Regulatory B cells in multiple sclerosis - functional characterization and therapeutic implication

多发性硬化症中的调节性 B 细胞 - 功能特征和治疗意义

• 批准号: 383699619
• 负责人: Professor Dr. Martin Weber
• 金额: --
• 依托单位: Institut für Neuropathologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2017
• 资助国家: 德国
• 起止时间: 2016-12-31 至 2022-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/383699619?language=en
• 关键词: Regulatory; cells; multiple; sclerosis; functional

Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system, in which disability can occur as acute relapses or as continuous chronic deterioration. In its pathogenesis, B cells and B cell-derived products may play a key role; in many MS patients, peripheral B cells show signs of chronic activation and pro-inflammatory differentiation. In the cerebrospinal fluid, clonally expanded plasma cells produce oligoclonal immunoglobulins, which remain a hallmark diagnostic finding. Moreover, anti-CD20-mediated depletion of B cells halted development of CNS lesions and reduced occurrence of relapses in recent clinical MS trials. Besides such evidence for their pathogenic contribution, B cells may exert anti-inflammatory properties in MS. Naïve B cells, in MS patients similar to healthy controls, are a relevant source of regulatory cytokines, such as IL-10, which dampens the activity of other immune cells. Mice deficient in releasing regulatory B cell cytokines fail to recover from an acute attack in the MS model experimental autoimmune encephalomyelitis (EAE) and instead chronically deteriorate. B cells are thus crucially involved in development of relapses caused by de novo CNS infiltration, and yet convey the potential to promote recovery and to prevent transition to chronic progression. To decrypt this apparent enigma with wide-ranging clinical implications, we will functionally characterize and possibly delineate regulatory B cell function from pathogenic B cell properties in MS. At first, we will characterize B and plasma cells in CNS tissues from MS patients. These studies are now possible by an imaging technique developed at our Institute. In conjunction with transcriptome analyses, we will investigate whether all B cells in MS lesions are uniformly pathogenic, and whether subtypes of patients or CNS lesions may vary in the extent of pathogenic versus regulatory B cells (aim 1). Second, we will determine whether MS patients differ in the relative extent of peripheral pro- and anti-inflammatory B cells. We will correlate this individual B cell phenotype to the loss of IL-10 and the relative increase of pro-inflammatory monocyte function upon anti-CD20 treatment. In perspective and correlation with the clinical outcome, these immunological parameters could develop into an urgently needed biomarker predicting the individual response to anti-CD20 treatment (aim 2). Lastly, we will investigate in EAE, whether, where and how B cells promote recovery and control chronic progression. For this purpose, we are utilizing a purely T cell-mediated EAE model, in which anti-CD20 substantially deteriorates disease severity. Using this model in combination with adoptive transfer and tracking of genetically modified B cells, we will investigate to what extent B cells can dampen CNS intrinsic circuits of inflammation, the assumed correlate of progression and which B cell property is required to mediate this effect (aim 3).

多发性硬化症（MS）是中枢神经系统的炎性脱髓鞘疾病，其中残疾可作为急性复发或作为持续慢性恶化而发生。在其发病机制中，B细胞和B细胞衍生产物可能发挥关键作用;在许多MS患者中，外周B细胞显示慢性活化和促炎分化的迹象。在脑脊液中，克隆扩增的浆细胞产生寡克隆免疫球蛋白，这仍然是一个标志性的诊断发现。此外，在最近的临床MS试验中，抗CD 20介导的B细胞耗竭阻止了CNS病变的发展并减少了复发的发生。除了这些致病作用的证据外，B细胞可能在MS中发挥抗炎特性。MS患者中的幼稚B细胞与健康对照相似，是调节细胞因子（如IL-10）的相关来源，其抑制其他免疫细胞的活性。缺乏释放调节性B细胞细胞因子的小鼠不能从MS模型实验性自身免疫性脑脊髓炎（EAE）的急性发作中恢复，而是慢性恶化。因此，B细胞在由从头中枢神经系统浸润引起的复发的发展中至关重要，但仍具有促进恢复和防止向慢性进展过渡的潜力。要解密这个明显的谜与广泛的临床意义，我们将在功能上的特点，并可能描绘调节B细胞的功能，从MS的致病性B细胞的属性。首先，我们将表征B和浆细胞在MS患者的CNS组织。这些研究现在可以通过我们研究所开发的成像技术进行。结合转录组分析，我们将研究MS病变中的所有B细胞是否都是一致的致病性，以及患者或CNS病变的亚型是否在致病性与调节性B细胞的程度上有所不同（目的1）。其次，我们将确定MS患者外周促炎和抗炎B细胞的相对程度是否不同。我们将把这种单个B细胞表型与IL-10的丧失和抗CD 20治疗后促炎单核细胞功能的相对增加相关联。从临床结局的角度和相关性来看，这些免疫学参数可以发展成为预测抗CD 20治疗个体应答的迫切需要的生物标志物（目的2）。 最后，我们将研究在EAE中，B细胞是否、在何处以及如何促进恢复和控制慢性进展。为此目的，我们正在利用一个纯粹的T细胞介导的EAE模型，其中抗CD 20大大恶化疾病的严重程度。使用该模型结合过继转移和遗传修饰的B细胞的追踪，我们将研究B细胞可以在多大程度上抑制CNS炎症的内在回路，假设的进展相关性以及介导该效应所需的B细胞特性（目的3）。