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）：自身免疫性是遗传易感性和环境刺激的阴谋作用的结果。有力的证据表明，感染可能参与自身免疫的启动。在这种关联的最佳例子中，爱泼斯坦Barr病毒感染似乎倾向于发展全身性红斑狼疮。感染如何促使免疫耐受性丧失尚不清楚。感染似乎以某种方式破坏了导致自动反应性细胞沉默的机制。三种此类机制在沉默自动反应性B细胞方面是可行的。受体编辑，克隆删除和无厌食。 Anergic B细胞是对自身免疫性的环境贡献最明显的靶标，因为这些细胞在一段时间内独特地在外围器官中持续存在，使它们暴露于传染性药物和先天免疫介体中，并且可以唤起它们。目前尚不清楚如何保持生物化学的抗原无反应性，或者传染剂或先天信号是否可以恢复或补充其对自身抗原的反应。我们最近的研究表明，维持B细胞的消失需要慢性抗原受体（BCR）占用率和信号转导。初步发现表明，这些“不反应维持”信号是由抑制性反馈信号传导电路的偏置BCR激活介导的，其中含有SH2域的含磷脂酰肌醇5-磷酸酶Ship-1是主要介体。我们假设Ship-1介导了Anergic B细胞对抗原以及生存因子BAFF的无反应性，并建议在AIM 1中测试这种可能性。在AIM 1中提出的研究将解决对γ疱疹病毒感染和与自身免疫性相关的γ疱疹病毒感染和TLR信号的影响。这些试剂是否靶向厌食的B细胞，并通过破坏Anergy维护信号传导或绕过该电路来介导其效果。这些代理会促使细胞偏离反应，并驱动它们制作自身抗体，并使它们能够被招募到对模仿自动抗原的外国免疫原的持续反应中。拟议的研究将采用B细胞消耗的免疫球蛋白转基因模型以及源自正常小鼠的自然发生的厌氧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感染的影响，以及先天免疫和T辅助信号对厌氧细胞功能。拟议的研究应通过定义免疫耐受性被传染剂和禁用分子调节机制破坏免疫耐受性的情况来提高我们对自身免疫的起源，从而使我们对自身免疫性的生成。