a thyroid problem, this person's probably got it. So we understood in the beginning that genetics was a big player. So, and then, and then there's the genetics. So we used to do the HLA DQ testing, and we would go, oh my God, you got the positive codes for it. You have it. And then now we know that that's not necessarily true. You can have the genetic code for it, not get it and not have it, so you can be treating it. And for a lot of people out there who are still going by the genetics, there are a lot of doctors out there treating people by the genetics for things that they don't have, their thing there's things that they could have, but they don't have. So having said that genetics genetics are involved. You usually have to have one of the genes that say, you can get Hashimoto's to get Hashimoto's. So this is why you'll see it in your family. And if you've got it, you'll see your sister's got it. Or maybe your grandmother's got it. Great. Grandma's got it. Her brother, you know, and, and usually that's a prerequisite. There used to be like two genes that we talk about. I think it was the HLA B 27. I forgot what the other one was, because it was so long ago. Why do I forget it? Because now there's 90 genes that are listed that indicate a vulnerability to Hashimoto's 90. So, so that doesn't mean you should go out and get genetic testing. Okay. It just means that if you really want to know the, cause there's been some sort of an evolutionary issue to where hypo thyroid are turning into into PR into problems. And maybe these genes have been there forever, but we haven't been doing the things that turn, turn it on. So so the things that make us more vulnerable to and that contribute to the expression of these genes is smoking. I mean, you're going to, I mean, you're going to get a lot of these things, but the reality is these are the things that make you vulnerable to these 90 genes being able to turn on smoking alcohol, you know, alcohol is one for sure a lack of selenium. http://powerhealthtalk.com http://drmartinrutherford.com Martin P. Rutherford, DC 1175 Harvard Way Reno, NV 89502 775 329-4402 http://powerhealthreno.com https://goo.gl/maps/P73T34mNB4xcZXXBA

Today's episode is dedicated to Critical Illness In Children With Hematopoietic Stem Cell Transplants. We are delighted to be joined by Dr. Muna Qayed, Associate Professor of Pediatrics Emory University School of Medicine , Atlanta, GA. She is also the Director of the Blood and Marrow Transplant Program at the Aflac Cancer and Blood Disorders Center at Children's Healthcare of Atlanta. Our Case: A 10 year old female with refractory high-risk ALL s/p mismatched unrelated donor transplantation T+13 days presents as a transfer to the PICU with abdominal distention, worsening jaundice, and escalating nasal cannula requirements. The patient's post-transplant course was complicated by gram-negative bacteremia requiring fluid resuscitation. A CXR upon transfer to the PICU is notable for bilateral airspace disease, a right sided pleural effusion, and hypoexpanded lung fields. The patient is promptly intubated, sedated and started on renal replacement therapy. Echo labs, and further imaging are pending. What are the classic pediatric indications for BMT? Autologous BMT (where donor cells are from the patient/recipient) is used as consolidation in some solid tumors such as High risk neuroblastoma, brain tumors like medulloblastoma, and germ cell tumors, and are a standard treatment approach in relapsed Hodgkin lymphoma Allogeneic BMT-where in the donor cells are derived from another individual are typically used for hematologic malignancies. ALL and AML are most common pediatric indications. Also allogeneic BMT are used for wide spectrum of nonmalignant hematology conditions such as hemoglobinopathies ( Sickle cell disease, Thalassemia), and severe aplastic anemia, and inherited bone marrow failure syndromes, as well as some metabolic disorders and immune-deficiency disorders such as SCID, HLH and other primary immune regulatory disorders. The sources of graft in BMT? Stem cells (which give rise to different types of blood cells - red cells, white cells and platelets are derived from the bone marrow. Thus the overall process is known as Bone Marrow Transplantation. Stem cells can be also derived from peripheral blood - when the donor is treated with granulocyte colony stimulating factor or G-CSF. There are some key advantages here, which include the ability to collect a much higher stem cell dose, with faster hematopoietic recovery. However the downside is a higher T cell content of the graft with subsequent increased risk of graft versus host disease. Umbilical cord blood is also used as a source of stem cells. Mega doses of stem cells are used to overcome histocompatibility barriers of mismatched transplantation. Majority of T cells have to be removed from donor pool to prevent severe GVHD., Increase risk of infection and relapse of patients original disease. Explain the human leucocyte antigen (HLA) and its role in BMT? The Major Histocompatibility complex (MHC) system known as the human leukocyte antigen (HLA) in humans is located on the short arm of chromosome 6 and contains the most polymorphic gene cluster of the entire human genome. The HLA consists of regions designated as "classes". Class I and class II are relevant to stem cell transplant. The main function of HLA class I gene products (HLA-A, -B, and -C) is to present endogenous peptides to responding CD8+ T Cells, HLA class I antigens are expressed on all nucleated cells and platelets. While the class II coded molecules HLA-DR, -DP, and –DQ have restricted expression and process exogenous peptides for presentation to CD4+ helper T Cells, and are expressed on antigen presenting cells. HLA-A, HLA-B, HLA-C and HLA-DR are traditionally the loci critical for matching for stem cell donor. In addition to deciding on the source of the graft, we have to make decisions on who the donor will be. If a matched sibling donor is not available (or in some inherited conditions that may not be an option as a donor), then matched unrelated donors or matched cord blood...

