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News Article | May 24, 2017
Site: www.eurekalert.org

It's one of the most common immune-mediated diseases in the U.S., causing red, patchy and scaly marks on the skin. Yet the 1 to 2 percent of the population who have psoriasis are still left to wonder why. A new study builds on the genetic architecture of psoriasis, the next step toward answering what in the genes causes the disease. University of Michigan researchers, working with partners across the globe, published the work in Nature Communications. It's the most recent publication in long-standing psoriasis work at U-M. "We know there are a lot of genes, each with a relatively small effect, in play. Those genes combined with the environment lead people to develop psoriasis," says senior author James T. Elder, M.D., Ph.D., professor of dermatology at the U-M Medical School. "This study identified 16 more genetic markers, bringing the total to 63 loci linked to psoriasis." Elder's team ran genome-wide tests, comparing frequencies of genetic variants of people with psoriasis to those of control subjects. They examined data from eight different cohorts, with a total effective sample size of more than 39,000. "This is by far the largest psoriasis meta-analysis to date in terms of sample size," says first author Alex Tsoi, Ph.D., a research assistant professor in dermatology, biostatistics and computational medicine and bioinformatics at the U-M Medical School. "We've been able to pinpoint pathways related to the disease as well as pointing to the right directions for the gene targets." Elder's team focused in on the loci they have identified, to learn more about them. Two pathways of note that are very important to the study of psoriasis include the IL-23 and HLA genes, Elder says. Many current therapies target IL-23 as well as IL-17, a cytokine that is produced in response to IL-23. HLA "is by far the biggest genetic signal of psoriasis," Elder says. "We see through the nerve center of the immune system that the structure is more complicated than ever suspected." In fact, that region of genes includes seven different signals of psoriasis. But even the largest psoriasis study so far doesn't turn up the data required to determine every genetic variant at play. "We still haven't found more than half of what's genetic about psoriasis," Elder says. "Some of the differences are so subtle that we'd need to study hundreds of thousands of subjects." The new study focused on subjects of European origin. Thanks to great partnerships across the globe, Elder says, other studies are investigating additional populations with psoriasis, including in India and China. "Researchers are focusing on individual populations for each study, in order to understand the particulars of that population's genetic backgrounds," he says. The work includes data from specialist-diagnosed psoriasis as well as self-reported, via the consumer genetics company 23andMe, one of the study collaborators. Researchers discovered some consumers might assume they have psoriasis without getting a formal diagnosis. "There was some misclassification when the diagnosis was not from a dermatologist, and we estimated close to 4 percent of unaffected individuals thought they had psoriasis but they must have had something else," Tsoi says. Once researchers adjusted for the false positives using a statistical approach, the self-reported cohort helped to not only identify the 16 new loci, but also confirm the others previously found. "Adding that chunk of data really gave us power to see more signals than we had seen in the past," Elder says. Although medications for psoriasis have come a long way over the years, Elder says only about 5 percent of the genes found so far are targeted by existing medications. Another issue in psoriasis treatment is high price tags for drugs, he adds. "Better treatments will come out of understanding these other untouched genes," Elder says. Elder, Tsoi and their colleagues from other institutions including Christian-Albrechts-University of Kiel in Germany, King's College London and the University of Toronto, performed their work using funding from the National Institutes of Health. Disclosure: Co-authors Chao Tian and David A. Hinds are employees of and own stock options in 23andMe, Inc., and co-author Nicholas Eriksson was an employee of 23andMe when the study was conducted.


News Article | May 17, 2017
Site: www.biosciencetechnology.com

A mutation in an immune system gene rapidly rose in frequency in Southeast Asia approximately 50,000 years ago because it likely conferred protection against leprosy, which spread to the region from Africa around the same time. The findings, published May 16th in Cell Reports, show that the gene variant, called HLA-B*46:01, encodes a protein that binds to molecules derived from the bacterium that causes leprosy--a chronic infection of the skin and peripheral nerves. This HLS protein then presents these foreign molecules to the immune system, which destroys the infected cells. "Our study suggests that HLA-B*46:01 may provide protection against severe leprosy because it is better adapted to present pathogen-derived peptide antigens for immunosurveillance by the immune system," said lead author Hugo Hilton of Stanford University School of Medicine. "The findings may explain why HLA-B*46:01 evolved 50,000 years ago and spread to become one of the most prevalent immunity gene variants in Southeast Asia." Population expansion, cultural changes, and migration during the last 100,000 years exposed humans to pathogens against which they had not evolved effective resistance. Due to strong selective pressure, human leukocyte antigen (HLA) genes have evolved to provide immunity against diverse and rapidly evolving pathogens. "New HLA gene variants, or alleles, are thought to arise in human populations during episodes of Darwinian selection, but there is little direct evidence for the nature of this process," said senior study author Peter Parham of Stanford University School of Medicine. One compelling example of such an episode is the HLA-B*46:01 allele, which is now carried by approximately 110 million individuals of Southeast Asian descent. This HLA-B gene variant formed through genetic recombination between its two parent alleles: HLA-B*15:01 and HLA-C*01:02. "HLA-B*46:01 has since become the most common HLA-B allele in Southeast Asia, suggesting that it fills an immunological niche not afforded by either parent or any other HLA variant found in the region," Hilton says. In the new study, Hilton and Parham set out to determine why HLA-B*46:01 rapidly rose in frequency in Southeast Asia over a relatively short period. To do so, the researchers used high-resolution mass spectrometry to compare the peptide sequences presented by the HLA-B*46:01 protein with those presented by its parent alleles. They found that HLA-B*46:01 binds a small, distinct, and less diverse set of peptides compared with its most closely related parent, suggesting that the HLA molecule is specialized to protect against one or a small number of closely related pathogens. Moreover, 21 percent of HLA-B*46:01 peptides strongly bind to a natural killer cell receptor called KIR2DL3, allowing the HLA molecule to trigger an effective immune response. Using an algorithm that predicts binding affinities of HLA molecules to peptides, the researchers found that HLA-B*46:01 is predicted to bind a significantly higher number of peptides derived from Mycobacterium leprae--the pathogen that causes leprosy--compared with its most closely related parent. But surprisingly, HLA-B*46:01 is predicted to bind equal or lower numbers of peptides derived from Salmonella Enteritidis, HIV-1, or H1N1-influenza as compared to its parents. The new findings are consistent with epidemiological studies showing that HLA-B*46:01 carriers are protected against a severe, life-threatening form of leprosy but are more susceptible to other infectious diseases, such as malaria, HIV, and SARS coronavirus. Moreover, this gene variant predisposes individuals to autoimmune disorders such as myasthenia gravis and Grave's disease, in addition to a rare type of head and neck cancer. "Taken together, these observations support the notion that HLA-B*46:01 poses an immunological trade-off between protection against leprosy and protection against other diseases," Hilton said. "This suggests that the selective pressure exerted by leprosy in Southeast Asia must have been a stronger force over the past tens of thousands of years compared with the collective fitness detriment imposed by many other serious diseases in the region."


