Finding Negatives Wherever

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Science  02 Jan 2009:
Vol. 323, Issue 5910, pp. 16
DOI: 10.1126/science.323.5910.16c

Many autoimmune diseases are associated with specific alleles of the major histocompatibility complex (MHC), but how a particular MHC allele contributes to a particular disease is often not known. The MHC class II allele HLA-DQ8 has been linked to celiac disease, an autoimmune disease driven by T cell responses against dietary gluten, as occurs in wheat, for example. In contrast to other MHC alleles, HLA-DQ8 lacks an aspartic acid residue in its peptide-binding pocket and thus preferentially binds to peptides and T cell receptors (TCRs) that carry a negative charge. In celiac disease, negatively charged gluten-derived peptides are generated by tissue transglutaminase (which converts glutamine to glutamic acid); however, how HLA-DQ8 contributes to disease is not clear because transglutaminase requires inflammation for its activation.

Hovhannisyan et al. demonstrate that antigluten T cell responses can be mediated by HLADQ8 bound to native (nondeamidated) gluten peptides. Recruited T cells contained negatively charged TCRs, which helped to stabilize HLA-DQ8 binding of nondeamidated peptide. Inflammation resulting from this response led to the activation of transglutaminase and to peptide deamidation. The T cells were highly cross-reactive and mounted stronger responses to deamidated gluten peptides due to the enhanced stability of TCR-peptide-HLA-DQ8 interaction. These studies suggest how HLA-DQ8 may drive an amplified T cell response to gluten in celiac disease. — KM

Nature 456, 534 (2008).

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