Malcolm J, Nyirenda M H, Brown J L, Adrados-Planell A, Campbell L, Butcher J P, Glass D G, Piela K, Goodyear C S, Wright A J, McInnes I B, Millington O R, Culshaw S
Oral Sciences, University of Glasgow Dental School, School of Medicine, Dentistry and Nursing, College of Medical, Veterinary and Life Sciences, University of Glasgow, UK; Centre for Immunobiology, School of Infection and Immunity, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK.
Centre for Immunobiology, School of Infection and Immunity, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK; Research Into Inflammatory Arthritis Centre Versus Arthritis (RACE), Universities of Glasgow, Birmingham, Newcastle and Oxford, UK.
J Autoimmun. 2023 Feb;135:102994. doi: 10.1016/j.jaut.2023.102994. Epub 2023 Jan 25.
In rheumatoid arthritis, the emergence of anti-citrullinated autoimmunity is associated with HLA-antigen-T cell receptor complexes. The precise mechanisms underpinning this breach of tolerance are not well understood. Porphyromonas gingivalis expresses an enzyme capable of non-endogenous C-terminal citrullination with potential to generate citrullinated autoantigens. Here we document how C-terminal citrullination of ovalbumin peptide alters the interaction between antigen-presenting cells and OTII T cells to induce functional changes in responding T cells. These data reveal that C-terminal citrullination is sufficient to breach T cell peripheral tolerance in vivo and reveal the potential of C-terminal citrullination to lower the threshold for T cell activation. Finally, we demonstrate a role for the IL-2/STAT5/CD25 signalling axis in breach of tolerance. Together, our data identify a tractable mechanism and targetable pathways underpinning breach of tolerance in rheumatoid arthritis and provide new conceptual insight into the origins of anti-citrullinated autoimmunity.
在类风湿性关节炎中，抗瓜氨酸化自身免疫的出现与HLA抗原 - T细胞受体复合物有关。这种耐受性破坏的确切机制尚未完全了解。牙龈卟啉单胞菌表达一种能够进行非内源性C末端瓜氨酸化的酶，具有产生瓜氨酸化自身抗原的潜力。在此，我们记录了卵清蛋白肽的C末端瓜氨酸化如何改变抗原呈递细胞与OTII T细胞之间的相互作用，从而诱导反应性T细胞的功能变化。这些数据表明，C末端瓜氨酸化足以在体内破坏T细胞外周耐受性，并揭示了C末端瓜氨酸化降低T细胞激活阈值的潜力。最后，我们证明了IL - 2/STAT5/CD25信号轴在耐受性破坏中的作用。总之，我们的数据确定了类风湿性关节炎中耐受性破坏的一个可处理的机制和可靶向的途径，并为抗瓜氨酸化自身免疫的起源提供了新的概念性见解。
