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，残疾可作为急性发作发生，以不可逆的方式消退或累积;慢性恶化归因于中枢神经系统（CNS）内的自我维持的炎症回路，其由CNS驻留细胞（如小胶质细胞和星形胶质细胞沿着CNS建立的血液来源的白细胞）的持续活化所推动。新出现的证据表明，B淋巴细胞在MS发病机制中可能具有多种作用。一方面，分化的促炎性B细胞似乎有助于导致急性疾病发作的新的局灶性CNS炎性病变的发展;另一方面，具有抗炎特性的B细胞亚群可能具有通过抑制慢性活化的CNS驻留细胞的活性来限制慢性恶化的潜力。我们假设这些调节性B细胞及其与CNS内在炎症过程的相互作用决定了CNS炎症是否消退或向慢性延伸的组织损伤转变。我们将从三个方面研究这一假说：1。 探讨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相互调节作用。在这个目标中，我们将在体外共培养系统中研究哪些分子特性使B细胞能够抑制CNS驻留和浸润免疫细胞的促炎活性。 评价调节性B细胞的特性，其预防和解决实验性慢性CNS炎症。在这个目标中，我们打算研究在何种情况下B细胞能够限制进展为慢性恶化，并评估体内哪种调节性B细胞特性限制实质性CNS炎症。 为了研究MS中B细胞调节的相关性。为此，我们将在功能上表征MS患者中具有调节潜力的B细胞，并确定其治疗去除的免疫学后果。概述的研究将确定哪些B细胞特征和/或亚群具有下调外周髓样细胞、小胶质细胞和星形胶质细胞活性的潜力，并限制慢性CNS炎症。通过将这些分析扩展到MS患者，我们将阐明功能相关的B细胞调节在人类疾病本身中的作用，即在慢性进展的遏制中，MS的这一方面实际上仍然无法治疗。从长远来看，我们的研究可能会产生一个更平衡的观点，B细胞在MS中的作用，并促进新的B细胞导向疗法的发展，根除致病性B细胞的特性，同时保持治疗所需的B细胞调节。