Podcasts about hla drb1

In this episode, we dive into the critical role of HLA gene variants, such as HLA-DRB1, and their profound impact on immune system function, particularly focusing on their significance in conditions like Lyme disease and mold toxicity. We'll explore how variations in these HLA genes, like the HLA-DRB1*0401 allele, influence the body's ability to recognize and respond to pathogens, potentially leading to chronic symptoms. The discussion will also cover HLA gene variant testing and how it can lend insight when it comes to taking a bioindividual approach to supporting the immune system. Topics: 1. Introduction - Explanation of HLA gene variants - Importance of HLA genes in immune system function 2. Basics of Genetics and Immunology - What is a chromosome? - Introduction to genes and their functions - Overview of DNA and protein synthesis 3. Major Histocompatibility Complex (MHC) - Description of the Major Histocompatibility Complex - Division of MHC genes into Class I, II, and III - Role of Class I MHC genes in antigen presentation - Role of Class II MHC genes in antigen presentation - Function of Class III MHC genes 4. HLA Genes and Immune Function - Explanation of Human Leukocyte Antigen (HLA) genes - Connection between MHC genes and HLA genes (human MHC) - Transcription and regulation of HLA genes - Response to internal and external signals - Role of Antigen-presenting cells (APCs) 5. Pathogen Recognition and Immune Activation - Mechanism of pathogen recognition by HLA genes - Activation of immune response by antigen presentation - Formation and function of peptide-HLA complexes 6. Impact of HLA Variants on Disease - Specific focus on Lyme disease and mold toxicity - Role of HLA Class II alleles in immune response - Association of HLA-DR alleles with chronic Lyme disease - Sensitivity to mold exposure linked to certain HLA gene variants 7. Testing and Implications of HLA Gene Variants - Importance of HLA gene variant testing - Broader implications for diseases like lupus and multiple sclerosis - Personalized approaches based on HLA gene variants 8. Biotoxin Illness and Poor Antigen Presentation Due to an HLA Gene Variant - Strategies to support immune system function in the presence of biotoxins - Importance of detoxification pathways and binders Thank you to our episode sponsor: ⁠⁠⁠⁠⁠Liver Medic⁠⁠⁠⁠⁠⁠ Use code Chloe20 to save 20% on ⁠⁠⁠⁠⁠⁠⁠"Leaky Gut Repair"⁠⁠⁠⁠⁠⁠⁠ ⁠⁠⁠⁠⁠⁠⁠Brendan's YouTube Channel⁠⁠⁠⁠⁠⁠⁠ ⁠⁠⁠⁠⁠⁠⁠https://x.com/livermedic⁠⁠⁠⁠⁠⁠⁠ Thanks for tuning in! Get Chloe's Book Today! "⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠75 Gut-Healing Strategies & Biohacks⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠" Follow Chloe on Instagram ⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠@synthesisofwellness⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠ Follow Chloe on TikTok @chloe_c_porter Visit ⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠synthesisofwellness.com⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠⁠ to purchase products, subscribe to our mailing list, and more! --- Support this podcast: https://podcasters.spotify.com/pod/show/chloe-porter6/support

Episode 146: RA vs OA    Future Dr. Magurany explains how to differentiate rheumatoid arthritis from osteoarthritis.  Written by Thomas Magurany, MSIV, Ross University School of Medicine. Comments by Hector Arreaza, MD. You are listening to Rio Bravo qWeek Podcast, your weekly dose of knowledge brought to you by the Rio Bravo Family Medicine Residency Program from Bakersfield, California, a UCLA-affiliated program sponsored by Clinica Sierra Vista, Let Us Be Your Healthcare Home. This podcast was created for educational purposes only. Visit your primary care provider for additional medical advice.1. Etiology: Rheumatoid Arthritis (RA): RA is an autoimmune disease wherein the immune system mistakenly attacks healthy tissues, particularly the synovial joints, usually between the ages of 30-50. Genetic predisposition, environmental factors such as smoking or infections, hormonal imbalances, and lower socioeconomic status have been associated with an increased risk of developing RA(1).Osteoarthritis (OA): OA primarily arises due to mechanical stress on the joints over time. Factors contributing to OA include age, obesity, joint injury or trauma, repetitive joint use or overuse, genetic abnormalities in collagen structure, and metabolic disorders affecting cartilage metabolism (2).The greatest risk factor for the development of OA is age with most patients presenting after 45 years of age. The greatest modifiable risk factor for OA is weight. People with a BMI >30 were found to have a 6.8 times greater risk of developing OA. (3) Primary OA is the most common and is diagnosed in the presence of associated risk factors such as: older age, female gender, obesity, anatomical factors, muscle weakness, and joint injury (occupation/sports activities) in the absence of trauma or disease. Secondary OA occurs alongside a pre-existing joint deformity including trauma or injury, congenital joint disorders, inflammatory arthritis, avascular necrosis, infectious arthritis, Paget disease, osteopetrosis, osteochondritis dissecans, metabolic disorders (hemochromatosis, Wilson's disease), Ehlers-Danlos syndrome, or Marfan syndrome.2. Pathogenesis:Rheumatoid Arthritis (RA):In some patients, RA is triggered by some sort of environmental factor in a genetically predisposed person. The best example is tobacco use in a patient with HLA-DRB1. The immune response in RA starts at sites distant from the synovial joints, such as the lung, gums, and GI tract. In these tissues, modified proteins are produced by biochemical reactions such as citrullination. (4)In RA, an abnormal immune response leads to chronic inflammation within the synovium lining the joints. The inflammatory cytokines released cause synovitis and lead to the destruction of articular cartilage and bone erosion through pannus formation. Immune cells infiltrate the synovium causing further damage. (4) In summary: formation of antibodies to citrullinated proteins, these antibodies begin attacking wrong tissues.Osteoarthritis (OA):The primary pathological feature of OA is the degeneration of articular cartilage that cushions the joints causing surface irregularity, and focal erosions. These changes progress down the bone and eventually involve the entire joint surface. Mechanical stress triggers chondrocyte dysfunction, leading to an imbalance between cartilage synthesis and degradation that cause cartilage outgrowths that ossify and form osteophytes. This results in the release of enzymes that degrade the extracellular matrix, leading to progressive cartilage loss. As more of the collagen matrix is damaged, chondrocytes undergo apoptosis. Improperly mineralized collagen causes subchondral bone thickening; in advanced disease, bone cysts infrequently occur (5). In summary: Osteophytes formation and cartilage loss.3. Clinical Presentation:Rheumatoid Arthritis (RA):The most common and predominant symptoms include joint pain and swelling, usually starting insidiously over a period of weeks to months. RA typically affects multiple joints symmetrically, commonly involving small joints of the hands, wrists, feet and progresses to involve proximal joints if left untreated. Morning stiffness lasting more than an hour is a characteristic feature. The affected joint will be painful if pressure is applied to the joint or on movement with or without joint swelling. Synovial thickening with a "boggy" feel on palpation will be noted. The classical physical findings of ulnar deviation, metacarpophalangeal joint subluxation, swan neck deformity, Boutonniere deformity, and the "bowstring" sign (prominent and tight tendons on the dorsum of the hand) are seen in advanced chronic disease. (4) Around ¼ of patients with RA may present with rheumatoid noduleswhich are well demarcated, flesh-colored subcutaneous lumps. They are usually described as being doughy or firm and are not typically tender unless they are inflamed. They are usually found on areas susceptible to repeated trauma or pressure and include the elbows, fingers and forearms. Osteoarthritis (OA):OA primarily affects weight-bearing joints such as knees, hips, spine, and hands. Symptoms include joint pain aggravated by activity and relieved with rest, morning stiffness lasting less than 30 minutes, joint swelling due to secondary inflammation, and occasionally the formation of bony outgrowths called osteophytes (6). Tenderness may be present at joint lines, and there may be pain upon passive motion. Classic physical exam findings in hand OA include Heberden's nodes (posterolateral swellings of DIP joints), Bouchard's nodes (posterolateral swellings of PIP joints), and “squaring” at the base of the thumb (first Carpal-Metarcapal or CMC joints), bony enlargement, crepitus, effusions (non-inflammatory), and a limited range of motion. Patients may also experience bony swelling, joint deformity, and instability (patients complain that the joint is “giving way” or “buckling,” a sign of muscle weakness). (5)4. Lab findings:Rheumatoid Arthritis: Laboratory testing often reveals anemia of chronic disease (increased ferritin, decreased iron and TIBC) and thrombocytosis. Neutropenia may be present if Felty syndrome is present. RF is present in 80-90% of patients with a sensitivity of 69%. In patients who are asymptomatic or those that have arthralgias, a positive RF and especially CCP predicts the onset of clinical RA. Patients with RA with RF, ACPA, or both are designated as having seropositive RA. About 10% of RA patients are seronegative. ESR and levels of CRP are usually elevated in patients with active disease and can be used to assess disease activity. The synovial fluid in RA will also reveal low C3 and C4 levels despite elevated serum levels.