Infectious Agents and B Cell Anergy

传染性病原体和 B 细胞无反应性

• 批准号: 8580189
• 负责人: John C Cambier
• 金额: $ 37.87万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-12-01 至 2015-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8580189
• 关键词: Address; Animals; Antibody Formation; Antigen Receptors; Antigens; Apoptotic; Autoantibodies; Autoantigens; Autoimmune Diseases; Autoimmune Process; Autoimmune Responses; Autoimmunity; B-Cell Activation; B-Lymphocytes; BCL2 gene; BCL2L11 gene; Bacteria; Biochemical Genetics; Biological Response Modifiers; Bone Marrow; Bypass; CD4 Positive T Lymphocytes; Cell Survival; Cell physiology; Cell surface; Cells; Chronic; Clonal Anergy; Clonal Deletion; Companions; Complement; Development; Diagnosis; Down-Regulation; Epitopes; Epstein-Barr Virus Infections; Event; Excision; Family member; Feedback; Generations; Genetic Predisposition to Disease; Helper-Inducer T-Lymphocyte; Herpesviridae; Herpesviridae Infections; Human; Human Herpesvirus 4; Immune; Immune Tolerance; Immunoglobulins; Infection; Infectious Agent; Knock-out; Left; Longevity; Lupus; Lymphoid; Maintenance; Measures; Mediating; Mediator of activation protein; Modeling; Molecular; Molecular Genetics; Mus; Mutation; Organ; Pathway interactions; Peripheral; Phenotype; Phosphatidylinositols; Phosphoric Monoester Hydrolases; Phosphotransferases; Physiological; Population; Prevention strategy; Publishing; Recruitment Activity; Relative (related person); Reporting; Risk; Role; Signal Pathway; Signal Transduction; Source; Stimulus; Systemic Lupus Erythematosus; T-Lymphocyte; Testing; Time; To autoantigen; Transgenic Animals; Transgenic Mice; Transgenic Model; Up-Regulation; Virus; Virus Diseases; anergy; autoreactive B cell; base; gammaherpesvirus; inositol-1,4,5-trisphosphate 5-phosphatase; member; prevent; public health relevance; receptor; response; src Homology Region 2 Domain

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.

描述（由申请人提供）：自身免疫是遗传倾向和环境刺激共同作用的结果。强有力的证据表明感染可能参与自身免疫的启动。也许是这种关联的最好例子，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。感染如何导致免疫耐受性丧失尚不清楚。感染似乎可能在某种程度上破坏了导致自身反应细胞沉默的机制。三种这样的机制可用于沉默自身反应性 B 细胞；受体编辑、克隆删除和无能。无能 B 细胞是环境对自身免疫影响最明显的目标，因为这些细胞独特地在外周器官中持续存在一段时间，在一段时间内它们暴露于可能重新唤醒它们的感染因子和先天免疫介质。目前还不清楚无反应细胞的抗原无反应性是如何在生化上维持的，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 细胞无反应性的维持需要慢性抗原受体 (BCR) 占据和信号转导。初步研究结果表明，这些“无反应维持”信号是由抑制性反馈信号通路的 BCR 偏向激活介导的，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 介导无反应性 B 细胞对抗原以及生存因子 BAFF 的无反应性，并建议在目标 1 中测试这种可能性。目标 2 中提出的研究将解决伽玛疱疹病毒感染对无反应性的影响已知与自身免疫相关的 TLR 信号。这些药物是否以无反应性 B 细胞为目标，并通过破坏无反应性维持信号或绕过该电路来介导其作用？这些药物是否会促使细胞脱离无能状态并驱使它们产生自身抗体，以及它们是否能够使它们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 B 细胞无反应性的免疫球蛋白转基因模型以及源自正常小鼠的天然无反应性 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使维持无反应性至关重要的分子调节机制失效的突变破坏免疫耐受的情况，来增进我们对自身免疫起源的理解。