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

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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.