Bulunduğumuz haftanın bilim dünyasından önemli gelişmeleri sizler için derledik. Pfizer and Biontech announce vaccine candidate against COVID-19 achieved success in first interim analysis from phase 3 study. https://www.pfizer.com/news/press-release/press-release-detail/pfizer-and-biontech-announce-vaccine-candidate-against Genome wide study identifies association between HLA-B∗55:01 and self reported penicillin allergy. https://doi.org/10.1016/j.ajhg.2020.08.008 Molecular repertoire of Deinococcus radiodurans after 1 year of exposure outside the International Space Station within the tanpopo mission. https://doi.org/10.1186/s40168-020-00927-5 People who eat chili pepper may live longer? www.sciencedaily.com/releases/2020/11/201109074114.htm Happiness in behaviour genetics, an update on heritability and changeability. https://doi.org/10.1007/s10902-016-9781-6 Functional polymorphism (5-HTTLPR) in the serotonin transporter gene is associated with subjective well-being: evidence from a US nationally representative sample. https://doi.org/10.1038/jhg.2011.39 Innate connectivity patterns drive the development of the visual word form area. https://doi.org/10.1038/s41598-020-75015-7 Catalytically propelled 3D printed colloidal microswimmers. https://doi.org/10.1039/d0sm01320j Bize 101.podcast.info@gmail.com adresinden ulaşabilirsiniz.

Abacavir is a nucleoside reverse transcriptase inhibitor used in the management of HIV. In patients who have the HLA-B*5701 allele, they are at much greater risk for hypersensitivity reactions. Lactic acidosis and hepatomegaly are potential complications with the use of abacavir. While abacavir is not known for a large number of drug interactions, I discuss a few that you have a chance to run into.

The Filtrate:Joel TopfSwapnil HiremathSamira FaroukAnd special guests:Katalin Susztak, Professor of Medicine Perlman School of Medicine, University of Pennsylvania. @KSusztakShow Notes:CKD-FIX: Effects of Allopurinol on the Progression of Chronic Kidney DiseasePERL: Serum Urate Lowering with Allopurinol and Kidney Function in Type 1 DiabetesCoverage at NephJC: Effects of Allopurinol on the Progression of Chronic Kidney DiseaseRichard Johnson’s theory in pay-walled Nature Reviews Nephrology: Hypothesis: fructose-induced hyperuricemia as a causal mechanism for the epidemic of the metabolic syndromeRichard Johnson’s theory in open access Nehrology Dialysis and Transplantation: Uric acid and chronic kidney disease: which is chasing which?PERL: Preventing early renal lossIohexol, good for measuring GFR as well as causing contrast associated nephropathy?Uric acid versus urate: The Crystallization of Monosodium UrateAssociation of HLA-B*5801 allele and allopurinol-induced Stevens Johnson syndrome and toxic epidermal necrolysis: a systematic review and meta-analysisWHO list of essential medicationsFixing the numbers, specifically phosphorousGFR Decline as an End Point for Clinical Trials in CKD: A Scientific Workshop Sponsored by the National Kidney Foundation and the US Food and Drug AdministrationCost of allopurinol: $7/month but it is only $9 for 3 monthsFebuxostat Therapy for Patients With Stage 3 CKD and Asymptomatic Hyperuricemia: A Randomized TrialTipping point analysis - multiple imputation for stress test under missing not at random (MNAR) or a YouTube video if that’s your speed (sorry, I couldn’t find a TikTok on imputation stress tests).Mendelian randomization study of urate and CKD by Ron Do and teamDad jokesFake systematic review by Johnson’s group showing Urate lowering prevented CKDHyperuricemia As a trigger of Immune Response in Hypertension and Chronic Kidney Disease by Claudio Ponticelli published the week after these two RCTs were published.NEJM Editorial: Urate-Lowering Therapy and Chronic Kidney Disease Progression by Daniel FeigCOVID and PPI manuscriptHashtag the cowboy‘WhatsApp®’ening in nephrology trainingArkana LIVE Pathology SessionsNephJC Summer Book Club. Read Rana Awdish’s In Shock

Dr. Jan Dutz speaks with JCMS Editor-in-chief Dr Kirk Barber about the article Dutz co-authored in the Nov/Dec 2019 edition of the Journal of Cutaneous Medicine and Surgery. The article focuses on how East Asians exposed to the urate-lowering drug allopurinol have a predilection for severe cutaneous drug reactions such as drug-induced hypersensitivity syndrome or drug reaction with eosinophilia and systemic symptoms and Stevens-Johnson syndrome/toxic epidermal necrolysis. Dr Barber and Dr Dutz discuss why screening of patients of East Asian descent for the presence of HLA-B*58:01 prior to allopurinol initiation has been a Canadian missed opportunity. And what more can be done to encourage wider use of this inexpensive screening test.Dr. Jan Dutz is Professor and Head of the Department of Dermatology and Skin Science at UBC. He is also a Senior Scientist with the British Columbia Children's Hospital Research Institute.Theme music by Lee RosevereProduced by David McGuffin - Explore Podcast Productions 

Dr. Jan Dutz speaks with JCMS Editor-in-chief Dr Kirk Barber about the article Dutz co-authored in the Nov/Dec 2019 edition of the Journal of Cutaneous Medicine and Surgery. The article focuses on how East Asians exposed to the urate-lowering drug allopurinol have a predilection for severe cutaneous drug reactions such as drug-induced hypersensitivity syndrome or drug reaction with eosinophilia and systemic symptoms and Stevens-Johnson syndrome/toxic epidermal necrolysis. Dr Barber and Dr Dutz discuss why screening of patients of East Asian descent for the presence of HLA-B*58:01 prior to allopurinol initiation has been a Canadian missed opportunity. And what more can be done to encourage wider use of this inexpensive screening test. Dr. Jan Dutz is Professor and Head of the Department of Dermatology and Skin Science at UBC. He is also a Senior Scientist with the British Columbia Children’s Hospital Research Institute. Theme music by Lee Rosevere Produced by David McGuffin - Explore Podcast Productions  