PHILADELPHIA and OXFORD, United Kingdom, May 25, 2017 (GLOBE NEWSWIRE) -- Adaptimmune Therapeutics plc (Nasdaq:ADAP), a leader in T-cell therapy to treat cancer, today announced that it has initiated its study of NY-ESO SPEAR T‑cells targeting NY-ESO in combination with KEYTRUDA® (pembrolizumab), an anti-PD-1 inhibitor marketed by Merck & Co., Inc., Kenilworth, NJ, USA (known as MSD outside the US and Canada), in patients with multiple myeloma. This study is now open for enrollment. This is Adaptimmune’s third clinical trial to initiate within the past month. The Company recently announced the initiation of clinical studies with its wholly-owned SPEAR T-cells targeting AFP in hepatocellular carcinoma, as well as its wholly-owned SPEAR T-cells targeting MAGE-A4 in seven malignant solid tumors. “We are excited to initiate this study as we have already seen encouraging data in a previous single‑agent study of NY‑ESO SPEAR T-cells in patients with advanced myeloma in the context of stem cell transplantation,” said Rafael Amado, Adaptimmune’s Chief Medical Officer. “KEYTRUDA has also shown preliminary evidence of activity in multiple myeloma in combination, and there is preclinical evidence to support the view that the combination of NY-ESO SPEAR T-cells and anti-PD-1 therapy may lead to meaningful antitumor activity.” This is an open-label, randomized pilot study designed to evaluate the safety and anti-tumor activity of Adaptimmune’s NY-ESO therapeutic candidate alone or in combination with KEYTRUDA in patients who are HLA-A*02 positive and have relapsed and refractory multiple myeloma expressing NY-ESO-1 and/or LAGE‑1a. The study will enroll up to 20 patients. The primary objective of the study is to evaluate the safety and tolerability of NY-ESO SPEAR T-cell therapy alone or in combination with KEYTRUDA. Additional objectives include anti‑tumor activity, persistence of genetically modified cells in the body, and evaluation of the phenotype and functionality of genetically modified cells isolated from peripheral blood or tumor post infusion. Adaptimmune is developing the NY-ESO SPEAR T-cell program under a strategic collaboration agreement with GSK. Clinical Trial Collaboration Agreement for use of KEYTRUDA Adaptimmune has a clinical trial collaboration agreement with Merck & Co., Inc., Kenilworth, NJ, USA for the use of KEYTRUDA in this study. The agreement is between Adaptimmune and Merck & Co., Inc., Kenilworth, NJ, USA, through a subsidiary. Under the agreement, the trial will be sponsored by Adaptimmune. The agreement also includes provision for potential expansion to include Phase III registration studies in the same indication. Additional details were not disclosed. KEYTRUDA is a registered trademark of Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA. Multiple myeloma is a cancer formed by malignancies of plasma cells, which are found in the bone marrow and are an important part of the immune system. It is estimated that approximately 30,280 new cases of multiple myeloma will be diagnosed in the United States in 2017 (17,490 in men and 12,790 in women). Multiple myeloma is characterized by several features, including low blood counts, bone and calcium problems, infections, kidney problems, monoclonal gammopathy, and by the proliferation of malignant plasma cells within bone marrow. The risk of multiple myeloma goes up as people age, and less than one percent of cases are diagnosed in people younger than 35. Most people diagnosed with this cancer are at least 65 years of age. Adaptimmune is a clinical-stage biopharmaceutical company focused on the development of novel cancer immunotherapy products. The Company’s unique SPEAR (Specific Peptide Enhanced Affinity Receptor) T-cell platform enables the engineering of T-cells to target and destroy cancer, including solid tumors. Adaptimmune has a number of proprietary clinical programs, and is also developing its NY-ESO SPEAR T-cell program under a strategic collaboration and licensing agreement with GlaxoSmithKline. The Company is located in Philadelphia, USA and Oxfordshire, U.K. For more information, please visit http://www.adaptimmune.com This release contains “forward-looking statements” within the meaning of the Private Securities Litigation Reform Act of 1995 (PSLRA). These forward-looking statements involve certain risks and uncertainties. Such risks and uncertainties could cause our actual results to differ materially from those indicated by such forward-looking statements, and include, without limitation: the success, cost and timing of our product development activities and clinical trials and our ability to successfully advance our TCR therapeutic candidates through the regulatory and commercialization processes. For a further description of the risks and uncertainties that could cause our actual results to differ materially from those expressed in these forward-looking statements, as well as risks relating to our business in general, we refer you to our Quarterly Report on Form 10-Q filed with the Securities and Exchange Commission (SEC) on May 10, 2017, and our other SEC filings. The forward-looking statements contained in this press release speak only as of the date the statements were made and we do not undertake any obligation to update such forward-looking statements to reflect subsequent events or circumstances.