(4) Some non-specific inflammatory markers such as ESR, CRP can help you guide your diagnosis of RA.Osteoarthritis:Lab findings are not significant. Clinical diagnosis if the following are present: 1) pain worse with activity and better with rest, 2) age more than 45 years, 3) morning stiffness lasting less than 30 minutes, 4) bony joint enlargement, and 5) limitation in range of motion. Blood tests such as CBC, ESR, rheumatoid factor, ANA are usually normal but usually ordered to rule out an inflammatory process. Synovial fluid should show a white blood cell count less than 2,000/microL, predominantly mononuclear cells (non-inflammatory). X-rays of the affected joint can show findings consistent with OA, such as marginal osteophytes, joint space narrowing, subchondral sclerosis, and cysts; however, radiographic findings do not correlate to the severity of the disease and may not be present early in the disease. (5)5. Treatment Approaches:Rheumatoid Arthritis (RA):There is no cure for RA.The goal of treatment in RA is inducing remission and optimizing quality of life. This is initially done by beginning DMARDs, include methotrexate, hydroxychloroquine, sulfasalazine, and leflunomide. Methotrexate is the initial DMARD of choice. Anti-TNF-alpha inhibitors include etanercept, infliximab, adalimumab, golimumab, and certolizumab may be used if DMARDs fail. NSAIDs are used to control joint pain and inflammation. Corticosteroids may be used as a bridge therapy to DMARDs in a newly diagnosed patient with a very active disease. (7) Coronary artery disease has a strong association with RA. RA is an independent risk factor for the development of coronary artery disease (CAD) and accelerates the development of CAD in these patients. Accelerated atherosclerosis is the primary cause of morbidity and mortality. There is increased insulin resistance and diabetes mellitus associated with RA and is thought to be due to chronic inflammation. When treated with specific DMARDs such as hydroxychloroquine, methotrexate, and TNF antagonists, there was a marked improvement in glucose control in these patients. (8) RA is not just a disease of the joints, it is able to affect multiple organ systems.Osteoarthritis (OA):OA treatment aims at reducing pain and improving joint function through a combination of non-pharmacological interventions like exercise programs tailored to strengthen muscles around affected joints, weight management strategies, and assistive devices like braces or walking aids if required (9). Medications including analgesics or nonsteroidal anti-inflammatory drugs may be prescribed for pain relief when necessary. Duloxetine has modest activity in relieving pain associated with OA. Intraarticular glucocorticoid joint injections have a variable response but are an option for those wanting to postpone surgical intervention. In severe cases where conservative measures fail, surgical options like joint replacement may be considered (9). Weight loss is a critical intervention in those who have overweight and obesity; each pound of weight loss can decrease the load across the knee 3 to 6-fold. (5) Summary: Medications (NSAIDs, topical, duloxetine), weight loss, PT, intraarticular injections of corticosteroids, and joint replacement.________________________________Conclusion: Now we conclude episode number 146, “RA vs. OA.” Future Dr. Magurany explained that rheumatoid arthritis is an autoimmune disease that presents with joint pain and inflammation, mostly on hands and small joints, accompanied by morning stiffness longer than 1 hour. The rheumatoid factor and ACPA may be positive in a percentage of patients but not always. The base of treatment is early treatment with disease-modifying antirheumatic drugs to induce remission of the disease. OA affects weight-bearing joints with little to no inflammation, treatment is mainly lifestyle modifications, analgesics, intraarticular injections, and joint replacement.This week we thank Hector Arreaza and Thomas Magurany. Audio editing by Adrianne Silva.Even without trying, every night you go to bed a little wiser. Thanks for listening to Rio Bravo qWeek Podcast. We want to hear from you, send us an email at RioBravoqWeek@clinicasierravista.org, or visit our website riobravofmrp.org/qweek. See you next week! _____________________References:Myasoedova E, Crowson CS & Gabriel SE et al. (2010). Is the incidence of rheumatoid arthritis rising?: Results from Olmsted County, Minnesota, 1955-2007. Arthritis and Rheumatism, 62(6), 1576-1582.Goldring MB & Goldring SR. (2007). Osteoarthritis. Journal of Cellular Physiology, 213(3), 626-634.King LK, March L, Anandacoomarasamy A. Obesity & osteoarthritis. Indian J Med Res. 2013;138(2):185-93. PMID: 24056594; PMCID: PMC3788203.Chauhan K, Jandu JS, Brent LH, et al. Rheumatoid Arthritis. [Updated 2023 May 25]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan-.Sen R, Hurley JA. Osteoarthritis. [Updated 2023 Feb 20]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2023 Jan-.Hunter DJ, Bierma-Zeinstra S. & Eckstein F. (2014). OARSI Clinical Trials Recommendations: Design and conduct of clinical trials for primary hip and knee osteoarthritis: An expert consensus initiative of the European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis (ESCEO) Task Force in collaboration with the Osteoarthritis Research Society International (OARSI). Osteoarthritis Cartilage, 22(7), 363-381.van Everdingen AA, Jacobs JW, Siewertsz Van Reesema DR, Bijlsma JW. Low-dose prednisone therapy for patients with early active rheumatoid arthritis: clinical efficacy, disease-modifying properties, and side effects: a randomized, double-blind, placebo-controlled clinical trial. Ann Intern Med. 2002 Jan 1;136(1):1-12. doi: 10.7326/0003-4819-136-1-200201010-00006. PMID: 11777359.Nicolau J, Lequerré T, Bacquet H, Vittecoq O. Rheumatoid arthritis, insulin resistance, and diabetes. Joint Bone Spine. 2017 Jul;84(4):411-416.Fernandes L, Hagen KB, Bijlsma JWJ et al. (2019). EULAR recommendations for non-pharmacological core management of hip and knee osteoarthritis. Annals of Rheumatic Diseases, 79(6), 715-722.Royalty-free music used for this episode: "Driving the Point." Downloaded on July 29, 2023, from https://www.videvo.net/ 

See all the Healthcasts at https://www.biobalancehealth.com/healthcast-blog/ (Quotes are from the 23 and me Blog. November 2021) Last week we talked about the research 23 and Me has done determining individual responses to the three Covid vaccine, based on the genetics of the HLA type of the individual. This week we will review their research on people who have gotten Covid infections and become Long-Haulers, those patients who develop long lasting illness and organ damage from getting the virus. We will look at the genetic characteristics of those patients who are at risk for Long Hauler condition after Covid. “A recent study by researchers at the Translational and Clinical Research Institute within Newcastle University found that an allele (gene) protective against severe COVID-19 symptoms in the HA gene, at HLA-DRB1*04:01, was found at much higher frequency in people of Northwestern European ancestry.” That means that if your inheritance, your ancestors come from northwestern Europe, you are less likely to develop a severe case of Covid, or “long haulers” complications. They have also found that those people with Blood type O and B are less likely to have severe effects to covid, the vaccine to covid and less likely to have severe long-term side effects of covid infection.   The way I look at this is that if you can determine your risk of severe infection or severe reaction to the Covid virus from your genetics, then you can decide whether you should take the risk of getting the vaccine, or not, and the risk of getting infected and having long-term reactions to it, so you can determine whether you should always wear a mask in public or not, get a vaccine or whether you should fly on a plane or not.  Without knowing your risk how can you determine how to run your life in a pandemic?  We should be concentrating on three things: Determining individual risk, based on genetics, so an individual can make an educated decision about his activity, vaccination and or use of masks. To find this risk you must know your blood type, your HLA type (which most of us don't know), and whether you are protected from severe long haulers, by ancestors who were from northwestern Europe. Be realistic about your risk dictated by your lifestyle, and that can be somewhat controlled by how we live our lives: If you are obese, smoke, are over 60, eat processed foods, drink alcohol daily, don't exercise, or if you have any diseases or take medications that suppress your immune system, you should take all precautions including getting vaccinated.  More importantly you should change your lifestyle and go on a mission to get healthy. Besides cleaning up your life, there is no magic bullet that protects everyone. We now know that Covid 19 can be deadly to certain individuals, and to others it doesn't even make them sick.  The same genetic HLA type people who have bad reactions to vaccines also have the most severe infections with Covid 19. This puts these patients in a trick box…they need to be vaccinated but they are at risk for complications, however if they get the covid virus they may die.  In this case looking at other health factors may tip the scales toward vaccination or the opposite toward quarantine for an unknown time.  A doctor should be the one to assist you in this decision. The one non-genetic factor that puts you more at risk for reactions to the vaccines is a previous Covid 19 infection.  If you are at risk otherwise and need to have the vaccine to protect yourself from death or long-haulers then waiting 6 or more months since your Covid infection to be vaccinated is advised. I wish the best to you all…this is a time of learning for doctors and virologists alike…we increase our knowledge every day and I will try to keep you up to date with the research and the advice based on that research. At this time, to be preventative, everyone should improve their immune status by eating a good whole food diet low in carbs, high in fruit and veggies, and by taking Vitamin C 500-1000mg/day, Zinc 15-50 mg/day with Copper 2-6mg/day, Quercetin, Methyl B complex, have your hormones replaced including estradiol and testosterone after menopause and testosterone for men after age 55-60, and exercising daily. Then determine your genetic status if possible and take the precautions necessary for your level of risk.

