Basu Dhiman, Liu Ying, Wu Ailing, Yarlagadda Sushma, Gorelik Gabriela J, Kaplan Mariana J, Hewagama Anura, Hinderer Robert C, Strickland Faith M, Richardson Bruce C
Department of Medicine, University of Michigan, Ann Arbor, MI 48109, USA.
J Immunol. 2009 Sep 1;183(5):3481-7. doi: 10.4049/jimmunol.0900034. Epub 2009 Aug 12.
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.
狼疮患者的T细胞存在DNA低甲基化现象，且通常受DNA甲基化抑制的基因过表达，这些基因参与疾病发病机制。我们发现，在实验性去甲基化的T细胞上，刺激性和抑制性杀伤细胞免疫球蛋白样受体（KIR）基因异常过表达。因此，我们探究狼疮T细胞是否也过表达KIR，以及这些蛋白是否具有功能。研究发现，狼疮患者的T细胞过表达KIR基因，且表达水平与疾病活动度成正比。针对刺激性分子KIR2DL4的抗体可触发狼疮T细胞释放γ干扰素，其产生量与疾病活动度成正比。同样，交联抑制性分子KIR3DL1可阻止狼疮T细胞特有的自身反应性巨噬细胞杀伤作用。这些结果表明，T细胞KIR表达异常可能导致人类狼疮中干扰素过度产生和巨噬细胞杀伤，提示针对抑制性KIR的抗体可能是治疗该疾病的一种方法。