CAMBRIDGE, Mass. - May 12, 2017 - ImmusanT, Inc., a clinical-stage company developing Nexvax2®, a therapeutic vaccine intended to protect against the effects of gluten exposure while maintaining a gluten-free diet in HLA-DQ2.5+ patients with celiac disease, today announced the publication of positive data from two Phase 1 clinical trials of Nexvax2 in celiac disease. The manuscript, titled "Epitope-specific immunotherapy targeting CD4-positive T cells in coeliac disease: two randomised, double-blind, placebo-controlled phase 1 studies," was published online in The Lancet Gastroenterology and Hepatology. "The results of these two Phase 1 studies suggest that Nexvax2, a therapeutic vaccine evaluated for the management of celiac disease, demonstrates relevant bioactivity and target engagement," said Robert Anderson, MBChB, Ph.D., Chief Scientific Officer of ImmusanT. "Moreover, patients treated with Nexvax2 in these trials experienced a modification in the recall immune response to gluten without apparent duodenal injury. The findings indicate that Nexvax2 reduces the responsiveness of gluten-specific T cells to antigenic stimulation in celiac disease." As reported in the manuscript, the studies met their primary endpoints and established a maximum tolerated dose of Nexvax2. After the first dose, some participants experienced nausea and vomiting, similar to symptoms observed following gluten ingestion in celiac disease. Later doses of Nexvax2 had clinical effects similar to placebo. The acute immune response stimulated by Nexvax2 after the first dose was similar to eating gluten, but was reduced and absent after later doses. There was no apparent difference between placebo and Nexvax2 in duodenal histology following twice-weekly dosing at the maximum tolerated dose for eight-weeks. "Celiac disease has a variety of manifestations in both adults and children ranging from digestive symptoms to fatigue, headaches and fractures due to osteoporosis," said Ramnik Xavier, M.D., Chief of the Gastrointestinal Unit at Massachusetts General Hospital. "The results published today demonstrate encouraging clinical and biologic effects for Nexvax2 consistent with its potential to protect against gluten exposure." Dr. Xavier is also a member of the Center for Computational and Integrative Biology at Massachusetts General Hospital, where his group performed integrative analysis of multidimensional data to confirm that activation of T cells by the vaccine was absent after repeated dosing without inducing any immunogenic effects. "In total, four Phase 1 clinical studies with Nexvax2 have supported the safety, tolerability and relevant bioactivity of Nexvax2 as an antigen-specific immunotherapy in celiac disease. This provides a strong basis for advancing the clinical development of Nexvax2 which is the first therapeutic vaccine designed for patients with celiac disease on a gluten-free diet," said Leslie J. Williams, Chief Executive Officer of ImmusanT. Celiac disease is an immune-mediated gastrointestinal disease caused by dietary gluten. Approximately 90% of celiac disease patients carry the human leukocyte antigen-DQ2.5 (HLA-DQ2.5) immune recognition gene. Currently, there is no pharmaceutical treatment for celiac disease and the only method of management is to maintain a gluten-free diet (GFD), which is onerous and often impractical. Persistent intestinal injury and frequent digestive symptoms in many patients are evidence of ongoing gluten exposure. Nexvax2, an epitope-specific immuno-therapy (ESIT) that consists of three immunodominant peptides, is designed to protect against gluten exposure. The Phase 1 trials were randomized, double-blind, placebo-controlled, multi-center studies evaluating the safety, tolerability, and relevant bioactivity of Nexvax2 in HLA-DQ2.5+ patients with celiac disease. In one study, patients received three fixed doses of Nexvax2 or placebo once per week over a three-week period. In the other study, patients received 16 fixed doses of Nexvax2 or placebo twice per week over an eight-week period. Both studies evaluated a range of fixed, intradermal dose administrations in a series of ascending dose cohorts, which included a crossover, double-blind, placebo-controlled oral gluten challenge in the screening and post-treatment periods. The primary outcome measures were the number and percentage of adverse events in the treatment period. The studies were conducted at sites in Australia, New Zealand, and the United States. Celiac disease is a T cell-mediated autoimmune disease triggered by the ingestion of gluten from wheat, rye and barley in genetically susceptible individuals. A gluten-free diet is the only current management for this disease. The community prevalence of celiac disease is approximately 1% in the U.S., but over 80% of cases go unrecognized. When a person with celiac disease consumes gluten, the individual's immune system responds by triggering T cells to fight the offending proteins, damaging the small intestine and inhibiting the absorption of important nutrients into the body. Undiagnosed, celiac disease is a major contributor to poor educational performance and failure to thrive in children. Untreated disease in adults is associated with osteoporosis and increased risk of fractures, anemia, reduced fertility, problems during pregnancy and birth, short stature, dental enamel hypoplasia, dermatitis, recurrent stomatitis and cancer. With no available drug therapy, the only option is a strict and lifelong elimination of gluten from the diet. Compliance is often challenging, and the majority of people continue to have residual damage to their small intestine in spite of adherence to a gluten-free diet. ImmusanT is a privately held biotechnology company focused on protecting patients with celiac disease against the effects of gluten. By harnessing new discoveries in immunology, ImmusanT aims to improve diagnosis and medical management of celiac disease by protecting against the effects of gluten exposure while patients maintain a gluten-free diet. The company is developing Nexvax2®, a therapeutic vaccine for celiac disease, and diagnostic and monitoring tools to improve celiac disease management. ImmusanT's targeted immunotherapy discovery platform can be applied to a variety of autoimmune diseases. Founded in 2010, ImmusanT is backed by Vatera Healthcare Partners. More information may be found at http://www. , or follow ImmusanT on Twitter.


News Article | May 10, 2017
Site: www.sciencedaily.com

A new study has generated the first comprehensive catalog of diseases associated with variations in human leukocyte antigen (HLA) genes that regulate the body's immune system.


News Article | May 10, 2017
Site: www.eurekalert.org

Revelations about a protein expressed in fetal cells could provide novel insights into its function and future immunosuppressive therapies. Researchers at Hokkaido University together with colleagues in Japan have uncovered the structure of a protein that protects embryos from being attacked by their mothers' immune system. Further understanding of this protein could give rise to immunosuppressive therapies. Trophoblasts are cells found in the outer layer of the developing embryo that form part of the placenta. They express a type of protein called human leukocyte antigens-G (HLA-G) which interacts with receptors on the maternal cells to suppress immune responses to the embryo during pregnancy. The structures of HLA-G1, the major form of HLA-G, are well understood. Interestingly, individuals whose cells lack HLA-G1 could be born and healthy. Researchers believe this is because they can express another form, HLA-G2, which should compensate for the loss of the former's function. But the structure of HLA-G2 has been largely unknown. In a study published in the Journal of Immunology, the team investigated the structure of HLA-G2 by a single particle electron microscopy. Surprisingly, the structure of HLA-G2 was completely different from HLA-G1, but was similar to another class of human leukocyte antigens called HLA class II. This suggests that the HLA-G gene evolved from the same ancestral gene as HLA class II. They also found that HLA-G2 make pairs called homodimers which strengthen the binding to the receptors. HLA-G1 is also known to form homodimers but in a different manner. Furthermore, their biochemical analysis revealed that HLA-G2 bound strongly to a leukocyte immunoglobulin-like receptor B2 (LILRB2), but not to LILRB1. By contrast, HLA-G1 binds strongly to both receptors. Previous research by the Hokkaido University team showed that, in addition to its protective role during pregnancy, the HLA-G2 protein had an anti-inflammatory effect when injected into collagen-induced arthritis mice. "A narrower target specificity of HLA-G2 could be advantageous in developing immunosuppressive drugs with less side-effects. We suggest further investigations to elucidate the structure of the HLA-receptor complex for a more precise understanding of this interaction," says Katumi Maenaka, the corresponding author at Hokkaido University.


