ROLE OF B CELL ANTIGEN PRESENTATION IN AUTOIMMUNE ENCEPHALOMYELITIS

描述(由申请人提供)：实验性自身免疫性脑脊髓炎(EAE)是一种针对人类多发性疾病(MS)的CD4T细胞依赖模型。多个抗原提呈细胞(APC)在免疫应答过程中协调和调节CD4T细胞的功能。B细胞可能在MS的发病机制中扮演着多种角色，它们作为APC发挥作用并驱动自身反应性CD4T细胞反应的能力得到了更多的认可。然而，抗原提呈在B细胞在EAE和MS中的作用的重要性仍然存在疑问。我们已经设计了一种新的工具，在这种工具中，APC的单个亚群能够在体内有条件地表达MHCII。为了利用Cre/loxP系统进行MHCII的条件表达，我们在小鼠中成功地将一个位于loxP位点两侧的终止序列定位到MHCII链上。利用B系特异性CRE小鼠成功地实现了条件操作，将MHCII的表达限制在B细胞上。仅MHCII的B细胞表达就足以支持脑源性CD4T细胞介导的中枢神经系统(CNS)炎性脱髓鞘，但前提是B细胞能够高效识别靶抗原。基于这些观察，我们推测B细胞协调抗原特异性的CD4T细胞自身免疫破坏髓鞘的过程依赖于B细胞在中枢神经系统的定位和在EAE传播过程中对靶抗原的有效捕获。我们的目标是：1)确定EAE期间由B细胞抗原提呈介导的抗原特异性体液反应的需求；2)确定EAE期间中枢神经系统对B细胞抗原提呈的需求；3)确定B细胞耗尽对EAE和MS中树突状细胞(DC)抗原提呈的影响。本研究利用一种新的系统来探索B细胞抗原提呈在EAE中的作用，这个强大的小鼠遗传系统被优化设计来研究不同APC在不同免疫和自身免疫模型中的细胞贡献。此外，追踪接受B细胞去除治疗的MS患者DC的功能变化的研究将揭示抗原特异性B细胞对CD4T细胞功能的调节与用于治疗MS患者的B细胞治疗之间的关系。这些研究将提供对MS中B细胞免疫调节的机制理解，并为未来设计最优的B细胞和CD4T细胞治疗方法提供可能性。

DESCRIPTION (provided by applicant): Experimental autoimmune encephalomyelitis (EAE) is a CD4 T cell-dependent model for the human disease multiple (MS). Several antigen presenting cells (APCs) coordinate and regulate CD4 T cell function during immune responses. B cells likely have multiple roles in the pathogenesis of MS, with their capacity to function as APCs and drive auto-reactive CD4 T cell responses gaining more recognition. However, questions remain as to the importance of antigen presentation in the role for B cells in EAE and MS. We have designed a new tool in which individual subsets of APCs are capable of conditionally expressing MHCII in vivo. We successfully targeted a stop sequence flanked by loxP sites to the MHCII ¿ chain locus in mice in order to utilize the Cre/loxP system for conditional expression of MHCII. Successful conditional manipulation was achieved using B lineage-specific Cre mice, restricting expression of MHCII to B cells. B cell expression of MHCII alone was sufficient to support inflammatory demyelination of the central nervous system (CNS) mediated by encephalitogenic CD4 T cells, but only when B cells were highly efficient at recognizing target antigen. Based on these observations, we hypothesize that the process by which B cells coordinate antigen- specific CD4 T cell autoimmune destruction of myelin is dependent upon B cell localization to the CNS and efficient capture of target antigen during the propagation of EAE. We aim to: 1) Determine the requirement for antigen-specific humoral responses during EAE mediated by B cell antigen presentation; 2) Determine the requirement for B cell antigen presentation in the CNS compartment during EAE; and 3) Determine the effect of B cell depletion on dendritic cell (DC) antigen presentation in EAE and MS. While the proposal herein utilizes a novel system to explore the role of B cell antigen presentation during EAE, this powerful murine genetic system is optimally designed to investigate the cellular contributions by various APCs in different models of immunity and autoimmunity. Furthermore, studies pursuing functional alterations in DCs from MS patients receiving B cell depletion therapy will bring into context the relation between antigen specific B cell regulation of CD4 T cell function and B cell therapies used to treat patients with MS. These studies will provide mechanistic understanding of immune regulation by B cells in MS and offer potential for future design of optimal B cell and CD4 T cell therapeutics.