Delineating the role of the HLA-DR4 "shared epitope" in susceptibility versus resistance to develop arthritis

Veena Taneja, Marshall Behrens, Eati Basal, Josh Sparks, Marie M. Griffiths, Harvinder Luthra, Chella S. David

Research output: Contribution to journalArticle

47 Scopus citations

Abstract

In humans, HLA-DR alleles sharing amino acids at the third hypervariable region with DRB1*0401(shared epitope) are associated with a predisposition to rheumatoid arthritis, whereas DRB1*0402 is not associated with such a predisposition. Both DRB1*0402 and DRB1*0401 occur in linkage with DQ8 (DQB1*0302). We have previously shown that transgenic (Tg) mice expressing HLA-DRB1*0401 develop collagen-induced arthritis. To delineate the role of "shared epitope" and gene complementation between DR and DQ in arthritis, we generated DRB1*0402, DRB1*0401. DQ8, and DRB1*0402. DQ8 Tg mice lacking endogenous class II molecules, AE o. DRB1*0402 mice are resistant to develop arthritis. In double-Tg mice, the DRB1*0401 gene contributes to the development of collagen-induced arthritis, whereas DRB1*0402 prevents the disease. Humoral response to type II collagen is not defective in resistant mice, although cellular response to type II collagen is lower in *0402 mice compared with *0401 mice. *0402 mice have lower numbers of T cells in thymus compared with *0401 mice, suggesting that the protective effect could be due to deletion of autoreactive T cells. Additionally, DRB1*0402 mice have a higher number of regulatory T cells and show increased activation-induced cell death, which might contribute toward protection. In DRB1*0401. DQ8 mice, activated CD4+ T cells express class II genes and can present DR4- and DQ8-restricted peptides in vitro, suggesting a role of class II+ CD4 T cells locally in the joints. The data suggest that polymorphism in DRB1 genes determines predisposition to develop arthritis by shaping the T cell repertoire in thymus and activating autoreactive or regulatory T cells.

Original languageEnglish (US)
Pages (from-to)2869-2877
Number of pages9
JournalJournal of Immunology
Volume181
Issue number4
DOIs
StatePublished - Aug 15 2008

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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