CAMBRIDGE, Mass.--(BUSINESS WIRE)--ImmusanT, Inc., a clinical-stage company developing Nexvax2®, a therapeutic vaccine intended to protect against the effects of gluten exposure while maintaining a gluten-free diet in HLA-DQ2.5+ patients with celiac disease, today announced the publication of positive data from two Phase 1 clinical trials of Nexvax2 in celiac disease. The manuscript, titled “Epitope-specific immunotherapy targeting CD4-positive T cells in coeliac disease: two randomised, double-blind, placebo-controlled phase 1 studies,” was published online in The Lancet Gastroenterology and Hepatology. “The results of these two Phase 1 studies suggest that Nexvax2, a therapeutic vaccine evaluated for the management of celiac disease, demonstrates relevant bioactivity and target engagement,” said Robert Anderson, MBChB, Ph.D., Chief Scientific Officer of ImmusanT. “Moreover, patients treated with Nexvax2 in these trials experienced a modification in the recall immune response to gluten without apparent duodenal injury. The findings indicate that Nexvax2 reduces the responsiveness of gluten-specific T cells to antigenic stimulation in celiac disease.” As reported in the manuscript, the studies met their primary endpoints and established a maximum tolerated dose of Nexvax2. After the first dose, some participants experienced nausea and vomiting, similar to symptoms observed following gluten ingestion in celiac disease. Later doses of Nexvax2 had clinical effects similar to placebo. The acute immune response stimulated by Nexvax2 after the first dose was similar to eating gluten, but was reduced and absent after later doses. There was no apparent difference between placebo and Nexvax2 in duodenal histology following twice-weekly dosing at the maximum tolerated dose for eight-weeks. “Celiac disease has a variety of manifestations in both adults and children ranging from digestive symptoms to fatigue, headaches and fractures due to osteoporosis,” said Ramnik Xavier, M.D., Chief of the Gastrointestinal Unit at Massachusetts General Hospital. “The results published today demonstrate encouraging clinical and biologic effects for Nexvax2 consistent with its potential to protect against gluten exposure.” Dr. Xavier is also a member of the Center for Computational and Integrative Biology at Massachusetts General Hospital, where his group performed integrative analysis of multidimensional data to confirm that activation of T cells by the vaccine was absent after repeated dosing without inducing any immunogenic effects. “In total, four Phase 1 clinical studies with Nexvax2 have supported the safety, tolerability and relevant bioactivity of Nexvax2 as an antigen-specific immunotherapy in celiac disease. This provides a strong basis for advancing the clinical development of Nexvax2 which is the first therapeutic vaccine designed for patients with celiac disease on a gluten-free diet,” said Leslie J. Williams, Chief Executive Officer of ImmusanT. Celiac disease is an immune-mediated gastrointestinal disease caused by dietary gluten. Approximately 90% of celiac disease patients carry the human leukocyte antigen-DQ2.5 (HLA-DQ2.5) immune recognition gene. Currently, there is no pharmaceutical treatment for celiac disease and the only method of management is to maintain a gluten-free diet (GFD), which is onerous and often impractical. Persistent intestinal injury and frequent digestive symptoms in many patients are evidence of ongoing gluten exposure. Nexvax2, an epitope-specific immuno-therapy (ESIT) that consists of three immunodominant peptides, is designed to protect against gluten exposure. The Phase 1 trials were randomized, double-blind, placebo-controlled, multi-center studies evaluating the safety, tolerability, and relevant bioactivity of Nexvax2 in HLA-DQ2.5+ patients with celiac disease. In one study, patients received three fixed doses of Nexvax2 or placebo once per week over a three-week period. In the other study, patients received 16 fixed doses of Nexvax2 or placebo twice per week over an eight-week period. Both studies evaluated a range of fixed, intradermal dose administrations in a series of ascending dose cohorts, which included a crossover, double-blind, placebo-controlled oral gluten challenge in the screening and post-treatment periods. The primary outcome measures were the number and percentage of adverse events in the treatment period. The studies were conducted at sites in Australia, New Zealand, and the United States. About Celiac Disease Celiac disease is a T cell-mediated autoimmune disease triggered by the ingestion of gluten from wheat, rye and barley in genetically susceptible individuals. A gluten-free diet is the only current management for this disease. The community prevalence of celiac disease is approximately 1% in the U.S., but over 80% of cases go unrecognized. When a person with celiac disease consumes gluten, the individual’s immune system responds by triggering T cells to fight the offending proteins, damaging the small intestine and inhibiting the absorption of important nutrients into the body. Undiagnosed, celiac disease is a major contributor to poor educational performance and failure to thrive in children. Untreated disease in adults is associated with osteoporosis and increased risk of fractures, anemia, reduced fertility, problems during pregnancy and birth, short stature, dental enamel hypoplasia, dermatitis, recurrent stomatitis and cancer. With no available drug therapy, the only option is a strict and lifelong elimination of gluten from the diet. Compliance is often challenging, and the majority of people continue to have residual damage to their small intestine in spite of adherence to a gluten-free diet. About ImmusanT Inc. ImmusanT is a privately held biotechnology company focused on protecting patients with celiac disease against the effects of gluten. By harnessing new discoveries in immunology, ImmusanT aims to improve diagnosis and medical management of celiac disease by protecting against the effects of gluten exposure while patients maintain a gluten-free diet. The company is developing Nexvax2®, a therapeutic vaccine for celiac disease, and diagnostic and monitoring tools to improve celiac disease management. ImmusanT’s targeted immunotherapy discovery platform can be applied to a variety of autoimmune diseases. Founded in 2010, ImmusanT is backed by Vatera Healthcare Partners. More information may be found at www.ImmusanT.com, or follow ImmusanT on Twitter.