Merhabalar… Sevdiğim çömezimin isteği üzerine bu yazımızda sizlere The Journal of Emergency Medicine' da Eylül 2021 yayınlanan derleme aracılığıyla Acil Serviste Trombotik Trombositopenik Purpuranın Değerlendirilmesi ve Yönetimi'nden bahsedeceğim. Derleme'nin tamamına buradan ulaşabilirsiniz. Trombotik trombositopenik purpura (TTP), acil serviste teşhis edilmesi güç lakin yüksek mortalite ve morbitidesi olmasından ötürü erken teşhisin elzem olduğu bir hastalıktır. TTP; mikroanjiyopatik hemolitik anemi, şiddetli trombositopeni ve multiorgan iskemik hasarı ile seyreden bir hastalıktır .Edinilmiş veya kalıtsal olabilir. Spesifik bir metalloproteaz olan ADAMTS-13 ile ilişkilendirilmiştir. TTP'de beklediğimiz klinik ateş, nörolojik anormallikler, purpuralı trombositopeni, mikroanjiyopatik hemolitik anemi ve akut böbrek hasarından oluşmaktadır. Ancak sadece

This podcast comments on a large registry study evaluating the effect of ultra-high-resolution HLA typing on outcomes of unrelated donor transplantation.   TRANSCRIPT This JCO Podcast provides observations and commentary on the JCO article ‘Impact of Previously Unrecognized HLA Mismatches Using Ultra-High-Resolution Typing in Unrelated Donor Hematopoietic Cell Transplantation” by Mayor et al. My name is Navneet Majhail, and I am the Director of the Blood and Marrow Transplant Program and the Vice-Chair for the Department of Hematology and Medical Oncology at the Taussig Cancer Institute, Cleveland Clinic. My oncologic specialty is transplantation and cellular therapy.    For patients who are potential candidates for allogeneic hematopoietic cell transplantation, the first critical step is finding an HLA-matched donor. The HLA genes are located within one of the most gene rich regions of the human genome, are highly polymorphic, and encode proteins that critically modulate the body’s immune responses against a variety of stimuli. When selecting an unrelated bone marrow or peripheral blood stem cell donor, we typically try to identify donors who are matched at HLA genes where polymorphism is predominantly present, namely, class I genes HLA-A, -B, -C, and class II genes HLA-DRB1, -DQB1 and –DPB1. Guidelines recommend using a donor who is matched at least at HLA-A, -B, -C, and –DRB1, and preferentially at -DPB1 and -DQB1 as well.    Graft-versus-host disease or GVHD is an immune-mediated complication that continues to be a major threat to successful patient outcomes after hematopoietic cell transplantation. Better matching between the donor and the recipient lowers risk of GVHD, and guidelines recommend use of an HLA 8/8 matched unrelated donor, though in clinical practice we prefer an HLA 10/10 and even a 12/12 matched donor if one is available. In the past, HLA typing methods used ‘antigen-level’ serological testing. However, with advances in technology, the field has moved on to ‘allele-level’ or high-resolution typing which can discriminate among HLA genes that encode cell-surface proteins that ultimately constitute the antigen recognition domain, which is the functionally active portion of the HLA molecule that ultimately interacts with T-cell and NK-cell receptors. Research has shown that matching at allele-level is associated with lower risks of GVHD and better survival compared to historical serotyping-based methods, and DNA-based HLA-typing is the current standard of care.    Further advances in technology to next-generation sequencing or ultra-high-resolution typing can now allow characterization of the full HLA gene sequence. This has raised the question of the clinical significance of HLA polymorphisms in regions outside the antigen recognition domain. Prior studies in smaller cohorts of patients have raised the possibility that transplants using ultra-high-resolution matched donors may be associated with better survival and lower risks of acute GVHD. To definitively validate these findings, Mayor et al conducted a study in a cohort of >5,000 allogeneic transplant recipients from the Center for International Blood and Marrow Transplant Research. Patients had received a matched unrelated donor transplant for acute leukemia or MDS between 2008 and 2017. The manuscript that accompanies this podcast provides details of their study population, but overall their cohort was fairly representative of unrelated bone marrow and peripheral blood stem cell transplant recipients.     To summarize some key findings of their study, first, among donor-recipient pairs deemed HLA 10/10 match using high-resolution typing, 18% were found to not be a 10/10 match on ultra-high-resolution typing. Overall, only 12% of patients had a 12/12 ultra-high-resolution matched donor. Second, overall survival was comparable between patients receiving 12/12 ultra-high-resolution matched and mismatched transplants. Furthermore, there was no association of survival with the degree of ultra-high-resolution mis-match, that is, the number of loci where there was a mismatch. Similarly, when considering a subgroup of patients who were ultra-high-resolution matched at 10/10 loci, there was no difference in survival between patients who were 12/12 matched, that is, matched at DPB1, and those permissively or non-permissively mis-matched at DPB1. The authors did report an association of ultra-high-resolution matching with acute GVHD for their whole cohort, and associations with GVHD and transplant-related mortality in some subgroups, and I refer you to their JCO manuscript for details.      There are some caveats to consider in applying their findings to clinical practice, and a good study always leads to more questions. The probability of finding an adult HLA 8/8 high-resolution matched unrelated donor varies from 16% to 75% depending on recipients race and ethnicity – the chances of finding a 10/10 or 12/12 donor who is ultra-high-resolution matched is going to be significantly lower. How do we factor in the role of other known non-HLA unrelated donor selection factors such as donor age, donor sex, CMV status, ABO type, and graft source vis-à-vis ultra-high-resolution matching? Even in this highly selected cohort of patients who were actually able to get a transplant, nearly 90% did not have a 12/12 ultra-high-resolution matched donor – in this setting, how do mismatches at different loci compare with respect to outcomes? Do we change our transplant conditioning and GVHD prophylaxis regimens in ultra-high-resolution mis-matched unrelated donor transplants to reduce the risk of GVHD? Several studies have indicated comparable survival between matched unrelated donor and haploidentical related donor transplants – does the use of an ultra-high-resolution 10/10 or 12/12 HLA matched donor offer any outcome advantage compared to the haploidentical transplantation? Taken together and at this time, their findings are primarily applicable to patients who have the luxury of choosing from several young 10/10 HLA matched unrelated donors. Cost of HLA typing using next-generation sequencing is also a factor that needs to be considered.    Notwithstanding these ‘yet to be answered’ questions, there are advantages to ultra-high-resolution typing, and current technology does allow for rapid and unambiguous characterization of HLA genes with a rapid turnaround time. Many HLA labs are already implementing third-generation typing methods, and with increasing use and demand, it is expected to become cheaper and will no longer be cost-prohibitive.    Overall, with HLA-identical sibling, matched unrelated, haploidentical related, mis-matched unrelated, and umbilical cord blood, nearly all patients who need a transplant have a donor. It is heartening to see that our research has pivoted from “Is there a donor available?” to “What is the best donor?” for a given patient.     This concludes this JCO podcast. Thank you for listening. 

Link to bioRxiv paper: http://biorxiv.org/cgi/content/short/2020.08.13.249920v1?rss=1 Authors: Goodin, D. S., Khankhanian, P., Gourraud, P.-A., Vince, N. Abstract: OBJECTIVE: To explore the nature of MS-susceptibility and, by extension, other complex-genetic diseases. BACKGROUND Basic-epidemiological parameters of MS (e.g., prevalence, recurrence-risks for siblings and twins, time-dependent changes in sex-ratio, etc.) are well-established. Moreover, >200 genetic-loci are unequivocally MS-associated, especially the HLA-DRB1*15:01~HLA-DQB1*06:02~a1 haplotype-association. DESIGN/METHODS: We define the genetically-susceptible subset-(G) to include everyone with any non-zero life-time chance of developing MS. We analyze, mathematically, the implications that these epidemiological observations have regarding genetic susceptibility. In addition, we use the sex-ratio change (observed over a 35-year interval), to derive the relationship between MS-probability and an increasing likelihood of a suitable environmental-exposure. RESULTS: We demonstrate that genetic-susceptibitly is restricted to less than 4.7% of populations across Europe and North America. Among carriers of the HLA-DRB1*15:01~HLA-DQB1*06:02~a1 haplotype, fewer than 20% are even in the subset-(G). Women are less likely to be susceptible than men although their MS-penetrance is considerably greater. Response-curves for MS-probability increase with an increasing likelihood of a suitable environmental-exposure, especially among women. These environmental response-curves plateau at under 50% for women and at a significantly lower level for men. CONCLUSIONS: MS is fundamentally a genetic disorder. Despite this, a suitable environmental-exposure is also critical for disease-pathogenesis. Genetic-susceptibility requires specific combinations of non-additive genetic risk-factors. For example, the HLA-DRB1*15:01~HLA-DQB1*06:02~a1 haplotype, by itself, poses no MS-risk. Moreover, the fact that environmental-response-curves plateau below 50%, indicates that disease-pathogenesis is partly stochastic. By extension, other diseases for which monozygotic-twin recurrence-risks greatly exceed disease-prevalence (e.g., rheumatoid arthritis, diabetes, and celiac disease), must have a similar genetic basis. Copy rights belong to original authors. Visit the link for more info

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.  

