Follicular dendritic cells and B cell tolerance

滤泡树突状细胞和 B 细胞耐受

• 批准号: 8431334
• 负责人: ROBERT C RICKERT
• 金额: $ 24.38万
• 依托单位: SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-03-01 至 2014-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8431334
• 关键词: Address; Antibodies; Antigen-Antibody Complex; Antigens; Autoantigens; Autoimmune Diseases; B cell differentiation; B-Cell Development; B-Lymphocytes; Binding; Bone Marrow; CD32 Antigens; Cell Maturation; Cells; Complement 3d Receptors; Complement Receptor; Data; Defect; Development; Ducks; Event; Failure; Follicular Dendritic Cells; Gene Expression; Gene Proteins; Genes; Genetic; Hematopoietic; Immigrant; Immune; Longevity; Lymphoid Tissue; Mature B-Lymphocyte; Membrane; MicroRNAs; Modeling; Muramidase; Mus; Outcome; Peripheral; Predisposition; Process; Reaction; Role; Signal Transduction; Spleen; Staging; Stimulus; Structure of germinal center of lymph node; System; Systemic Lupus Erythematosus; T-Lymphocyte; Time; Validation; Work; autoreactive B cell; base; design and construction; egg; insight; mouse model; novel; peripheral tolerance; progenitor; protein function; research study

DESCRIPTION (provided by applicant): Follicular dendritic cells (FDCs) are recognized as critical stromal components of the secondary lymphoid tissues that retain antigen and immune complexes, but also respond to environmental stimuli and provide soluble factors, including BAFF, that impact late B cell differentiation. We hypothesize that FDCs may also be important for the retention of self-antigens such that the transient or episodic presence of a self-antigen can be captured. We propose that retention of autoantigens by FDCs may provide an important function in the continual elimination of autoreactive B cells as they complete late maturation in the spleen as "transitional" B cells. Selection events at this stage of development are not well understood and contrast with those described for early B cell maturation in the bone marrow. In this proposal, we introduce a new mouse model of B cell tolerance based upon the conditional expression of a membrane-bound self-antigen on FDCs. We provide the first direct evidence for FDCs as having a role in peripheral B cell tolerance. In the proposed work, we will: (i) Characterize the late B cell development block imposed by FDC-bound self-antigen. (ii) Use forced expression of microRNAs that are differential expressed in transitional and mature B cells to identify genes that are important for tolerance susceptibility of T1 cells.

描述（由申请人提供）：滤泡树突细胞 (FDC) 被认为是次级淋巴组织的关键基质成分，其保留抗原和免疫复合物，但也对环境刺激做出反应并提供可溶性因子，包括影响晚期 B 细胞分化的 BAFF。我们假设 FDC 对于保留自身抗原也可能很重要，这样可以捕获短暂或偶发的自身抗原的存在。我们认为，FDC 保留自身抗原可能在持续消除自身反应性 B 细胞中发挥重要作用，因为它们作为“过渡”B 细胞在脾脏中完成晚期成熟。这一发育阶段的选择事件尚未得到充分理解，并且与骨髓中早期 B 细胞成熟的选择事件形成鲜明对比。在本提案中，我们引入了一种新的 B 细胞耐受小鼠模型，该模型基于 FDC 上膜结合自身抗原的条件表达。我们首次提供了 FDC 在外周 B 细胞耐受中发挥作用的直接证据。在拟议的工作中，我们将： (i) 表征由 FDC 结合的自身抗原造成的晚期 B 细胞发育障碍。 (ii) 使用在过渡 B 细胞和成熟 B 细胞中差异表达的 microRNA 的强制表达来识别对 T1 细胞耐受敏感性重要的基因。