Jane Ferguson:                Hello everyone, and happy new year. Welcome to episode 24 of Getting Personal: Omics of the Heart. It's January 2019, I am Jane Ferguson, an assistant professor at Vanderbilt University Medical Center and an associate editor at Circulation Genomic and Precision Medicine. We have a great line-up of papers this month in the journal, so let's jump right into the articles.                                            First up, a paper from Christopher Nelson, Nilesh Samani, and colleagues from the University of Lester entitled, "Genetic Assessment of Potential Long-Term On-Target Side Effects of PCSK9 Inhibitors."                                            I think most listeners are well aware of the efficacy of PCSK9 inhibition in reducing cardiovascular risk. However, as a relatively new treatment option, we do not yet have data on potential long-term side effects of PCSK9 inhibition. In this study, they utilized genetics as a proxy to understand potential long-term consequences of lower PCSK9 activity. They examined a PCSK9 variant that associates with lower LDL, as well as examining two LDL-lowering variants in HMGCR, the target of statins, which served as a positive control of sorts. They used data from over 479,000 individuals in the UK Biobank and looked for associations between the three LDL-lowering variants and 80 different phenotypes.                                            For the PCSK9 variant, the allele which is associated with lower LDL was significantly associated with the higher risk of type 2 diabetes, higher BMI, higher waist circumference, higher waist-hip ratio, higher diastolic blood pressure, as well as increased risk of type 2 diabetes and insulin use. The HMGCR variants were similarly associated with type 2 diabetes as expected.                                            Mediation analysis suggested that the effect of the PCSK9 variant on type 2 diabetes is independent of its effect on obesity. There were nominal associations between the PCSK9 variant and other diseases, including depression, asthma, chronic kidney disease, venous thromboembolism, and peptic ulcer.                                            While genetics cannot fully recapitulate the information that would be gained from long-term clinical follow up, these data suggest that like statins, PCSK9 inhibition may increase the risk of diabetes and potentially other disease. Overall, the cardiovascular efficacy of PCSK9 inhibition may outweigh these other risks, however, future studies should carefully examine these potential side effects.                                            Next up, we have a paper from Xiao Cui, Fang Qin, Xinping Tian, Jun Cai, and colleagues from Peking Uni and Medical College, on "Novel Biomarkers for the Precise Diagnoses and Activity Classification of Takayasu's Arteritis."                                            They were interested in identifying protein biomarkers of Takayasu arteritis, to improve diagnosis and understanding of disease activity in this chronic vascular disease. They ran a proteomic panel including 440 cytokines on 90 individuals, including individuals with active disease, inactive disease, and healthy controls. They found a number of candidates and validated one protein, TIMP-1, as a specific diagnostic biomarker for Takayasu arteritis. For assessing disease activity, there was no single biomarker that could be used for classification, however, the combination of eight different cytokines identified through random forest-based recursive feature elimination and [inaudible] regression, including CA 125, FLRG, IGFBP-2, CA15-3, GROa, LYVE-1, ULBP-2, and CD 99, were able to accurately discriminate disease activity versus inactivity.                                            Overall, this study was able to identify novel biomarkers that could be used for improved diagnosis and assessment of Takayasu arteritis, and may give some clues as to the mechanisms of pathogenesis.                                            Our next paper is entitled, "Familial Sinus Node Disease Caused By Gain of GIRK Channel Function," and comes from Johanna Kuß, Birgit Stallmeyer, Marie-Cécile Kienitz, and Eric Schulze-Bahr, from University Hospital Münster. They were interested in understanding novel genetic underpinnings of inherited sinus node dysfunction.                                            A recent study identified a gain of function mutation in GNB2 associated with sinus node disease. This mutation led to enhanced activation of the G-protein activated inwardly rectifying potassium channel, or GIRK, prompting the researchers to focus their interest on the genes encoding the GIRK subunits, KCNJ3 and KCNJ5. They sequenced both genes in 52 patients with idiopathic sinus node disease, and then carried out whole exome sequencing in family members of patients with potential disease variants in either gene. They identified a non-synonymous variant in KCNJ5, which was not present in the EVS or ExAC databases, and which segregated with disease in the affected family. This variant was associated with increased GIRK currents in a cell system, and in silico models, predicted the variant altered or spermine binding site within the GIRK channel. Thus, this study demonstrated that a gain of function mutation in a GIRK channel subunit associates with sinus node disease, and suggests that modulation of GIRK channels may be a viable therapeutic target for cardiac pacemaking.                                            Our next paper, "Key Value of RNA Analysis of MYBPC3 Splice-Site Variants in Hypertrophic Cardiomyopathy," comes from Emma Singer, Richard Bagnall, and colleagues from the Centenary Institute and the University of Sydney.                                            They wanted to understand the impact of variants in MYBCP3, a known hypertrophic cardiomyopathy gene, on splicing. They recruited individuals with a clinical diagnosis of hypertrophic cardiomyopathy and genetic testing of cardiomyopathy-related genes. They further examined individuals with a variant in MYBCP3 which had an in silico prediction to affect splicing. They sequenced RNA from blood or from fixed myocardial tissue and assessed the relationship between each DNA variant and gene splicing variation.                                            