Center for Translational Immunology, Benaroya Research Institute at Virginia Mason, Seattle, Washington, USA.
Kennedy Institute of Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, United Kingdom.
JCI Insight. 2021 Mar 8;6(5):145217. doi: 10.1172/jci.insight.145217.
Tenascin-C (TNC), an extracellular matrix protein that has proinflammatory properties, is a recently described antibody target in rheumatoid arthritis (RA). In this study, we utilized a systematic discovery process and identified 5 potentially novel citrullinated TNC (cit-TNC) T cell epitopes. CD4+ T cells specific for these epitopes were elevated in the peripheral blood of subjects with RA and showed signs of activation. Cit-TNC-specific T cells were also present among synovial fluid T cells and secreted IFN-γ. Two of these cit-TNC T cell epitopes were also recognized by antibodies within the serum and synovial fluid of individuals with RA. Detectable serum levels of cit-TNC-reactive antibodies were prevalent among subjects with RA and positively associated with cyclic citrullinated peptide (CCP) reactivity and the HLA shared epitope. Furthermore, cit-TNC-reactive antibodies were correlated with rheumatoid factor and elevated in subjects with a history of smoking. This work confirms cit-TNC as an autoantigen that is targeted by autoreactive CD4+ T cells and autoantibodies in patients with RA. Furthermore, our findings raise the possibility that coinciding epitopes recognized by both CD4+ T cells and B cells have the potential to amplify autoimmunity and promote the development and progression of RA.
Tenascin-C(TNC)是一种细胞外基质蛋白,具有促炎特性,是类风湿关节炎(RA)中最近描述的抗体靶标。在这项研究中,我们利用系统发现过程鉴定了 5 个潜在的新型瓜氨酸化 TNC(cit-TNC)T 细胞表位。RA 患者外周血中这些表位的 CD4+T 细胞升高,并表现出激活迹象。滑膜液 T 细胞中也存在 cit-TNC 特异性 T 细胞,并分泌 IFN-γ。这两个 cit-TNC T 细胞表位也被 RA 个体血清和滑膜液中的抗体识别。RA 患者中存在可检测到的 cit-TNC 反应性抗体,且与环状瓜氨酸肽(CCP)反应性和 HLA 共享表位呈正相关。此外,cit-TNC 反应性抗体与类风湿因子相关,在有吸烟史的患者中升高。这项工作证实 cit-TNC 是一种自身抗原,在 RA 患者中被自身反应性 CD4+T 细胞和自身抗体靶向。此外,我们的研究结果提出了一个可能性,即被 CD4+T 细胞和 B 细胞共同识别的重叠表位有可能放大自身免疫,并促进 RA 的发生和进展。