The role of HLA-DQ8 β57 polymorphism in the anti-gluten T-cell response in coeliac disease

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

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Abstract

Major histocompatibility complex (MHC) class II alleles HLA-DQ8 and the mouse homologue I-Ag7 lacking a canonical aspartic acid residue at position β57 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 β57 polymorphism promotes the recruitment of T-cell receptors bearing a negative signature charge in the complementary determining region 3β (CDR3β) 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 CDR3β. Thus, the lack of a negative charge at position β57 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.

Original languageEnglish (US)
Pages (from-to)534-538
Number of pages5
JournalNature
Volume456
Issue number7221
DOIs
StatePublished - Nov 27 2008

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Glutens
Celiac Disease
T-Lymphocytes
Peptides
T-Cell Antigen Receptor
Major Histocompatibility Complex
T-Lymphocyte Epitopes
HLA-DQ8 antigen
Thomsen-Friedenreich antibodies
Glutamine
Type 1 Diabetes Mellitus
Proline
Aspartic Acid
Disease Progression
Alleles
Inflammation

ASJC Scopus subject areas

  • General

Cite this

Hovhannisyan, Z., Weiss, A., Martin, A., Wiesner, M., Tollefsen, S., Yoshida, K., ... Jabri, B. (2008). The role of HLA-DQ8 β57 polymorphism in the anti-gluten T-cell response in coeliac disease. Nature, 456(7221), 534-538. https://doi.org/10.1038/nature07524

The role of HLA-DQ8 β57 polymorphism in the anti-gluten T-cell response in coeliac disease. / Hovhannisyan, Zaruhi; Weiss, Angela; Martin, Alexandra; Wiesner, Martina; Tollefsen, Stig; Yoshida, Kenji; Ciszewski, Cezary; Curran, Shane A.; Murray, Joseph A; David, Chella S.; Sollid, Ludvig M.; Koning, Frits; Teyton, Luc; Jabri, Bana.

In: Nature, Vol. 456, No. 7221, 27.11.2008, p. 534-538.

Research output: Contribution to journalArticle

Hovhannisyan, Z, Weiss, A, Martin, A, Wiesner, M, Tollefsen, S, Yoshida, K, Ciszewski, C, Curran, SA, Murray, JA, David, CS, Sollid, LM, Koning, F, Teyton, L & Jabri, B 2008, 'The role of HLA-DQ8 β57 polymorphism in the anti-gluten T-cell response in coeliac disease', Nature, vol. 456, no. 7221, pp. 534-538. https://doi.org/10.1038/nature07524
Hovhannisyan Z, Weiss A, Martin A, Wiesner M, Tollefsen S, Yoshida K et al. The role of HLA-DQ8 β57 polymorphism in the anti-gluten T-cell response in coeliac disease. Nature. 2008 Nov 27;456(7221):534-538. https://doi.org/10.1038/nature07524
Hovhannisyan, Zaruhi ; Weiss, Angela ; Martin, Alexandra ; Wiesner, Martina ; Tollefsen, Stig ; Yoshida, Kenji ; Ciszewski, Cezary ; Curran, Shane A. ; Murray, Joseph A ; David, Chella S. ; Sollid, Ludvig M. ; Koning, Frits ; Teyton, Luc ; Jabri, Bana. / The role of HLA-DQ8 β57 polymorphism in the anti-gluten T-cell response in coeliac disease. In: Nature. 2008 ; Vol. 456, No. 7221. pp. 534-538.
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