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

在多发性硬化症（MS）中，残疾可能以急性发作的形式出现，这种急性发作会消退，或以不可逆的方式积累；慢性恶化归因于中枢神经系统（CNS）内自我维持的炎症循环，这是由中枢神经系统驻留细胞（如小胶质细胞和星形胶质细胞以及中枢神经系统建立的血液来源的白细胞）的持续激活所推动的。新的证据表明，B淋巴细胞可能在多发性硬化症的发病机制中发挥多种作用。一方面，分化的促炎B细胞似乎在新的局灶性中枢神经系统炎性病变的发展中起着重要作用，引起急性疾病发作；另一方面，具有抗炎特性的B细胞亚群可能通过抑制慢性激活的中枢神经系统驻留细胞的活性来限制慢性恶化。我们假设这些调节性B细胞及其与中枢神经系统内在炎症过程的相互作用决定了中枢神经系统炎症是消退还是转变为慢性延伸组织损伤。我们将从三个方面来研究这一假设：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调节相互作用。为此，我们将在体外共培养系统中研究B细胞的分子特性，使其能够抑制中枢神经系统驻留和浸润性免疫细胞的促炎活性。目的：评价调节B细胞在预防和解决实验性慢性中枢神经系统炎症中的作用。在此目的中，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细胞特性限制实质中枢神经系统炎症。为了研究B细胞调节在MS中的相关性，我们将对MS患者中具有调节潜力的B细胞进行功能表征，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/或亚群有可能下调外周髓细胞、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炎症。通过将这些分析扩展到多发性硬化症患者，我们将阐明在人类疾病本身中，即在控制慢性进展方面，B细胞调节的功能是如何相关的，这是多发性硬化症几乎无法治疗的方面。从这个角度来看，我们的研究可能会对B细胞在MS中的作用产生更平衡的看法，并促进新的B细胞定向疗法的发展，消除致病的B细胞特性，同时保持治疗所需的B细胞调节。

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.