Dr. Veronica Anderson, Host, Functional Medicine Specialist and Medical Intuitive interviews Dr. Tom O'Bryan, an internationally recognized speaker and workshop leader specializing in the impact of celiac disease and non-celiac gluten sensitivity, and the development of autoimmune conditions. He has been in practice for over 32 years and is on the teaching faculty of the institute for functional medicine. While traveling the world, he teaches physicians about developing the big picture as to what's causing the symptoms that patients are coming in with. In this episode, Tom translates complex medical information into simple to understand ideas. We will discuss breakthrough plans to stop autoimmune triggers, restore your health and ways to prevent Alzheimer's and reverse Diabetes. Listen to the end to hear Tom’s vaccine administration strategy for infants.   Dr. Veronica Anderson's Links https://www.linkedin.com/in/drveronicaanderson/ https://www.facebook.com/drveronicaanderson/ https://twitter.com/DrVeronicaEyeMD?lang=en https://www.pinterest.com/drveronicaeyemd/?eq=dr.%20veronica&etslf=14837 https://www.instagram.com/drveronica/?hl=en   Recommended Books: http://amzn.to/2p9LK8L   Discussed: Betrayal Series:- http://www.bit.ly/TheBetrayal7PartSeries   Show Notes: 01:58 - What is Autoimmune disease? 08:40 - Thyroid problems in women 16:45 - Food promoting intestinal permeability ( leaky gut ) 19:00 - How your diet affects your thyroid 23:20 - How an autoimmune thyroid disease is triggered 29:40 - Preventing Alzheimer's and Diabetes 31:50 - Wheat sensitivity and inflammation in the brain 33:00 - Reversing Diabetes with a raw food diet 36:00 - Interviewing world experts of autoimmunity 38:20 - Vaccine administration strategy for infants   If you enjoyed this episode, do us a favor and share it! Also if you haven’t already, please take a minute to leave us a 5-star review on iTunes and claim your bonus here!     Want to regain your health? Go to http://drveronica.com/   Transcript Female VO: Welcome to Wellness Revolution Podcast, the radio show all about wellness, in your mind, body, spirit, personal growth, sex, and relationships. Stay tuned for weekly interviews featuring guests that have achieved physical, mental, and spiritual health in their lives. If you'd like to have access to our entire back catalog visit drveronica.com for instant access. And here's your host, Dr. Veronica. Dr. Veronica: Thanks again for joining for another episode of Dr. Veronica's Wellness Revolution. We're going to talk today. I want to jump right into this. I want to have enough time to be able to talk to this gentleman who is a guru. The gentleman I have with me today is Dr. Thomas O'Bryan. He is originally a doctor of chiropractic medicine, but you know what I've found? I feel really silly sometimes because I feel like I went to school before medical school with the chiropractors and I was getting really good grades and they weren't doing as well. And I felt like all these people they're not so smart at going into chiropractor. Then I realized on the back half of my career that I was the dumb one and they're the smart one and I better learn from them. So those of us who were the conventional smart doctors have now kind of thrown away a lot of what we learned. We know about the body and all that, and jumped in the pool with our colleagues because we're all colleagues out to help people get well who were the chiropractors of natural path and nutritionists. And we all collectively are out there getting the word out on how you can heal your own body. Dr. Thomas O'Bryan has a new book out there, The Autoimmune Fix. I see so many people every day who say, "I've been told I have autoimmune disease and they haven't quite given it a name but I have autoimmune disease."  The Autoimmune Fix talks about this but also talks about what's been going on in the health care system. What's been going on or not going on when you'd go to your doctor and here's the latest and greenest. And we also have a surprise coming up on some information that you can get where you can go and hear the world experts in autoimmune disease. Dr. Thomas O'Bryan, welcome to Dr. Veronica's Wellness Revolution. Dr. Thomas: Thank you so much. It's a pleasure to be with you. Thank you. Dr. Veronica: First define for us what it's meant by autoimmune disease? Because as I told you and I said in the intro I get a lot of people who said, "I've been told I have autoimmune." The big diagnosis these days is, "I have Hashimoto's." Every other person has Hashimoto's. "Oh, you have an autoimmune disease too. Autoimmune disease, give us the definition. Dr. Thomas: Sure. Your immune system is the armed forces in your body. It's the army, the Air Force, the Marines, the Coast Guard, the Navy. It's there to protect you. And it's all we have to protect us. And you have exactly the same immune system that your ancestors had thousands of years ago. We haven't genetically changed.  What was it that our immune system was designed to fight? Parasites, bugs, viruses, molds, and fungus. That's it. There was no Polysorbate 80, or red dye number 3, or Bisphenol A, or mercury in the fish. There weren’t any of the toxins that we're supposed to every day. So our immune system is the same as our ancestors, so it's built to protect us from parasites, bugs, viruses, molds, and fungus. There is no way for it to adapt. When you get exposed to Bisphenol A for example, which is the chemical that softens plastic like water bottles, or pop bottles, or soft contact lenses, or credit card receipts have Bisphenol A. There is just millions and millions of pounds of this stuff being dumped every year here.  But when you're exposed to Bisphenol A this chemical gets into your body and it binds on to your cells. It grabs to on to proteins inside your body like an estrogen cell or a testicular cell. Now the immune system that's there to protect you from bugs, parasites, viruses, molds, and fungus has to attach this molecule that got in there that's not supposed to be there. "This is an invader. What is this thing?"  Your immune system attacks this Bisphenol molecule or lead molecule if you have lead poisoning, where mercury molecule, and you create this inflammation as the immune system is trying to destroy this invader. And the inflammation has collateral damage which damages your own cell that the Bisphenol A grabbed on to. And now your immune system has just damaged your cell. When the immune system attacks yourself it's called an autoimmune mechanism. It's the immune system attacking cells.  In the example I just gave you we make antibodies every day to ourself. There's a normal reference range for thyroid antibodies and brain antibodies. There's a normal range, why? Because your immune system is the garbage collector. It's got to get rid of the old and damaged cells, the ones that are breaking down or just worn out to make room for new cells to be built.  You have a whole new body every 7 years. We regenerate every cell in our body. But to make room for cells to regenerate you've got to get rid of the old and damaged ones. There's a normal level of thyroid antibodies. It's normal. But when you have a chemical binding on to the thyroid for this example, the chemical might be chlorine or it could be Bisphenol A binding to a thyroid cell, and your immune system says, "What is this stuff? That's not good for me. I better attack it.  Your immune system attacks that cell and causes the inflammation that damages the thyroid that the Bisphenol A's grabbed on to. Now the antibodies that your body makes to get rid of old thyroid cells, it has to make some more antibodies to get rid of the damaged thyroid Bisphenol A cell, because the thyroid cell's been damaged you got to get rid of it. So you make some extra antibodies to your thyroid. That's not a problem. But you're exposed to Bisphenol A every day. One hundred percent of the infants born today have Bisphenol A in their urine, 100% of them, because mom has it. Mom's toxic with this stuff, right? It binds on to your cells. And so every day you're exposed to this stuff, and then your body makes more antibodies to your thyroid to get rid of the damaged thyroid cell that the Bisphenol A was grabbing on to. And you make more thyroid cells.  And if you did a blood test you'd see you had a high thyroid antibody levels and you make more thyroid antibodies. Until one day this thyroid antibody production becomes self-perpetuating. It's got a life of its own. Now you develop the autoimmune disease, so you're on the autoimmune spectrum with elevated antibodies, but now it moves into an autoimmune disease because you've killed off enough thyroid cells because of the elevated antibodies, the thyroid can't function very well anymore. That's the autoimmune disease.  Mrs. Patient, you pull at a chain, the chain always breaks at the weakest link. It's at one end, the middle, the other end, your heart, your brain, your liver, your kidneys, wherever your genetic weak link is that's where the chain's going to break when you pull too hard. Inflammation is the pull on the chain.  