Infectious Agents and B Cell Anergy

描述（由申请人提供）：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，感染可参与自身免疫的启动。在这种联系的最好的例子中，爱泼斯坦巴尔病毒感染似乎容易导致系统性红斑狼疮的发展。感染如何促使免疫耐受性丧失尚不清楚。感染似乎在某种程度上破坏了使自身反应性细胞沉默的机制。三种这样的机制在自身反应性B细胞的沉默中起作用；受体编辑，克隆删除和能量。无能B细胞是环境对自身免疫最明显的影响目标，因为这些细胞在暴露于感染因子和先天免疫介质时，能在外周器官中持续存在一段时间。目前尚不清楚无能细胞的抗原无反应性是如何维持生化的，也不清楚感染因子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细胞能量的维持需要慢性抗原受体（BCR）的占用和信号的转导。初步研究结果表明，这些“能量维持”信号是由BCR偏态激活的抑制性反馈信号通路介导的，其中含有SH2结构域的磷脂酰肌醇5-磷酸酶SHIP-1是主要介质。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，并提出在aim 1中验证这种可能性。目标2中提出的研究将解决已知与自身免疫相关的伽玛疱疹病毒感染和TLR信号对能量的影响。这些药物是否针对无能B细胞，并通过破坏能量维持信号或绕过该电路来调节其作用？这些药物是否促使细胞脱离能量并促使它们产生自身抗体，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？拟议的研究将采用免疫球蛋白转基因B细胞能量模型以及来自正常小鼠的自然产生的无能B细胞。这些模型将与生物化学和分子遗传学方法结合使用，以定义调节信号通路，并阐明MgHV感染以及先天免疫和T辅助信号对无能细胞功能的影响。拟议的研究应该通过定义感染因子和突变破坏对维持能量至关重要的分子调节机制的情况来促进我们对自身免疫起源的理解。

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.