The role of HLA-DQ8 β57 polymorphism in the anti-gluten T-cell response in coeliac disease
| Autor: | Joseph A. Murray, Martina Wiesner, Kenji Yoshida, Angela Weiss, Zaruhi Hovhannisyan, Shane A. Curran, Bana Jabri, Cezary Ciszewski, Stig Tollefsen, Luc Teyton, Alexandra Martin, Frits Koning, Ludvig M. Sollid, Chella S. David |
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| Rok vydání: | 2008 |
| Předmět: |
CD4-Positive T-Lymphocytes
Cellular immunity Glutens Tissue transglutaminase Static Electricity Receptors Antigen T-Cell Epitopes T-Lymphocyte Mice Transgenic Cross Reactions Biology Major histocompatibility complex Gliadin Article Coeliac disease Epitope Mice Antigen HLA-DQ Antigens medicine Animals Humans Deamidation Genetics chemistry.chemical_classification Hybridomas Polymorphism Genetic Multidisciplinary nutritional and metabolic diseases medicine.disease Amides Complementarity Determining Regions Gluten Celiac Disease Biochemistry chemistry biology.protein |
| Zdroj: | Nature. 456:534-538 |
| ISSN: | 1476-4687 0028-0836 |
| DOI: | 10.1038/nature07524 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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