Of 557 subjects, 10% carried rare splice site variants. Of 29 potential variants identified, they examined 9 which were predicted to affect splicing, and found that 7 of these were indeed associated with splicing errors.                                            Going back to the families, they were able to reclassify four variants in four families from uncertain clinical significance to likely pathogenic, demonstrating the utility of using RNA analysis to understand pathogenicity in genetic testing.                                            The next paper this issue comes from Catriona Syme, Jean Shin, Zdenka Pausova, and colleagues from the University of Toronto, and is entitled, "Epigenetic Loci of Blood Pressure: Underlying Hemodynamics in Adolescents and Adults."                                            A recent large meta epigenome-wide association study identified methylation loci that associate with blood pressure. In this study, they wanted to understand more about how these loci related to blood pressure and hemodynamics. They recruited adolescents and middle-aged adults and assessed 13 CPG loci for associations with hemodynamic markers, including systolic and diastolic blood pressure, heart rate, stroke volume, and total peripheral resistance, measured over almost an hour during normal activities. Several of the loci replicated associations with blood pressure, and two of these also showed age-specific associations with hemodynamic variables. One site in PHGDH was particularly associated with blood pressure and stroke volume in adolescents, as well as with body weight and BMI, where lower methylation resulting in higher gene expression associated with higher blood pressure. A second site in SLC7A11 associated with blood pressure in adults but not adolescents, with lower methylation and consequent higher gene expression associated with increased blood pressure.                                            Overall, this study indicates that methylation mediated changes in gene expression may modulate blood pressure and hemodynamic responses in an age-dependent manner.                                            Next up is a research letter from Ben Brumpton, Cristen Willer, George Davey Smith, Bjørn Olav Åsvold, and colleagues from the Norwegian University of Science and Technology, entitled, "Variation in Serum PCSK9, Cardiovascular Disease Risk, and an Investigation of Potential Unanticipated Effects of PCSK9 Inhibition: A GWAS and Mendelian Randomization Study in the Nord-Trøndelag Health Study, Norway."                                            As we heard about from the first study this issue, the long-term side effects of PCSK9 inhibition remain unknown. In this study, they also applied a genetic approach to understand potential unanticipated consequences of PCSK9 inhibition. They analyzed phenotypes from over 69,000 participants in the Nord-Trøndelag Health Study and measured serum PCSK9 in a subset.                                            In PCSK9 GWAS of over 3,600 people, with replication in over 5,000 individuals from the twin gene study. They defined a genetic risk score for serum PCSK9 and assessed the relationship between genetically predicted PCSK9 and outcomes. They saw the expected associations between lower PCSK9 and lower LDL and coronary heart disease risk. However, there was minimal evidence for associations with other outcomes.                                            While our first study in this issue, from Nelson, et al, found that lower PCSK9 from a single genetic variant was associated with higher diabetes risk, this risk was not found here using the genetic risk score. Differences in the genetic definitions and in the populations used can perhaps explain these differences between the two studies, but overall, the studies are consistent in suggesting that long-term PCSK9 inhibition is unlikely to be associated with major adverse outcomes.                                            Our second research letter comes from Young-Chang Kwon, Bo Kyung Sim, Jong-Keuk Lee, and colleagues from Asan Medical Center in Seoul, on behalf of the Korean Kawasaki Disease Genetics Consortium. The title is, "HLA-B54:01 is Associated with Susceptibility to Kawasaki Disease," and reports on novel Kawasaki disease variants.                                            HLA genes have been previously associated with disease, and in this report, the authors sequenced selected axons in HLA-DRB1, HLA-DQB1, HLA-A, HLA-B, HLA-C, and HLA-DBP1 in 160 Kawasaki disease patients and 278 controls. They find a significant association with HLA-B, and replicated this in a sample of 618 Kawasaki disease patients, compared with over 14,000 in-house controls. They identified specific amino acid residues conferring disease susceptibility, highlighting HLA-B as a potential modulator of Kawasaki disease.                                            Our third and final research letter concerns "Serum Magnesium and Calcium Levels and Risk of Atrial Fibrillation: a Mendelian Randomization Study," and comes to us from Susanna Larsson, Nikola Drca, and Karl Michaëlsson, from the Karolinska Institute.                                            Because magnesium and calcium are known to influence atrial fibrillation, this group was interested in whether genetic predictors of serum methyls associated with disease. They constructed genetic predictors from GWAS of calcium in over 61,000 individuals, and GWAS of magnesium in over 23,000 individuals. They applied these predictors to an AF GWAS including over 65,000 cases and over 522,000 controls. Genetically predicted magnesium was inversely associated with atrial fibrillation, while there was no association with genetically predicted calcium.                                            While this study does not definitively prove causality, future studies aimed at assessing whether dietary or other strategies to raise serum magnesium are protective against AF may yield novel strategies for disease prevention.                                            And that's it from us for this month. Thank you for listening, and come back next month for more from Circulation Genomic and Precision Medicine.                                            This podcast was brought to you by Circulation Genomic and Precision Medicine and the American Heart Association Council on Genomic and Precision Medicine. This program is copyright American Heart Association, 2019.  

