A structural and immunological basis for the role of human leukocyte antigen DQ8 in celiac disease

Kate Henderson, Jason A Tye-Din, Hugh Harrington Reid, Zhenjun Chen, Natalie Borg, Tim Beissbarth, Arthur Tatham, Stuart I Mannering, Anthony W Purcell, Nadine L Dudek, David A van Heel, James McCluskey, Jamie Rossjohn, Robert P Anderson

Research output: Contribution to journalArticleResearchpeer-review

120 Citations (Scopus)

Abstract

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.
Original languageEnglish
Pages (from-to)23 - 34
Number of pages12
JournalImmunity
Volume27
Issue number1
Publication statusPublished - 2007

Cite this