Translational Research Project Effector and Regulatory B cells in SLE

目前关于B细胞在自身免疫中作用的知识的一个重要局限性是，人们对B细胞在自身免疫中的作用知之甚少 人类疾病超越了自身抗体的产生。然而，随着各种自身免疫性疾病数据的积累， 包括系统性红斑狼疮(SLE)在内，表明B细胞可能通过多个 包括抗体依赖和抗体非依赖功能的机制。后者包括抗原提呈， 我们认为，T细胞的激活和极化以及树突状细胞的调节是由 B细胞产生细胞因子的能力。B细胞可能通过产生促炎性物质而有害 细胞因子和致病性自身抗体或通过产生抗炎细胞因子如IL-1来调节 10和TGFp，以及Tregs的扩张和/或抑制效应性T细胞。理解两国之间的不平衡 这些对立的B细胞在疾病中的功能是该项目和整个ACE提案的首要概念。它是 基于大量的初步证据表明人类B细胞表现出表型多样性，这反映了 SLE患者中效应器和调节功能的分工、它们的分裂失衡和它们的逆转 B细胞耗尽重建后临床反应良好。这种不平衡可能是由以下任一原因造成的：1) 在一个群体中的数量优势；或2)在一个群体内的致病增益功能和/或调控功能丧失 给定的人口数量。我们对活动期系统性红斑狼疮特征的初步看法包括 效应亚群(切换的CD27+和CD27-细胞)和/或具有调节潜力的人群的缺陷 (移行细胞、NATve细胞和MZ细胞)。这些假设将在目标1中得到解决。然而，我们认识到表面 表型不足以决定任何给定子集的功能，因此，目标2将测试 根据细胞因子的产生潜力和调节T细胞功能的能力来分离亚群。最后，我们猜测 在SLE PBL中产生独特B细胞特征的波动的B细胞失衡反映了系统性复发 自身免疫反应由已知的抗原特异性主导，随疾病活动而波动。这一争论 代表目标3的基础，该目标将测试特定的自身反应性对效应器和 调节性B细胞亚群。总体而言，我们预测效应器B细胞将具有激活的表型和 增强复制、向非淋巴系统组织迁移的可能性和促炎因子的产生 细胞因子。相比之下，调节性B细胞将表现出有限的复制，并专门生产抗炎物质 细胞因子。从这些目的中获得的信息对于理解致病基因的获得者是否 保护性B细胞功能的功能和/或丧失有助于解释为什么临床疾病通常会在接下来的几年里发生 在最初的耐受性崩溃后，哪种类型的B细胞失衡(无论是在数量上还是功能上)是疾病的基础 发病、加重和缓解，以及如何运用这些知识进行诊断、预后和治疗 优势。

An important limitation of current knowledge regarding the role of B cells in autoimmunity is that very little is known in human disease beyond the production of autoantibodies. Yet, accumulating data in diverse autoimmune diseases, including Systemic Lupus Erythematosus (SLE), indicates that B cells likely contribute to disease through multiple mechanisms that include both antibody-dependent and antibody-independent functions. The latter include antigenpresentation, T-cell activation and polarization, and dendritic cell modulation and we propose are critically mediated by the ability of B cells to produce cytokines. B cells may be deleterious through the production of pro-inflammatory cytokines and pathogenic autoantibodies or regulatory through the production of anti-inflammatory cytokines such as IL- 10 and TGFp and the expansion of Tregs and/or inhibition of effector T cells. Understanding the imbalance between these opposing B cell functions in disease is the overarching concept of this project and overall ACE proposal. It is founded on substantial preliminary evidence indicating that human B cells display phenotypic diversity that reflects division of labor for effector and regulatory functions, their sriking imbalance in SLE, and their reversal in patients experiencing good clinical response after B cell depletion and reconstitution. This imbalance could result from either: 1) numerical advantage in one population; or 2) a gain-of-pathogenic function and/or loss-of-regulatory function within a given population. Our preliminary view of a profile characteristic of active SLE includes the expansion of presumed effector subsets (switched CD27+ and CD27- cells) and/or the deficit of populations with regulatory potential (transitional, naTve and MZ cells). These assumptions will be addressed in Aim 1. We recognize however that surface phenotype is insufficient to determine the function of any given subset and therefore, Aim 2 will test the function of separate subsets in terms of cytokine producing potential and ability to modulate T cell function. Finally, we surmise that the fluctuating B cell imbalances that create a distinctive B cell signature in SLE PBL reflect recurrent systemic autoimmune responses dominated by antigen specificities known to fluctuate with disease activity. This contention represents the basis for Aim 3 which will test the contribution of specific autoreactivity to the expansion of effector and regulatory B cell subsets. Overall, we predict that effector B cells will be characterized by an activated phenotype and enhanced replication, potential for migration to non-lymphoid systemic tissues and production of pro-inflammatory cytokines. In contrast, regulatory B cells will display limited replication and specialize in the production of antiinflammatory cytokines. The information derived from these aims will be critical to understand whether a gain-ofpathogenic function and/or loss of protective B cell function help explain why clinical disease typically ensues years after the initial breakdown of tolerance, what type of B cell imbalance (either in number or function) underlies disease onset, exacerbation and remission and how to manipulate this knowledge for diagnostic, prognostic and therapeutic advantage.