Nguyen Linh T, Jacobs Jonathan, Mathis Diane, Benoist Christophe
Joslin Diabetes Center, Brigham and Women's Hospital, and Harvard Medical School, Boston, MA 02215, USA.
Arthritis Rheum. 2007 Feb;56(2):509-20. doi: 10.1002/art.22272.
Regulatory T cells play a suppressive role in many autoimmune diseases and can potentially affect various steps in the progression of disease. The purpose of this study was to analyze the role of Treg cells in the control of arthritis development.
Using crosses and cell transfers, we tested the effect of the scurfy loss-of-function mutation of the Foxp3 gene in the K/BxN mouse model. In this model, arthritis develops as the result of the production of high levels of pathogenic autoantibodies.
The absence of Treg cells in K/BxN mice led to faster and more aggressive arthritis. Strikingly, disease also spread to joints not normally affected in this model. The absence of Treg cells resulted in an acceleration of the immunologic phase of disease, with significantly earlier autoantibody production. However, the broadened spectrum of affected joints in Foxp3-mutant mice was not due to the earlier appearance of autoantibodies and could not be reproduced by increasing the anti-glucose-6-phosphate isomerase antibody load, which demonstrates an impact of Treg cells on effector phase manifestations. In addition, FoxP3+,CD25+ Treg cells accumulated in inflamed joints, even in nontransgenic animals. This preferential localization mimics that in human arthritides and indicates a preferential homing/retention of Treg cells to sites of inflammation.
These results indicate that Treg cells play a role in antibody-mediated arthritis at several levels. Treg cells are involved in constraining the immune phase of disease, as well as limiting the articular damage provoked by the pathogenic autoantibodies in terms of severity and of the range of affected joints, which may contribute to the limited distal predominance of many arthritides.
调节性T细胞在多种自身免疫性疾病中发挥抑制作用，并可能影响疾病进展的各个阶段。本研究旨在分析调节性T细胞在控制关节炎发展中的作用。
利用杂交和细胞转移技术，我们在K/BxN小鼠模型中测试了Foxp3基因的斯库夫功能缺失突变的影响。在该模型中，关节炎是由于产生高水平的致病性自身抗体而发展的。
K/BxN小鼠中调节性T细胞的缺失导致关节炎发展更快且更严重。令人惊讶的是，疾病还蔓延到该模型中通常不受影响的关节。调节性T细胞的缺失导致疾病免疫阶段加速，自身抗体产生明显提前。然而，Foxp3突变小鼠中受影响关节范围的扩大并非由于自身抗体出现更早，且通过增加抗葡萄糖-6-磷酸异构酶抗体负荷无法重现，这表明调节性T细胞对效应阶段表现有影响。此外，即使在非转基因动物中，FoxP3 +、CD25 +调节性T细胞也在炎症关节中积累。这种优先定位类似于人类关节炎中的情况，表明调节性T细胞优先归巢/滞留于炎症部位。
这些结果表明调节性T细胞在抗体介导的关节炎的多个层面发挥作用。调节性T细胞参与限制疾病的免疫阶段，以及在严重程度和受影响关节范围方面限制致病性自身抗体引起的关节损伤，这可能导致许多关节炎在远端的局限性优势。
