Glial Responses to B cells in Neuroinflammatory Demyelinating Disease
Open AccessMultiple sclerosis (MS) is a chronic neurodegenerative disorder of the central nervous system (CNS) that affects more than 2.8 million people worldwide. MS is characterized by an influx of immune cells into the CNS and the presence of demyelinating lesions, leading to a range of symptoms, including vision and motor impairment and cognitive dysfunction. Without treatment, more than half of MS patients experience progressive neurological decline. Immunomodulatory treatments, especially B cell targeted therapies, have shown great success in reducing CNS lesion volumes and improving neurological function in early relapsing remitting disease, however, they have been less successful in later progressive forms of MS and often leave patients immunocompromised. The majority of studies on B cell depletion therapy in MS has focused on the immunological component of disease; however, it is critical to consider the CNS response to B cell depletion to understand the underlying mechanisms contributing to progressive neurodegeneration. Here, we examine the cellular and molecular responses of astrocytes and microglia to the depletion of B cells in an animal model of MS. Using novel CNS cell isolation approaches we developed, the first study explores the morphological and transcriptional changes in microglia and astrocytes during a period of rapid disease progression and immune cell infiltration into the CNS. We found that peripheral B cell depletion resulted in immediate transcriptional changes in genes associated with neurovascular coupling and glutamate signaling in astrocytes and cell migration and cytoskeletal organization in microglia. These findings identified selective B cell-glial cell interactions that are implicated in disease progression and recovery. Based on these observations, in the second study, we investigate the role of CNS infiltrating B cells on glial reactivity using a novel animal model that allows for spatial depletion of B cells specifically in the CNS. We found that depletion of CNS infiltrating B cells without affecting peripheral B cell populations reduces peripheral macrophage influx into the CNS and moderately reduces astrocyte reactivity, suggesting B cells invade the CNS and propagate inflammation within CNS compartments. These data may explain the reduced or lack of response in progressive MS after peripheral B cell depleting treatments where the B cells are protected by the CNS environment. Thus, these studies have the potential to guide the development of more CNS targeted therapies that will improve disease outcomes and quality of life for patients with progressive MS.
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