Follicular dendritic cells and B cell tolerance

滤泡树突状细胞和 B 细胞耐受

• 批准号: 8321386
• 负责人: ROBERT C RICKERT
• 金额: $ 29.25万
• 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/8321386
• 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. PUBLIC HEALTH RELEVANCE: In the proposed work, we address peripheral tolerance at the transitional stage of B cell development corresponding to the recent B cell immigrants to the spleen. We provide evidence that follicular dendritic cells of the spleen are important in the elimination of self-reactive "transitional" B cells, thus defining a novel checkpoint in peripheralB cell tolerance. These findings and the model we developed with be of direct relevance to understanding defects in peripheral tolerance that are noted to occur in systemic lupus erythematosus and likely other antibody-dependent autoimmune diseases.

描述（由申请人提供）：卵泡树突状细胞（FDC）被认为是保留抗原和免疫复合物的次级淋巴组织的关键基质成分分化。我们假设FDC对于保留自我抗原也可能很重要，因此可以捕获自我抗原的短暂或情节存在。我们提出，FDC对自身抗原的保留可能会在不断消除自动反应性B细胞中提供重要功能，因为它们以“过渡性” B细胞的形式完成脾脏后期成熟。在此发育阶段的选择事件与骨髓中早期B细胞成熟所描述的事件没有很好地理解和形成对比。在此提案中，我们基于FDC上膜结合的自我抗原的条件表达引入了B细胞耐受性的新小鼠模型。我们为FDC提供了第一个直接证据，因为它在外围B细胞耐受性中起作用。在拟议的工作中，我们将：（i）表征由FDC结合的自我抗原施加的晚期B细胞发育块。 （ii）使用在过渡和成熟的B细胞中表达差异的microRNA的强制表达来鉴定对T1细胞耐受性敏感性很重要的基因。 公共卫生相关性：在拟议的工作中，我们在B细胞发育过渡阶段的外围耐受性解决与最近B细胞移民相对应的脾脏。我们提供的证据表明，脾脏的卵泡树突状细胞对于消除自反应的“过渡” B细胞很重要，从而定义了外围alb细胞耐受性的新检查点。这些发现和我们开发的模型与理解周围耐受性的缺陷具有直接相关性，这些缺陷在系统性红斑狼疮和可能其他抗体依赖性自身免疫性疾病中发生。