Abstract
T cells from lupus patients have hypomethylated DNA and overexpress genes normally suppressed by DNA methylation that contribute to disease pathogenesis. We found that stimulatory and inhibitory killer cell Ig-like receptor (KIR) genes are aberrantly overexpressed on experimentally demethylated T cells. We therefore asked if lupus T cells also overexpress KIR, and if the proteins are functional. T cells from lupus patients were found to overexpress KIR genes, and expression was proportional to disease activity. Abs to the stimulatory molecule KIR2DL4 triggered IFN-gamma release by lupus T cells, and production was proportional to disease activity. Similarly, cross-linking the inhibitory molecule KIR3DL1 prevented the autoreactive macrophage killing that characterizes lupus T cells. These results indicate that aberrant T cell KIR expression may contribute to IFN overproduction and macrophage killing in human lupus, and they suggest that Abs to inhibitory KIR may be a treatment for this disease.
Highlights
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We found that stimulatory and inhibitory killer cell Ig-like receptor (KIR) genes are aberrantly overexpressed on experimentally demethylated T cells
KIR genes are expressed on a small subset of CD4ϩ and CD8ϩ T cells in healthy individuals, and on a somewhat larger senescent CD28Ϫ subset found in patients with acute coronary syndromes, chronic inflammatory diseases such as rheumatoid arthritis, and in the elderly (20 –23)
Summary
M, macrophage; KIR, killer cell Ig-like receptor; SLE, systemic lupus erythematosus; SLEDAI, systemic lupus erythematosus disease activity index; MS-PCR, methylation-sensitive PCR; 5-azaC, 5-azacytidine. We recently identified the killer cell Ig-like receptor (KIR) gene family as methylation sensitive in human T cells [11]. Since lupus T cells have hypomethylated DNA and aberrantly overexpress other methylation-sensitive genes, we hypothesized that the KIR genes would be overexpressed in T cells from patients with active lupus. We hypothesized that Abs to inhibitory KIR molecules might inhibit the autoreactive, cytotoxic responses that characterize this subset in lupus patients. We compared KIR expression and function on experimentally demethylated T cells and on T cells from patients with active and inactive systemic lupus erythematosus (SLE)
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