Epitopes described in "The role of HLA-DQ8 beta57 polymorphism in the anti-gluten T-cell response in coeliac disease."

Article Authors:Zaruhi Hovhannisyan; Angela Weiss; Alexandra Martin; Martina Wiesner; Stig Tollefsen; Kenji Yoshida; Cezary Ciszewski; Shane A Curran; Joseph A Murray; Chella S David; Ludvig M Sollid; Frits Koning; Luc Teyton; Bana Jabri
Article Title:The role of HLA-DQ8 beta57 polymorphism in the anti-gluten T-cell response in coeliac disease.
Reference Detail
Reference ID:1014000
Abstract:Major histocompatibility complex (MHC) class II alleles HLA-DQ8 and the mouse homologue I-A(g7) lacking a canonical aspartic acid residue at position beta57 are associated with coeliac disease and type I diabetes. However, the role of this single polymorphism in disease initiation and progression remains poorly understood. The lack of Asp 57 creates a positively charged P9 pocket, which confers a preference for negatively charged peptides. Gluten lacks such peptides, but tissue transglutaminase (TG2) introduces negatively charged residues at defined positions into gluten T-cell epitopes by deamidating specific glutamine residues on the basis of their spacing to proline residues. The commonly accepted model, proposing that HLA-DQ8 simply favours binding of negatively charged peptides, does not take into account the fact that TG2 requires inflammation for activation and that T-cell responses against native gluten peptides are found, particularly in children. Here we show that beta57 polymorphism promotes the recruitment of T-cell receptors bearing a negative signature charge in the complementary determining region 3beta (CDR3beta) during the response against native gluten peptides presented by HLA-DQ8 in coeliac disease. These T cells showed a crossreactive and heteroclitic (stronger) response to deamidated gluten peptides. Furthermore, gluten peptide deamidation extended the T-cell-receptor repertoire by relieving the requirement for a charged residue in CDR3beta. Thus, the lack of a negative charge at position beta57 in MHC class II was met by negatively charged residues in the T-cell receptor or in the peptide, the combination of which might explain the role of HLA-DQ8 in amplifying the T-cell response against dietary gluten.
Affiliations:Department of Medicine, Pathology, Pediatrics and Committee of Immunology, University of Chicago, Chicago, Illinois 60637, USA.
Reference Type:Literature
PubMed ID:19037317
Journal Volume:456
Article Pages:534-8
Journal ISSN:1476-4687
Article Chemical List:Amides;Complementarity Determining Regions;Epitopes, T-Lymphocyte;HLA-DQ Antigens;HLA-DQ8 antigen;Receptors, Antigen, T-Cell;Glutens;Gliadin
Article MeSH List:Amides(chemistry); Animals; CD4-Positive T-Lymphocytes(immunology); Celiac Disease(genetics; immunology); Complementarity Determining Regions(chemistry; immunology); Cross Reactions; Epitopes, T-Lymphocyte(chemistry; immunology); Gliadin(chemistry; immunology); Glutens(chemistry; immunology); HLA-DQ Antigens(chemistry; genetics; immunology); Humans; Hybridomas(immunology); Mice; Mice, Transgenic; Polymorphism, Genetic(genetics); Receptors, Antigen, T-Cell(chemistry; immunology); Static Electricity
Curation Last Updated:2015-06-05 01:32:11