B Cell Subsets as Antigen-presenting Cells in Peripheral Self-tolerance

描述（由申请人提供）：本研究的长期目标是鉴定诱导外周对自身抗原耐受的重要抗原呈递细胞（APC），重点是弱自身反应性B细胞亚群。B细胞对于与其抗原受体结合的抗原是特别有效的APC，因此自身反应性B细胞可以比常规耐受性APC更有效地在胸腺和外周中呈递自身抗原。为了避免致病性T和B细胞相互激活的恶性循环中的正反馈，在那些T细胞被感染激活之前，自身反应性B细胞可能需要诱导辅助性T细胞对它们有效识别和呈递的那些自身抗原的耐受性。已知B细胞亚群在募集T细胞辅助的能力和分泌自身抗体的倾向方面彼此显著不同，但尚未比较它们在幼稚CD 4 T细胞中诱导耐受的能力。自身反应性B细胞的三个亚群可能作为CD 4 T细胞的致耐受性APC特别重要。一个亚群是短寿命的、无反应性的、未成熟的过渡性B细胞，其保留在T细胞区域中并且不能进入长寿命的B细胞区室，因为它们的抗原受体被自身抗原接合。另一种是自我更新的边缘区B细胞，它们被自身抗原选择进入这种特殊的B细胞亚群，并准备对血液传播的病原体进行快速抗体反应。第三种是自我更新的B-1 B细胞，它们在早期发育中被接种到外周，通过自身抗原反应性被选择和维持，并产生种系编码的、天然的和T非依赖性的抗体，以保护免受细菌感染。本项目的目的是首次确定抗原呈递和耐受诱导的内在效率，由B细胞亚群在其自然位置在稳定状态下在健康的淋巴器官，使用一种独特的转基因动物模型，其中抗原呈递可限于某些子集的B细胞。所提出的实验还将测试缺乏特定B细胞亚群的动物是否缺乏对由那些B细胞呈递的自身抗原的CD 4 T细胞耐受性。 相关性：自身耐受性的失败是自身免疫性疾病的基础。该应用程序研究了保持自我耐受性的机制，同时允许对感染做出有力的反应。了解免疫耐受的机制可能会导致新的干预措施，用于预防或治疗自身免疫性疾病，如红斑狼疮，类风湿性关节炎和糖尿病。诱导免疫耐受的新方法也将在器官和组织移植、基因治疗和慢性感染的治疗中具有重要应用。

DESCRIPTION (provided by applicant): The long-range goal of this research is to identify the significant antigen presenting cells (APC) that induce peripheral tolerance to self antigens, with a focus on weakly autoreactive B cell subsets. B cells are particularly efficient APC for antigens bound to their antigen receptors, so self-reactive B cells may present self-antigens more efficiently than conventional tolerizing APC in the thymus and periphery. To avoid positive feedback in a vicious cycle of mutual activation by pathogenic T and B cells, it may be necessary for autoreactive B cells to induce helper T cell tolerance to those self-antigens that they recognize and present efficiently, before those T cells are activated by infections. It is known that B cell subsets differ substantially from one another in their ability to recruit T cell help and their propensity to secrete autoantibodies, but they have not been compared with regard to their ability to induce tolerance in naive CD4 T cells. Three subsets of self-reactive B cells may be particularly important as tolerogenic APC for CD4 T cells. One subset is the short-lived, anergic, immature transitional B cells that are retained in T cell areas and fail to enter the longlived B cell compartments because their antigen receptors are engaged by self-antigens. Another is the self-renewing marginal zone B cells that are selected into this special B cell subset by self antigens, and are poised for a rapid antibody response to blood-borne pathogens. The third is the self-renewing B-1 B cells that are seeded to the periphery in early development, are selected and sustained by self-antigen reactivity, and produce germline-encoded, natural and T-independent antibodies that protect against bacterial infections. The objective of this project is to determine for the first time the intrinsic efficiency of antigen presentation and tolerance induction by B cell subsets in their natural locations in the steady state in healthy lymphoid organs, using a unique transgenic animal model in which antigen presentation can be limited to B cells of certain subsets. The proposed experiments will also test whether animals deficient in particular B cell subsets are deficient in CD4 T cell tolerance to self-antigens presented by those B cells. Relevance: The failure of self-tolerance underlies autoimmune disease. This application investigates the mechanisms that maintain self-tolerance while allowing a vigorous response to infections. Understanding mechanisms of immunological tolerance may lead to new interventions for prevention or cure of autoimmune diseases, such as lupus erythematosus, rheumatoid arthritis, and diabetes. New methods to induce immunological tolerance will also have important applications in organ and tissue transplantation, gene therapy, and treatment of chronic infections.