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（由申请方提供）：滤泡树突状细胞（FDC）被认为是次级淋巴组织的关键基质成分，保留抗原和免疫复合物，但也对环境刺激作出反应，并提供影响晚期B细胞分化的可溶性因子，包括BAFF。我们假设，FDCs也可能是重要的保留自身抗原，这样的自身抗原的短暂或偶发的存在可以被捕获。我们认为，FDCs对自身抗原的保留可能在自身反应性B细胞的持续消除中发挥重要作用，因为它们在脾脏中作为"过渡性" B细胞完成晚期成熟。在这个发育阶段的选择事件没有得到很好的理解，并与骨髓中早期B细胞成熟所描述的那些形成对比。在该提案中，我们引入了一种新的B细胞耐受性小鼠模型，该模型基于膜结合自身抗原在FDC上的条件表达。我们提供了第一个直接的证据表明，FDCs在外周B细胞耐受中发挥作用。在拟议的工作中，我们将：（i）表征由FDC结合的自身抗原施加的晚期B细胞发育阻滞。(ii)使用在过渡期和成熟B细胞中差异表达的microRNA的强制表达来鉴定对T1细胞耐受易感性重要的基因。 公共卫生相关性：在拟议的工作中，我们解决外周耐受性在过渡阶段的B细胞的发展相应的最近B细胞移民到脾脏。我们提供的证据表明，滤泡树突状细胞的脾脏是重要的消除自我反应的"过渡" B细胞，从而定义了一个新的检查点外周B细胞的耐受性。这些发现和我们开发的模型与理解外周耐受缺陷直接相关，外周耐受缺陷在系统性红斑狼疮和其他可能的抗体依赖性自身免疫性疾病中发生。