That's why we here about anti-inflammatory lifestyles. It's that you want to live as much of an anti-inflammatory lifestyle with all that that means. And your show talks about that a lot, about anti-inflammatory lifestyles, so that you don't have that link of the chain break and get an autoimmune disease. What's pulling on the chain? What's pulling on the chain is the gasoline or the kerosene that you're getting in your body, if it's air pollution or if it's food you're eating that aren't good for you. The question is it a kidney or a brain cell, is it gasoline or kerosene? When you want to start fixing these problems you have to ask the questions, "Where is my immune system attacking right now and why is my immune system attacking there?" That's the way you uncover what the mechanism is that's causing the diseases that we have. Dr. Veronica: Talk a little bit about thyroid because I think all of us that are in the functional medicine wellness arena, the thyroid people come in because they just seem for whatever reason they're the most miserable... There's other miserable people, but the thyroid people seem to be miserable and go seek their help. Why thyroid and why mostly women, although there's a lot of men now prop up with it. Dr. Thomas: Yeah, but the ratio of women to men with Hashimoto's is 9:1. It's much more prevalent in women. There's a number of reasons for that. The first reason is receptor sites are catcher's mitts. The pitcher throws the ball to the catcher. You have receptor sites on the outside of your cells facing the bloodstream. So as the blood's going by it goes past these receptor sites. Hormones get inside the cell to do whatever they're supposed to do by going through the receptor site. Estrogen in your bloodstream only goes into an estrogen receptor site. It won't go into a thyroid receptor site. And it goes into the estrogen receptor site, it opens the door and the estrogen goes inside the cell and the body will do what it's going to do. Insulin won't go into an estrogen receptor site, it won't go into a thyroid receptor site. It only goes into an insulin receptor site. All the hormones have specific receptor sites. There are chemicals that we're exposed to now every day, never before in the history of humanity but now every day. And there are three chemicals known to compete on thyroid receptor sites.  Now, back up for a minute. There's only two substances for which there are receptor sites on every cell of your body. No, it's not testosterone, no not estrogen, no not insulin, the only substances for which there are receptor sites on every cell of your body are vitamin D... That's why vitamin D is so important for us because every cell needs it, and thyroid hormone. Because your thyroid hormone is the thermostat on the wall in your house.  At night you turn the thermostat down so the furnace goes down. It's colder in the house, so that you sleep and you save fuel. In the morning it automatically turns back on before you get up, and so it warms up the house but you save fuel during the night. Thyroid hormone controls the thermostat. That's called your metabolism and how hot your cells burn, how many calories you burn, that's your thyroid hormone. Every cell needs control as to how hot it should burn, that's what thyroid hormone does. Thyroid hormones in the bloodstream, and it goes past the thyroid receptor site and it goes right into it. It opens the door and the thyroid hormone goes into the cell. As you know many people will feel like they've got thyroid symptoms. They come in and the doctor does a blood test and sees that their thyroid hormone levels are normal but they've got thyroid symptoms so they write a prescription for thyroid hormone. And we're shot gunning thyroid hormone into someone that has normal levels because it's going to help feel a little better. How is it possible that their thyroid hormone levels are normal but a blood test that many doctors do is called TSH and it's a measure in the brain telling the thyroid how much hormone to make. TSH stands for thyroid stimulating hormone. How come the TSH can be a little high but the thyroid hormone levels are normal? And you see that all the time in practice. We all see that. How does that happen? It's because the thyroid hormone is not getting into the cell, it's in the bloodstream. Your bloodstream's just a highway. There's lots of traffic on the highway so you do a blood test and you're looking for are there Chevrolet's on the highway. Is there a thyroid hormone on the highway. There's enough hormone but it's not getting into the cell, so the brain says, "I need more thyroid hormone in these cells." The TSH goes up to say, "Make more hormone, make hormone." But you've got plenty of hormones. And doctor shot gunned with synthetic hormone and people will feel a little bit better. It doesn't fix them but they feel a little better.  How come the thyroid hormone is not getting into the cell? Because there are three chemicals that compete and will go into thyroid hormone receptor sites. But when they go into thyroid hormone receptor sites they don't open the door. They just sit there. The pitcher throws a fastball to the catcher but the catcher's got three baseballs in the mitt. And so the fastball just bounces out. The thyroid hormone just keeps going down the bloodstream, it can't get in.  What are the chemicals that compete in thyroid receptor sites? The most common one... Mrs. Patient, you're in an elevator in a hotel. The elevator doors open. Can you tell right away the swimming pools on that floor? Oh yeah. They smell it. But everybody else in the elevator can't smell it. But they smell it. Why do they smell it? Because they have a chlorine sensitivity. Their detox capabilities are not breaking down the chlorine, so the chlorine is sitting in the receptor sites of the thyroid hormone.  So the thyroid hormone is going by, it can't get into the cell. The thyroid hormone keeps going by, and yet the brain says, "I need more hormone. I need more hormone," and it's chlorine. It's a very common competitor for thyroid receptor sites. Those women, especially the women, cold hands and feet, sometimes they wear socks to bed, or your husband says you got really cold feet. You can't get up in the morning. You wish you had 20 more minutes in bed. Can't lose that last 5 pounds even if you don't eat for a couple of days. Bowels are sluggish, emotions are kind of sluggish, brain's sluggish, you kind of feel a little depressed, all signs of a sluggish thyroid.  Your thyroid hormone levels are normal but your doctor gives you thyroid hormone anyway because we know it's going to help a little bit. And they haven't had the chance to read about this competitive inhibition of chlorine into the thyroid receptor sites. That's a very common mechanism for thyroid dysfunction. How does that relate in terms of autoimmunity? Dr. Veronica: Let me just interrupt. Because you said there are three things, and you mentioned the chlorine, but tell people the other two that go along with chlorine just because people are going to start connecting the dots and say, "That could be me." Dr. Thomas: You won't like this. Fluoride is very, very common. It's a very common thyroid inhibitor substance. It's in your toothpaste, it's in your mouthwash, it's in your drinking water and it competes on thyroid receptor sites. And the result is your thyroid hormone doesn't work as well as supposed to. You gain weight, you feel sluggish, sometimes you can pack on an extra 20-30 pounds over five years that it just creeps up little by little by little. Fluoride is the second one. The third one is bromide.  So it's chlorine, fluoride, and bromide. Bromide is in baked goods. A lot of bromide is used in baked goods. Those are the three chemicals that will compete on thyroid receptor sites. And they don't breakdown, they just stay there. Dr. Veronica: Okay. That's chemicals. I know you're an expert on another food that everybody loves and when you tell them they have to give it up they want to murder you practically because they're addicted. Talk about that food. You don't have to talk to me about... Dr. Thomas: Unfortunately it's the most common food in America today. It's 132.5 pounds per person per year that we're eating. That's wheat. You have toast for breakfast, a sandwich for lunch, a pasta for dinner, croutons on your salad, a cookie or a muffin, and it goes on a day, after a week, after a month, after year, after year.  Harvard's published another study last year. Hollon and his team published a study and they showed that every single human when they eat wheat gets intestinal permeability. The slang term is leaky gut. And that's the gateway into the development of autoimmune diseases that we'll talk about a little bit later, but that's the gateway. And every single person, every time they eat wheat, not just once in a while, every time. And their language was all humans develop intestinal permeability. Anyone that's watching this interview, if you're a human, I think most of you are, that means every time you eat wheat you get tears in your lining in your gut. It's called pathogenic intestinal permeability. Even for those that don't feel bad. Those that feel bad when they eat wheat they're the blessed ones. Because you can't argue with them, they know when they eat it they get sick. But the ones where the weak link in the chain is their brain they don't want to associate the pasta they had last night with the brain fog they've got today. They just don't want to associate it, or with seizures.  In the Journal of Gastroenterology children with drug resistant seizures, that means that they've been to at least two specialists and they've tried at least three drugs before they can get the classification of drug resistant seizures, 50% of those children go into complete remission on a wheat-free diet. Why don't our neurologists know this? Because it's in the gastroenterology journal, and neurologists don't read gastroenterology journals, they read neurology journals. So they just don't know this. Wheat can affect any tissue of your body. I'm going to give you an example of how it affects the thyroid. When you eat wheat, Mrs. Patient. Proteins are like a pearl necklace, hydrochloric acid made in your stomach undoes the clasp of the pearl necklace. Now you have a string of pearls. Our digestive enzymes are supposed to act like scissors to break the pearl necklace into smaller clumps of pearls, then smaller clumps, and smaller clumps, and smaller clumps. Until they get broken down into each pearl of the pearl necklace. That's called an amino acid. And the amino acids go right through the walls of the intestines, and then your body uses those as building blocks to make a new muscle, or a new bone, or a new nerve hormones called neurotransmitters that your body uses the amino acids.  