PD-1H (VISTA)-mediated suppression of autoimmunity in systemic and cutaneous lupus erythematosus
PD-1H (VISTA)-mediated suppression of autoimmunity in systemic and cutaneous lupus erythematosus
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DOI：
10.1126/scitranslmed.aax1159
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发表时间：
2019-12-11
影响因子：
17.1
通讯作者：
Chen, Lieping
中科院分区：
文献类型：
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作者：
Han, Xue;Vesely, Matthew D.;Chen, Lieping
系统性红斑狼疮（SLE）和盘状红斑狼疮（DLE）的皮肤是自身免疫性疾病，其特征是对自身蛋白的不适当的免疫反应;决定疾病发病机制和进展的关键因素在很大程度上是未知的。在这里，我们表明，小鼠缺乏免疫抑制受体VISTA或程序性死亡-1同源物（PD-1H KO）的BALB/c背景自发发展皮肤和全身性自身免疫性疾病，类似于人类狼疮。PD-1H KO小鼠的皮肤狼疮病变具有类似于人DLE的浆细胞样树突状细胞（pDC）的聚集。使用质谱细胞仪，我们确定了促炎性中性粒细胞作为关键的早期免疫浸润细胞在皮肤狼疮病变的PD-1H KO小鼠。我们还发现PD-1H在人SLE、DLE病变和MRL/lpr小鼠皮肤病变中的免疫细胞上高度表达。MRL/lpr小鼠中的PD-1H激动性单克隆抗体减少皮肤疾病、自身抗体、炎性细胞因子、趋化因子和免疫细胞扩增。此外，T细胞和骨髓细胞（包括中性粒细胞和pDC）上的PD-1H可传递抑制信号，导致活化和功能降低，从而确立PD-1H作为T细胞和骨髓细胞上的抑制性受体。基于这些发现，我们提出PD-1H是狼疮发病机制和进展的关键因素，PD-1H活化可有效治疗系统性和皮肤狼疮。
Systemic lupus erythematosus (SLE) and discoid lupus erythematosus (DLE) of the skin are autoimmune diseases characterized by inappropriate immune responses against self-proteins; the key elements that determine disease pathogenesis and progression are largely unknown. Here, we show that mice lacking immune inhibitory receptor VISTA or programmed death-1 homolog (PD-1H KO) on a BALB/c background spontaneously develop cutaneous and systemic autoimmune diseases resembling human lupus. Cutaneous lupus lesions of PD-1H KO mice have clustering of plasmacytoid dendritic cells (pDCs) similar to human DLE. Using mass cytometry, we identified proinflammatory neutrophils as critical early immune infiltrating cells within cutaneous lupus lesions of PD-1H KO mice. We also found that PD-1H is highly expressed on immune cells in human SLE, DLE lesions, and cutaneous lesions of MRL/lpr mice. A PD-1H agonistic monoclonal antibody in MRL/lpr mice reduces cutaneous disease, autoantibodies, inflammatory cytokines, chemokines, and immune cell expansion. Furthermore, PD-1H on both T cells and myeloid cells including neutrophils and pDCs could transmit inhibitory signals, resulting in reduced activation and function, establishing PD-1H as an inhibitory receptor on T cells and myeloid cells. On the basis of these findings, we propose that PD-1H is a critical element in the pathogenesis and progression of lupus, and PD-1H activation could be effective for treatment of systemic and cutaneous lupus.