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

B 细胞亚群作为外周自我耐受中的抗原呈递细胞

• 批准号: 7266093
• 负责人: DAVID C PARKER
• 金额: $ 38.46万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-03-01 至 2012-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7266093
• 关键词: Adjuvant; Animal Model; Animals; Antibodies; Antibody Formation; Antigen Presentation; Antigen Receptors; Antigen-Presenting Cells; Antigens; Area; Autoantibodies; Autoantigens; Autoimmune Diseases; B-Lymphocyte Subsets; B-Lymphocytes; Back; Bacterial Infections; Blood-Borne Pathogens; CD4 Positive T Lymphocytes; Cell division; Cells; Chronic; Dendritic Cells; Development; Diabetes Mellitus; Failure; Feedback; Flow Cytometry; Frequencies; Goals; Helper-Inducer T-Lymphocyte; Histology; Immune system; Immunoglobulins; In Vitro; Infection; Inflammation; Knock-out; Label; Lead; Life; Location; Lupus Erythematosus; Lymphoid; Measures; Methods; Mus; Numbers; Organ; Peptide/MHC Complex; Peripheral; Play; Population; Prevention intervention; Problem Solving; Production; Property; Range; Recruitment Activity; Research; Research Personnel; Rest; Rheumatoid Arthritis; Role; Self Tolerance; T-Cell Activation; T-Lymphocyte; Testing; Thymus Gland; Time; Tissue Survival; Tissue Transplantation; Transgenic Animals; Transgenic Organisms; antigen binding; autoreactive B cell; cell type; cytokine; gene therapy; in vivo; programs; research study; response

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.

描述（由申请人提供）：这项研究的远距离目标是确定对自抗原诱导外围耐受性的重要抗原呈递细胞（APC），重点是弱自动反应性B细胞子集。 B细胞对于与其抗原受体结合的抗原特别有效，因此，自我反应性B细胞可能比在胸腺和外围的常规耐受性APC更有效地表现出自我抗原。为了避免致病性T和B细胞相互激活的恶性循环中的积极反馈，自动反应性B细胞可能有必要在这些T细胞被感染激活之前诱导辅助T细胞耐受性。众所周知，B细胞子集在募集T细胞帮助的能力和分泌自身抗体的倾向方面彼此之间有很大差异，但是尚未将其诱导幼稚CD4 T细胞耐受性的能力进行比较。自反应性B细胞的三个子集可能是CD4 T细胞的耐受性APC尤其重要。一个子集是短暂的，无效的，不成熟的过渡性B细胞，该细胞保留在T细胞区域，并且由于其抗原受体由自我抗原吸收而无法进入长期的B细胞室。另一个是通过自抗原选择为特殊的B细胞子集中的自我更新边缘区B细胞，并有助于对血传播病原体产生快速抗体反应。第三个是在早期发育中播种到周围的自我更新的B-1 B细胞，由自我抗原反应性选择和维持，并产生针对细菌感染的生殖线编码，天然和T非独立抗体。该项目的目的是首次使用独特的转基因动物模型，在健康淋巴机器人中，B细胞亚群在其自然位置中抗原表现和耐受性诱导的固有效率，其中抗原呈递可以限于某些亚亚群的B细胞。提出的实验还将测试特定B细胞亚群缺乏的动物是否缺乏CD4 T细胞耐受性对这些B细胞呈现的自我抗原的耐受性。 相关性：自我耐受的失败是自身免疫性疾病的基础。该应用调查了维持自我耐受性的机制，同时允许对感染产生剧烈反应。了解免疫耐受性的机制可能会导致预防或治愈自身免疫性疾病的新干预措施，例如红斑狼疮，类风湿关节炎和糖尿病。诱导免疫耐受性的新方法还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。