Your intestines are 20-25 feet long. It starts at the mouth and goes to the other end. It's one long tube. It kind of winds around in your abdomen. It twists around quite a bit, but it's one long tube. If you could take a doughnut and stretch a doughnut straight down and look down the doughnut it's one tube. When you swallow food it's not in your body yet, it's still in the tube. It's got to go through the walls to get into the bloodstream and go everywhere else in your body. But there's a cheesecloth that lines the intestines so that only the single pearls of the pearl necklace can fit through the cheesecloth to get into the bloodstream, only the amino acids. The problem with wheat is that no human can breakdown the pearl necklace in each pearl of the pearl necklace. The best we can do is break it into clumps of pearls. There's a 33-pearl clump, a 17-pearl clump, an 11-pearl clump. And these clumps of pearls are gasoline and the fire in the intestines. They cause inflammation. And it's the inflammation that tears the cheesecloth. When you tear the cheesecloth now larger clunks of the pearl necklace of any food can go through the permeability into the bloodstream before there's been enough time for the digestive enzymes to break that food going down the track until it's small enough to get through. Does that make sense? Dr. Veronica: Yeah. Dr. Thomas: You got these clumps of pearls going through into the bloodstream. They're called macro molecules, big molecules. And your immune system says, "What's this? This is not good for me. I better fight this. If you had prime rib for dinner and you chew it three or four times instead of the 15-20 that you should... You chew a couple of times and swallow it down, we shovel more than we chew and you shovel it down you got this clump of stringy meat that's kind of hard to break down. And the enzymes are trying to cut off each pearl of the pearl necklace but it takes a while. That's why you got 20 feet of intestines for the scissors to work on that.  So it's going down in the first part of the intestines now, but there are tears in the cheesecloth. So these macro molecules of prime rib get into the bloodstream. Your immune systems says, "Whoa, I better fight this." Now you make antibodies to beef, and you're allergic to beef, or to bananas, or to chicken, or to potatoes, or to cantaloupe.  And the doctor that does the 90-food panel to see what foods a person is sensitive to, and it comes back with 20-25 foods and the patient goes, "Oh my god, that's everything I eat." Of course it is, because your body is trying to protect you. You don't shut down the immune system, you stop the tears of the cheesecloth. So you have to find out why is the cheesecloth tearing. And when you find out why the cheesecloth is tearing then 6 months to a year later you check again the 90 foods, now you're sensitive to two or three and not 20. That's the mechanism in the development of intestinal permeability, the leaky gut. Let's tie that now to the thyroid. How does this trigger an autoimmune thyroid disease? When this macro molecule of beef gets into the bloodstream and your immune system says, "Whoa, what's this?" The brain says, "You General, you now are General Beef. Take care of this."  General Beef builds an assembly line. The assembly line starts producing soldiers. They're called antibodies. The soldiers are trained to go after beef, that's all they do. They're in the bloodstream looking for beef. And when they see beef clumps they fire their chemical bullets to destroy the beef clumps. Remember your bloodstream's just a highway. There's no lanes of traffic. Everything's bouncing around in there. It's going in the same direction but it's bouncing around.  Think of the antibodies like Arnold Schwarzenegger and he's got his head out of the big Humvee. He's got those dark glasses on. He's got a big submachine gun. "Over there." And he's firing these chemical bullets at beef because he's been trained to go after beef.  The beef macro molecule may be 15 amino acids long because it hadn't had enough time to be broken down into each pearl of the pearl necklace. So there's 15 amino acids there and Arnold has been trained to go after what anything that looks like that 15 amino acids. I'm going to sat AA, B, C, D, but it really is 15 letters long in this example. Let's say Arnold is going after wheat because wheat got in, it tears the cheesecloth, it gets in as a macro molecule. Your immune system makes antibodies to wheat. I said beef to start with but I'm going to talk about wheat now. Let's say Arnold's looking for AA, B, C, D. Bouncing around in the bloodstream looking for AA, B, C, D. He's got these dark glasses on. The surface of your thyroid facing the bloodstream is made up of proteins and fats. That's what the surface is made of facing the bloodstream. Proteins are made up of amino acids. There are hundreds of amino acids long, the surface of the proteins of the thyroid, hundreds of amino acids long. But part of the thyroid includes AA, B, C, D.  Arnold that's looking for wheat, AA, B, C, D, he's like, "Oh look, over there." And he fires his chemical bullets at the thyroid to damage the thyroid cell because it's got AA, B, C, D. That's called molecular mimicry. And it's a big problem for people today, they just don't know it. It's a big problem as to why autoimmune disease is so prevalent.  Arnold starts firing his chemical bullet at the thyroid damaging the thyroid cell. Remember you have a normal amount of thyroid cells but now you have to make a few extra because there's more damaged thyroid cells than normal. That's after having toast for breakfast. But now you have a sandwich for lunch. More Arnold, more damage to the thyroid, AA, B, C, D, if that's the weak link in your chain.  If it's your brain Arnold goes after your brain with molecular mimicry. If it's your kidneys Arnold goes after your kidneys with molecular mimicry. It just depends on what the weak link is in your chain. With wheat it doesn't matter because AA, B, C, D is very common to the structure of the human body. It's a component of... If you think of proteins like it's big, long brick wall, many colors of bricks in there, but there's this pattern. Any time you see that pattern, "Oh look it's there. Oh look it's over too. Oh, it's there too. And that's AA, B, C, D in our bodies. It's very common in our bodies.  So whoever the weak link is in your chain that's where Arnold's going to go. And then you have to make more antibodies to your thyroid until this antibody production to your thyroid becomes self-perpetuating. Now you're on the autoimmune spectrum, killing off your thyroid in this example or your thyroid, killing off cells, until eventually you've killed off so many cells now you're starting to get cold hands and feet, or it's hard to wake up in the morning. Now your thyroid's not working so well for you. You go to a doctor and they take your thyroid hormone. The hormone levels are normal but you're not functioning very well. And they don't check to look for the autoimmunity that's causing all the inflammation in your thyroid and killing off the cells in your thyroid. That's the autoimmune spectrum. Dr. Veronica: Okay. First of all I love your analogies. They're just so beautiful. Thank you. I'm into this story and I'm just like... When you've heard the story before and explained in the medical health and all the lingo with all the stuff behind it it's like, "I've heard about that." But with the Arnold Schwarzenegger behind it with glasses it's like... Dr. Thomas: Yeah, it helps. Dr. Veronica: Thank you so much for that. I would've jumped over because that's a beautiful explanation. Now you're talking about the autoimmune fix and we talked a little bit before we came on about type 1 diabetes which people think, you just got it. There's nothing you can do about it. And also Alzheimer's, you just get old and you just get it. There's nothing you can do. You got the tangles in your brain. You're going to get it.  Talk a bit about can we fix this. Because most people think, "I'm a victim. I just got it. There's nothing I could do about it. I got the pill. I keep going to the doctor and gets adjusted. I feel miserable. This is just my luck in life. My family had it. My mom was like this. Too bad. Oh well." But that's not true. Dr. Thomas: No. That's not true at all. I was just  looking for something. I can't find them quickly so I'll just skip that. No one gets Alzheimer's in their 60's or 70's. It's a decades long process, slowly killing off brain cells. Until you've killed off enough brain cells that the system doesn't work very well anymore just like your thyroid. Dr. Dale Bredesen is at UCLA. He runs the Buck Institute at UCLA. That's the Alzheimer's Research Center. He published a paper in November of 2014 showing complete reversal of Alzheimer's in 9 out of 10 people within 5 years at UCLA. They reversed it within 5 years. How did he do it? There's a 34-point checklist. "They have this. They have this. Do they have this? Do they have this?" Top of the list, wheat sensitivity. Next, dairy sensitivity. Because AA, B, C, D is so very common with the brain when you have a sensitivity to wheat. When I give my lectures to doctors, there's 200 doctors in the room how many know we're suspecting of a sensitivity to wheat? Let me see a show of hands? And I say, "Hold your hands high for a minute please," and they do. I say, "Look around the room," and it's about 80% of the room. Then I'll say, "How many of you know or suspect if you have an inadvertent exposure to wheat it seems to affect your brain? Let me see your hands again? Come on, hold them up." And about 50%-60% of those people raise their hand again. And I said look around the room. This is a talk to doctors, health care practitioners. This is not a celiac group. This is your practice doctors. This is how often it's in your practice. "How many of you are finding it this often?" And maybe there'll be one person that raises her hand. In other words in clinical practice six to seven out of ten people will test positive if you do the right test, looking for a sensitivity to wheat. And of that number the most common system affected for molecular mimicry AA, B, C, D is the brain. Most common for most people it affects the brain. You've got Arnold firing at your brain causing inflammation in the brain, that's pulling on the chain. And eventually one day you say, "I'm getting old. I don't remember the way I used to. Haha..." "Really? How old are you?" "I'm 38." No, that's not supposed to happen. No, that's not normal, you're getting older. No, it's a brain that's on fire. You've got inflammation in your brain. Why? I don't know why. Let's find out.  