The blood group typing market is projected to reach USD 3.12 billion by 2021 from USD 1.95 billion in 2016, at a CAGR of 9.8%. Growth in the blood group typing market is primarily attributed to the increasing demand for blood and blood products, growing number of road accidents and trauma cases that necessitate blood transfusion, need for blood grouping during prenatal testing, and increasing usage of blood group typing in forensic sciences. Stringent regulatory standards for blood transfusion are also expected to fuel the growth of the blood group typing market during the forecast period. Based on product and service, the market is segmented into consumables, instruments, and services. The consumables segment is further categorized into antisera reagents, anti-human globulin reagents, red blood cells reagents, and blood bank saline. The consumables segment is expected to grow at the highest CAGR during the forecast period. The increase in blood donation rates and major surgical procedures (including organ transplant procedures) are the key factors driving the growth of this segment. Based on test type, the market is segmented into antibody screening, HLA typing, cross-matching tests, ABO blood tests, and antigen typing. The antibody screening segment is expected to grow at the highest CAGR during the forecast period. The growth of this market segment is primarily driven by the increasing prevalence of chronic disorders and growing demand for the early diagnosis of diseases. Key Topics Covered: 1 Introduction 2 Research Methodology 3 Executive Summary 4 Premium Insights 5 Market Overview 6 Blood Group Typing Market, By Product and Service 7 Blood Group Typing Market, By Technique 8 Blood Group Typing Market, By Test Type  9 Blood Group Typing Market, By End User 10 Blood Group Typing Market, By Region 11 Competitive Landscape 12 Company Profiles 13 Appendix For more information about this report visit http://www.researchandmarkets.com/research/8vhgc9/blood_group To view the original version on PR Newswire, visit:http://www.prnewswire.com/news-releases/blood-group-typing-market-to-reach-3-billion-by-2021---rising-need-for-blood-grouping-during-prenatal-testing---research-and-markets-300455371.html


