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

描述(申请人提供)：这项研究的长期目标是确定诱导外周对自身抗原耐受的重要抗原提呈细胞(APC)，重点是弱自身反应的B细胞亚群。B细胞是与其抗原受体结合的抗原的特别有效的APC，因此在胸腺和外周，自我反应性B细胞可能比传统的耐受APC更有效地递送自身抗原。为了避免由致病T和B细胞相互激活的恶性循环中的正反馈，在感染激活T细胞之前，自身反应性B细胞可能有必要诱导辅助T细胞对它们识别和呈现的那些自身抗原产生耐受。众所周知，B细胞亚群在招募T细胞帮助的能力和分泌自身抗体的倾向方面存在很大差异，但它们在诱导初始CD4T细胞耐受方面尚未被比较。自身反应性B细胞的三个亚群作为CD4T细胞的耐受性APC可能特别重要。其中一个亚群是短暂的、无能的、未成熟的过渡性B细胞，它们保留在T细胞区，由于其抗原受体与自身抗原结合，因此无法进入长寿的B细胞室。另一种是自我更新的边缘带B细胞，它们被自身抗原选入这个特殊的B细胞亚群，并准备对血液传播的病原体做出快速抗体反应。第三种是自我更新的B-1B细胞，在发育早期种植到外围，通过自身抗原反应来选择和维持，并产生种系编码的、自然的和T非依赖的抗体，以保护免受细菌感染。本项目的目的是利用一种独特的转基因动物模型，首次确定在健康淋巴器官中，B细胞亚群在其自然位置稳定状态下诱导抗原递呈和耐受的内在效率，在该动物模型中，抗原递呈可以限制在某些亚群的B细胞。拟议的实验还将测试特定B细胞亚群缺陷的动物是否缺乏对这些B细胞提出的自身抗原的CD4T细胞耐受性。 相关性：自我耐受性的失败是自身免疫性疾病的基础。这个应用程序研究了在保持自我耐受性的同时允许对感染做出有力反应的机制。了解免疫耐受的机制可能导致新的干预措施来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在器官和组织移植、基因治疗和慢性感染治疗方面也将有重要应用。

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.