Follicular dendritic cells and B cell tolerance

描述(申请人提供)：滤泡树突状细胞(FDCs)被认为是次级淋巴组织的关键基质成分，它保留抗原和免疫复合体，但也对环境刺激做出反应，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对于自身抗原的保留也可能是重要的，这样就可以捕捉到自身抗原的一过性或间歇性存在。我们认为，当自身反应性B细胞作为“过渡性”B细胞在脾内完成后期成熟时，FDCs对自身抗原的保留可能在持续消除自身反应性B细胞方面起着重要作用。在发育的这个阶段的选择事件还没有被很好地理解，并且与骨髓中的早期B细胞成熟的描述形成对比。在这个方案中，我们介绍了一种新的B细胞耐受小鼠模型，该模型基于膜结合的自身抗原在FDCs上的有条件表达。我们首次提供了FDC在外周B细胞耐受中起作用的直接证据。在拟议的工作中，我们将：(I)表征FDC结合的自身抗原对晚期B细胞发育的阻碍作用。(Ii)使用在过渡期和成熟期B细胞中差异表达的microRNAs的强制表达来识别与T1细胞耐受易感性有关的重要基因。 公共卫生相关性：在拟议的工作中，我们解决了B细胞发育过渡阶段的外周耐受问题，与最近B细胞迁移到脾中相对应。我们提供的证据表明，脾的滤泡树突状细胞在消除自身反应性“过渡性”B细胞方面起着重要作用，从而定义了外周B细胞耐受性的一个新的检查点。这些发现和我们开发的模型对于理解外周耐受缺陷有直接关系，这些缺陷被注意到发生在系统性红斑狼疮和其他可能的抗体依赖型自身免疫性疾病中。

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.