Infectious Agents and B Cell Anergy

描述(申请人提供)：自身免疫是遗传易感性和环境刺激共同作用的结果。强有力的证据表明，感染可以参与自身免疫的启动。在可能是这种联系的最好例子中，爱泼斯坦-巴尔病毒感染似乎易于发生系统性红斑狼疮。感染是如何促使免疫耐受性丧失的尚不清楚。感染似乎以某种方式破坏了导致自身反应细胞沉默的机制。有三种这样的机制可以使自身反应性B细胞沉默：受体编辑、克隆性删除和无能。无能B细胞是环境对自身免疫贡献最明显的目标，因为这些细胞独特地在外周器官中持续一段时间，在那里它们暴露在可能重新唤醒它们的感染剂和先天免疫介质中。目前尚不清楚无能细胞的抗原无反应性是如何通过生物化学的方式维持的，也不清楚感染性因素或先天信号是否可以恢复或补充它们对自身抗原的反应。我们最近的研究表明，B细胞无能的维持需要慢性抗原受体(BCR)的占据和信号转导。初步研究结果表明，这些“无能维持”信号是由抑制反馈信号通路的偏向BCR激活所介导的，其中含有SH2结构域的磷脂酰肌醇5-磷酸酶SHIP-1是主要的介导者。我们假设SHIP-1介导了无能B细胞对抗原和生存因子BAFF的无反应性，并建议在AIM 1中测试这种可能性。AIM 2中提出的研究将讨论与自身免疫相关的伽玛疱疹病毒感染和TLR信号对无能的影响。这些药物是否以无能B细胞为靶点，并通过干扰无能维持信号或绕过这一回路来调节它们的影响。这些药物是否促使细胞脱离无能状态并促使它们产生自身抗体，以及它们是否使它们能够被招募到对模仿自身抗原的外来免疫原的持续反应中。拟议的研究将使用免疫球蛋白转基因的B细胞无能模型，以及来自正常小鼠的自然产生的无能B细胞。这些模型将与生化和分子遗传学方法结合使用，以定义调节信号回路，并阐明镁病毒感染以及先天性免疫和T辅助信号对无能细胞功能的影响。拟议中的研究应该通过定义感染病原体破坏免疫耐受的情况以及使维持无能的关键分子调控机制失效的突变来促进我们对自身免疫起源的理解。 公共卫生相关性：自身免疫性疾病的发展，如系统性红斑狼疮(Lupus)，通常是由感染特定病毒和细菌引起的。这些关联表明，某些感染破坏了使自身抗原特异的B细胞沉默的机制。我们建议确定伽玛疱疹病毒感染的分子机制，例如人类的EBV和小鼠的gHV68，从而重新唤醒无能B细胞从而导致自身免疫。这些研究结果可能为自身免疫的预防、诊断和治疗提供新的策略。

DESCRIPTION (provided by applicant): Autoimmunity is the consequence of conspiring effects of genetic predisposition and environmental stimuli. Strong evidence indicates that infection can be involved in initiation of autoimmunity. In what is perhaps the best example of this association, Epstein Barr Virus infection appears to predispose to development of Systemic Lupus Erythematosus. How infection prompts the loss of immune tolerance is unknown. It seems likely that infection somehow undermines mechanisms responsible for the silencing of autoreactive cells. Three such mechanisms are operative in silencing of autoreactive B cells; receptor editing, clonal deletion and anergy. Anergic B cells are the most obvious targets of environmental contributions to autoimmunity because these cells uniquely persist in peripheral organs for a period of time where they are exposed to infectious agents and innate immune mediators that could reawaken them. It is unclear how the antigen unresponsiveness of anergic cells is maintained biochemically or whether infectious agents or innate signals can restore or complement their response to autoantigen. Our recent studies indicate that maintenance of B cell anergy requires chronic antigen receptor (BCR) occupancy and transduction of signals. Preliminary findings indicate that these "anergy maintenance" signals mediated by biased BCR activation of inhibitory feedback signaling circuitry in which the SH2 domain- containing phosphatidylinositol 5-phosphatase SHIP-1 is a primary mediator. We hypothesize that SHIP-1 mediates the unresponsiveness of anergic B cells to antigen as well as to the survival factor BAFF, and propose to test this possibility in aim 1. Studies proposed in aim 2 will address the effect on anergy of gamma herpes virus infections and TLR signals known to be associated with autoimmunity. Do these agents target anergic B cells and mediate their effects by disrupting anergy maintenance signaling or by bypassing this circuitry. Do these agents prompt departure of cells from the anergy and drive them to make autoantibodies, and do they enable them to be recruited into ongoing responses to autoantigen-mimicking foreign immunogens. The proposed studies will employ immunoglobulin transgenic models of B cell anergy as well as naturally occurring anergic B cells derived from normal mice. These models will be used in conjunction with biochemical and molecular genetic approaches to define regulatory signaling circuitry, and elucidate the effect of MgHV infection, as well as innate immune and T helper signals on anergic cell function. The proposed studies should advance our understanding of the genesis of autoimmunity by defining circumstances in which immunologic tolerance is broken by infectious agents and by mutations that disable molecular regulatory mechanisms critical for maintenance of anergy. PUBLIC HEALTH RELEVANCE: The development of autoimmune diseases, such as systemic lupus erythematosus (Lupus), is often proceeded by infection with specific viruses and bacteria. These associations suggest that certain infections disrupt mechanisms that silence B cells specific for self antigens. We propose to define the molecular mechanisms by which gamma herpesvirus infections, e.g. EBV in human and gHV68 in mouse, re-awaken anergic B cells thereby leading to autoimmunity. Results of these studies may provide new strategies for prevention, diagnosis and treatment of autoimmunity.