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    Jefferson Adams
    Celiac.com 02/18/2015 - It's well documented that HLA-DQ molecules play a role in the pathogenesis of celiac disease through the presentation of gluten peptides to CD4(+) T cells. The α- or β-chain sharing HLA molecules DQ2.5, DQ2.2, and DQ7.5 display different risks for the disease.
    Researchers have recently showed that T cells of DQ2.5 and DQ2.2 patients recognize distinct sets of gluten epitopes, which indicates that these two DQ2 variants select different peptides for display.
    To figure out if this is the case, the research team performed a comprehensive comparison of the endogenous self-peptides bound to HLA-DQ molecules of B-lymphoblastoid cell lines. The research team included E. Bergseng, S. Dørum, M. Arntzen, M. Nielsen, S. Nygård, S. Buus, G.A. de Souza, and L.M. Sollid. They are variously affiliated with the Centre for Immune Regulation, Department of Immunology, University of Oslo and Oslo University Hospital-Rikshospitalet, Oslo, Norway.
    The team began by isolating peptides from affinity-purified HLA molecules of nine cell lines. They then subjected the isolated peptides to quadrupole orbitrap mass spectrometry and MaxQuant software analysis. They identified 12,712 endogenous peptides at very different relative abundances. Hierarchical clustering of normalized quantitative data revealed significant differences in repertoires of peptides between the three DQ variant molecules.
    They identified peptide-binding motifs using the neural network-based method, NNAlign. The binding motifs of DQ2.5 and DQ7.5 concurred with previously established binding motifs, but the binding motif of DQ2.2 was remarkably different from that of DQ2.5, with position, P3 being a major anchor having a preference for threonine and serine.
    This is interesting for the reason that three recently identified epitopes of gluten recognized by T cells of DQ2.2 celiac patients harbor serine at position P3.
    This study shows that relative quantitative comparison of endogenous peptides sampled from our protein metabolism by HLA molecules can provide clues to understand HLA association with disease.
    Source:
    Immunogenetics. 2015 Feb;67(2):73-84. doi: 10.1007/s00251-014-0819-9. Epub 2014 Dec 12.

    Jefferson Adams
    Celiac.com 06/03/2015 - Although dietary gluten is the trigger for celiac disease, risk is strongly influenced by genetic variation in the major histocompatibility complex (MHC) region.
    A team of researchers recently set out to fine map the MHC association signal to identify additional celiac disease risk factors independent of the HLA-DQA1 and HLA-DQB1 alleles. The researchers included J. Gutierrez-Achury, A. Zhernakova, S.L. Pulit, G. Trynka, K.A. Hunt, J. Romanos, S. Raychaudhuri, D.A. van Heel, C. Wijmenga, and P.I. de Bakker.
    Their team fine mapped the MHC association signal looking for risk factors other than the HLA-DQA1 and HLA-DQB1 alleles, and the found five new associations that account for 18% of the genetic risk.
    Taking these new loci together with the 57 known non-MHC loci, genetic variation can now explain up to 48% of celiac disease heritability.
    Nailing down exactly what genetic factors influence the heritability of celiac disease will help researchers to better understand the disease, and to develop better treatments and screening options.
    Research team members are variously affiliated with the Department of Genetics, University Medical Center, University of Groningen, Groningen, the Netherlands, the Department of Medical Genetics at the Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, the Netherlands, the Wellcome Trust Sanger Institute, Wellcome Trust Genome Campus, Cambridge, UK, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK, the Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA, the Division of Genetics, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA, the Program in Medical and Population Genetics, Broad Institute, Cambridge, Massachusetts, USA, the Arthritis Research UK Epidemiology Unit, Centre for Musculoskeletal Research, Institute of Inflammation and Repair, University of Manchester, Manchester, UK, the Department of Medical Genetics, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht, the Netherlands, and with the Department of Epidemiology, Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, the Netherlands.
    Source:
    Nat Genet. 2015 Apr 20. doi: 10.1038/ng.3268.

    Jefferson Adams
    Celiac.com 09/16/2015 - Autoimmune disease, such as type 1 diabetes, Crohn's disease, and juvenile idiopathic arthritis, affect about 7 to 10 percent of the population in the Western Hemisphere.
    Using genome-wide association studies (GWASs), researchers have identified hundreds of susceptibility genes, including shared associations across clinically distinct autoimmune diseases.
    A team of researchers recently conducted an inverse χ2 meta-analysis across ten pediatric-age-of-onset autoimmune diseases (pAIDs) in a case-control study including more than 6,035 cases and 10,718 shared population-based controls.
    The research team included Yun R Li, Jin Li, Sihai D Zhao, Jonathan P Bradfield, Frank D Mentch, S Melkorka Maggadottir, Cuiping Hou, Debra J Abrams, Diana Chang, Feng Gao, Yiran Guo, Zhi Wei, John J Connolly, Christopher J Cardinale, Marina Bakay, Joseph T Glessner, Dong Li, Charlly Kao, Kelly A Thomas, Haijun Qiu, Rosetta M Chiavacci, Cecilia E Kim, Fengxiang Wang, James Snyder, and Marylyn D Richie.
    The are variously affiliated with The Center for Applied Genomics, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA; Medical Scientist Training Program, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA; the Department of Biostatistics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.; the Division of Allergy and Immunology, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.; the Department of Biological Statistics and Computational Biology, Cornell University, Ithaca, New York, USA; the Program in Computational Biology and Medicine, Cornell University, Ithaca, New York, USA, and the Department of Computer Science, New Jersey Institute of Technology, Newark, New Jersey, USA.
    For their study, the team identified 27 genome-wide significant loci associated with one or more pAIDs, mapping to in silico–replicated autoimmune-associated genes (including IL2RA) and new candidate loci with established immunoregulatory functions such as ADGRL2, TENM3, ANKRD30A, ADCY7 and CD40LG.
    The team functionally enriched the pAID-associated single-nucleotide polymorphisms (SNPs) for deoxyribonuclease (DNase)-hypersensitivity sites, expression quantitative trait loci (eQTLs), microRNA (miRNA)-binding sites and coding variants.
    They also identified biologically correlated, pAID-associated candidate gene sets on the basis of immune cell expression profiling and found evidence of genetic sharing.
    Network and protein-interaction analyses demonstrated converging roles for the signaling pathways of type 1, 2 and 17 helper T cells (TH1, TH2 and TH17), JAK-STAT, interferon and interleukin in multiple autoimmune diseases.

