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.

中文翻译：

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PD-1H（VISTA）介导的系统性和皮肤性红斑狼疮自身免疫抑制。

皮肤的系统性红斑狼疮（SLE）和盘状红斑狼疮（DLE）是自身免疫性疾病，其特征是针对自身蛋白的免疫反应不适当。决定疾病发病机理和进展的关键因素尚不清楚。在这里，我们表明小鼠在BALB / c背景上缺乏免疫抑制受体VISTA或程序性死亡1同源物（PD-1H KO）自发发展出皮肤和全身性自身免疫性疾病，类似于人的狼疮。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）聚集。使用大规模流式细胞仪，我们确定促炎性中性粒细胞是PD-1H KO小鼠皮肤狼疮病变内的关键早期免疫浸润细胞。我们还发现PD-1H在人SLE，DLE病变中的免疫细胞上高度表达，和MRL / lpr小鼠的皮肤损伤。MRL / lpr小鼠中的PD-1H激动性单克隆抗体可减少皮肤疾病，自身抗体，炎性细胞因子，趋化因子和免疫细胞扩增。此外，T细胞和髓样细胞（包括嗜中性粒细胞和pDC）上的PD-1H均可传递抑制信号，导致活化和功能降低，从而将PD-1H建立为T细胞和髓样细胞上的抑制性受体。基于这些发现，我们认为PD-1H是狼疮的发病机理和进展的关键因素，PD-1H激活可能有效治疗系统性和皮肤性狼疮。T细胞和髓样细胞（包括嗜中性粒细胞和pDC）上的PD-1H均可以传递抑制信号，导致活化和功能降低，从而将PD-1H建立为T细胞和髓样细胞上的抑制性受体。基于这些发现，我们认为PD-1H是狼疮的发病机理和进展的关键因素，PD-1H激活可能有效治疗系统性和皮肤性狼疮。T细胞和髓样细胞（包括嗜中性粒细胞和pDC）上的PD-1H均可以传递抑制信号，导致活化和功能降低，从而将PD-1H建立为T细胞和髓样细胞上的抑制性受体。基于这些发现，我们认为PD-1H是狼疮的发病机理和进展的关键因素，PD-1H激活可能有效治疗系统性和皮肤性狼疮。