Patients who were included in the study all had Goodpasture disease and fulfilled the following key diagnostic criteria: (1) serum anti-α3(IV)NC1 IgG by enzyme-linked immunosorbent assay (ELISA), (2) linear IgG staining of the GBM and (3) necrotizing and crescentic glomerulonephritis. HLA-DR15 typing of patients was done by monoclonal antibody staining (BIH0596, One Lambda) and flow cytometry. Blood from HLA-typed healthy humans was collected via the Australian Bone Marrow Donor Registry. HLA-DR15, HLA-DR1 and HLA-DR15/DR1 donors were molecularly typed and were excluded if they expressed DQB1*03:02, which is potentially weakly associated with susceptibility to anti-GBM disease2. Studies were approved by the Australian Bone Marrow Donor Registry and Monash Health Research Ethics Committees, and informed consent was obtained from each individual. Mouse MHCII deficient, DR15 transgenic mice and mouse MHCII deficient, DR1 transgenic mice were derived from existing HLA transgenic colonies and intercrossed so that they were on the same background as previously described4. The background was as follows: 50% C57BL/10, 43.8% C57BL/6, 6.2% DBA/2; or with an Fcgr2b−/− background: 72% C57BL/6, 25% C57BL/10 and 3% DBA/2. To generate mice transgenic for both HLA-DR15 and HLA-DR1, mice transgenic for either HLA-DR15 or HLA-DR1 were intercrossed. FcγRIIb intact HLA transgenic mice and cells were used for all experiments, except those in experimental Goodpasture disease, where Fcgr2b−/− HLA transgenic strains were used. While DR15+ mice readily break tolerance to α3(IV)NC1 when immunized with human α3 or mouse α3 , renal disease is mild4. As genetic changes in fragment crystallizable (Fc) receptors have been implicated in the development of nephritis in rodents and in humans18, Fcgr2b−/− HLA transgenic strains were used when end organ injury was an important endpoint. For in vitro experiments, cells from either male or female mice were used. For in vivo experiments both male and female mice were used, for immunization aged 8–12 weeks and for the induction of experimental Goodpasture disease aged 8–10 weeks. Experiments were approved by the Monash University Animal Ethics Committee (MMCB2011/05 and MMCB2013/21). HLA-DR15-α3 and HLA-DR1-α3 were produced in High Five insect cells (Trichoplusia ni BTI-Tn-5B1-4 cells, Invitrogen) using the baculovirus expression system essentially as described previously for HLA-DQ2/DQ8 proteins19, 20. Briefly, synthetic DNA (Integrated DNA Technologies, Iowa, USA) encoding the α- and β-chain extracellular domains of HLA-DR15 (HLA-DR1A*0101, HLA-DRB1*15:01), HLA-DR1 (HLA-DR1A*0101, HLA-DRB1*01:01) and the α3 peptide were cloned into the pZIP3 baculovirus vector19, 20. To promote correct pairing, the carboxy (C) termini of the HLA-DR15 and HLA-DR1 α- and β-chain encoded enterokinase cleavable Fos and Jun leucine zippers, respectively. The β-chains also encoded a C-terminal BirA ligase recognition sequence for biotinylation and a poly-histidine tag for purification. HLA-DR15-α3 and HLA-DR1-α3 were purified from baculovirus-infected High Five insect cell supernatants through successive steps of immobilized metal ion affinity (Ni Sepharose 6 Fast-Flow, GE Healthcare), size exclusion (S200 Superdex 16/600, GE Healthcare) and anion exchange (HiTrap Q HP, GE Healthcare) chromatography. For crystallization, the leucine zipper and associated tags were removed by enterokinase digestion (Genscript, New Jersey, USA) further purified by anion exchange chromatography, buffer exchanged into 10 mM Tris, pH 8.0, 150 mM NaCl and concentrated to 7 mg ml−1. Purified HLA-DR15-α3 and HLA-DR1-α3 proteins were buffer exchanged into 10 mM Tris pH 8.0, biotinylated using BirA ligase and tetramers assembled by addition of Streptavidin-PE (BD Biosciences) as previously described19. In mice, 107 splenocytes or cells from kidneys were digested with 5 mg ml−1 collagenase D (Roche Diagnostics, Indianapolis, Indiana, USA) and 100 mg ml−1 DNase I (Roche Diagnostics) in HBBS (Sigma-Aldrich) for 30 min at 37 °C, then filtered, erythrocytes lysed and the CD45+ leukocyte population isolated by MACS using mouse CD45 microbeads (Miltenyi Biotec); they were then surface stained with Pacific Blue-labelled anti-mouse CD4 (BD), antigen-presenting cell (APC)-Cy7-labelled anti-mouse CD8 (BioLegend) and 10 nM PE-labelled tetramer. Cells were then incubated with a Live/Dead fixable Near IR Dead Cell Stain (Thermo Scientific), permeabilized using a Foxp3 Fix/Perm Buffer Set (BioLegend) and stained with Alexa Fluor 647-labelled anti-mouse Foxp3 antibody (FJK16 s). To determine Vα2 and Vβ6 usage, cells were stained with PerCP/Cy5.5 anti-mouse Vα2 (B20.1, Biolegend) and antigen-presenting cell labelled anti-mouse Vβ6 (RR4-7, Biolegend). For each mouse a minimum of 100 cells were analysed. The tetramer+ gate was set on the basis of the CD8+ population. In humans, 3 × 107 white blood cells were surface stained with BV510-labelled anti-human CD3 (BioLegend), Pacific Blue-labelled anti-human CD4 (BioLegend), PE-Cy7-labelled anti-human CD127 (BioLegend), FITC-labelled anti-human CD25 (BioLegend) and 10 nM PE-labelled tetramer. Then, cells were incubated with a Live/Dead fixable Near IR Dead Cell Stain (Life Technologies), permeabilized using a Foxp3 Fix/Perm Buffer Set (BioLegend) and stained with Alexa Fluor 647-labelled anti-human Foxp3 antibody (150D). The tetramer+ gate was set on the basis of the CD3+CD4− population. As validation controls, we found that HLA-DR1-α3 tetramer+ cells did not bind to HLA-DR1-CLIP tetramers (data not shown). The human α3 peptide (GWISLWKGFSF), the mouse α3 peptide (DWVSLWKGFSF) and control OVA peptide (ISQAVHAAHAEINEAGR) were synthesized at >95% purity, confirmed by high-performance liquid chromatography (Mimotopes). Recombinant murine α3(IV)NC1 was generated using a baculovirus system21 and recombinant human α3(IV)NC1 expressed in HEK 293 cells22. The murine α3(IV)NC1 peptide library, which consists of 28 20-amino-acid long peptides overlapping by 12 amino acids, was synthesized as a PepSet (Mimotopes). To measure peptide specific recall responses, IFN-γ and IL-17A ELISPOTs and [3H]thymidine proliferation assays were used (Mabtech for human ELISPOTs and BD Biosciences for mouse ELISPOTs). To measure pro-inflammatory responses of HLA-DR15-α3 tetramer+ CD4+ T cells in patients with Goodpasture disease, HLA-DR15-α3 tetramer+ CD4+ T cells were enumerated then isolated from peripheral blood mononuclear cells of patients with Goodpasture disease (frozen at the time of presentation) by magnetic bead separation (Miltenyi Biotec) then co-cultured at a frequency of 400 HLA-DR15-α3 tetramer+ CD4+ T cells per well with 2 × 106 HLA-DR15-α3 tetramer-depleted mitomycin C-treated white blood cells and stimulated with either no antigens, α3 (10 μg ml−1) or whole recombinant human α3(IV)NC1 (10 μg ml−1) in supplemented RPMI media (10% male AB serum, 2 mM l-glutamine, 50 μM 2-ME, 100 U ml−1 penicillin and 0.1 mg ml−1 streptomycin) (Sigma-Aldrich). Cells were cultured for 18 h at 37 °C, 5% CO and the data expressed as numbers of IFN-γ or IL-17A spots per well. To measure pro-inflammatory responses of HLA-DR15-α3 tetramer+ CD4+ T cells in DR15+ transgenic mice, HLA-DR15-α3 tetramer+ CD4+ T cells were enumerated then isolated from pooled spleen and lymph node cells of DR15+ transgenic mice, immunized with mouse α3 10 days previously by magnetic bead separation. They were then co-cultured at a frequency of 400 HLA-DR15-α3 tetramer+ CD4+ T cells per well with 106 HLA-DR15-α3 tetramer-depleted mitomycin C-treated white blood cells and stimulated with either no antigens, mouse α3 (10 μg ml−1), human α3 (10 μg ml−1), whole recombinant mα3(IV)NC1 (10 μg ml−1) or whole recombinant hα3(IV)NC1 (10 μg ml−1) in supplemented RPMI media (10% FCS, 2 mM l-glutamine, 50 μM 2-ME, 100 U ml−1 penicillin and 0.1 mg ml−1 streptomycin). Cells were cultured for 18 h at 37 °C, 5% CO and the data expressed as numbers of IFN-γ or IL-17A spots per well. To determine the immunogenic portions of α3(IV)NC1, mice were immunized subcutaneously with peptide pools (containing α3 amino acids 1–92, 81–164, or 153–233; 10 μg per peptide per mouse), the individual peptide or in some experiments mα3 at 10 μg per mouse in Freund’s complete adjuvant (Sigma-Aldrich). Draining lymph node cells were harvested 10 days after immunization and stimulated in vitro (5 × 105 cells per well) with no antigen, peptide (10 μg ml−1) or whole α3(IV)NC1 (10 μg ml−1) in supplemented RPMI media (10% FCS, 2 mM l-glutamine, 50 μM 2-ME, 100 U ml−1 penicillin and 0.1 mg ml streptomycin). For [3H]thymidine proliferation assays, cells were cultured in triplicate for 72 h with [3H]thymidine added to culture for the last 16 h. To measure human α3 - or mouse α3 -specific responses in CD4+ T cells from naive transgenic mice or blood of healthy humans, we used a modification of a previously published protocol23. One million CD4+ T cells were cultured with 106 mitomycin-treated CD4-depleted splenocytes for 8 days in 96-well plates with or without 100 μg ml−1 of human α3 or mouse α3 . T cells were depleted from mouse cultures by sorting out CD4+CD25+ and in humans by sorting out CD4+CD25hiCD127lo cells using antibodies and a cell sorter. Cytokine secretion was detected in the cultured supernatants by cytometric bead array (BD Biosciences) or ELISA (R&D Systems). To determine proliferation, magnetically separated CD4+ T cells were labelled with CellTrace Violet (CTV; Thermo Scientific) before culture. To measure the expansion of T cells, mice