Regulation of B cells in the CNS

CNS 中 B 细胞的调节

• 批准号: 8869063
• 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 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8869063
• 关键词: Abbreviations; 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 - brain barrier anatomy; Blood Circulation; Bone Marrow; CD19 gene; CD4 Positive T Lymphocytes; Central Nervous System Infections; Central Nervous System Viral Diseases; Chronic; Coronavirus; Demyelinating Diseases; Demyelinations; Detection; Development; Disease; Encephalomyelitis; Environment; Environmental Risk Factor; Fluorescence; Goals; Health; Human; Humoral Immunities; Immune; Immune response; Immunization; Immunoglobulin Class Switching; Immunoglobulin G; Immunoglobulin-Secreting Cells; Immunoglobulins; Immunohistochemistry; Infection; Inflammatory; Life; Lymphoid; Lymphoid Follicle; Lymphoid Tissue; Lytic; Mediating; Memory B-Lymphocyte; Modeling; Monitor; Monoclonal Antibody CD20; Multiple Sclerosis; Murine hepatitis virus; Neuraxis; Organ; Pathology; Patients; Peripheral; Plasma Cells; Population; Production; Progressive Multifocal Leukoencephalopathy; Recrudescences; Recruitment Activity; Regulation; Relative (related person); Rheumatoid Arthritis; Role; Serum; Site; Source; Specificity; Spleen; Stimulus; Structure of germinal center of lymph node; Subacute Sclerosing Panencephalitis; Supplementation; T-Lymphocyte; Testing; Time; Transgenic Mice; Variant; Viral; Viral Antibodies; Viral Encephalitis; Virus; Virus Diseases; base; chemokine receptor; defined contribution; immune activation; insight; lymph nodes; migration; migratory population; neuroinflammation; neurotropic; novel; residence; response; rituximab; trafficking

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）：在患有脱髓鞘疾病、多发性硬化症（MS）和患有嗜神经性感染的人类中，中枢神经系统（CNS）内抗体（Ab）的产生和B细胞的存在已有充分记录。目前尚不清楚它们在多发性硬化症中的作用。然而，由于异位 B 细胞滤泡形成而导致的持续免疫激活，以及用抗 CD20 单克隆 Ab 利妥昔单抗治疗以减少循环 B 细胞的 MS 患者的改善，暗示着有害的体液反应。如果抗体与自身抗原发生交叉反应或直接靶向自身抗原，那么抗体分泌细胞 (ASC) 也是有害的。相比之下，在病毒性中枢神经系统感染期间，鞘内体液反应与保护功能相关。局部产生的抗病毒抗体与中枢神经系统内的持续免疫控制相一致，没有明显的病理学暗示有效的非裂解性抗病毒作用。此外， 在类风湿性关节炎和多发性硬化症治疗期间，利妥昔单抗治疗后出现进行性多灶性白质脑病，从而使临床上不明显的持续性病毒失去控制的潜在危险变得明显。尽管体液免疫在不同的神经炎症环境中具有生物学意义，但中枢神经系统中抗体的产生如何持续以及哪些 B 细胞群和环境因素支持 ASC 的分化仍然知之甚少。 该提案使用与脱髓鞘相关的急性和持续感染的神经性冠状病毒模型来定义外周和中枢神经系统体液反应在支持中枢神经系统抗体产生中的相互作用。总体目标是拓宽对多发性硬化症等炎症性疾病治疗方案的认识，同时不会引起内源性病毒的出现，并针对急性病毒性脑炎。追求三个具体目标。目标 1 将定义外周淋巴组织衍生的 B 细胞在补充和维持 CNS 内 ASC 方面的贡献。结果将揭示中枢神经系统内的所有 B 细胞是否均源自生发中心，以及迁移至中枢神经系统的 ASC 是否在中枢神经系统内分化成为长寿的 ASC。此外，还将定义不产生抗体的记忆 B 细胞 (Bmem) 对 CNS 体液免疫的未探索的作用。抗原 (Ag) 和 CD4 T 细胞在促进 CNS 内 B 细胞分化为无柄 ASC 中的作用将分别在目标 2 和 3 中确定。这些方法基于转基因小鼠的免疫，其中生发中心来源的 B 细胞通过荧光标记，以分离 ASC 和 Bmem 进行过继转移。将在抗体产生缺陷的接受者中监测它们的中枢神经系统迁移、分化和保护能力。通过供体 B 细胞特异性的变化和炎症损伤来检查同源 Ag 的影响。 T 细胞的“帮助”将通过 CD4 T 细胞消融和补充方法进行评估。该结果将首次定义调节人类自身免疫和中枢神经系统感染期间与 B 细胞相关的保护性和致病性反应的参数。