Distinguir lo propio de lo ajeno, y lo normal de lo aberrante, no es tarea fácil. De hecho, una parte importantísima de nuestra energía se consume en las operaciones del sistema inmune, el encargado de esta tarea. Para el efecto, es vital el complejo mayor de histocompatibilidad, o CMH (MHC en inglés) y su expresión en la superficie de nuestras células, a saber, las moléculas del sistema de antígenos leucocitarios o HLA, por sus siglas en inglés. Conocer a profundidad este tema nos permitirá comprender su implicación en enfermedades alérgicas, autoinmunes, cáncer y muchas más. Existen, básicamente, dos grupos de moléculas del HLA: las HLA-A, HLA-B y HLA-C, pertenecientes a la clase I; y las HLA-DP, HLA-DQ y HLA-DR, de la clase II. Las primeras, presentes en la gran mayoría de células, presentan antígenos provenientes de péptidos de síntesis endógena, que han sido fraccionados por el proteasoma, y las segundas, más característicamente halladas en células presentadoras de antígeno profesionales, albergan péptidos que vinieron de proteínas captadas del exterior de la célula, digeridas en el complejo de vesículas de los endosomas y lisosomas. Las moléculas del CMH clase I presentan sus péptidos a los linfocitos T CD8+, citotóxicos, y son el blanco de estas últimas en caso de presentar algo "indebido", por ser reconocido como ajeno o aberrante. Por otra parte, las moléculas del CMH clase II son responsables de presentar los antígenos a linfocitos T colaboradores, es decir, CD4+. Revisaremos su estructura, su síntesis, ensamblaje y transporte, y las excepciones a la regla que hemos relatado en párrafos anteriores. Revisaremos la sorprendente (y descubriremos por qué no es tan soprendente) forma en que con poquísimos aminoácidos, este complejo de moléculas de superficie puede ayudar a distinguir las proteínas propias y normales de las que no lo son, y revisaremos el fantástico rol que cumplen en esta ecuación los linfocitos NK o natural killers, las células del sistema inmunitario "asesinas por naturaleza". ¿Quieres enterarte semana a semana de las nuevas publicaciones, y acceder a contenido exclusivo? Únete a la lista de correo de Leucocitos isotópicos. Para suscribirte al Podcast de Medicina, estas son las opciones más recomendadas: Apple Podcasts Google Podcasts Si prefieres explorar más alternativas, haz clic aquí. ¿Te gustó el episodio? Seguro disfrutarás este también: El sistema inmunitario y su dualidad (027) Además, puedes acceder a la lista curada y actualizada de los episodios con mayor aceptación. Este show es para ti. Puedes apoyarlo entrando a iTunes y dejando allí una calificación positiva. Encuentra las notas de este episodio y dirige a tus amigos a isotopicos.com/020 El objetivo de Leucocitos isotópicos es entretenerte mientras complementas lo que recibes en tu Escuela o Facultad de Medicina. Soy Médico Internista, y comprendo lo demandante que puede ser nuestra Carrera. Por eso decidí crear el Podcast como un curso de Medicina ameno y sin una estructura rígida, que despierte tu interés y curiosidad por esta maravillosa Ciencia. Nunca reemplazará a la Universidad, ni a los libros, pero cumplirá con la misión que lo fundamenta: Ser el lugar donde descansamos de leer, sin dejar de aprender. No olvides que la mejor manera de ayudar a que el proyecto crezca, es contarle a todos de él. ¡Gracias por compartir este episodio con alguien!

