Where FoxP3-dependent regulatory T cells impinge on the development of inflammatory arthritis
Where FoxP3-dependent regulatory T cells impinge on the development of inflammatory arthritis
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DOI：
10.1002/art.22272
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发表时间：
2007-02-01
影响因子：
--
通讯作者：
Benoist, Christophe
中科院分区：
文献类型：
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作者：
Nguyen, Linh T.;Jacobs, Jonathan;Benoist, Christophe
Objective.调节性T细胞在许多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步骤。本研究的目的是分析调节性T细胞在关节炎发展控制中的作用。使用杂交和细胞转移，我们测试了K/BxN小鼠模型中Foxp 3基因的scurfy功能丧失突变的影响。在这个模型中，关节炎的发展是由于高水平的致病性自身抗体的产生。在K/BxN小鼠中缺乏Treg细胞导致更快和更具侵略性的关节炎。引人注目的是，疾病也会扩散到这种模型中通常不受影响的关节。Treg细胞的缺乏导致疾病的免疫阶段加速，具有显著更早的自身抗体产生。然而，Foxp 3突变小鼠受影响关节的范围扩大不是由于自身抗体的早期出现，并且不能通过增加抗葡萄糖-6-磷酸来重现。异构酶抗体负荷，这证明了Treg细胞对效应期表现的影响。此外，FoxP 3+、CD 25 + Treg细胞在炎症关节中积累，即使在非转基因动物中也是如此。这种优先定位模拟了人类关节炎中的情况，并表明Treg细胞优先归巢/保留至炎症部位。这些结果表明，Treg细胞在抗体介导的关节炎中在几个水平上发挥作用。Treg细胞参与限制疾病的免疫阶段，以及限制由致病性自身抗体引起的关节损伤的严重程度和受影响关节的范围，这可能导致许多关节炎的有限远端优势。
Objective. 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.Methods. 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.Results. 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.Conclusion. 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.