were immunized with 100 μg of α3 emulsified in Freund’s complete adjuvant, then boosted 7 days later in Freund’s incomplete adjuvant. Draining lymph node cells were stained with the HLA-DR15-α3 tetramer, CD3, CD4, CXCR5, PD-1, CD8 and Live/Dead Viability dye. To determine the potency of HLA-DR1-α3 tetramer+ T cells, 106 cells per well of CD4+CD25− T effectors isolated by CD4+ magnetic beads and CD25− cell sorting from naive DR15+DR1+ mice were co-cultured with CD4+CD25+ T cells with or without depletion of HLA-DR1-α3 tetramer+ T cells from DR1+ mice at different concentrations: 0, 12.5 × 103, 25 × 103, 50 × 103 and 100 × 103 cells per well in the presence of 106 CD4-depleted mitomycin C-treated spleen and lymph node cells from DR15+DR1+mice in supplemented RPMI media (10% FCS, 2 mM l-glutamine, 50 μM 2-ME, 100 U ml−1 penicillin and 0.1 mg ml−1 streptomycin) containing 100 μg ml−1 of mouse α3 . To determine proliferation, the CD4+CD25− T effector cells were labelled with CTV before culture. Cells were cultured in triplicate for 8 days in 96-well plates. HLA transgenic mice, on an Fcgr2b−/− background, were immunized with 100 μg of α3 or mα3 subcutaneously on days 0, 7 and 14, first in Freund’s complete, and then in Freund’s incomplete, adjuvant. Mice were killed on day 42. Albuminuria was assessed in urine collected during the last 24 h by ELISA (Bethyl Laboratories) and expressed as milligrams per micromole of urine creatinine. Blood urea nitrogen and urine creatinine were measured using an autoanalyser at Monash Health. Glomerular necrosis and crescent formation were assessed on periodic acid-Schiff (PAS)-stained sections; fibrin deposition using anti-murine fibrinogen antibody (R-4025) and DAB (Sigma); CD4+ T cells, macrophages and neutrophils were detected using anti-CD4 (GK1.5), anti-CD68 (FA/11) and anti-Gr-1 (RB6-8C5) antibodies. The investigators were not blinded to allocation during experiments and outcome assessment, except in histological and immunohistochemical assessment of kidney sections. To deplete regulatory T cells, mice were injected intraperitoneally with 1 mg of an anti-CD25 monoclonal antibody (clone PC61) or rat IgG (control) 2 days before induction of disease. In these experiments, mice were randomly assigned to receive control or anti-CD25 antibodies. Individual DR15-α3 -specific CD4+ T cells were sorted into wells of a 96-well plate. Multiplex single-cell reverse transcription and PCR amplification of TCR CDR3α and CDR3β regions were performed using a panel of TRBV- and TRAV-specific oligonucleotides, as described24, 25. Briefly, mRNA was reverse transcribed in 2.5 μl using a Superscript III VILO cDNA Synthesis Kit (Thermo Fisher Scientific, Waltham, Massachusetts, USA) (containing 1× Vilo reaction mix, 1× superscript RT, 0.1% Triton X-100), and incubated at 25 °C for 10 min, 42 °C for 120 min and 85 °C for 5 min. The entire volume was then used in a 25 μl first-round PCR reaction with 1.5 U Taq DNA polymerase, 1× PCR buffer, 1.5 mM MgCl , 0.25 mM dNTPs and a mix of 25 mouse TRAV or 40 human TRAV external sense primers and a TRAC external antisense primer, along with 19 mouse TRBV or 28 human TRBV external sense primers and a TRBC external antisense primer (each at 5 pmol μl−1), using standard PCR conditions. For the second-round nested PCR, a 2.5 μl aliquot of the first-round PCR product was used in separate TRBV- and TRAV-specific PCRs, using the same reaction mix described above; however, a set of 25 mouse TRAV or 40 human TRAV internal sense primers and a TRAC internal antisense primer, or a set of 19 mouse TRBV or 28 human TRBV internal sense primers and a TRBV internal antisense primer, were used. Second-round PCR products were visualized on a gel and positive reactions were purified with ExoSAP-IT reagent. Purified products were used as template in sequencing reactions with internal TRAC or TRBC antisense primers, as described. TCR gene segments were assigned using the IMGT (International ImMunoGeneTics) database26. In mouse experiments, three mice were pooled per HLA and the number of sequences obtained were as follows. For TRAV: DR15, n = 81; DR1 n = 84; for TRBV: DR15, n = 100; DR1 n = 87; for TRAJ: DR15, n = 81; DR1 n = 84; and for TCR beta joining (TRBJ): DR15, n = 100; DR1 n = 87. Red-blood-cell-lysed splenocytes from DR1+ and DRB15+DR1+ mice were sorted on the basis of surface expression of CD4 and CD25 and being either DR1-α3 tetramer positive or negative into three groups: (1) CD4+CD25−HLA-DR1-α3 tetramer− T cells; (2) CD4+CD25+HLA-DR1-α3 tetramer− T cells; and (3) CD4+CD25+HLA-DR1-α3 tetramer+ T cells. A minimum of 1,000 cells were sorted. Immediately after sorting, the RNA was isolated and complementary DNA (cDNA) generated using a Cells to Ct Kit (Ambion) followed by a preamplification reaction using Taqman Pre Amp Master Mix (Applied Biosystems), which preamplified the following cDNAs: Il2ra, Foxp3, Ctla4, Tnfrsf18, Il7r, Sell, Pdcd1, Entpd1, Cd44, Tgfb3, Itgae, Ccr6, Lag3, Lgals1, Ikzf2, Tnfrsf25, Nrp1, Il10. The preamplified cDNA was used for RT–PCR reactions in duplicate using Taqman probes for the aforementioned genes. Each gene was expressed relative to 18S, logarithmically transformed and presented as a heat map. The Epstein-Barr-virus-transformed human B lymphoblastoid cell lines IHW09013 (SCHU, DR15-DR51-DQ6) and IHW09004 (JESTHOM, DR1-DQ5) were maintained in RPMI (Invitrogen) supplemented with 10% FCS, 50 IU ml−1 penicillin and 50 μg ml−1 streptomycin. Confirmatory tissue typing of these cells was performed by the Victorian Transplantation and Immunogenetics Service. The B-cell hybridoma LB3.1 (anti-DR) was grown in RPMI-1640 with 5% FCS at 37 °C and secreted antibody purified using protein A sepharose (BioRad). HLA-DR-presented peptides were isolated from naive DR15+Fcgr2b+/+ or DR1+Fcgr2b+/+ mice. Spleens and lymph nodes (pooled from five mice in each group) or frozen pellets of human B lymphoblastoid cell lines (triplicate samples of 109 cells) were cryogenically milled and solubilized as previously described12, 27, cleared by ultracentrifugation and MHC peptide complexes purified using LB3.1 coupled to protein A (GE Healthcare). Bound HLA complexes were eluted from each column by acidification with 10% acetic acid. The eluted mixture of peptides and HLA heavy chains was fractionated by reversed-phase high-performance liquid chromatography as previously described10. Peptide-containing fractions were analysed by nano-liquid chromatography–tandem mass spectrometry (nano-LC–MS/MS) using a ThermoFisher Q-Exactive Plus mass spectrometer (ThermoFisher Scientific, Bremen, Germany) operated as described previously10. LC–MS/MS data were searched against mouse or human proteomes (Uniprot/Swissprot v2016_11) using ProteinPilot software (SCIEX) and resulting peptide identities subjected to strict bioinformatic criteria including the use of a decoy database to calculate the false discovery rate28. A 5% false discovery rate cut-off was applied, and the filtered data set was further analysed manually to exclude redundant peptides and known contaminants as previously described29. The mass spectrometry data have been deposited in the ProteomeXchange Consortium via the PRIDE30 partner repository with the data set identifier PXD005935. Minimal core sequences found within nested sets of peptides with either N- or C-terminal extensions were extracted and aligned using MEME (http://meme.nbcr.net/meme/), where motif width was set to 9–15 and motif distribution to ‘one per sequence’31. Graphical representation of the motif was generated using IceLogo32. Crystal trials were set up at 20 °C using the hanging drop vapour diffusion method. Crystals of HLA-DR15-α3 were grown in 25% PEG 3350, 0.2 M KNO and 0.1 M Bis-Tris-propane (pH 7.5), and crystals of HLA-DR1-α3 were grown in 23% PEG 3350, 0.1 M KNO , and 0.1 M Bis-Tris-propane (pH 7.0). Crystals were washed with mother liquor supplemented with 20% ethylene glycol and flash frozen in liquid nitrogen before data collection. Data were collected using the MX1 (ref. 33) and MX2 beamlines at the Australian Synchrotron, and processed with iMosflm and Scala from the CCP4 program suite34. The structures were solved by molecular replacement in PHASER35 and refined by iterative rounds of model building using COOT36 and restrained refinement using Phenix37 (see Extended Data Table 2 for data collection and refinement statistics). No statistical methods were used to predetermine sample size. For normally distributed data, an unpaired two-tailed t-test (when comparing two groups). For non-normally distributed data, non-parametric tests (Mann–Whitney U-test for two groups or a Kruskal–Wallis test with Dunn’s multiple comparison) were used. Statistical analyses, except for TCR usage, was by GraphPad Prism (GraphPad Software). For each TCR type/region (TRAV, TRBV, TRAJ, TRBJ), we compared the TCR distribution (frequencies of different TCRs) between DR15 and DR1 using Fisher’s exact test. This was applied both to mice and to human samples. The P values associated with those TCR distributions are indicated above the pie-charts. To correct for multiple testing for individual TCRs, we used Holm’s method. *P < 0.05, **P < 0.01, ***P < 0.001. The data that support the findings of this study are available from the corresponding authors upon request. Self-peptide repertoires have been deposited in the Proteomics Identifications Database archive with the accession code PXD005935. Structural information has been deposited in the Protein Data Bank under accession numbers 5V4M and 5V4N.


