Immune Regulation of CNS Viral Recrudescence

描述（由申请人提供）：负责维持体液免疫的主要细胞类型是抗体分泌细胞（ASC）。外周感染后，ASC优先迁移到骨髓（BM），在骨髓中分化为长寿命的无根浆细胞（PC），专门分泌免疫球蛋白（Ig）。然而，ASC也被吸引到炎症部位，在那里它们可以像BM一样持续很长时间。鞘内抗体（Ab）合成在与神经系统并发症和脱髓鞘疾病多发性硬化症（MS）相关的感染期间得到了充分的证明。虽然抗体可能导致病理，但中枢神经系统（CNS）内的局部分泌也可能对控制嗜神经病毒具有保护作用。然而，B细胞向中枢神经系统的迁移和局部存活尚不清楚。本提案的总体目标是确定嗜神经性冠状病毒诱导的急性脑脊髓炎后中枢神经系统中介导ASC归巢、分化和维持的因素。我们已经证明，在感染病毒被清除后，病毒特异性ASC （vASC）在中枢神经系统中达到峰值，它们在高频率的保留可防止病毒复发。具体目的是：1)表征中枢神经系统内ASC的分化和特异性；2)识别调节vASC向中枢神经系统优先迁移的信号；3)确定中枢神经系统定位的Ag与趋化因子在调节ASC保留中的相对作用；4)证明BAFF是中枢神经系统内ASC的主要存活因子。使用一种新型转基因小鼠，称为bllimpgfp /+，流式细胞术和ELISPOT技术的结合将表征GFP+ ASC群体独特的中枢神经系统及其分化为无根PC的潜力。利用部分骨髓嵌合体和趋化因子抑制来评估病毒诱导的趋化因子作为中枢神经系统ASC募集到中枢神经系统的主要信号的作用。用示踪剂Ag免疫将监测病毒感染后“旁观者”ASC向中枢神经系统的招募和保留。了解与持续性中枢神经系统感染相关的体液免疫调节将揭示在人类中枢神经系统（即麻疹病毒、风疹病毒、JC病毒和HIV）持续感染期间鞘内ASC存活的新见解。它们在与有限持续炎症相关的病毒持久性模型中的保护作用可能将它们与慢性炎症性自身免疫性疾病中普遍存在的有害事件区分开来。

DESCRIPTION (provided by applicant): The major cell types responsible for maintaining humoral immunity are antibody secreting cells (ASC). Following peripheral infections, ASC preferentially migrate to bone marrow (BM), where they differentiate into long lived sessile plasma cells (PC) dedicated to immunoglobubulin (Ig) secretion. However, ASC are also drawn to inflammatory sites, where they can persist for prolonged periods similar to the BM. Intrathecal antibody (Ab) synthesis is well documented in humans during infections associated with neurological complications and the demyelinating disease multiple sclerosis (MS). Although antibody may contribute to pathology, local secretion within the central nervous system (CNS) may also be protective in controlling neurotropic viruses. However, B cell migration to the CNS, and local survival are poorly understood. The overall goal of this proposal is to identify factors mediating ASC homing, differentiation and maintenance in the CNS following acute encephalomyelitis induced by neurotropic coronavirus. We have shown that virus specific ASC (vASC) peak in the CNS after infectious virus is cleared and their retention at high frequencies prevents viral recrudescence. The Specific Aims are to 1) characterize differentiation and specificities of ASC within the CNS; 2) identify signals regulating preferential vASC migration into the CNS; 3) determine the relative role of CNS localized Ag versus chemokines in regulating ASC retention and 4) demonstrate that BAFF is the major survival factor for ASC within the CNS. Using a novel transgenic mouse, termed Blimpgfp/+, a combination of flow cytometry and ELISPOT techniques will characterize GFP+ ASC populations unique to the CNS and their potential to differentiate into sessile PC. The role of virus induced chemokines as major signals for CNS ASC recruitment into the CNS are assessed using partial bone marrow chimeras as well as chemokine inhibition. Immunization with a tracer Ag will monitor recruitment and retention of 'bystander' ASC to the CNS following viral infection. Understanding the regulation of humoral immunity associated with persistent CNS infection will reveal novel insights into intrathecal ASC survival during persistent infections of the human CNS, i.e. measles virus, rubella virus, JC virus, and HIV. Their protective role in a model of viral persistence associated with limited ongoing inflammation may distinguish them from detrimental events prevailing during chronic inflammatory autoimmune diseases.