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

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

Research output: Contribution to journalArticle

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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
StatePublished - Aug 15 2008

Fingerprint

HLA-DR4 Antigen
Arthritis
Epitopes
T-Lymphocytes
Transgenic Mice
Experimental Arthritis
Collagen Type II
Regulatory T-Lymphocytes
Thymus Gland
Genes
MHC Class II Genes
HLA-DR Antigens
Rheumatoid Arthritis
Cell Death
Joints
Alleles
Amino Acids
Peptides

ASJC Scopus subject areas

  • Immunology
  • Medicine(all)

Cite this

Taneja, V. D., Behrens, M., Basal, E., Sparks, J., Griffiths, M. M., Luthra, H., & David, C. S. (2008). Delineating the role of the HLA-DR4 "shared epitope" in susceptibility versus resistance to develop arthritis. Journal of Immunology, 181(4), 2869-2877.

Delineating the role of the HLA-DR4 "shared epitope" in susceptibility versus resistance to develop arthritis. / Taneja, Veena D; Behrens, Marshall; Basal, Eati; Sparks, Josh; Griffiths, Marie M.; Luthra, Harvinder; David, Chella S.

In: Journal of Immunology, Vol. 181, No. 4, 15.08.2008, p. 2869-2877.

Research output: Contribution to journalArticle

Taneja, VD, Behrens, M, Basal, E, Sparks, J, Griffiths, MM, Luthra, H & David, CS 2008, 'Delineating the role of the HLA-DR4 "shared epitope" in susceptibility versus resistance to develop arthritis', Journal of Immunology, vol. 181, no. 4, pp. 2869-2877.
Taneja VD, Behrens M, Basal E, Sparks J, Griffiths MM, Luthra H et al. Delineating the role of the HLA-DR4 "shared epitope" in susceptibility versus resistance to develop arthritis. Journal of Immunology. 2008 Aug 15;181(4):2869-2877.
Taneja, Veena D ; Behrens, Marshall ; Basal, Eati ; Sparks, Josh ; Griffiths, Marie M. ; Luthra, Harvinder ; David, Chella S. / Delineating the role of the HLA-DR4 "shared epitope" in susceptibility versus resistance to develop arthritis. In: Journal of Immunology. 2008 ; Vol. 181, No. 4. pp. 2869-2877.
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