TNF deficiency induces breach of B cell tolerance via altering B cell regulatory signals

项目摘要 在用TNF抑制剂（TNFi）治疗的患者中诱导自身抗体和自身免疫是众所周知的; 然而，TNFi诱导B细胞耐受性破坏机制还有待确定。在人类中， TNF1通过破坏生发中心（GC）的形成影响B和T细胞的稳态，生发中心（GC）的形成是高血压的关键。 亲和抗原特异性抗体产生和自身反应性B细胞的阴性选择。同样，在小鼠中， TNF信号传导缺陷阻止GC形成，诱导产生TFH和CD4 + IL-17的细胞扩增， 改变自身抗体谱。这项小型的重点研究提出，TNF缺乏，加上第二个 诱导刺激，通过减少负B细胞信号传导和增强B细胞选择， T效应细胞活性。为了检验这一假设，第一个目的利用：1）2种不同的TNF缺陷型小鼠， 背景，用TLR9激动剂和NZM2328.TNFR1/2双重诱导的自身反应性Sle1.TNF-/-小鼠 缺陷小鼠，和2）Sle1.TNF-/-. Yaa，其中雄性小鼠过表达TLR7，以确定 活化B细胞的信号传导缺陷，通过GC和/或滤泡外途径改变B细胞选择。 第二个目标将通过识别CD22结合的变化来解决TNFi治疗患者中的类似问题。 动力学，从而影响自身反应性B细胞中的BCR信号传导。这一目标之所以成为可能，是因为 开发新的ANA试剂，鉴定人和小鼠中富集的自身反应性B细胞。的 本研究的结果将阐明TNFi对调节B细胞耐受性的作用，并改善我们的免疫功能。 了解免疫系统如何调节GC和滤泡外途径中的B细胞耐受性。

PROJECT SUMMARY The induction of autoantibody and autoimmunity in patients treated with TNF inhibitors (TNFi) is well-known; however, the mechanism by which TNFi induce breach of B cell tolerance is yet to be determined. In humans, TNFi affect B and T cell homeostasis via disruption of germinal center (GC) formation which is pivotal for high affinity antigen-specific antibody production and negative selection of autoreactive B cells. Similarly, in mice, TNF signaling deficiency prevents GC formation, induces TFH and CD4+IL-17 producing cell expansion, and alters autoantibody profiles. This small focused study proposes that TNF deficiency, together with a second inducing stimulus, compromises B cell selection via reduction of negative B cell signaling and enhancement of T effector cell activities. To test this hypothesis, the first aim utilizes: 1) TNF deficient mice of 2 different backgrounds, autoreactive Sle1.TNF-/- mice induced with a TLR9 agonist and NZM2328.TNFR1/2 double deficient mice, and 2) Sle1.TNF-/-.Yaa, in which male mice over express TLR7, to determine the mechanism for the signaling defect of activated B cells that alters B cell selection via either GC and/or extrafollicular pathway. The second aim will address similar questions in TNFi treated patients by identifying changes in CD22 binding dynamics which thereby affect BCR signaling in autoreactive B cells. This aim is made possible due to the development of the novel ANA reagent that identify enriched autoreactive B cells in both humans and mice. The results from this study will elucidate the effects of TNFi on regulating B cell tolerance and improve our understanding of how the immune system regulates B cell tolerance in GC and extrafollicular pathways.