Regulation of B cells in the CNS

描述（由申请人提供）：在患有脱髓鞘疾病多发性硬化症（MS）和嗜神经性感染的患者中，中枢神经系统（CNS）中抗体（Ab）的产生和B细胞的存在是有充分记录的。它们在多发性硬化症中的作用目前尚不清楚。然而，由于异位B细胞卵泡形成导致的持续免疫激活，以及使用抗cd20单克隆Ab利妥昔单抗治疗减少循环B细胞的MS患者的改善，都暗示了有害的体液反应。如果Ab与自身抗原发生交叉反应或直接靶向自身抗原，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有关。局部产生的抗病毒抗体与中枢神经系统内持续的免疫控制一致，没有明显的病理暗示有效的非溶性抗病毒作用。此外,

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.