Regulation of B cells in the CNS

CNS 中 B 细胞的调节

• 批准号: 8652162
• 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 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8652162
• 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; 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; public health relevance; residence; response; rituximab; trafficking

ABSTRACT 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 by 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.

抽象的 抗体（AB）产生和中枢神经系统内B细胞的存在很好 在人类中记录了脱髓鞘疾病多发性硬化症（MS），而疾病 神经性感染。他们在MS中的作用目前尚不清楚。但是，有害的体液反应是 由于异位B细胞卵泡的形成引起的持续免疫激活所暗示，并改善了MS 用抗CD20单克隆AB利妥昔单抗治疗的患者可减少循环的B细胞。抗体分泌细胞 （ASC）如果AB与或直接靶向自抗原，AS也有害。相比之下， 病毒中枢神经系统感染鞘内体液反应与保护功能有关。本地生产 抗病毒AB与中枢神经系统内的持续免疫控制一致，没有明显的病理学 有效的非裂解抗病毒作用。此外，失去对临床上不适当的控制的潜在危险 持续存在的病毒变得显而易见 在治疗类风湿关节炎和MS的治疗过程中，利妥昔单抗治疗。尽管具有生物学意义 神经炎症的各种环境中的体液免疫力，如何维持中枢神经系统的AB产生以及 哪些B细胞群体和环境因素支持ASC的分化仍然很差。 该提案使用与急性和持续感染的神经性冠状病毒模型 脱髓鞘以定义支撑CNS中外周和中枢体响应之间的相互作用 AB生产。总体目标是扩大对炎症性疾病的治疗选择的见解，例如 MS，没有引起内源性病毒的出现，也没有靶向急性病毒脑炎。三 追求具体目标。 AIM 1将定义周围淋巴组织衍生的B细胞的贡献 在中枢神经系统内补充和维护ASC。结果将揭示中枢神经系统中的所有B细胞是否为 生发中心得出的中心，以及ASC是否迁移到中枢神经系统中的中心会变长以变长 生活ASC。此外，非AB产生记忆B细胞（BMEM）对CNS的尚未探索的作用 免疫将被定义。抗原（Ag）和CD4 T细胞在促进B细胞分化为无梗中的作用 中枢神经系统内的ASC将分别在目标2和3中确定。方法基于免疫 荧光标记生发中心衍生的B细胞的转基因小鼠的构造，以分离ASC和 BMEM进行收养。他们的中枢神经系统迁移，差异化和保护能力将受到监控 接受者在AB生产中有缺陷。供体B细胞的变化来检查同源Ag的影响 特异性和炎症性侮辱。 T细胞“帮助”将通过CD4 T细胞消融和补充评估 方法。结果将首次定义调节保护性和致病性的参数 人自身免疫和中枢神经系统感染期间与B细胞相关的反应。