Regulation of B cells in the CNS

项目摘要 由于病毒感染、组织损伤或自身免疫引起的中枢神经系统（CNS）炎症是 与各种B细胞亚群的募集相关，包括幼稚、同种型类别未转换、同种型 转换记忆B细胞（BCLs）和抗体分泌细胞（ASC）。ASC一直是研究的主要焦点 由于它们对多发性硬化症（MS）、视神经肌萎缩症和Ab脑炎中的自身抗原的反应性， 疾病然而，除了Ab分泌之外，B细胞通过充当免疫应答的调节剂而成为免疫应答的重要调节剂。 抗原提呈细胞，产生促炎和抗炎细胞因子，并参与形成三级 非淋巴器官中的淋巴样结构（TLS）。TLS在慢性炎症期间加重局部免疫反应 炎症它们在脑膜中的存在与软膜下皮质脱髓鞘和残疾相关 TLS的一个潜在特征是脑膜基质细胞的激活，包括滤泡细胞， 网状细胞（FRC），提供引导白细胞聚集和协调CNS的结构网络 免疫反应。激活的FRC以粘蛋白型跨膜蛋白PDPN的上调为标志， 淋巴样趋化因子CXCL 13、CCL 19和CCL 21，细胞外基质（ECM）和整联蛋白，例如ICAM-1， 它们一起支持基质小生境中的免疫细胞相互作用。虽然一些慢性炎症性疾病 包括MS与持续活化的FRC依赖性TLS形成、CNS病毒感染诱发 短暂FRC激活，尽管在病毒RNA持续存在期间持续炎症，但无TLS证据。 FRC的环境依赖性可塑性和/或异质性得到组织和损伤特异性介质的支持， 基质网络活化和稳定化以在不同模型中形成慢性TLS。的机制 CNS感染期间的短暂与慢性脑膜FRC网络激活和TLS仍然存在 未开发的本提案的目的是确定B细胞/基质细胞相互作用如何形成适应性抗病毒药物 嗜神经冠状病毒建立的急性和持续感染期间的免疫应答。具体 目的是确定1）早期CNS积聚B细胞在促进脑膜基质细胞增殖中的作用 活化和2）维持CNS基质细胞活化的信号和对局部B细胞分化的影响， 多样性以及对病毒持久性的控制。我们将检验IgD+ B细胞参与LTβR的假设 通过使用选择性阻断方法来定义激活基质细胞的介质（抗- PDPN和-CD 20治疗、LTβR阻断和细胞类型特异性LTβ消融）。目的2 检验了在病毒控制期间使用不同免疫调节剂维持FRC活化保留 在基质龛中募集B细胞，从而促进局部B细胞成熟。更好地理解互惠 FRC/B细胞在特定微环境中的相互作用将影响重塑FRC网络的策略， 提高抗微生物功能，同时使病理后果最小化。

Project Summary Central nervous system (CNS) inflammation as a result of viral infection, tissue injury, or autoimmunity is associated with recruitment of various B cell subsets ranging from naïve, isotype class unswitched, isotype switched memory B cells (Bmem) and antibody secreting cells (ASC). ASC have been a major focus of research due to their reactivity to autoantigens in multiple sclerosis (MS), neuromyelitis optica and Ab encephalitic diseases. However, beyond Ab secretion B cells are important modulators of immune responses by serving as antigen presenting cells, producing pro- and anti-inflammatory cytokines, and participating in formation of tertiary lymphoid structures (TLS) in non-lymphoid organs. TLS exacerbate local immune responses during chronic inflammation. Their presence in the meninges correlates with subpial cortical demyelination and disability progression in MS. An underlying feature of TLS is the activation of meningeal stromal cells, including follicular reticular cells (FRC) which provide a structural network guiding leukocyte accumulation and orchestrating CNS immune responses. Activated FRC are marked by upregulation of the mucin-type transmembrane protein PDPN, lymphoid chemokines CXCL13, CCL19 and CCL21, extracellular matrix (ECM) and integrins, such ICAM-1, which together support immune cell interactions in stromal niches. While some chronic inflammatory diseases including MS are associated with sustained activated FRC dependent TLS formation, CNS viral infection elicits transient FRC activation with no evidence for TLS despite ongoing inflammation during viral RNA persistence. Context dependent plasticity and/or heterogeneity of FRC is supported by tissue and insult specific mediators of stromal network activation and stabilization to form chronic TLS in distinct models. The mechanisms underlying transient versus chronic meningeal FRC network activation and TLS during CNS infections remain unexplored. The goal of this proposal is to define how B cell/stromal cell interactions shape adaptive antiviral immune responses during acute and persistent infection established by neurotropic coronavirus. The Specific Aims are to determine 1) the role of early CNS accumulating B cells in promoting meningeal stromal cell activation and 2) signals sustaining CNS stromal cell activation and effects on local B cell differentiation and diversity as well as control of viral persistence. We will test the hypothesis that IgD+ B cells participate in LTβR dependent FRC activation by using select blocking approaches to define mediators activating stromal cells (anti- PDPN and -CD20 treatment, LTβR blockade and cell type specific LTβ ablation) during acute infection. Aim 2 tests the hypothesis that sustaining FRC activation with distinct immune modulators during viral control retains recruited B cells in stromal niches, thereby promoting local B cell maturation. A better understanding of reciprocal FRC/B cell interactions within defined microenvironments will impact strategies to remodel FRC networks to improve antimicrobial function, while minimizing pathological consequences.