 [intro music]   Hello, and welcome to Episode Thirty-Four of Multiple Sclerosis Discovery, the podcast of the MS Discovery Forum. I’m your host, Dan Keller.   This week’s podcast features a follow-up interview from last week’s episode with Dr. Pierre-Antoine Gourraud. This week, we interview Dr. Jill Hollenbach about killer immunoglobulin-like receptors – or KIR – and their relationship with human leukocyte antigen and MS. But to begin, here’s a brief summary of some of the latest developments on the MS Discovery Forum at msdiscovery.org.   Take some time to check out our most recent data visualization on our website. Under the research resources tab, you can find a series of interactive data visualizations useful for MS researchers. Our most recent one organizes 142 ongoing clinical trials into an interactive bubble chart. We have another visualization on the natural history of MS symptoms. The interactive bar chart allows you to see the change of various symptom severity in MS over a 30-year period.   If you enjoy this podcast and find MSDF helpful, please consider supporting us with a donation. MSDF is run by a small team of full-time employees and a few regular contributors. We are devoted to bridging the gaps between scientific disciplines to speed the flow of information from the lab bench to the bedside. Our ultimate goal is to facilitate the discovery of a cure. We believe one of the best ways to do that is to bring independent, research-focused news to a professional audience on a platform that fosters discussion and discourse. Help keep us going by visiting our website and clicking on the green “Support MSDF” button next to the “Research Resources” tab on the top right of our screen.   [transition music]   Now to the interview. Dr. Jill Hollenbach is an assistant professor in the department of neurology at the University of California, San Francisco. She met with science journalist Cynthia McKelvey, to talk about KIR in MS.   Interviewer – Cynthia McKelvey Why don’t we start by introducing what KIR is, how it’s different from the potassium channel and what its relationship is to HLA.   Interviewee – Jill Hollenbach Well, KIR is an acronym, it stands for killer immunoglobulin-like receptor. These are receptors on the surface on the surface of natural killer cells. They use generally, not in every case, but use HLA as their ligand and they have either an activating or inhibitory effect on natural killer cells.   MSDF You mentioned in your talk earlier today at UCSF that they are difficult to study. Why is that?   Dr. Hollenbach Just in terms of their genetic architecture. KIR occupy a complex on chromosome 19, it’s a multigene complex. And so on any individual haplotype that’s one chromosome, an individual can have between 4 and 14 KIR genes. These genes are really recently evolved, and so they’ve kind of arisen in humans as a result of repeated events of recombination and gene duplication. So what that means is that one KIR gene often at the nucleotide level looks an awful lot like another KIR gene. And so we’ve had a lot of issues. A lot of the methodologies that are available right now in terms of sequencing, part of this has to do with a lack of human genome reference alignments, but there has been a lot of difficulty in examining these genes because they look so much like one another.   MSDF How does that relate to why they haven’t really seen them on genome-wide association studies?   Dr. Hollenbach There’s a couple of reasons why we don’t see them on genome-wide association studies. One is that, as I mentioned, there haven’t been a lot of good reference alignments, so as a result we don’t actually see a lot of SNP markers on most of the common platforms that are used for genome-wide association studies. And then the markers that are there are often lost to quality control, because we have a lot of gene content variation, which is kind of like a copy number variant. And so if we only see a result for one chromosome, for example, for a given SNP, that is not going to pass general quality control thresholds. And, of course, you have to recognize that when you’re doing these GWAS studies, you’re looking at a hundred thousand, five hundred thousand, a million markers, two and a half million markers, so you’re not going one-by-one and saying, well this KIR-1, we expect to only see one copy or that sort of thing. So it just gets thrown out in the mix with things that don’t pass QC.   MSDF How does KIR relate to multiple sclerosis specifically?   Dr. Hollenbach Well, we’re trying to figure that out. So there’s been a small number of studies examining KIR in multiple sclerosis, and what seems clear is that variation in the KIR does play a role in susceptibility to multiple sclerosis. It may play a role in progression; we’re just not sure. There’s not been enough work done to say definitely what’s going on, but there’s enough evidence to say that something is going on. And some of the work that I talked about in my talk today, an analysis of KIR variation along with HLA in an African-American MS cohort, a very large study population, it seems clear that there is some association of KIR variation with susceptibility or protection for multiple sclerosis.   MSDF Why study the African-American cohort? What does that tell us about MS in general?   Dr. Hollenbach We want to study them because they’re different from one another; so an African-American population is going to look very different genetically with respect to KIR and HLA from a European-American population. So we want to know two things. We want to know is there something different going on with these genes with respect to disease in these different populations, OR at the same time we want to know is something the same going on? And so we can learn something both from these commonalities and differences, and both can be really important in genetics. So if there’s something that is important that’s specific in the African-American population, we want to know that, and we can only find out by looking at a number of different ethnic groups.   MSDF Let’s talk a little bit more about interaction between KIR and the HLA ligand, and how that plays in with Bw4. And if we can define all of those things, too, that would be great.   Dr. Hollenbach Okay. Well, so KIR molecules, as I mentioned before, need to see something, they need to have a ligand on their target cell. We have both inhibitory receptors and activating receptors. The job of the NK cell is to perform immune surveillance. So NK cells kind of wander around the body, and what they’re looking for are cells that don’t look healthy. So what does that look like and what is an unhealthy cell? It’s a cell that is virally infected, it’s a tumor cell. Those are the two main things that NK cells are looking for. And it’s a really important function because they’re part of what we refer to as the innate immune system; it’s the first line of defense against these kind of unhealthy events.   And so what does an unhealthy cell look like? Well, one of the things that happens in both viral infection and tumors is downregulation of MHC class I. That’s what the KIR are looking for. So when an NK cell encounters a healthy cell, it will see HLA class I, it immediately recognizes this is self, this is healthy cell at least in terms of what I’m able to see as an NK cell, and it will move on and it won’t cause any damage to the cell after making contact between the KIR and that ligand.   On the other hand, if the KIR doesn’t see this HLA ligand, the inhibitory KIR, an activating KIR – and we’re still not completely sure what the activating KIR ligands are – but the activating KIR is also bound to something on the surface of this cell. If the activating KIR is bound but the inhibitory KIR is not, what happens is the NK cell is going to lyse that cell which is presumably unhealthy in some ways – tumor or viral infected.   Now HLA class I – actually all HLA molecules – have another primary really important role which is antigen presentation to T cells. Class I molecules present antigen to the CD8-positive T cells, and so that’s how these T cells perform their role in terms of the active immune response. KIRs see a different part of the HLA molecule than the T cell receptors, and so they see kind of this piece of the HLA class I molecule that’s kind of on the side of where the T cell receptors sit. And the variation that they see on that HLA class I molecule can kind of be defined by these broad categories based on the particular amino acid residues. And it’s generally just from two to four amino acid residues that determine whether or not a given KIR can see a given HLA class I molecule.   So one of these epitopes, as we call them – and if they were originally defined on a serological basis because specific antibodies could recognize them – so one of these epitopes is referred to as Bw4; these are epitopes that we mainly see on HLA-B molecules – not all – so depending on the population, human population, may be from 40 to 60 or 70% of HLA-B molecules will have this Bw4 epitope. Some HLA-A molecules also bear the Bw4 epitope. So that’s what some KIR molecules, specifically KIR3DL1, is seeing is Bw4.   The results of the study that I talked about today and what we saw is in this African-American multiple sclerosis cohort, individuals that have both 3DL1 and HLA alleles with the Bw4 epitope appear to be protected from multiple sclerosis. And so we see higher frequencies of this combination in our control population relative to patients. So that suggests a protective effect of that combination, 3DL1 plus Bw4.   MSDF Where do you see the research going from here?   Dr. Hollenbach Right now the data that we’re looking at is strictly in terms of carrying frequencies for these particular genes. So these genes are actually highly variable at the allele level, so any given gene like KIR3DL1 has many, many variants that are already known, and likely many variants that we haven’t identified yet because the technology has not been there. The technology is just about now caught up to the point where we are able to examine at the sequence level the variation within these specific KIR genes, and so I think that that’s really the next step. And we’re actually taking steps to start examining this cohort and others in terms of this fine-grained variation in the KIR genes.   MSDF Very good. Thanks.   [transition music]   Thank you for listening to Episode Thirty-Four 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]

