ROLE OF B CELL ANTIGEN PRESENTATION IN AUTOIMMUNE ENCEPHALOMYELITIS

B 细胞抗原呈递在自身免疫性脑脊髓炎中的作用

• 批准号: 8687759
• 负责人: Gregory Wu
• 金额: $ 32.92万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-01 至 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8687759
• 关键词: Address; Affect; Aftercare; Animal Model; Antibodies; Antibody Formation; Antigen Presentation; Antigen Receptors; Antigen Targeting; Antigen-Presenting Cells; Antigens; Autoimmune Process; Autoimmunity; B-Lymphocytes; Blood - brain barrier anatomy; Brain; CD4 Positive T Lymphocytes; Cell Therapy; Cell physiology; Cells; Clinical; Cre-LoxP; Demyelinations; Dendritic Cells; Disease; Disease Progression; Disease model; Dose; Ensure; Experimental Autoimmune Encephalomyelitis; Frequencies; Future; Genetic; Genetically Engineered Mouse; Goals; Immune; Immune response; Immunity; Immunoglobulins; Individual; Inflammation; Inflammatory; Lymphoid Follicle; MS4A1 gene; Major Histocompatibility Complex; Mediating; Meninges; Modeling; Multiple Sclerosis; Mus; Myelin; Neuraxis; Outcome; Pathogenesis; Patients; Phase; Play; Population; Process; Production; Regulation; Relapsing-Remitting Multiple Sclerosis; Role; Site; Spinal Cord; Staging; System; T cell response; T-Cell Activation; T-Cell Proliferation; Testing; Therapeutic; Time; base; cytokine; design; human disease; in vivo; novel; prevent; public health relevance; response; tool; trafficking; treatment strategy

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.

描述（由申请人提供）：实验性自身免疫性脑脊髓炎（EAE）是人类疾病多发性（MS）的CD4 T细胞依赖模型。几种抗原提呈细胞（APCs）在免疫应答过程中协调和调节CD4 T细胞的功能。B细胞在MS的发病机制中可能有多种作用，它们作为apc的功能和驱动自身反应性CD4 T细胞反应的能力得到了更多的认可。然而，抗原呈递对B细胞在EAE和ms中的作用的重要性仍然存在疑问。我们设计了一个新的工具，其中apc的单个亚群能够在体内有条件地表达MHCII。为了利用Cre/loxP系统条件表达MHCII，我们成功地将一个loxP位点两侧的停止序列靶向到小鼠MHCII¿链位点上。使用B系特异性Cre小鼠成功地实现了条件操作，限制了MHCII在B细胞中的表达。B细胞单独表达MHCII足以支持脑源性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细胞自身免疫破坏髓磷脂的过程依赖于B细胞定位到中枢神经系统和在EAE繁殖过程中有效捕获目标抗原。我们的目标是：1)确定B细胞抗原呈递介导的EAE对抗原特异性体液反应的需求；2)测定EAE时中枢神经室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。本研究利用一个新的系统来探索B细胞抗原呈递在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细胞耗竭治疗的MS患者dc功能改变的研究将使抗原特异性B细胞对CD4 T细胞功能的调节与用于治疗MS患者的B细胞疗法之间的关系成为可能。这些研究将提供MS中B细胞免疫调节的机制理解，并为未来设计最佳的B细胞和CD4 T细胞疗法提供可能。