Major histocompatibility complex class I-recognizing receptors are diseaserisk genes in rheumatoid arthritis

Rheumatoid arthritis JRA) is a heterogeneous syndrome of which a subset of patients develops vascular inflammation. The genetic determinants that conf er risk for rheumatoid vasculitis are not known, but patients with vascular complications are known to have an expansion of CD4(+)CD28(null) T cells, a cell population potentially involved in endothelial damage. CD4(+)CD28(nu ll) T cell clones isolated from RA patients with vasculitis were found to e xpress killer cell immunoglobulin-like receptors (KIRs) with the stimulator y KIR2DS3 often present in the absence of opposing inhibitory receptors wit h related specificities. To test the hypothesis that the KIR2DS2, gene is i nvolved in the development of vasculitis, association studies were performe d. The KIR2DS2 gene was significantly enriched among patients with rheumato id vasculitis compared with normal individuals (odds ratio 5.56, P = 0.001) and patients with KA but no vasculitis (odds ratio 7.96, P = 0.001). Also, the distribution of human histocompatibility leukocyte antigen (HLA)-C, th e putative ligand for KIRs, was significantly different in patients with rh eumatoid vasculitis in comparison with the control populations. These data suggest that HLA class I-recognizing receptors and HLA class I genes are ge netic risk determinants that modulate the pattern of KA expression. Specifi cally, KIR2DS3 in conjunction with the appropriate HLA-C ligand may have a role in vascular damage by regulating CD4(+)CD28(null) T cells.