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Showing results for tags 'molecules'.
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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.
Celiac.com 12/05/2011 - Class II major histocompatibility molecules are one of the main points of susceptibility for a number of autoimmune disorders, including type 1 diabetes. A team of researchers recently set out to investigate structure-based selection of small molecules to alter allele-specific MHC Class II antigen presentation The research team included Aaron W. Michels, David A. Ostrov, Li Zhang, Maki Nakayama, Masanori Fuse, Kristen McDaniel, Bart O. Roep, Peter A. Gottlieb, Mark A. Atkinson, and George S. Eisenbarth. They are variously affiliated with the Barbara Davis Center for Childhood Diabetes at the University of Colorado Denver, the Department of Pathology, Immunology and Laboratory Medicine, University of Florida College of Medicine, in Gainesville, FL, and with the Department of Immunohaematology and Blood Transfusion at Leiden University Medical Center in Leiden, The Netherlands. In the NOD mouse model of spontaneous autoimmune diabetes, Human DQ8 and I-Ag7 imparts diabetes risk by modulating presentation of specific islet peptides in the thymus and surrounding area. To define small molecules that could live in specific structural pockets along the I-Ag7 binding groove, the research team made use of an in-silico molecular docking program to review a vast “drug-like” chemical library. They were hoping to either promote or inhibit presentation to T cells of the autoantigen insulin B chain peptide, which consists of amino acids 9–23. By making use of both murine and human cells, the team's results show that small molecules can in fact influence specific TCR signals in the presence of cognate target peptides, based upon the targeted structural pocket. The effect of a compound on TCR response varied among targeted pockets, with pocket 1 and 6 compounds inhibiting TCR response, and molecules targeted at pocket 9 promoting peptide responses. It takes just nanomolar levels of the inhibitory molecules to block the insulin B chain peptide, which consists of amino acids 9–23, endogenous insulin, and islet-stimulated T cell responses. At concentrations as low as 10 nM, Glyphosine, a pocket 9 compound, enhances insulin peptide presentation to T cells, upregulates IL-10 secretion, and prevents diabetes in NOD mice. These studies offer a new way to identify small molecules that can both stimulate and inhibit T cell responses, thus offering a potential for future therapeutic treatment options. Source: Journal of Immunology doi: 10.4049/â€‹jimmunol.1100746