Department of Rheumatology and Inflammation Research, Institute of Medicine, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
Centre for Bone and Arthritis Research, The Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden.
Front Immunol. 2019 Jun 18;10:1384. doi: 10.3389/fimmu.2019.01384. eCollection 2019.
The autoimmune regulator AIRE controls the negative selection of self-reactive T-cells as well as the induction of regulatory T-cells in the thymus by mastering the transcription and presentation of tissue restricted antigens (TRAs) in thymic cells. However, extrathymic AIRE expression of hitherto unknown clinical significance has also been reported. Genetic polymorphisms of have been associated with rheumatoid arthritis (RA), but no specific disease-mediating mechanism has been identified. Rheumatoid arthritis is characterized by a systemic immune activation and arthritis. Activated fibroblast-like synoviocytes (FLS) are key effector cells, mediating persistent inflammation, and destruction of joints. In this study, we identified AIRE as a cytokine-induced RA risk gene in RA FLS and explored its role in these pathogenic stroma cells. Using RNA interference and RNA sequencing we show that AIRE does not induce TRAs in FLS, but augments the pro-inflammatory response induced by tumor necrosis factor and interleukin-1β by promoting the transcription of a set of genes associated with systemic autoimmune disease and annotated as interferon-γ regulated genes. In particular, AIRE promoted the production and secretion of a set of chemokines, amongst them CXCL10, which have been associated with disease activity in RA. Finally, we demonstrate that AIRE is expressed in podoplanin positive FLS in the lining layer of synovial tissue from RA patients. These findings support a novel pro-inflammatory role of AIRE at peripheral inflammatory sites and provide a potential pathological mechanism for its association with RA.
自身免疫调节因子 AIRE 控制自身反应性 T 细胞的阴性选择以及调节性 T 细胞在胸腺中的诱导，方法是掌握组织受限抗原 (TRA) 在胸腺细胞中的转录和呈递。然而，也有报道称 AIRE 在胸腺外的表达具有未知的临床意义。 的遗传多态性与类风湿关节炎 (RA) 相关，但尚未确定具体的疾病介导机制。类风湿关节炎的特征是全身免疫激活和关节炎。活化的成纤维样滑膜细胞 (FLS) 是关键的效应细胞，介导持续的炎症和关节破坏。在这项研究中，我们确定 AIRE 是 RA FLS 中细胞因子诱导的 RA 风险基因，并探讨了其在这些致病基质细胞中的作用。使用 RNA 干扰和 RNA 测序，我们表明 AIRE 不会在 FLS 中诱导 TRA，而是通过促进与系统性自身免疫疾病相关并注释为干扰素-γ 调节基因的一组基因的转录来增强肿瘤坏死因子和白细胞介素-1β诱导的促炎反应。特别是，AIRE 促进了一组趋化因子的产生和分泌，其中包括与 RA 疾病活动相关的 CXCL10。最后，我们证明 AIRE 在 RA 患者滑膜组织衬里层的 podoplanin 阳性 FLS 中表达。这些发现支持 AIRE 在周围炎症部位发挥新的促炎作用，并为其与 RA 相关提供了潜在的病理机制。
