The Role of Follicular Helper T Cell Molecules and Environmental Influences in Autoantibody Production and Progression to Inflammatory Arthritis in Mice
The Role of Follicular Helper T Cell Molecules and Environmental Influences in Autoantibody Production and Progression to Inflammatory Arthritis in Mice
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DOI：
10.1002/art.39481
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发表时间：
2016-04-01
影响因子：
13.3
通讯作者：
Mackay, Charles R.
中科院分区：
文献类型：
--
作者：
Chevalier, Nina;Macia, Laurence;Mackay, Charles R.
抗体介导的自身免疫涉及在生发中心（GC）反应期间自身反应性T细胞和B细胞之间的同源相互作用。本研究的目的是确定必需的滤泡辅助T（Tfh）细胞分子的作用（CXCR 5，信号淋巴细胞活化分子相关蛋白）对自身反应性CD 4+细胞的作用，以及某些环境影响的作用，这些影响可能决定GC驱动的自身抗体产生和关节炎的发展。从而诱发自身抗体和自身炎性关节炎。该模型允许操纵环境效应，如炎症，并使用在重要的Tfh细胞相关分子中遗传缺陷的转移细胞。结果来自KRN-Tg小鼠的CD 4+细胞中信号淋巴细胞活化分子相关蛋白（SAP）的缺陷完全保护免受关节炎，表明稳定的T细胞-B细胞相互作用是GC形成，自身抗体产生，和关节炎诱导。相比之下，当KRN-Tg小鼠的CD 4+细胞被转移到野生型小鼠中时，这些细胞中的CXCR 5缺陷仍然诱导疾病，这表明T细胞对B细胞的帮助可能依赖于其他迁移机制。然而，各种操作影响了该系统，包括通过使用CD 28（-/-）受体小鼠（减少疾病）或使用炎症诱导的弗氏完全佐剂（进展为关节炎）来消除旁观者效应。我们还研究了预先存在的GC的能力与nonautoimmune特异性，以增选自身免疫性T细胞，并没有观察到任何influence.ConclusionIn除了同源的CD 4+细胞的质量和数量的帮助，外部因素，如炎症和noncognate的CD 4+细胞旁观者激活触发自身免疫性自身免疫性GC反应内的塑造事件。SAP是自身免疫抗体产生的重要分子，而CXCR 5的重要性取决于情况。
ObjectiveAntibody-mediated autoimmunity involves cognate interactions between self-reactive T cells and B cells during germinal center (GC) reactions. The aim of this study was to determine the role of essential follicular helper T (Tfh) cell molecules (CXCR5, signaling lymphocytic activation molecule-associated protein) on autoreactive CD4+ cells and the role of certain environmental influences that may determine GC-driven autoantibody production and arthritis development.MethodsWe transferred self-reactive CD4+ cells from KRN-Tg mice into recipient mice, which induced autoantibodies and autoinflammatory arthritis. This model allowed manipulation of environmental effects, such as inflammation, and use of transferred cells that were genetically deficient in important Tfh cell-associated molecules.ResultsA deficiency of signaling lymphocytic activation molecule-associated protein (SAP) in CD4+ cells from KRN-Tg mice completely protected against arthritis, indicating that stable T cell-B cell interactions are required for GC formation, autoantibody production, and arthritis induction. In contrast, a CXCR5 deficiency in CD4+ cells from KRN-Tg mice still induced disease when these cells were transferred into wild-type mice, suggesting that T cell help for B cells could rely on other migration mechanisms. However, various manipulations influenced this system, including elimination of bystander effects through use of CD28(-/-) recipient mice (reduced disease) or use of inflammation-inducing Freund's complete adjuvant (progression to arthritis). We also examined the capacity of preexisting GCs with a nonautoimmune specificity to co-opt autoimmune T cells and observed no evidence for any influence.ConclusionIn addition to the quality and quantity of cognate CD4+ cell help, external factors such as inflammation and noncognate CD4+ cell bystander activation trigger autoimmunity by shaping events within autoimmune GC responses. SAP is an essential molecule for autoimmune antibody production, whereas the importance of CXCR5 varies depending on the circumstances.