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

Article

关键词: MAJOR HISTOCOMPATIBILITY COMPLEX;    CLASS-II MOLECULES;    SMALL-INTESTINAL MUCOSA;    GLIADIN;    SUSCEPTIBILITY;    RECOGNITION;    REPERTOIRE;    PEPTIDES;    MOUSE;    GENE;   

DOI  :  10.1038/nature07524

来源: SCIE

【 摘 要 】

Major histocompatibility complex ( MHC) class II alleles HLA-DQ8 and the mouse homologue I-A(g7) lacking a canonical aspartic acid residue at position beta 57 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 beta 57 polymorphism promotes the recruitment of T- cell receptors bearing a negative signature charge in the complementary determining region 3 beta (CDR3 beta) 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 CDR3 beta. Thus, the lack of a negative charge at position beta 57 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.

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