News Article | May 10, 2017
Site: www.eurekalert.org

A study led by researchers at Vanderbilt University Medical Center (VUMC) and the University of Arizona College of Pharmacy has generated the first comprehensive catalog of diseases associated with variations in human leukocyte antigen (HLA) genes that regulate the body's immune system. The catalog could help identify individuals who are at risk for certain autoimmune diseases, or who may generate antibodies that attack their own tissues in response to an infection. The report, published in this week's issue of the journal Science Translational Medicine, supports the power of electronic health records (EHRs) to advance understanding, treatment and ultimately prevention of disease, said senior author Joshua Denny, M.D., M.S., professor of Biomedical Informatics and Medicine at Vanderbilt. The report confirmed a slew of previously described associations and identified some potential new associations. "In one fell swoop we essentially replicated decades of research on autoimmune associations with the HLA," said Jason Karnes, Ph.D., Pharm.D., co-first author of the paper with Lisa Bastarache, M.S. The researchers published the catalog online at http://www. . "To my knowledge no other investigations have made this level of data available" to the wider research community, Karnes said. Karnes is an assistant professor in the University of Arizona College of Pharmacy in Tucson. He contributed to the study as a former postdoctoral fellow in Clinical Pharmacology at Vanderbilt. Bastarache is lead data scientist in the Vanderbilt Center for Precision Medicine, which Denny directs. HLAs (human leukocyte antigens) are proteins expressed on the surfaces of cells that -- like nametags -- enable the immune system to distinguish "self" tissues of the body from "non-self," such as invading pathogens. Individual variations in HLA genes also have been linked to adverse drug reactions, rejection of transplanted organs and autoimmune diseases including type 1 diabetes and rheumatoid arthritis, in which the immune system mistakes normal tissue for a foreign invader and attacks it. Previous studies have identified associations between the HLA system and individual "phenotypes," including autoimmune and other diseases, symptoms and other characteristics. The current investigation -- called a "phenome-wide association study" or PheWAS -- scanned patients' entire "phenome" of all health characteristics as noted in the EHR. Prior studies have typically studied only one or a handful of diseases at a time. By studying many diseases at once this study was able to show that many HLA types affect multiple diseases but in different ways. For example, some HLA types place a person at risk for both type1 diabetes and rheumatoid arthritis, while others place one at risk for type 1 diabetes but protected against rheumatoid arthritis. The study was made possible by DNA databases maintained at VUMC and the Marshfield Clinic Personalized Medicine Research Project in Marshfield, Wisconsin. To date, more than 230,000 samples from different individuals have been stored in BioVU, Vanderbilt's massive DNA database. Genetic samples are linked to the corresponding EHRs in which identifying information has been deleted to protect patient privacy. From the genetic code, the researchers inferred which HLAs would be expected to be expressed in nearly 29,000 individuals whose DNA samples were stored in BioVU and another 8,400 samples provided by Scott Hebbring, Ph.D., and colleagues from the Marshfield Clinic. The EHRs from these individuals were screened for the presence of nearly 1,400 different phenotypes that could be linked to the HLA genes. Type 1 diabetes was the strongest previously described HLA association confirmed by the study but the researchers also found evidence for several new potential associations with multiple sclerosis and cervical cancer. The latter is known to be driven by a viral infection. It's thought that people with certain HLA variants may -- in response to an infection, for example -- generate antibodies that attack their own tissues, Denny said. This suggests that certain auto-immune diseases could be prevented in high-risk people by identifying and treating their co-infections first, he said. Denny directs the Data and Research Center of the federal All of Us Research Program, formerly the Precision Medicine Initiative Cohort Program, which is recruiting a million or more Americans for a landmark study of genetic, environmental and lifestyle factors that affect their health. "Just imagine what we'll be able to do with a million people," he said. "That will produce truly comprehensive catalogs of all these kinds of associations across HLA and everything else. The detail with which we'll be able to resolve these questions will be staggering." Other Vanderbilt faculty members who contributed to the current study were Elizabeth Phillips, M.D., Dan Roden, M.D., and Simon Mallal, MBBS.

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