RESEARCH - Delineating the role of the HLA-DR4 shared epitope is susceptibility versus resistance to develop arthritis

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J Immunol. 2008 Aug 15;181(4):2869-77.

Delineating the role of the HLA-DR4 " shared epitope " in susceptibility

versus resistance to develop arthritis.

Taneja V, Behrens M, Basal E, Sparks J, Griffiths MM, Luthra H, CS.

Department of Immunology, Mayo Clinic, Rochester, MN 55905, USA.

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.

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Read the full article here:

http://www.jimmunol.org/cgi/content/full/181/4/2869

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