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The role of HLA-DQ8 beta 57 polymorphism in the anti-gluten T-cell response in coeliac disease

Academic Article
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Overview

authors

  • Hovhannisyan, Z.
  • Weiss, A.
  • Martin, A.
  • Wiesner, M.
  • Tollefsen, S.
  • Yoshida, K.
  • Ciszewski, C.
  • Curran, S. A.
  • Murray, J. A.
  • David, C. S.
  • Sollid, L. M.
  • Koning, F.
  • Teyton, Luc
  • Jabri, B.

publication date

  • 2008

journal

  • Nature  Journal

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.

subject areas

  • Amides
  • Animals
  • CD4-Positive T-Lymphocytes
  • Celiac Disease
  • Complementarity Determining Regions
  • Cross Reactions
  • Epitopes, T-Lymphocyte
  • Gliadin
  • Glutens
  • HLA-DQ Antigens
  • Humans
  • Hybridomas
  • Mice
  • Mice, Transgenic
  • Polymorphism, Genetic
  • Receptors, Antigen, T-Cell
  • Static Electricity
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Identity

PubMed Central ID

  • PMC3784325

International Standard Serial Number (ISSN)

  • 0028-0836

Digital Object Identifier (DOI)

  • 10.1038/nature07524

PubMed ID

  • 19037317
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Additional Document Info

start page

  • 534

end page

  • 538

volume

  • 456

issue

  • 7221

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