The role of regulatory B lymphocytes for the containment of chronic inflammation in the central nervous system

调节性 B 淋巴细胞在抑制中枢神经系统慢性炎症中的作用

• 批准号: 466545931
• 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
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/466545931?language=en
• 关键词: role; regulatory; lymphocytes; containment; chronic

In multiple sclerosis (MS), disability can occur as acute flares that resolve, or accumulate in an irreversible manner; chronic deterioration is attributed to a self-sustained circuit of inflammation within the central nervous system (CNS), which is fueled by persistent activation of CNS resident cells, such as microglia and astrocytes along with CNS-established, blood-derived leucocytes. Emerging evidence suggest that B lymphocytes may have multiple roles in MS pathogenesis. On the one hand, differentiated, pro-inflammatory B cells appear to be instrumental in the development of new focal CNS inflammatory lesions causing acute disease flares; on the other hand, a subset of B cells with anti-inflammatory properties may have the potential to limit chronic deterioration by dampening the activity of chronically activated CNS resident cells. We hypothesize that these regulatory B cells and their interaction with CNS-intrinsic, inflammatory processes determine whether CNS inflammation resolves or alternatively transitions towards chronically extending tissue damage. We will investigate this hypothesis in three aims: 1. To investigate the regulatory interaction of B cells with monocytes, macrophages, microglia and astrocytes. In this aim, we will investigate in an in-vitro co-culture system which molecular properties enable B cells to dampen the pro-inflammatory activity of both CNS resident and –infiltrating immune cells.2. To evaluate regulatory B cell properties, which are preventing and resolving experimental chronic CNS inflammation. In this aim, we intent to study under which circumstances B cells are capable of limiting progression to chronic deterioration and to assess in-vivo which regulatory B cell property limits parenchymal CNS inflammation.3. To investigate the relevance of B cell regulation in MS. In this aim, we will functionally characterize B cells with regulatory potential in MS patients and determine the immunological consequences of their therapeutic removal. The outlined studies will determine which B cell features and/or subsets have the potential to down-regulate the activity of peripheral myeloid cells, microglia and astrocytes and to limit chronic CNS inflammation. By extending these analyses to patients with MS, we will elucidate how functionally relevant B cell regulation may be in the human condition itself, namely in containment of chronic progression, the aspect of MS that remains virtually untreatable. In perspective, our study may generate a more balanced view on the role of B cells in MS and foster development of novel B cell-directed therapies eradicating pathogenic B cell properties, while maintaining therapeutically desirable B cell regulation.

在多发性硬化症（MS）中，残疾可能是以不可逆转的方式解决的急性耀斑或丙烯酸的急性耀斑。慢性检测归因于中枢神经系统（CNS）内炎症的自我维持回路，这是由于CNS居民细胞的持续激活（例如小胶质细胞和星形胶质细胞）以及CNS建立的，血液衍生的白细胞的持续激活所推动的。新兴的证据表明，B淋巴细胞可能在MS发病机理中具有多个作用。一方面，分化的促炎性B细胞似乎有助于新的局灶性中枢神经系统炎症病变的发展，从而导致急性疾病。另一方面，具有抗炎特性的B细胞的子集可能有可能通过污染慢性激活的CNS居民细胞的活性来限制慢性检测。我们假设这些调节性B细胞及其与CNS Intrinsic的炎症过程的相互作用决定了中枢神经系统注射是否能够解决或过渡到长期延伸组织损伤。我们将在三个目的中研究这一假设：1。研究B细胞与单核细胞，巨噬细胞，小胶质细胞和星形胶质细胞的调节相互作用。在此目的中，我们将在体外共培养系统中进行研究，该系统的分子特性使B细胞能够抑制CNS常驻和 - 灌输免疫细胞的促炎活性。2。评估正在预防和解决实验性慢性中枢神经系统感染的调节B细胞特性。在此目标中，我们意图研究B细胞能够将进展限制为慢性恶化的情况并评估体内的体内b细胞特性限制了副CNS感染。3。研究B细胞调节在MS中的相关性。在此目标中，我们将在功能上表征MS患者具有调节潜力的B细胞，并确定其治疗性去除的免疫学后果。概述的研究将确定哪些B细胞特征和/或子集具有下调外周髓样细胞，小胶质细胞和星形胶质细胞的活性，并限制慢性中枢神经系统注射。通过将这些分析扩展到MS患者，我们将阐明与功能相关的B细胞调节可能在人类状态本身可能存在的方式，即在慢性进展的遏制中，MS的方面几乎无法治疗。从角度来看，我们的研究可能会对B细胞在MS中的作用和促进新型B细胞定向疗法的发育产生更平衡的看法，同时维持治疗理想的B细胞调节。