Clanchy Felix I L, Borghese Federica, Bystrom Jonas, Balog Attila, Penn Henry, Hull Dobrina N, Wells Graham M A, Kiriakidis Serafim, Taylor Peter C, Sacre Sandra M, Williams Lynn M, Stone Trevor W, Mageed Rizgar A, Williams Richard O
Kennedy Institute for Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Roosevelt Drive, Oxford, OX3 7FY, UK; Botnar Research Centre, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, UK.
Kennedy Institute for Rheumatology, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Roosevelt Drive, Oxford, OX3 7FY, UK.
J Autoimmun. 2021 Mar;118:102597. doi: 10.1016/j.jaut.2021.102597. Epub 2021 Jan 22.
The role of the innate immune system has been established in the initiation and perpetuation of inflammatory disease, but less attention has been paid to its role in the resolution of inflammation and return to homeostasis. Toll-like receptor (TLR) expression profiles were analysed in tissues with differing disease status in rheumatoid arthritis (RA), ankylosing spondylitis (AS), and in experimental arthritis. TLR gene expression was measured in whole blood and monocytes, before and after TNF blockade. In RA and osteoarthritis synovia, the expression of TLRs was quantified by standard curve qPCR. In addition, four distinct stages of disease were defined and validated in collagen-induced arthritis (CIA), the gold standard animal model for RA - pre-onset, early disease, late disease and immunised mice that were resistant to the development of disease. TLR expression was measured in spleens, lymph nodes, blood cells, liver and the paws (inflamed and unaffected). In RA whole blood, the expression of TLR1, 4 and 6 was significantly reduced by TNF blockade but the differences in TLR expression profiles between responders and non-responders were less pronounced than the differences between RA and AS patients. In RA non-responders, monocytes had greater TLR2 expression prior to therapy compared to responders. The expression of TLR1, 2, 4 and 8 was higher in RA synovium compared to control OA synovium. Circulating cytokine levels in CIA resistant mice were similar to naïve mice, but anti-collagen antibodies were similar to arthritic mice. Distinct profiles of inflammatory gene expression were mapped in paws and organs with differing disease status. TLR expression in arthritic paws tended to be similar in early and late disease, with TLR1 and 2 moderately higher in late disease. TLR expression in unaffected paws varied according to gene and disease status but was generally lower in resistant paws. Disease status-specific profiles of TLR expression were observed in spleens, lymph nodes, blood cells and the liver. Notably, TLR2 expression rose then fell in the transition from naïve to pre-onset to early arthritis. TLR gene expression profiles are strongly associated with disease status. In particular, increased expression in the blood precedes clinical manifestation.
固有免疫系统在炎症性疾病的起始和持续过程中的作用已得到确认，但人们对其在炎症消退和恢复内环境稳定方面的作用关注较少。分析了类风湿关节炎（RA）、强直性脊柱炎（AS）以及实验性关节炎中不同疾病状态组织的Toll样受体（TLR）表达谱。在肿瘤坏死因子（TNF）阻断前后，检测全血和单核细胞中的TLR基因表达。在RA和骨关节炎滑膜中，通过标准曲线定量聚合酶链反应（qPCR）对TLR的表达进行定量。此外，在胶原诱导的关节炎（CIA）中定义并验证了四个不同的疾病阶段，CIA是RA的金标准动物模型——发病前、疾病早期、疾病晚期以及对疾病发展具有抗性的免疫小鼠。检测脾脏、淋巴结、血细胞、肝脏和爪子（发炎和未发炎）中的TLR表达。在RA全血中，TNF阻断可显著降低TLR1、4和6的表达，但应答者与非应答者之间TLR表达谱的差异不如RA患者与AS患者之间的差异明显。在RA非应答者中，治疗前单核细胞的TLR2表达高于应答者。与对照骨关节炎滑膜相比，RA滑膜中TLR1、2、4和8的表达更高。CIA抗性小鼠的循环细胞因子水平与未感染小鼠相似，但抗胶原抗体与关节炎小鼠相似。在爪子和具有不同疾病状态的器官中绘制了不同的炎症基因表达谱。关节炎爪子中的TLR表达在疾病早期和晚期往往相似，晚期疾病中TLR1和2略高。未受影响爪子中的TLR表达因基因和疾病状态而异，但抗性爪子中的表达通常较低。在脾脏、淋巴结、血细胞和肝脏中观察到疾病状态特异性的TLR表达谱。值得注意的是，在从未感染到发病前再到早期关节炎的转变过程中，TLR2表达先升高后下降。TLR基因表达谱与疾病状态密切相关。特别是，血液中表达的增加先于临床表现。