But you're on the autoimmune spectrum, and that's what this book is about. The Autoimmune Fix just came out two weeks ago. What it's about is to understand this big picture concept. Everybody wants a cure. May I be gentle and say this to your listeners. Wake up. There's no such thing as a cure. There's no magic pill that fixes your diabetes. Wake up. A cure means you don't have the symptoms anymore. You have no markers of the symptoms like blood test or urine test, and you can do whatever you want. Remission means you don't have the symptoms anymore. There is no markers of the symptoms, urine or blood test. And as long as you live the lifestyle that got you feeling better you're going to stay healthy. There's no cure. You want to read about a cure for diabetes? Go to YouTube and type in Type 2 diabetes and raw food diets. And you'll see the videos of African-American post-menopausal women which is a very high-risk group for diabetes, you'll see a video of them. They go on a raw food diet for 30 days and you see the doctors talk about their blood tests, and this is unbelievable, their diabetes is completely gone. Their cholesterol's come down 85 points. I'm taking them off their cholesterol medication. You see the doctors saying this. The most potent thing you can do for your health is what's at the end of your fork. That's it. It's like, wake up people, wake up. And the reason I'm so direct about this is because for the first time in the history of human species, for the very first time the New England Journal of Medicine tells us today that children born today are going to get sick at an earlier age than their parents. They're going to get diagnosed with diseases at an earlier age than their parents, and they're going to die at an earlier age than when their parent's died.  For the first time in the history of the human species. This has never happened before. We're going down. Now, the statistics are very clear, our health care system is one of the worst. The U.S. is ranked second from the bottom in quality of health care at the World Health Organization, yet we spend more for health than anywhere else on the planet. It's in pharma's big interest to keep us dumbed down and not understanding any of this.  That's why I spent a year with Betrayal, The Autoimmune Disease Solution They're Not Telling You. When you guys wake up to this common sense stuff that's in here and that's in Betrayal you're just going to start asking different questions. And when you ask different questions your doctors are being demanded upon to get more answers. Because the things that I write about in this book just make common sense.  Stop throwing gasoline on the fire. Everybody knows that diseases are inflammatory. Alright, stop throwing gasoline on the fire. "How do I do that?" Well, you have to learn. And so it's going to take a while to learn. There's no cure that you take this pill and you're fine. There's no cure. There is remission. And you can have a wonderfully vibrant, dynamic life you can. But we have to learn how to ask the right kind of questions. Dr. Veronica: You mentioned Betrayal, I think so many people feel betrayed by the health care system, betrayed by their doctors, betrayed by the government, society, just betrayed by everything. We talk about Betrayal and we're going to talk about how people can get access to Betrayal and learn. Dr. Thomas: I've traveled the world, literally. For the last few I put 165,000 air miles now in this last year. Lisbon, Barcelona, Leipzig, Germany, three times in London, Dublin, Sao Paolo, all over the world, interviewing world experts, the godfathers and godmothers of autoimmunity. And they know all of this and it's shocking when you hear them talk about it. They've know about this for years these kinds of concepts, but no one's carrying the message out and putting it together. We put it all together. It's a seven-part series online, everything's free. It's about an hour a day for seven days. And you can register for it here with your website, so people can click on it and register and they can watch Betrayal. They're going to hear from the experts.  You're going to hear from Dr. Marta Vives Pi in Barcelona, Spain who is reversing type 1 diabetes with diet and nutrition, regenerating beta cells of the pancreas. So your body starts making insulin again. What we've been told it's impossible. No, it's not. Read her papers. Here's the evidence. It works. It's simple. It's not a drug, and it works.  You're going to read Prof. Yehuda Shoenfeld, the godfather of predictive autoimmunity. His book is there on the shelf, Vaccines and Autoimmunity. It just came out. Dr. Shoenfeld, to get a sense of who this guy is, 28 of the PhD students who got their PhD's under him, many more than that, but 28 of them share departments of immunology in med schools and hospitals around the world. This is the godfather. I interviewed him three times. And you hear him say, "Dr. O'Bryan, I am very much in favor of vaccinations. They have saved millions of lives. However, if the person carries the gene HLA-DRB1, and 30% of the population does, they are very sensitive to having an acute reaction to the adjuvants in vaccine. Thus, it is of wisdom to perhaps be cautious in administering the vaccines. Perhaps a smaller time scale of administration, not seven in one day, not three in one day to these infants that have a weakened, not developed immune system yet. So you give one and you wait two weeks. You give another one.  Sean tells all four vaccinations but he's saying for these patients that are HLA-DRB1 you got to wake up. You can't throw this toxic poison in them because their bodies can't handle it that well. Other bodies may be able to handle it okay. So it's not saying don't vaccinate, he's just saying vaccinate with caution if they have that weak link in their chain. That's the kind of stuff you're going to hear from these experts. It's just such useful information and it saves lives. It's going to save thousands and thousands of lives. I want everyone to watch this. It's all free. Because if you watch it you're going to ask different questions of your doctor. Dr. Veronica: I just got to share because we're just meeting for the first time a little bit before the podcast of how I personally felt betrayed by my medical education. I also felt betrayed in my health care. I realized that I was sensitive to certain things because my sons, one got depressed and one got bipolar, and we figured out that they were sensitive to wheat and soy. One had thyroid symptoms major. Dr. Thomas: AA, B, C, D. Dr. Veronica: The doctor came to me who was my [Unintelligible 00:38:56] Dr. Veronica who's a chiropractic at... "Come here mom. Let me test you." And then what do you know, I'm sensitive. I'm not eating tons of these food so I would get six sometimes and say, "What's going on. I don't even know what happened?" And all of a sudden it answered questions for me. And the other thing that I will say is as an African-American I used to feel, "That's a white people disease." And I realized it's not a white people disease. And probably everybody in my family is suffering from these things and oh my god we better wake up. My mother and my father has diabetes. I'm an eye surgeon by training. My grandmother went blind from diabetes. This is this betrayal that you're talking about needs to get out there into the whole world. So when people go to my Facebook page, to my website, even if it's after the date don't think that you still can have access to it because the world needs to see this. Dr. Thomas O'Bryan I thank you for your work, your book The Autoimmune Fix. For those of you who like to read go get the book. You need it on your shelves so you can pick it up and read it over and over again, because it takes a while to digest this. Dr. Thomas: May I say something about the book? Dr. Veronica: Yes.  Dr. Thomas: Here's the thing on the book. Right now it's on Amazon for 16 bucks. Amazon is selling it at a loss because it's getting more traffic. More people are coming. And then when you're on Amazon you're likely to buy something else, so that's their philosophy. But it's 16 bucks. If I make The New York Times Best Seller list that means I get invitations. I'm now a candidate for Ellen, Oz, Bill Maher, all these shows where I can carry this message out even further. For 16 bucks I promise if you're not happy I'll give you a refund. You just send me a note and I'll give you a refund. I'm very proud of it. It's 30 years of work. But help me carry this message out. Help me if you would by getting the book. There's no profit in this. You make a couple of bucks a book. This is not for that. This is really to carry the message out to wake the world up because our kids are dying younger than their parents, and that's what this is about. So help me and watch Betrayal. Tell your friends about Betrayal. Help us carry the message out there so we can reach a million people with this. Dr. Veronica: Yay, and I'm going to help you reach those million people with the followers of Dr. Veronica and all my posting on social media. Dr. O'Bryan, again, with much gratitude for your work and your time, those 165,000 miles to get Betrayal put together so we all could figure out what we need to do to heal ourselves. Thank you so much. Dr. Thomas: Thank you. Female VO: Thank you for listening to The Wellness Revolution Podcast. If you want to hear more on how to bring wellness into your life visit drveronica.com. See you all next week. Take care. _______________________________ Dr. Veronica Anderson is an MD, Functional Medicine practitioner, Homeopath. and Medical Intuitive. As a national speaker and designer of the Functional Fix and Rejuvenation Journey programs, she helps people who feel like their doctors have failed them. She advocates science-based natural, holistic, and complementary treatments to address the root cause of disease. Dr. Veronica is a highly-sought guest on national television and syndicated radio and hosts her own radio show, Wellness for the REAL World, on FOX Sports 920 AM “the Jersey” on Mondays at 7:00 pm ET.   To get started transforming your health, schedule a consult HERE.  

