Autoantibody production and regulatory T cells

描述(由申请人提供)：自身免疫性疾病是一个主要的医疗保健问题，也是导致妇女和幼儿死亡的主要原因。自身反应性B细胞在自身免疫的发展中起着关键作用，主要是通过分泌自身抗体。在健康个体中，自身反应性B细胞受到包括B细胞无能在内的耐受机制的调节。B细胞无能衰竭是自身免疫发展的驱动力之一。尽管如此，调节B细胞无能的机制仍然不清楚。我们的长期目标是了解维持B细胞无能的机制。调节性T细胞(Tregs)在免疫动态平衡中起关键作用。关于树突状细胞如何调节树突状细胞和T细胞(CD4+和CD8+)的研究进展很快。然而，定义它们在调节其他细胞类型中的作用的研究，如B细胞，一直没有那么积极。这是令人惊讶的，因为缺乏Tregs会导致深刻的自身免疫和自身抗体的产生。我们最近报道，在缺乏Tregs的情况下，由于B细胞无能的丧失而产生自身抗体。这项建议的目的是确定缺乏Treg支持B细胞无能丧失的机制(S)。我们的初步研究表明，在缺乏Tregs的情况下，自身抗体的产生依赖于CD4+T细胞的存在。此外，我们已经证明，缺乏Tregs会导致滤泡辅助T细胞(TFH细胞)的扩张。我们还表明，这些TFH细胞是致病的，因为它们足以驱动B细胞无能的丧失。因此，我们假设致病的TFH细胞的扩张是在Tregs相对减少或缺失的情况下产生自身抗体的基本机制。这一建议将确定致病性TFH细胞如何支持B细胞无能的丧失，并探讨致病性TFH细胞扩张的机制。这些研究将有助于确定一种调节无能B细胞的新机制，并有可能为自身免疫的治疗开发新的治疗策略。

DESCRIPTION (provided by applicant): Autoimmune disease is a major healthcare problem and a leading cause of mortality amongst women and young children. Autoreactive B cells play a key role in the development of autoimmunity, predominately by secreting autoantibodies. In healthy individuals, autoreactive B cells are regulated by tolerance mechanisms that include B cell anergy. Failure of B cell anergy represents a driving force in the development of autoimmunity. Despite this, the mechanisms that regulate B cell anergy remain poorly defined. Our long-term goal is to understand the mechanisms that maintain B cell anergy. Regulatory T cells (Tregs) play a key role in immune homeostasis. Studies defining how Tregs regulate dendritic cells and T cells (CD4+ and CD8+) have occurred at a rapid pace. However, studies defining their role in the regulation of other cell types, such as B cells, have been less aggressive. This is surprising since the absence of Tregs results in profound autoimmunity and autoantibody production. We recently reported that the production of autoantibodies, in the absence of Tregs, occurs due to loss of B cell anergy. The objective of this proposal is to define the mechanism(s) by which the absence of Tregs supports loss of B cell anergy. Our preliminary studies indicate that autoantibody production, mediated by the absence of Tregs, is dependent on the presence of CD4+ T cells. In addition, we have shown that the absence of Tregs results in the expansion of follicular helper T cells (TFH cells). We also show that these TFH cells are pathogenic, in that they are sufficient to drive loss of B cell anergy. We therefore hypothesize that expansion of pathogenic TFH cells is a fundamental mechanism responsible for the generation of autoantibody production in situations where there is a relative decrease or absence of Tregs. This proposal will determine how pathogenic TFH cells support loss of B cell anergy and investigate the mechanism responsible for the expansion of pathogenic TFH cells. These studies will help define a novel mechanism by which anergic B cells are regulated, with potential for developing new therapeutic strategies for the treatment of autoimmunity.