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

项目总结 在接受肿瘤坏死因子抑制剂(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细胞耐受破坏的机制尚不清楚。在人类身上， TNFi通过破坏生发中心(GC)的形成来影响B和T细胞的动态平衡，而生发中心(GC)的形成是HIGH的关键 亲和力抗原特异性抗体的产生和自身反应性B细胞的阴性选择。同样，在老鼠身上， 肿瘤坏死因子信号缺陷阻止了GC的形成，诱导TFH和CD4+IL-17产生细胞扩张，并 改变自身抗体特征。这项小而有针对性的研究表明，肿瘤坏死因子缺乏，连同第二个 诱导刺激，通过减少负B细胞信号和增强B细胞选择来妥协B细胞选择 T效应细胞活性。为了验证这一假设，第一个目的是利用：1)两种不同类型的肿瘤坏死因子缺陷小鼠 背景：TLR9激动剂和NZM2328.TNFR1/2双基因诱导的自身反应性Sle1.TNF-/-小鼠 以及2)Sle1.TNF-/-.Yaa，其中雄性小鼠过表达TLR7，以确定TLR7的作用机制 激活的B细胞的信号缺陷通过GC和/或卵泡外途径改变B细胞的选择。 第二个目标将通过确定CD22结合的变化来解决接受TNFi治疗的患者的类似问题 从而影响自身反应性B细胞中bcr信号的动力学。这一目标之所以成为可能，是因为 新型ANA试剂的开发，用于鉴定人类和小鼠体内丰富的自身反应性B细胞。这个 这项研究的结果将阐明TNFi在调节B细胞耐受性方面的作用，并改善我们的 了解免疫系统如何调节GC和卵泡外途径中的B细胞耐受。

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.