HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Taneja, V. Articles by David, C. S. Search for Related Content PubMed PubMed Citation Articles by Taneja, V. Articles by David, C. S.

Delineating the Role of the HLA-DR4 "Shared Epitope" in Susceptibility versus Resistance to Develop Arthritis¹

Veena Taneja^2,*, Marshall Behrens^*, Eati Basal^*, Josh Sparks, Marie M. Griffiths, Harvinder Luthra and Chella S. David^*

^* Department of Immunology, Mayo Clinic, Rochester, MN 55905; Department of Medicine, University of Utah, Salt Lake City, UT 84148; Department of Rheumatology, Mayo Clinic, Rochester, MN 55905; and Summer Student from Berea College, Berea, KY 40604

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°. 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.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This study was supported by National Institutes of Health Grant AR 30752 and by the Mayo Foundation.

² Address correspondence and reprint request to Dr. Veena Taneja, Department of Immunology, Mayo Clinic, 200 First Street SW, Rochester, MN 55905. E-mail address: taneja.veena{at}mayo.edu

³ Abbreviations used in this paper: RA, rheumatoid arthritis; AICD, activation-induced cell death; CIA, collagen-induced arthritis; CII, type II collagen; LNC, lymph node cell; RF, rheumatoid factor; Tg, transgenic.