A Structural and Immunological Basis for the Role of Human Leukocyte Antigen DQ8 in Celiac Disease.
Henderson, Kate N. 1,9; Tye-Din, Jason A. 2,3,9; Reid, Hugh H. 1; Chen, Zhenjun 4; Borg, Natalie A. 1; Beissbarth, Tim 5; Tatham, Arthur 6; Mannering, Stuart I. 2; Purcell, Anthony W. 7; Dudek, Nadine L. 7; van Heel, David A. 8; McCluskey, James 4; Rossjohn, Jamie 1,10,*; Anderson, Robert P. 2,3,10,**
[Article]
Immunity.
27(1):23-34, July 2007.
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: The risk of celiac disease is strongly associated with human leukocyte antigen (HLA) DQ2 and to a lesser extent with HLA DQ8. Although the pathogenesis of HLA-DQ2-mediated celiac disease is established, the underlying basis for HLA-DQ8-mediated celiac disease remains unclear. We showed that T helper 1 (Th1) responses in HLA-DQ8-associated celiac pathology were indeed HLA DQ8 restricted and that multiple, mostly deamidated peptides derived from protease-sensitive sites of gliadin were recognized. This pattern of reactivity contrasted with the more absolute deamidation dependence and relative protease resistance of the dominant gliadin peptide in DQ2-mediated disease. We provided a structural basis for the selection of HLA-DQ8-restricted, deamidated gliadin peptides. The data established that the molecular mechanisms underlying HLA-DQ8-mediated celiac disease differed markedly from the HLA-DQ2-mediated form of the disease. Accordingly, nondietary therapeutic interventions in celiac disease might need to be tailored to the genotype of the individual.
(C) 2007Elsevier, Inc.