Research ArticleAutoimmunity

PD-1H (VISTA)–mediated suppression of autoimmunity in systemic and cutaneous lupus erythematosus

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Science Translational Medicine  11 Dec 2019:
Vol. 11, Issue 522, eaax1159
DOI: 10.1126/scitranslmed.aax1159

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Supporting a suppressor for lupus treatment

Autoimmunity can result when the intricate checks and balances in the immune system are disrupted. Han et al. discovered a potential treatment target for lupus erythematosus: the inhibitory receptor PD-1H. PD-1H knockout mice on a BALB/c background developed cutaneous lesions and were more susceptible to pristane-induced autoimmunity. Treating lupus-prone MRL/lpr mice with an antibody that activated PD-1H reduced skin symptoms and some markers of autoimmunity. The antibody was shown to act on myeloid cells and T cells and could potentially restore immune balance in patients with lupus.

Abstract

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.

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