Nickdel M B, Conigliaro P, Valesini G, Hutchison S, Benson R, Bundick R V, Leishman A J, McInnes I B, Brewer J M, Garside P
Centre for Biophotonics, Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow, UK.
Ann Rheum Dis. 2009 Jun;68(6):1059-66. doi: 10.1136/ard.2008.089300. Epub 2008 Jul 17.
The relative roles of innate immunity and antigen-specific T cells in rheumatoid arthritis remain controversial. Previous studies demonstrated that T-helper type 1 cells of irrelevant antigen specificity (ovalbumin) induced a transient arthritis in BALB/c mice, which recapitulates many of the pre-articular and articular features of human disease and is associated with the emergence of autoreactive T and B-cell responses to joint-specific antigens. However, the mechanisms underlying this phenomenon were unclear.
The aim of this study was to dissect the relative contribution of innate and heterologous antigen-specific pathways to the breach of self-tolerance and pathology observed in this model and how this may result from modified T and B-cell interactions.
To address this issue, experimental arthritis was elicited either by a non-specific inflammatory stimulus alone, by activation of T cells of an irrelevant specificity or a combination of both.
The non-specific inflammatory response generated by lipopolysaccharide led to articular inflammation and cartilage erosion, but did not break tolerance to joint-specific antigens. In contrast, local activation of T cells of an irrelevant specificity produced a similar pathological picture but, in addition, induced T-cell responses to unrelated joint-specific antigens with associated activation of autoreactive B cells. These effects could be further potentiated by the addition of lipopolysaccharide.
These data demonstrate that non-specific inflammation alone is insufficient to breach self-tolerance. In contrast, T cells of an irrelevant specificity, when triggered locally in an antigen-specific manner, can breach self-tolerance leading to arthritis and autoantibody production, which can then be amplified in a non-specific manner.
在类风湿性关节炎中，固有免疫和抗原特异性T细胞的相对作用仍存在争议。先前的研究表明，具有无关抗原特异性（卵清蛋白）的辅助性T1细胞可在BALB/c小鼠中诱发短暂性关节炎，该关节炎概括了人类疾病的许多关节前和关节特征，并与针对关节特异性抗原的自身反应性T细胞和B细胞反应的出现有关。然而，这一现象背后的机制尚不清楚。
本研究旨在剖析固有和异源抗原特异性途径对该模型中观察到的自身耐受性破坏和病理变化的相对贡献，以及这可能如何由T细胞和B细胞相互作用的改变导致。
为解决此问题，通过单独的非特异性炎症刺激、激活无关特异性的T细胞或两者结合来诱发实验性关节炎。
脂多糖产生的非特异性炎症反应导致关节炎症和软骨侵蚀，但未破坏对关节特异性抗原的耐受性。相比之下，激活具有无关特异性的T细胞产生了类似的病理表现，但此外，还诱导了对无关关节特异性抗原的T细胞反应以及自身反应性B细胞的相关激活。添加脂多糖可进一步增强这些效应。
这些数据表明，单独的非特异性炎症不足以破坏自身耐受性。相比之下，具有无关特异性的T细胞在局部以抗原特异性方式被触发时，可破坏自身耐受性，导致关节炎和自身抗体产生，然后可通过非特异性方式放大。
