Regulation of B cells in the CNS

项目摘要 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 与各种B细胞亚群的招募有关，范围从幼稚、同型类未转换、同型 交换记忆B细胞(Bmem)和抗体分泌细胞(ASC)。ASC一直是研究的主要焦点 多发性硬化症、视神经脊髓炎和脑炎患者对自身抗原的反应性 疾病。然而，除了抗体分泌外，B细胞是免疫反应的重要调节器，其作用是 抗原提呈细胞，产生促炎和抗炎细胞因子，并参与三级细胞的形成 非淋巴器官中的淋巴结构(TLS)。TLS在慢性阻塞性肺疾病中加剧局部免疫反应 发炎。它们在脑膜中的存在与软膜下皮质脱髓鞘和残疾相关。 多发性硬化症的进展TLS的一个基本特征是脑膜基质细胞的激活，包括滤泡 网状细胞(FRC)，提供引导白细胞聚集和协调中枢神经系统的结构网络 免疫反应。激活的FRC通过上调粘蛋白类型的跨膜蛋白PDPN来标记， 淋巴趋化因子CXCL13、CCL19和CCL21、细胞外基质(ECM)和整合素，如ICAM-1， 它们共同支持基质壁龛中的免疫细胞相互作用。而一些慢性炎症性疾病 包括MS与持续激活的FRC依赖的TLS的形成有关，CNS病毒感染引发 在病毒RNA持续期间，尽管持续炎症，但FRC瞬时激活，没有TLS的证据。 FRC的上下文相关可塑性和/或异质性受到组织和损伤特定介质的支持 在不同的模型中，基质网络的激活和稳定形成慢性TLS。潜在的机制 中枢神经系统感染期间短暂和慢性脑膜FRC网络激活和TLS仍然存在 未被开发的。这项提议的目标是定义B细胞/基质细胞相互作用如何形成适应性抗病毒药物 嗜神经性冠状病毒急性和持续感染期间的免疫反应。具体的 目的是确定1)早期中枢神经系统积聚的B细胞在促进脑膜基质细胞中的作用 激活和2)支持中枢神经系统基质细胞激活的信号及其对局部B细胞分化和 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 依赖FRC激活，通过使用选择阻断方法来定义激活基质细胞的介体(抗 PDPN和-CD20治疗、LTβR阻断和特定细胞类型的LTβ消融)。目标2 测试在病毒控制期间用不同的免疫调节剂维持FRC激活的假设 在基质壁龛中招募B细胞，从而促进局部B细胞成熟。更好地理解互惠 定义的微环境中的FRC/B细胞相互作用将影响将FRC网络重塑为 改善抗菌功能，同时将病理后果降至最低。

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.