Control of human cytomegalovirus (HCMV) depends on CD8+ T cell responses that are shaped by an individual's repertoire of MHC molecules. MHC class I presentation is modulated by a set of HCMV-encoded proteins. Here we show that HCMV immunoevasins differentially impair T cell recognition of epitopes from the same viral antigen, immediate-early 1 (IE-1), that are presented by different MHC class I allotypes. In the presence of immunoevasins, HLA-A- and HLA-B-restricted T cell clones were ineffective, but HLA-C*0702-restricted T cell clones recognized and killed infected cells. Resistance of HLA-C*0702 to viral immunoevasins US2 and US11 was mediated by the alpha3 domain and C-terminal region of the HLA heavy chain. In healthy donors, HLA-C*0702-restricted T cells dominated the T cell response to IE-1. The same HLA-C allotype specifically protected infected cells from attack by NK cells that expressed a corresponding HLA-C-specific KIR. Thus, allotype-specific viral immunoevasion allows HCMV to escape control by NK cells and HLA-A- and HLA-B-restricted T cells, while the virus becomes selectively vulnerable to an immunodominant population of HLA-C-restricted T cells. Our work identifies a T cell population that may be of particular efficiency in HCMV-specific immunotherapy.

Die bullöse Dermatose Pemphigoid gestationis ist eine äußerst seltene schwangerschaftsassoziierte Autoimmunerkrankung, bei der Antikörper gegen Strukturen der Plazenta produziert werden, die mit dem BP180 der mütterlichen Haut kreuzreagieren und schließlich zur Blasenbildung führen. Ziel der vorliegenden Arbeit war die Assoziation der Erkrankung mit sämtlichen klassischen Humanen Leukozyten-Antigenen (HLA) zu überprüfen. Dafür wurden HLA-Kompletttypisierungen (HLA-A, -B, -C, -DRB1, -DQB1, -DPB1) bei 18 betroffenen Patientinnen und falls vorhanden von Partnern und Kindern der Betroffenen vorgenommen. Von Kindern und Partnern standen insgesamt 27 DNA-Proben zur Verfügung. Diverse Studien wiesen eine Assoziation der Erkrankung mit den HLA-Klasse II-Allelen HLA-DRB1*03 und *04 nach. Eine pathogenetische Rolle paternaler HLA-Moleküle bei der Erkrankung wird aufgrund der Häufung des HLA-DRB1*02-Phänotyps im Kollektiv der Partner vermutet. Die statistischen Berechnungen der Typisierungsergebnisse dieser Arbeit zeigten im Kollektiv der PG-Patientinnen eine signifikante Häufung der HLA-Allele B*08 (p=0,0019), B*18 (p=0,0455), DRB1*03 (p=0,001), DQB1*02 (p=0,0283) und DPB1*0101 (p=0,0011). In Übereinstimmung mit Daten aus der Literatur trat im PG-Patientinnen-Kollektiv der DRB1*03/*04-Phänotyp und im Kollektiv der Partner der HLA-DR02-Phänotyp signifikant gehäuft auf. Untersuchungen auf Aminosäureebene zeigten Gemeinsamkeiten der HLA-DRB1-Allele, die in dem Kollektiv der Mütter vertreten waren auf. Bei der Betrachtung der Genkonstellationen kompletter Stammbäume war ersichtlich, dass im Fall von 3 der 6 aufgeführten Stammbäume die Vererbung des väterlichen DRB1*02-Alleles mit der Krankheitsentwicklung in der entsprechenden Schwangerschaft zusammenfiel. Es wurden keine Hinweise gefunden, dass die Interaktion von HLA-C bzw. HLA-B mit KIR (killer cell immunglobulin-like receptors) für das Auftreten der Krankheit eine Rolle spielen. Die Ergebnisse legen einerseits nahe, dass aufgrund der Häufung von Allelen verschiedener HLA-Loci mehrere Gene eine ätiopathogenetische Rolle spielen, andererseits die Häufung mehrerer Gene verschiedener Loci auf einer Kopplung beruhen könnte. Desweiteren liefern die Untersuchungen der Aminosäurensequenzen Hinweise darauf, dass sich bestimmte Aminosäurensubstitutionen in der Bindungsgrube der HLA-Klasse II-Moleküle als protektiv 72 oder als erhöhtes Risiko auswirken könnten. Die Rolle des väterlichen HLA-DR bleibt weiterhin ungeklärt. Die Konstellation der HLA-DR-Vererbung innerhalb kompletter Familien suggeriert, dass die Vererbung des HLA-DRB1*02 an das Kind als zusätzlicher Risikofaktor zu bewerten ist, aber nicht als ursächlich für die Erkrankung betrachtet werden kann. Zur weiteren Klärung der paternalen Rolle wäre die Überprüfung der HLA-Klasse II-Expression in PG-Plazenten mit modernen molekularbiologischen Methoden von großem Interesse.