[intro music]   Host – Dan Keller Hello, and welcome to Episode Thirty-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. Pierre-Antoine Gourraud about the function of human leukocyte antigens and their role in MS. But to begin, here's a brief summary of some of the latest developments on the MS Discovery Forum at msdiscovery.org.   Early in January, the journal Nature Reviews Neurology published a highlights issue of research advances in MS in 2014. The milestones included successful phase 2 trials for simvastatin in progressive MS, new clinical phenotype categories, and more. We summarized each of these advances, supplemented with interviews from some of the authors. Go to the “News and Future Directions” section of our website and click on “Top 8 MS Research Advances of 2014” to read it. And please do make use of our comment section, especially if you believe that we – and Nature Reviews Neurology – failed to list any equally important advances.   Dimethyl fumarate, also known as Tecfidera, may lower CD8-positive T cells in patients with MS, according to a new study out last week. This news follows an earlier story of a patient who died of complications from the rare brain infection, progressive multifocal leukoencephalopathy, or PML, after taking dimethyl fumarate. The drug is known to lower leukocyte levels, including lymphocytes, but many patients are able to maintain normal white cell counts while on the drug. This study showed that even patients with normal leukocyte counts may have dangerously low levels of CD8-positive T cells. These cells are involved in viral immunity, and lower levels of them may leave the gate open for opportunistic infections, such as JC virus, that causes PML.   If you enjoy this podcast and find MSDF helpful, please consider supporting us with a donation. MSDF is run by a small team of three 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. Pierre-Antoine Gourraud is the leader of the translational digital medicine group in the Department of Neurology at the University of California, San Francisco. He’s also a distinguished member of our scientific advisory board. He met with science writer, Cynthia McKelvey, to talk about human leukocyte antigen in MS.     Interviewer – Cynthia McKelvey Let’s begin by defining the major histocompatibility complex and human leukocyte antigen; what those are and how they relate to multiple sclerosis.   Interviewee – Pierre-Antoine Gourraud So the MHC, the major histocompatibility complex is one of the most important region of the genome. It’s 1000 of the genomes, 3.6 megabase, but it represent about 1% of the total number of genes. So a region that is very dense in genes that are very, very important in neurological functions. It’s also one of the most polymorphic region of the genome, which mean that there are many, many version, many diversity, a lot of alleles, as we call these different forms of a given gene for that particular region of the genome. Basically, it’s encode for or identity or genetic identity, and it has been studied a lot for transmutation. So for multiple sclerosis, since 1972 has been recognized that something in that region had to do with multiple sclerosis risks or the susceptibility; why people are getting multiple sclerosis whatever or not. So back in 1972, researchers realized that people carrying an HLA-DR2 type were actually more susceptible to multiple sclerosis. So doing that in a very simple and comparative manner, we took a bunch of people that have MS, a bunch of people that don’t have MS, and you just see that people that have MS tends to have more HLA-DR2. At that time, the HLAs so the genes that bears the immunity identity of [?] – very important for transmutation again – they were typed by serological techniques. So we were using antibodies to distinguish different types. Over the years, serology has been replaced by PCR-based technique, molecular techniques, and we are now doing HLA typing by sequencing. And for 30 years basically this result has been confirmed, and many additional findings we find the initial association between the MHC region and multiple sclerosis.   MSDF So you’re looking at a cohort of African American MS patients and comparing them to people of European descent with MS. And, you're seeing some differences in the major histocompatibility complexes with these. And how do those relate to MS? What are they telling you about the disease?   Dr. Gourraud You know, if we're stepping back a little bit, it's very important to get very large samples to do genetic studies. The more people we are looking at the easier the findings easy to find alleles. So UCSF and other groups in the world have been organizing to coordinate their effort in structuring the International Multiple Sclerosis Genetic Consortium, IMSGC, and we have been really, really successful in gathering large number of MS patients of European ancestry, as well as controls. Within that consortium, UCSF and Dr. Cree and Dr. Oksenberg, have been pushing an effort to coordinate as well African American cohort of MS patients. So we have been working on that, and for the past two to three years we have done a tremendous effort to actually type the HLA of these patients and these controls. And we have gathered more than about 1600 African American MS patients – and we are still collecting them – and roughly 2000 African American controls to do the comparison.   So the first thing we want to do is to see if we are confirming what we see in the European patients – and that is true – we have found  HLA-DRB1 15:01, 15:03 as a specific allele for African American. The HLA-DRB1 03:01 is also to some extent a risk allele in African American. And we also confirm that in the class I HLA-02:01 has a protective effect on MS. So, it's not necessarily obvious, because some of these alleles are actually not found in people of African ancestry, and they also have a much larger diversity. So we are starting to accumulate evidence showing that other alleles that are not present in the Europeans are associated with MS risk. And that’s a very important finding, because now we are in a position where we're going to find structural, functional commonalities between the African American alleles and the European alleles that are both associated to MS.   MSDF And where do you see the research going from here?   Dr. Gourraud So one also very important topic that's being working on both in Europeans and African American is trying not to consider HLA on its own, even if we have really put a lot of samples and money and effort in that, but also consider another very complex family of genes that interact with HLA. These are called KIR (K-I-R), and they are receptor at the cell surface of NK cells, the natural killer cells that have a very important role in immune regulation, and it has been reported that NK cells are actually present in the brain in active MS lesions. So we looked at these two system as potentially interacting to define the risk of MS. So we started typing also for these KIR genes in our African American to be able to study at the same time the MHC or the HLA genes, the KIR genes on a different region of the genome, and also the rest of the genome where we've used a simple marker called SNP.   MSDF That’s great. Thank you very much.   Dr. Gourraud You’re very welcome. Thank you.   [transition music]   Thank you for listening to Episode Thirty-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]

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.

Background: Recent evidence suggests that distinction of subsets of rheumatoid arthritis (RA) depending on anticyclic citrullinated peptide antibody (anti-CCP) status may be helpful in distinguishing distinct aetiopathologies and in predicting the course of disease. HLA-DRB1 shared epitope (SE) and peptidylarginine deiminase type 4 (PADI4) genotype, both of which have been implicated in anti-CCP generation, are assumed to be associated with RA. Objectives: To elucidate whether PADI4 affects the clinical characteristics of RA, and whether it would modulate the effect of anti-CCPs on clinical course. The combined effect of SE and PADI4 on autoantibody profile was also analysed. Methods: 373 patients with RA were studied. SE, padi4_94C.T, rheumatoid factor, anti-CCPs and antinuclear antibodies (ANAs) were determined. Disease severity was characterised by cumulative therapy intensity classified into ordinal categories (CTI-1 to CTI-3) and by Steinbrocker score. Results: CTI was significantly associated with disease duration, erosive disease, disease activity score (DAS) 28 and anti-CCPs. The association of anti-CCPs with CTI was considerably influenced by padi4_94C.T genotype (C/C: ORadj=0.93, padj=0.92; C/T: ORadj=2.92, padj=0.093; T/T: ORadj=15.3, padj=0.002). Carriage of padi4_94T exhibited a significant trend towards higher Steinbrocker scores in univariate and multivariate analyses. An association of padi4_94C.T with ANAs was observed, with noteworthy differences depending on SE status (SE2: ORadj=6.20, padj,0.04; SE+: ORadj=0.36, padj=0.02) and significant heterogeneity between the two SE strata (p=0.006). Conclusions: PADI4 genotype in combination with anti- CCPs and SE modulates clinical and serological characteristics of RA.

Peptidylarginine deiminase type 4 (PADI4) genotypes were shown to influence susceptibility to rheumatoid arthritis ( RA) in the Japanese population. Such an association could not previously be confirmed in different European populations. In the present study, we analysed exons 2 - 4 of PADI4 in 102 German RA patients and 102 healthy individuals to study the influence of PADI4 variability on RA susceptibility by means of haplotype-specific DNA sequencing. Analyses of the influence of PADI4 and HLA-DRB1 genotypes on disease activity and on levels of anti-cyclic citrullinated peptide antibodies were performed. Comparing the frequencies of PADI4 haplotype 4 (padi4_89* G, padi4_90* T, padi4_92* G, padi4_94* T, padi4_104* C, padi4_95* G, padi4_96* T) ( patients, 14.7%; controls, 7.8%; odds ratio = 2.0, 95% confidence interval = 1.1 - 3.8) and carriers of this haplotype ( patients, 27.5%; controls, 13.7%; odds ratio = 2.4, 95% confidence interval = 1.2 - 4.8), a significant positive association of PADI4 haplotype 4 with RA could be demonstrated. Other PADI4 haplotypes did not differ significantly between patients and controls. Regarding the individual PADI4 variants, padi4_89 ( A. G), padi4_90 (C --> T), and padi4_94 (C --> T) were significantly associated with RA ( patients, 49.5%; controls, 38.7%; odds ratio = 1.6, 95% confidence interval = 1.1 - 2.3). Considering novel PADI4 variants located in or near to exons 2, 3, and 4, no quantitative or qualitative differences between RA patients (8.8%) and healthy controls (10.8%) could be demonstrated. While the PADI4 genotype did not influence disease activity and the anticyclic citrullinated peptide antibody level, the presence of the HLA-DRB1 shared epitope was significantly associated with higher anti-cyclic citrullinated peptide antibody levels ( P = 0.033). The results of this small case - control study support the hypothesis that variability of the PADI4 gene may influence susceptibility to RA in the German population. Quantitative or qualitative differences in previously undefined PADI4 variants between patients and controls could not be demonstrated.