Abstract
ObjectivesANCA-associated vasculitides (AAV) affect small- and medium-sized blood vessels. In active disease, vessel wall infiltrates are mainly composed of monocytes and macrophages. Immune checkpoint molecules are crucial for the maintenance of self-tolerance and the prevention of autoimmune diseases. After checkpoint inhibitor therapy, the development of autoimmune vasculitis has been observed. However, defects of immune checkpoint molecules in AAV patients have not been identified yet.MethodsMonocytes and monocyte-derived macrophages from AAV patients and healthy age-matched controls were tested for surface expression of immunoinhibitory checkpoint programmed cell death ligand-1 (PD-L1). Using in vitro co-culture approaches, the effect of monocyte PD-L1 expression on CD4+ T cell activation and proliferation was tested.ResultsMonocytes from AAV patients displayed lower PD-L1 expression and a defective PD-L1 presentation upon activation, an effect that was correlated with disease activity. Lower PD-L1 expression was due to increased lysosomal degradation of PD-L1 in AAV monocytes. We identified a reduced expression of CMTM6, a protein protecting PD-L1 from lysosomal breakdown, as the underlying molecular defect. PD-L1low AAV monocytes showed increased stimulatory capacity and induced T cell activation and proliferation. Inhibiting lysosomal function corrected this phenotype by increasing PD-L1, thus normalizing the pro-stimulatory behavior of AAV monocytes.ConclusionsThis study identifies a defect of the immunoinhibitory checkpoint PD-L1 in monocytes from patients with AAV. Low expression of CMTM6 results in enhanced lysosomal degradation of PD-L1, thus providing insufficient negative signaling to T cells. Correcting this defect by targeting lysosomal function may represent a novel strategy to treat AAV.
Highlights
Antineutrophil cytoplasmic antibody (ANCA)–associated vasculitides (AAV) are characterized by necrotizing inflammation of small blood vessels and the presence of ANCA with specificity for proteinase-3 (PR3) or myeloperoxidase (MPO)
Monocytes from patients with PR3- or MPO-ANCA-positive AAV were tested for surface expression of the immune checkpoint molecule Programmed death ligand-1 (PD-L1)
The frequency of PD-L1+ monocytes in AAV patients was reduced compared to cells from healthy control (HC) donors (Figure 1A)
Summary
Antineutrophil cytoplasmic antibody (ANCA)–associated vasculitides (AAV) are characterized by necrotizing inflammation of small blood vessels and the presence of ANCA with specificity for proteinase-3 (PR3) or myeloperoxidase (MPO). Frequent target tissues are the respiratory tract, kidneys, skin, and peripheral nerves. AAV present with an absence or paucity of immunoglobulin and complement deposition in affected vessels. Vascular lesions of AAV consist of neutrophils with admixed monocytes. The initial inflammatory lesion is replaced by inflammation with a predominance of monocytes and macrophages [1]. Monocytes and macrophages are the predominant cells in glomeruli of patients with AAV [2, 3]
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