Regulation of B cells in the CNS

摘要 中枢神经系统（CNS）内的抗体（Ab）产生和B细胞的存在是良好的。 在患有脱髓鞘疾病多发性硬化症（MS）的人和患有 嗜神经性感染他们在MS中的作用目前尚不清楚。然而，有害的体液反应是 由于异位B细胞卵泡形成以及MS改善而导致的持续免疫激活暗示了这一点 用抗CD20单克隆抗体利妥昔单抗治疗以减少循环B细胞的患者。抗体分泌细胞 (ASC)如果抗体与自身抗原发生交叉反应或直接靶向自身抗原，也是有害的。相比之下， 病毒CNS感染鞘内体液应答与保护功能有关。当地生产 抗病毒抗体与CNS内的持续免疫控制一致，而没有明显的病理学提示 有效的非溶解性抗病毒作用。此外，临床上不明显的疾病失控的潜在危险 持续存在的病毒通过以下进行性多灶性白质脑病的发展变得明显： 利妥昔单抗治疗类风湿性关节炎和MS的治疗过程中。 在不同的神经炎症环境中的体液免疫，中枢神经系统中抗体的产生如何持续， 支持ASC分化的B细胞群体和环境因素仍然很少被表征。 该提案使用了一种嗜神经性冠状病毒模型，该模型与急性和持续性感染相关， 脱髓鞘，以确定外周和CNS体液反应之间的相互作用， Ab生产。总体目标是拓宽对炎症性疾病治疗选择的见解， MS，不引起内源性病毒的出现，以及针对急性病毒性脑炎。三 追求具体目标。目的1将明确外周淋巴组织来源的B细胞在淋巴结转移中的作用。 补充和维持CNS内的ASC。结果将揭示CNS内的所有B细胞是否都是 以及迁移到CNS的ASC是否在CNS内分化， 生活ASC此外，未探索的非Ab产生记忆B细胞（BCLs）对CNS体液免疫的作用， 将确定豁免权。抗原和CD4 T细胞在促进B细胞向无蒂分化中的作用 将分别在目标2和3中确定CNS内的ASC。方法基于免疫接种 用荧光标记来自生发中心的B细胞以分离ASC的转基因小鼠， 收养转移的许可证。他们的中枢神经系统迁移，分化和保护能力将在 抗体产生缺陷的受体。通过供体B细胞的变化来检查同源Ag的影响 特殊性和煽动性的侮辱将通过CD4 T细胞消融和补充来评估T细胞“帮助” 接近。研究结果将首次确定调节保护性和致病性的参数 在人类自身免疫和CNS感染期间与B细胞相关的应答。

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.