The role of B cells in the inflamed central nervous system: antigen presentation and phenotype-related migration

多发性硬化症（MS）是一种中枢神经系统（CNS）的慢性炎症性疾病。在多发性硬化症中测试B细胞消耗抗体的临床试验使B细胞成为人们关注的焦点。B细胞可能在中枢神经系统自身免疫性疾病的发病机制中起双重作用。除了作为分泌潜在致病抗体的浆细胞来源外，它们还可能作为抗原提呈细胞（APC）促进自身反应性T细胞的激活，从而促进疾病的发展。与这些致病性功能相反，b细胞亚群可能发挥调节特性，这些特性在治疗性b细胞耗竭的同时被消除，这是一种不利的效应。T细胞的激活发生在APC上的主要组织相容性复合体（MHC） II的背景下。与树突状细胞和巨噬细胞一样，B细胞是专业的APC，组成性地表达MHC II。该项目的第一部分旨在阐明B细胞在中枢神经系统自身免疫性疾病中对MHC ii限制性抗原呈递的贡献。建立一种新的转基因小鼠模型，其中MHC II的表达仅限于B细胞，我们将测试B细胞单独抗原呈递是否足以启动MS动物模型，实验性自身免疫性脑脊髓炎（EAE）。数据表明，活化的致病性B细胞特异性地迁移到发炎的中枢神经系统，而antigen-naïve B细胞可能调节外周的自身免疫过程。为了验证这一假设，本项目的第二个目标将通过EAE的体内成像来监测不同b细胞表型的迁移。此外，基于致病性b细胞功能的潜在区隔化，将对EAE小鼠局部（鞘内）应用b细胞消耗抗体进行测试。如果中枢神经系统的致病B细胞特性可以因此被废除，同时保留外周的调节性B细胞，这种方法可能成为MS的未来治疗选择。

Multiple Sclerosis (MS) is a chronic inflammatory disorder of the central nervous system (CNS). Promising clinical trials testing B-cell depleting antibodies in MS have brought B cells into the spotlight. B cells may play a dual role in the pathogenesis of CNS autoimmune disease. Besides serving as the source of plasma cells secreting potentially pathogenic antibodies, they may also contribute to disease development as antigen presenting cells (APC) for activation of autoreactive T cells. In contrast to these pathogenic functions B-cell subsets may exert regulatory properties which are collaterally abolished by therapeutic B-cell depletion - an effect that is not favourable.Activation of T cells occurs in the context of Major histocompatibility complex (MHC) II on APC. Like dendritic cells and macrophages, B cells are professional APC and express MHC II constitutively. The first part of this project aims to elucidate the contribution of B cells to MHC II-restricted antigen presentation in CNS autoimmune disease. Creating a novel transgenic mouse model in which MHC II expression is restricted to B cells, we will test whether antigen presentation by B cells alone is sufficient to initiate the animal model of MS, experimental autoimmune encephalomyelitis (EAE).Data suggest that activated pathogenic B cells specifically migrate into the inflamed CNS, whereas antigen-naïve B cells may regulate autoimmune processes in the periphery. In order to test this hypothesis, in the second aim of this project migration of different B-cell phenotypes will be monitored by in vivo imaging in EAE. Additionally, and based on a potential compartmentalization of pathogenic B-cell function, local (intrathecal) application of B-cell depleting antibodies into mice with EAE will be tested. In case that pathogenic B-cell properties in the CNS can hereby be abrogated while sparing regulatory B cells in the periphery, this approach could constitute a future therapeutic option for MS.