Details

Autor(en) / Beteiligte

• HOVHANNISYAN, Zaruhi
• WEISS, Angela
• SOLLID, Ludvig M
• KONING, Frits
• TEYTON, Luc
• JABRI, Bana
• MARTIN, Alexandra
• WIESNER, Martina
• TOLLEFSEN, Stig
• YOSHIDA, Kenji
• CISZEWSKI, Cezary
• CURRAN, Shane A
• MURRAY, Joseph A
• DAVID, Chella S

Titel

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

Ist Teil von

• Nature (London), 2008-11, Vol.456 (7221), p.534-538

Ort / Verlag

London: Nature Publishing Group

Erscheinungsjahr

2008

Link zum Volltext

Quelle

PBSC : Psychology and Behavioral Sciences Collection - Journals

Beschreibungen/Notizen

• Major histocompatibility complex (MHC) class II alleles HLA-DQ8 and the mouse homologue I-A g7 lacking a canonical aspartic acid residue at position β57 are associated with coeliac disease 1 , 2 and type I diabetes 3 , 4 . 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 5 , 6 on the basis of their spacing to proline residues 7 . 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 8 and that T-cell responses against native gluten peptides are found 9 , 10 , particularly in children 11 . 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.