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）是人类多发性疾病（MS）的 CD4 T 细胞依赖性模型。多种抗原呈递细胞 (APC) 在免疫反应过程中协调和调节 CD4 T 细胞功能。 B 细胞可能在 MS 的发病机制中发挥多种作用，它们作为 APC 发挥作用并驱动自身反应性 CD4 T 细胞反应的能力得到了更多的认可。然而，关于抗原呈递对于 B 细胞在 EAE 和 MS 中的作用的重要性仍然存在疑问。我们设计了一种新工具，其中 APC 的各个子集能够在体内有条件地表达 MHCII。我们成功地将侧翼为 loxP 位点的终止序列靶向小鼠的 MHCII ¿ 链基因座，以便利用 Cre/loxP 系统条件表达 MHCII。使用 B 谱系特异性 Cre 小鼠成功实现了条件操作，将 MHCII 的表达限制在 B 细胞上。仅 B 细胞表达 MHCII 就足以支持由致脑炎 CD4 T 细胞介导的中枢神经系统 (CNS) 炎症性脱髓鞘，但前提是 B 细胞能够高效识别靶抗原。基于这些观察结果，我们假设 B 细胞协调抗原特异性 CD4 T 细胞自身免疫性破坏髓磷脂的过程取决于 B 细胞定位到 CNS 以及在 EAE 传播过程中有效捕获靶抗原。我们的目标是： 1) 确定 B 细胞抗原呈递介导的 EAE 期间对抗原特异性体液反应的需求； 2) 确定EAE期间CNS室中B细胞抗原呈递的要求； 3) 确定 B 细胞耗竭对 EAE 和 MS 中树突状细胞 (DC) 抗原呈递的影响。虽然本文的提议利用一种新的系统来探索 B 细胞抗原呈递在 EAE 过程中的作用，但这种强大的小鼠遗传系统经过优化设计，可研究各种 APC 在不同免疫和自身免疫模型中的细胞贡献。此外，对接受 B 细胞耗竭疗法的多发性硬化症患者的 DC 进行功能改变的研究将了解 CD4 T 细胞功能的抗原特异性 B 细胞调节与用于治疗多发性硬化症患者的 B 细胞疗法之间的关系。这些研究将提供对 MS 中 B 细胞免疫调节的机制理解，并为未来设计最佳 B 细胞和 CD4 T 细胞疗法提供潜力。

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.