Regulation of B cells in the CNS

CNS 中 B 细胞的调节

• 批准号: 10574598
• 负责人: Cornelia Bergmann
• 金额: $ 37.84万
• 依托单位: CLEVELAND CLINIC LERNER COM-CWRU
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-15 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10574598
• 关键词: Abbreviations; Ablation; Acute; Anti-Inflammatory Agents; Antibodies; Antigen-Presenting Cells; Antigens; Area; Autoantigens; Autoimmune; Autoimmune encephalitis; Autoimmunity; B cell differentiation; B-Cell Activation; B-Lymphocyte Subsets; B-Lymphocytes; Binding; Biological Assay; Blood Vessels; CCL19 gene; CCL21 gene; CXCL13 gene; Cell Aggregation; Cell Communication; Cell Maturation; Cells; Central Nervous System; Central Nervous System Infections; Central Nervous System Viral Diseases; Chronic; Coronavirus; Cues; Demyelinating Diseases; Demyelinations; Disease; Experimental Models; Flow Cytometry; Goals; Heterogeneity; Histologic; Histology; Human; Immune; Immune response; Immunity; Immunoglobulin Class Switching; Immunoglobulin D; Immunoglobulin M; Immunoglobulin-Secreting Cells; Immunoglobulins; Immunomodulators; Infection; Infiltration; Inflammation; Integral Membrane Protein; Integrins; Intercellular adhesion molecule 1; Interleukin-13; Investigation; Knowledge; Leukocytes; Lymphoid; MS4A1 gene; Mediating; Mediator; Memory B-Lymphocyte; Meningeal; Meninges; Modeling; Mucins; Multiple Sclerosis; Murine hepatitis virus; Neuromyelitis Optica; Organ; Pathogenicity; Pathologic; Pathology; Peripheral; Phase; Play; Population; Positioning Attribute; Receptor Signaling; Recombinants; Regulation; Research; Resolution; Reticular Cell; Role; Shapes; Signal Transduction; Site; Specificity; Stromal Cells; Structure; Structure of germinal center of lymph node; Testing; Tissues; Tumor Necrosis Factor-Beta; Up-Regulation; Viral; Viral Physiology; Viral hepatitis; Virus; Virus Diseases; acute infection; adaptive immune response; antimicrobial; cell type; chemokine; chronic infection; chronic inflammatory disease; cytokine; disability; enzyme linked immunospot assay; immune activation; improved; interleukin-22; lymph nodes; lymphotoxin beta; lymphotoxin beta receptor; microbial; migration; multiple sclerosis patient; neurotropic; novel strategies; podoplanin; recruit; response; scaffold; secondary lymphoid organ; tertiary lymphoid organ; tissue injury; vector; viral RNA

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.

项目概要 病毒感染、组织损伤或自身免疫导致的中枢神经系统 (CNS) 炎症是 与各种 B 细胞亚群的募集相关，包括幼稚的、同种型类别未转换的、同种型的 切换记忆 B 细胞 (Bmem) 和抗体分泌细胞 (ASC)。 ASC一直是研究的重点 由于它们对多发性硬化症 (MS)、视神经脊髓炎和 Ab 脑炎中的自身抗原有反应 疾病。然而，除了抗体分泌之外，B 细胞也是免疫反应的重要调节剂，其作用是 抗原呈递细胞，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 会加剧慢性疾病期间的局部免疫反应 炎。它们在脑膜中的存在与软膜下皮质脱髓鞘和残疾相关 MS 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）提供指导白细胞积累和协调中枢神经系统的结构网络 免疫反应。激活的 FRC 的标志是粘蛋白型跨膜蛋白 PDPN 的上调， 淋巴趋化因子 CXCL13、CCL19 和 CCL21、细胞外基质 (ECM) 和整合素，例如 ICAM-1， 它们共同支持基质微环境中免疫细胞的相互作用。而一些慢性炎症性疾病 包括 MS 与持续激活的 FRC 依赖性 TLS 形成相关，中枢神经系统病毒感染引发 尽管病毒 RNA 持续存在期间持续存在炎症，但 FRC 短暂激活，没有 TLS 的证据。 FRC 的环境依赖性可塑性和/或异质性由组织和损伤特异性介质支持 基质网络激活和稳定以在不同模型中形成慢性 TLS。其背后的机制 CNS 感染期间短暂与慢性脑膜 FRC 网络激活和 TLS 仍然存在 未经探索。该提案的目标是定义 B 细胞/基质细胞相互作用如何塑造适应性抗病毒药物 嗜神经冠状病毒引起的急性和持续感染期间的免疫反应。具体 目的是确定 1) 早期 CNS 积累的 B 细胞在促进脑膜基质细胞中的作用 激活和 2) 维持中枢神经系统基质细胞激活的信号以及对局部 B 细胞分化和 多样性以及病毒持久性的控制。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 急性感染期间的 PDPN 和 -CD20 治疗、LTβR 阻断和细胞类型特异性 LTβ 消融。目标2 检验了以下假设：在病毒控制期间用不同的免疫调节剂维持 FRC 激活保留 在基质微环境中募集 B 细胞，从而促进局部 B 细胞成熟。更好地理解相互关系 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，同时最大限度地减少病理后果。