Major Histocompatibility Complex Class I-recognizing Receptors Are Disease Risk Genes in Rheumatoid Arthritis

doi:10.1084/jem.193.10.1159

Published online 14 May 2001.

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© The Rockefeller University Press, 0022-1007/2001/5/1159/ $5.00
The Journal of Experimental Medicine, Volume 193, Number 10, May 21, 2001 1159-1168

Original Article

Major Histocompatibility Complex Class I–recognizing Receptors Are Disease Risk Genes in Rheumatoid Arthritis

Jeng-Hsien Yen^a, Brenda E. Moore^a, Takako Nakajima^a, Dirk Scholl^a, Daniel J. Schaid^b, Cornelia M. Weyand^a, and Jörg J. Goronzy^a
^a Department of Medicine and the Department of Immunology, Mayo Clinic, Rochester, Minnesota 55905
^b Department of Health Sciences Research, Mayo Clinic, Rochester, Minnesota 55905

Correspondence to: Jörg J. Goronzy, Mayo Clinic, Guggenheim 401, 200 First St. SW, Rochester, MN 55905. Tel:507-284-1650 Fax:507-284-5045 E-mail:goronzy.jorg{at}mayo.edu.

Rheumatoid arthritis (RA) is a heterogeneous syndrome of whicha subset of patients develops vascular inflammation. The geneticdeterminants that confer risk for rheumatoid vasculitis arenot known, but patients with vascular complications are knownto have an expansion of CD4⁺CD28^null T cells, a cell populationpotentially involved in endothelial damage. CD4⁺CD28^null T cellclones isolated from RA patients with vasculitis were foundto express killer cell immunoglobulin–like receptors (KIRs)with the stimulatory KIR2DS2 often present in the absence ofopposing inhibitory receptors with related specificities. Totest the hypothesis that the KIR2DS2 gene is involved in thedevelopment of vasculitis, association studies were performed.The KIR2DS2 gene was significantly enriched among patients withrheumatoid vasculitis compared with normal individuals (oddsratio 5.56, P = 0.001) and patients with RA but no vasculitis(odds ratio 7.96, P = 0.001). Also, the distribution of humanhistocompatibility leukocyte antigen (HLA)-C, the putative ligandfor KIRs, was significantly different in patients with rheumatoidvasculitis in comparison with the control populations. Thesedata suggest that HLA class I–recognizing receptors andHLA class I genes are genetic risk determinants that modulatethe pattern of RA expression. Specifically, KIR2DS2 in conjunctionwith the appropriate HLA-C ligand may have a role in vasculardamage by regulating CD4⁺CD28^null T cells.

Key Words: killer cell immunoglobulin–like receptor, T cell, geneticsusceptibility, rheumatoid arthritis, vasculitis

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