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Zeisbrich, M; Chevalier, N; Sehnert, B; Rizzi, M; Venhoff, N; Thiel, J; Voll, RE.
CMTM6-Deficient Monocytes in ANCA-Associated Vasculitis Fail to Present the Immune Checkpoint PD-L1.
Front Immunol. 2021; 12:673912 Doi: 10.3389/fimmu.2021.673912 [OPEN ACCESS]
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Co-authors Med Uni Graz: Thiel Jens
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Abstract:: OBJECTIVES: ANCA-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. METHODS: Monocytes 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. RESULTS: Monocytes 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-L1^low 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. CONCLUSIONS: This 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.
Find related publications in this database (using NLM MeSH Indexing): Aged - administration & dosage; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis - immunology; Antigen Presentation - immunology; B7-H1 Antigen - immunology; CD4-Positive T-Lymphocytes - immunology; Female - administration & dosage; Humans - administration & dosage; Lymphocyte Activation - immunology; MARVEL Domain-Containing Proteins - metabolism; Male - administration & dosage; Middle Aged - administration & dosage; Monocytes - immunology, metabolism; Myelin Proteins - metabolism
Find related publications in this database (Keywords): ANCA vasculitis; PD-L1; macrophages; lysosomes; immune checkpoint; vasculitis < rheumatic diseases; monocytes