Regulation of B cells in the CNS

CNS 中 B 细胞的调节

• 批准号: 9296196
• 负责人: Cornelia Bergmann
• 金额: $ 34.67万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-15 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9296196
• 关键词: Ablation; Acute; Adoptive Transfer; Affinity; Antibodies; Antibody Formation; Antigens; Autoantigens; Autoimmune Process; Autoimmunity; Automobile Driving; B cell differentiation; B-Lymphocyte Subsets; B-Lymphocytes; Biological; Blood; Blood Circulation; Bone Marrow; CD19 gene; CD4 Positive T Lymphocytes; Central Nervous System Infections; Central Nervous System Viral Diseases; Chronic; Clinical; Coronaviridae; Coronavirus; Demyelinating Diseases; Demyelinations; Detection; Development; Disease; Encephalomyelitis; Environment; Environmental Risk Factor; Fluorescence; Goals; Human; Humoral Immunities; Immune; Immune response; Immunization; Immunoglobulin Class Switching; Immunoglobulin G; Immunoglobulin-Secreting Cells; Infection; Inflammatory; Lymphoid; Lymphoid Follicle; Lymphoid Tissue; Mediating; Memory B-Lymphocyte; Modeling; Monitor; Monoclonal Antibody CD20; Multiple Sclerosis; Neuraxis; Organ; Pathogenicity; Pathology; Peripheral; Plasma Cells; Population; Production; Progressive Multifocal Leukoencephalopathy; Recrudescences; Recruitment Activity; Regulation; Rheumatoid Arthritis; Role; Serum; Site; Source; Specificity; Spleen; Stimulus; Structure of germinal center of lymph node; Supplementation; T-Lymphocyte; Testing; Time; Transgenic Mice; Variant; Viral; Viral Antibodies; Viral Encephalitis; Virus; Virus Diseases; base; chemokine receptor; cross reactivity; defined contribution; differentiated B cell; immune activation; inflammatory milieu; insight; lymph nodes; migration; migratory population; multiple sclerosis patient; neuroinflammation; neurotropic; novel; public health relevance; residence; response; rituximab

DESCRIPTION (provided by applicant): Antibody (Ab) production and the presence of B cells within the central nervous system (CNS) is well documented in humans with the demyelinating disease multiple sclerosis (MS) and those afflicted by neurotropic infections. Their role in MS is currently unclear. However, detrimental humoral responses are implied by ongoing immune activation due to ectopic B cell follicle formation, as well as improvement in MS patients treated with anti-CD20 monoclonal Ab rituximab to reduce circulating B cells. Antibody secreting cells (ASC) are also detrimental if Ab are cross-reactive with, or directly target, self antigens. By contrast, during viral CNS infections intrathecal humoral responses are associated with protective functions. Locally produced anti-viral Ab coincide with sustained immune control within the CNS without overt pathology implicating a potent non lytic anti-viral role. Furthermore, the potential danger of losing control of clinically inapparent persisting viruses became apparent by development of progressive multifocal leukoencephalopathy following rituximab treatment during therapy for rheumatoid arthritis and MS. Despite the biological significance of humoral immunity in diverse settings of neuroinflammation, how Ab production in the CNS is sustained and which B cell populations and environmental factors support differentiation of ASC remain poorly characterized. This proposal uses a neurotropic coronavirus model of acute and persistent infection associated with demyelination to define the interactions between peripheral and CNS humoral responses in supporting CNS Ab production. The overall goal is to broaden insights into treatment options for inflammatory diseases such as MS, without provoking emergence of endogenous viruses, as well as targeting acute viral encephalitis. Three Specific Aims are pursued. Aim 1 will define the contribution of peripheral lymphoid tissue derived B cells in replenishing and maintaining ASC within the CNS. Results will reveal whether all B cells within the CNS are germinal center derived, and whether ASC migrating to the CNS differentiate within the CNS to become long lived ASC. Furthermore, the unexplored role of non Ab producing memory B cells (Bmem) to CNS humoral immunity will be defined. The role of antigen (Ag) and CD4 T cells in promoting B cell differentiation to sessile ASC within the CNS will be determined in Aims 2 and 3, respectively. Approaches are based on immunization of transgenic mice in which germinal center derived B cells are marked by fluorescence to isolate ASC and Bmem for adoptive transfer. Their CNS migration, differentiation and protective capacity will be monitored in recipients defective in Ab production. The influence of cognate Ag is examined by variations in donor B cell specificities, and inflammatory insult. T cell "help" will be assessed b CD4 T cell ablation and supplementation approaches. The results will for the first time define the parameters regulating both protective and pathogenic responses associated with B cells during human autoimmunity and CNS infections.

描述（由申请人提供）：中枢神经系统（CNS）内的抗体（AB）产生（CNS）的存在在患有脱髓鞘性疾病多发性硬化症（MS）的人类中，以及神经旋转感染的疾病。他们在MS中的作用目前尚不清楚。然而，由于异位B细胞卵泡形成引起的持续的免疫激活暗示了有害的体液反应，以及用抗CD20单克隆AB利妥昔单抗治疗的MS患者的改善，以减少循环的B细胞。如果AB与或直接靶向自抗原，则抗体分泌细胞（ASC）也有害。相比之下，在病毒中枢神经系统感染期间，鞘内体液反应与保护功能有关。局部产生的抗病毒AB与中枢神经系统内的持续免疫控制一致，而没有明显的病理，这涉及有效的非裂解抗病毒作用。此外， 在治疗类风湿关节炎和MS治疗期间，在利妥昔单抗治疗后进行性多焦点白血病患者的发展，失去控制临床不存在病毒的潜在危险变得显而易见。尽管在神经炎症的各种环境中，体液免疫具有生物学意义，但中枢神经系统中的AB产生如何持续以及哪些B细胞群体和环境因素支持ASC的区分仍然很差。 该提案使用与脱髓鞘相关的急性和持续感染的神经冠状病毒模型，以定义外围和中枢神经系统的体液反应之间的相互作用，以支持CNS AB产生。总体目标是扩大对炎症性疾病（例如MS）的治疗选择的见解，而不会引起内源性病毒的出现以及靶向急性病毒性脑炎。追求三个具体目标。 AIM 1将定义周围淋巴组织衍生的B细胞在CNS内补充和维持ASC时的贡献。结果将揭示中枢神经系统内的所有B细胞是否均为生发中心，以及ASC是否迁移到中枢神经系统中的中枢神经系统中CNS内的分化，以变为长期的ASC。此外，将定义非AB产生记忆B细胞（BMEM）对CNS体液免疫的未开发作用。抗原（Ag）和CD4 T细胞在促进B细胞分化为CNS内的副ASC中的作用将分别在目标2和3中确定。方法是基于转基因小鼠的免疫，其中生发中心衍生的B细胞以荧光标记，以分离ASC和BMEM以进行过继转移。他们的中枢神经系统迁移，差异化和保护能力将在受体中有缺陷的AB生产中受到监测。通过供体B细胞特异性和炎症性损伤的变化来检查同源Ag的影响。 T细胞“帮助”将评估B CD4 T细胞消融和补充方法。结果将首次定义在人自身免疫和中枢神经系统感染期间调节与B细胞相关的保护性和致病反应的参数。