狼疮性肾炎是系统性红斑狼疮累及肾脏所引起的免疫复合物性肾炎。Tfh细胞直接辅助效应性B细胞，是启动多克隆B细胞过度活化的关键环节。NK细胞，依据其抑制性受体是否识别自身MHC-I类分子，可分为"Licensed" 和"Unlicensed"两个亚群。以狼疮样小鼠作为研究对象，申请人最近发现，狼疮性肾炎的发生与NK细胞亚群失衡密切相关。"Licensed"NK细胞亚群被体内清除后，狼疮样小鼠的血清抗双链DNA抗体和尿蛋白含量显著升高；而"Unlicensed"NK细胞亚群的作用恰恰相反。本课题拟选用诱导性狼疮样小鼠模型，继续证明 "Licensed" 与"Unlicensed"NK细胞亚群在狼疮性肾炎发生中的不同作用，阐明NK细胞扮演双重角色的原因；从固有免疫调节适应性免疫的角度，揭示狼疮性肾炎发生早期，NK细胞亚群失衡对Tfh细胞及B细胞表型及功能的影响，为狼疮性肾炎防治提供新思路。

Lupus nephritis is caused by immune complex deposition in kidneys of patients with systemic lupus erythematosus (SLE). It is well recognized that T-follicular helper (Tfh) cells provide help to effector B cells, which has been shown to be critical in initiating excessive activation of multiclonal B cells. Based on the inhibitory receptors of NK cells recognizing self MHC-I molecules or not, NK cells can be divided into two sub-populations: “licensed” or “unlicensed” NK cell subsets. Recently, we found the imbalance between these NK cell subsets is closely related to the occurrence of lupus nephritis in an induced murine model of lupus. Depletion of “licensed” NK cells in lupus-like mice resulted in significant increase of proteinuria and serum anti-ssDNA Ab, whereas elimination of “unlicensed” NK cells had opposite effect. We are going to continue the investigations on the platform of induced lupus-like murine model to study the different role of “licensed” and “unlicensed” NK cell subsets in the occurrence of lupus nephritis, so as to determine the immune mechanism of the complex dual roles of NK cells in the pathogenesis of lupus nephritis. Given that innate immune response could regulate the adaptive immune response, the effects of NK cells subsets imbalance on phenotype and function of Tfh cells and B cells will be assessed at the early times of lupus nephritis. The data from this project will provide novel means for the prevention and treatment of lupus nephritis.

NK细胞在狼疮性肾炎发病中的作用备受瞩目，但结论并不一致。在狼疮性肾炎发病中, 滤泡辅助性T细胞（ Follicular helper T cell, Tfh细胞）直接辅助效应性B细胞，是启动多克隆B细胞过度活化的关键环节。基于固有免疫对适应性免疫的调节作用，探讨NK细胞在狼疮性肾炎早期发病阶段如何影响Tfh细胞和效应性B细胞，极具临床意义。本课题发现，在降植烷诱导的狼疮样小鼠模型中，持续清除NK细胞组小鼠脾脏Tfh细胞绝对数与B细胞绝对数均显著高于早期清除NK细胞组或造模组。与此相一致，持续清除NK细胞组小鼠血清抗双链 DNA 水平显著高于早期清除NK细胞组或造模组。令人意外的是，在降植烷诱导的致死性狼疮样小鼠模型中，早期清除NK细胞或仅仅清除“Licensed”或“Unlicensed” NK细胞亚群并不能明显改善死亡率，只有持续清除NK细胞既可改善狼疮小鼠临床症状，还能提高生存率。我们发现，在降植烷诱导的狼疮样小鼠模型中，持续清除NK细胞组小鼠的脾脏/腹腔活化巨噬细胞绝对数显著低于早期清除NK细胞组或造模组,并且持续清除NK细胞组小鼠的脾脏调节性T细胞绝对数显著高于早期清除NK细胞组或造模组。这些实验结果提示NK细胞在狼疮性肾炎发病早期具有复杂的双重免疫调节机制，将为狼疮性肾炎防治提供新的思路。