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

多发性硬化(MS)是一种慢性中枢神经系统炎症性疾病。测试多发性硬化症B细胞耗竭抗体的有前景的临床试验将B细胞带到了聚光灯下。B细胞在中枢神经系统自身免疫性疾病的发病机制中可能起双重作用。除了作为浆细胞分泌潜在致病抗体的来源外，它们还可能作为抗原提呈细胞(APC)激活自身反应性T细胞而促进疾病的发展。与这些致病功能相反，B细胞亚群可能发挥调节特性，而这些特性通过治疗性B细胞耗尽而被旁路消除--这是一种不利的效果。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细胞是专职的APC，结构性地表达MHC II。本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MHC II限制性抗原提呈中的作用。我们将建立一种新型的转基因小鼠模型，在该模型中MHC II的表达仅限于B细胞，我们将测试B细胞的抗原提呈是否足以启动MS的动物模型，实验性自身免疫性脑脊髓炎(EAE)。数据表明，激活的致病B细胞特异性地迁移到炎症的中枢神经系统，而抗原未成熟的B细胞可能调节外围的自身免疫过程。为了验证这一假设，在该项目的第二个目标中，将通过在EAE中的活体成像来监测不同B细胞表型的迁移。此外，基于对致病B细胞功能的潜在划分，将测试局部(鞘内)B细胞耗竭抗体在患有EAE的小鼠中的应用。如果中枢神经系统中的致病B细胞属性因此可以被取消，同时保留外围的调节性B细胞，这种方法可能成为MS未来的治疗选择。

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.