Identification of proteinase 3 autoreactive CD4+T cells and their T-cell receptor repertoires in antineutrophil cytoplasmic antibody–associated vasculitis

蛋白酶3 免疫学 细胞毒性T细胞 自身抗体 T细胞 抗中性粒细胞胞浆抗体 生物 T细胞受体 抗体 免疫系统 医学 血管炎 病理 疾病 生物化学 体外
作者
Ravi Sharma,Niyaz Yoosuf,M. Gomes Afonso,Andrea Scheffschick,Aune Avik,Alice Bartoletti,Begum Horuluoglu,Juan Sebastian Diaz Boada,Sanjay Kumar Boddul,Asta Dögg Jonasdottir,Björn Lövström,Hanna Brauner,Bruno Raposo,Karine Chemin,Annette Bruchfeld,Iva Gunnarsson,Vivianne Malmström
出处
期刊:Kidney International [Elsevier]
卷期号:103 (5): 973-985
标识
DOI:10.1016/j.kint.2023.01.023
摘要

Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is an autoimmune disease involving autoreactivity to proteinase 3 (PR3) as demonstrated by presence of ANCAs. While autoantibodies are screened for diagnosis, autoreactive T cells and their features are less well-studied. Here, we investigated PR3-specific CD4+T cell responses and features of autoreactive T cells in patients with PR3-AAV, using a cohort of 72 patients with either active or inactive disease. Autoreactive PR3-specific CD4+T cells producing interferon γ in response to protein stimulation were found to express the G-protein coupled receptor 56 (GPR56), a cell surface marker that distinguishes T cells with cytotoxic capacity. GPR56+CD4+T cells were significantly more prominent in the blood of patients with inactive as compared to active disease, suggesting that these cells were affected by immunosuppression and/or that they migrated from the circulation to sites of organ involvement. Indeed, GPR56+CD4+T cells were identified in T-cell infiltrates of affected kidneys and an association with immunosuppressive therapy was found. Moreover, distinct TCR gene segment usage and shared (public) T cell clones were found for the PR3-reactive TCRs. Shared T cell clones were found in different patients with AAV carrying the disease-associated HLA-DP allele, demonstrating convergence of the autoreactive T cell repertoire. Thus, we identified a CD4+T cell signature in blood and in affected kidneys that display PR3 autoreactivity and associates with T cell cytotoxicity. Our data provide a basis for novel rationales for both immune monitoring and future therapeutic intervention in PR3-AAV.
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