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保健问题，也是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细胞受包括B细胞能量在内的耐受性机制调节。B细胞能量衰竭是自身免疫发展的一个驱动力。尽管如此，调节B细胞能量的机制仍然不明确。我们的长期目标是了解维持B细胞能量的机制。调节性T细胞（Tregs）在免疫稳态中起关键作用。关于Tregs如何调节树突状细胞和T细胞（CD4+和CD8+）的研究进展迅速。然而，关于它们在调节其他细胞类型（如B细胞）中的作用的研究却没有那么积极。这是令人惊讶的，因为Tregs的缺失导致了深刻的自身免疫和自身抗体的产生。我们最近报道了自身抗体的产生，在缺乏Tregs的情况下，由于B细胞能量的损失而发生。该建议的目的是确定Tregs缺失支持B细胞能量损失的机制。我们的初步研究表明，由Tregs缺失介导的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Tregs的缺失会导致滤泡辅助性T细胞（TFH细胞）的扩增。我们还表明，这些TFH细胞是致病性的，因为它们足以驱动B细胞能量的损失。因此，我们假设致病性TFH细胞的扩增是在Tregs相对减少或缺乏的情况下产生自身抗体的基本机制。本研究将确定致病性TFH细胞如何支持B细胞能量损失，并研究致病性TFH细胞扩增的机制。这些研究将有助于确定无能性B细胞调节的新机制，并有可能开发出治疗自身免疫的新治疗策略。

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.