    Source:
    Nature Medicine 21, 1018–1027 (2015) doi:10.1038/nm.3933

    Jefferson Adams
    Early Gluten Introduction in Susceptible Infants Increases Celiac Risk
    Celiac.com 12/14/2015 - Recently, several studies have set out to determine how intake of gluten during infancy influences later risk of celiac disease.
    One such study, conducted in Sweden, investigated whether gluten intake before 2 years of age increases the risk for celiac disease in genetically susceptible children. The research team included Carin Andrén Aronsson, Hye-Seung Lee, Sibylle Koletzko, Ulla Uusitalo, Jimin Yang, Suvi M. Virtanen, Edwin Liu, Åke Lernmark, Jill M. Norris, and Daniel Agardh.
    They are variously affiliated with the Digestive Health Institute, Children's Hospital Colorado, University of Colorado Denver, Aurora, Colorado, the Department of Epidemiology, Colorado School of Public Campus, University of Colorado Denver in Aurora, Colorado, the Department of Clinical Sciences at Lund University and Skåne University Hospital in Malmö, Sweden, with Dr. von Hauner Children's Hospital, Ludwig Maximilians University in Munich, Germany, the National Institute for Health and Welfare, Nutrition Unit in Helsinki, Finland, the School of Health Sciences, University of Tampere, Finland, the Research Center for Child Health, Tampere University and University Hospital, Science Center of Pirkanmaa Hospital District, University of Tampere, Finland, and with the Health Informatics Institute, Morsani College of Medicine, University of South Florida, Tampa, Florida.
    The research team conducted a case-control study of 436 pairs of children, generated from a Swedish database of 2525 children with genetic susceptibility to celiac disease, matched for sex, birth year, and HLA genotype from September 2004 to February 2010.
    The children were screened each year for celiac disease using an assay for tissue transglutaminase autoantibodies (tTGAs). To confirm celiac disease, the team conducted intestinal biopsy on children who tested positive for tTGA. The team also calculated gluten intake from 3-day food records collected when the children were 9, 12, 18, and 24 months old.
    The results showed that the duration of breastfeeding, lasting 32 weeks, on average, and average age at first introduction to gluten of 22 weeks was basically the same for the target group and the tTGA-negative control group.
    At the visit prior to tTGA seroconversion, the target group reported a larger intake of gluten, 4.9 grams a day, compared to 3.9 grams a day for controls (odds ratio [OR], 1.28; 95% confidence interval [CI], 1.13–1.46; P = .0002).
    More of the target group consumed amounts of gluten in the upper third tertile (ie, >5.0 g/d) before they tested positive for tTGA seroconversion compared to control subehects (OR, 2.65; 95% CI, 1.70–4.13; P < .0001).
    Interestingly, this increased risk was similar for children homozygous for DR3-DQ2 (OR, 3.19; 95% CI, 1.61–6.30; P = .001), heterozygous for DR3-DQ2 (OR, 2.24; 95% CI, 1.08≥4.62; P = .030), and for children not carrying DR3-DQ2 (OR, 2.43; 95% CI, 0.90–6.54; P = .079).
    Intake of gluten before 2 years of age at least doubles the risk of celiac disease in genetically susceptible children. This association was uniform among HLA-DR3-DQ2 haplotypes.
    These findings may be taken into account for future infant feeding recommendations. So, basically, if kids have a genetic susceptibility to celiac disease, regardless of their genetic haplotypes, then parents should wait until after 2 yearss of age to introduce gluten into the child's diet.
    This study, taken together with another recent study that shows that introduction of gluten after six months of age might promote an increased risk of celiac disease, might help provide some guidance for parents looking to introduce gluten to their children's diets.
    The earlier study, the children did not have a genetic predisposition to celiac disease.
    That means that, according to research, the best window for optimal gluten introduction is after two years, especially for children with genetic predisposition, and before six months, regardless of genetic status. 
    SOURCE: Clinical Gastroenterology and Hepatology, October 07, 2015. DOI: http://dx.doi.org/10.1016/j.cgh.2015.09.030

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