Im Mittelpunkt der Arbeit stehen die Auswirkungen des Prostanoids Prostaglandin E2 (PGE2) auf die Fähigkeit von Monozyten-abgeleiteten dendritischen Zellen (MoDC) zur Antigenpräsentation auf MHC-I- und MHC II Molekülen. Die Kreuzpräsentation von exogenem Antigen auf MHC I Molekülen ist eine entscheidende Fähigkeit der dendritischen Zellen (DC), die es ihnen ermöglicht zytotoxische T-Zellen zu aktivieren. PGE2 wird in Aktivierungsprotokollen als „Goldstandard“ in Kombination mit Zytokinen, wie TNF-α, IL-1β und IL 6, als Reifestimulus für DC in klinischen DC-basierten Tumorvakzinierungsstudien verwendet. Bisher wurde über den Effekt von PGE2 auf die Antigenpräsentation von Tumorantigen in Proteinform nicht berichtet. In dieser Arbeit wurde die Auswirkung von PGE2 und spezifischen EP Rezeptoragonisten auf verschiedene Funktionen von MoDC, die für die Antigenpräsentation auf MHC-I- und MHC-II-Molekülen relevant sind, untersucht. Zuerst wurde die Auswirkung von PGE2 und den EP Rezeptoragonisten auf die Ausreifung der MoDC untersucht. Hierbei wurde ersichtlich, dass MoDC nach Inkubation mit PGE2, vermittelt über EP2/4 Rezeptoren, die Aktivierungsmarker HLA A, HLA-B und HLA-C3, HLA-DR, CD83 und CD86 hochregulieren. Als nächstes wurde der Einfluss von PGE2 auf die Antigenaufnahmefähigkeit der MoDC untersucht. Hierbei wurde die Phagozytosefähigkeit anhand von Zelllysat und apoptotischen Tumorzellen und die Makropinozytosefähigkeit anhand von Dextran Partikeln analysiert. Es konnte gezeigt werden, dass weder PGE2 noch spezifische EP Rezeptoragonisten die Antigenaufnahme signifikant beeinflussten. Durch Präsentation von Antigen auf MHC-II-Molekülen sind DC in der Lage, tumorspezifische CD4+ T-Zellen zu aktivieren. Die MHC-II Präsentationsfähigkeit der MoDC unter dem Einfluss von PGE2 wurde mit NY-ESO-1157-170 Peptid, NY-ESO-1 Protein sowie mit NY ESO 1-transfiziertem CHO Zelllysat als Antigenquellen untersucht. PGE2 wurde zu den MoDC entweder 24 h vor (Präinkubation) oder zur gleichen Zeit wie das Antigen (Simultaninkubation) hinzugefügt. Die Versuche ergaben, dass die MHC-II-Antigenpräsentation der MoDC durch PGE2 nicht signifikant beeinflusst wird. Die Auswirkung von PGE2 auf die Kreuzpräsentationsfähigkeit der MoDC wurde mit einer Formulierung aus NY-ESO-1 Protein und dem ISCOMATRIX® adjuvant (NY ESO-1/IMX) und einem Immunkomplex bestehend aus NY-ESO-1 Protein und dem Antikörper anti NY ESO-1 mAk (Klon ES121; NY-ESO-1/IC) untersucht. Hierbei konnte gezeigt werden, dass sowohl die Kreuzpräsentation von NY-ESO-1/IMX als auch von NY ESO 1/IC durch PGE2 dosisabhängig signifikant gehemmt wurde. Dieser Effekt wird, ähnlich wie die Zell-Reifung, über die EP2/4-Rezeptoren vermittelt. Zusammenfassend erlauben die Ergebnisse den Schluss, dass PGE2 über einen EP2/4-Rezeptor-vermittelten Mechanismus die Kreuzpräsentationsfähigkeit der MoDC inhibiert, ohne jedoch die Antigenaufnahme oder die MHC-II Präsentation signifikant zu beeinflussen. Eine klinische Relevanz der Ergebnisse besteht bei der Verwendung von DC für therapeutische Tumorvakzinierungen zur Induktion einer gegen Malignome gerichteten Immunantwort. Die Benutzung von PGE2 als Reifestimulus für MoDC, die mit Protein-Antigenen gepulst werden, birgt das Risiko, die Induktion von tumorantigenspezifischen CD8+ T-Zellen negativ zu beeinflussen.

Experimental autoimmune uveitis ( EAU) in Lewis rats is a well-established model for human uveitis. During the last years we used this model to demonstrate extraocular induction of uveitis by antigenic mimicry of environmental antigens with retinal autoantigen and investigated the migration and intraocular reactivation of autoreactive green fluorescent protein ( GFP)+ T cells. We could also elaborate several differences between EAU induced with S-antigen peptide PDSAg or R14, a peptide derived from interphotoreceptor retinoid-binding protein, suggesting two differently regulated diseases in the same rat strain. R14-mediated EAU in Lewis rats has been shown to relapse, thus we have a new model to test therapeutic approaches in an ongoing immune response instead of just preventing disease. Finally, we show antigenic mimicry of PDSAg and an HLA-B peptide for oral tolerance induction. After the successful first therapeutic trial this approach will now proceed with international multicenter clinical trials. Copyright (c) 2008 S. Karger AG, Basel.

Several new HLA-B (B8, B51, Bw62)- and HLA-C (Cw6, Cw7)-specific genes were isolated either as genomic cosmid or cDNA clones to study the diversity of HLA antigens. The allele specificities were identified by sequence analysis in comparison with published HLAB and -C sequences, by transfection experiments, and Southern and northern blot analysis using oligonucleotide probes. Comparison of the classical HLA-A, -B, and -C sequences reveals that allele-specific substitutions seem to be rare events. HLA-B51 codes only for one allelespecific residue: arginine at position 81 located on the cd helix, pointing toward the antigen binding site. HLA-B8 contains an acidic substitution in amino acid position 9 on the first central/3 sheet which might affect antigen binding capacity, perhaps in combination with the rare replacement at position 67 (F) on the Alpha-l helix. HLA-B8 shows greatest homology to HLA-Bw42, -Bw41, -B7, and -Bw60 antigens, all of which lack the conserved restriction sites Pst I at position 180 and Sac I at position 131. Both sites associated with amino acid replacements seem to be genetic markers of an evolutionary split of the HLA-B alleles, which is also observed in the leader sequences. HLA-Cw7 shows 98% sequence identity to the JY328 gene. In general, the HLA-C alleles display lower levels of variability in the highly polymorphic regions of the Alpha 1 and Alpha 2 domains, and have more distinct patterns of locusspecific residues in the transmembrane and cytoplasmic domains. Thus we propose a more recent origin for the HLA-C locus.

Gene cloning and sequencing of the HLA-B locus split antigens B38 (B16.1) and B39 (B16.2) allowed localization of their subtypic as well as their public specificities HLA-Bw4 or -Bw6 to the c~-helical region of the c~ 1 domain flanked by the amino acid positions 74-83. Comparison of their amino acid sequences with those of other HLA-B-locus alleles established HLA-Bw6 to be distinguished by Ser at residue 77 and Asn at residue 80. In contrast, HLA-Bw4 is characterized by at least seven different patterns of amino acid exchanges at positions 77 and 80-83. Reactivity patterns of Bw4- or Bw6-specific monoclonal antibodies reveal two alloantigenic epitopes contributing to the HLA-Bw4 or -Bw6 specificity residing next to the region of highest diversity of the cr domain.