Regulation of B cells in the CNS

CNS 中 B 细胞的调节

基本信息

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
项目类别：
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

项目摘要

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.