Breaching Brain Barriers: B Cell Migration in Multiple Sclerosis

Abstract

Multiple sclerosis (MS) is an inflammatory disease of the central nervous system (CNS) known for the manifestation of demyelinated lesions throughout the CNS, leading to neurodegeneration. To date, not all pathological mechanisms that drive disease progression are known, but the clinical benefits of anti-CD20 therapies have put B cells in the spotlight of MS research. Besides their pathological effects in the periphery in MS, B cells gain access to the CNS where they can contribute to disease pathogenesis. Specifically, B cells accumulate in perivascular infiltrates in the brain parenchyma and the subarachnoid spaces of the meninges, but are virtually absent from the choroid plexus. Hence, the possible migration of B cells over the blood–brain-, blood–meningeal-, and blood–cerebrospinal fluid (CSF) barriers appears to be a crucial step to understanding B cell-mediated pathology. To gain more insight into the molecular mechanisms that regulate B cell trafficking into the brain, we here provide a comprehensive overview of the different CNS barriers in health and in MS and how they translate into different routes for B cell migration. In addition, we review the mechanisms of action of diverse therapies that deplete peripheral B cells and/or block B cell migration into the CNS. Importantly, this review shows that studying the different routes of how B cells enter the inflamed CNS should be the next step to understanding this disease.

The immunopathology of B lymphocytes during stroke-induced injury and repair

“…B cells then infiltrate the brain via the vessels bilaterally following stroke [65], and are capable of producing pro-or anti-inflammatory cytokines, depending on subtype, to exert influence on processes including T-cell antigen-dependent inflammation and neuronal survival [98]. Another mechanism by which B cells may infiltrate the CNS is across the blood-cerebrospinal fluid barrier (BCSFB) in the choroid plexus, which occurs in a two-step process [76]. First, B cells must diapedese across capillaries into the choroid plexus stroma and then breach the transepithelial cell barrier to enter the CSF.…”

“…While much attention has been given to the diapedesis of leukocytes across the blood-brain barrier, immune cells may also infiltrate the brain by migrating over the bloodmeningeal barrier (BMB) and the BCSFB in the choroid plexus [76]. Recent research has greatly advanced our understanding of how these alternative barriers in the meninges and choroid plexus are immunologically vibrant sites of not just B cell migration, but also maturation, tolerance, and dysregulation.…”

The role of CD56bright NK cells in neurodegenerative disorders

“…Another brain barrier is the blood–cerebrospinal fluid barrier (BCSFB), which is formed by the epithelial cells lining the choroid plexus [ 94 ]. Besides acting as the main producer of cerebrospinal fluid (CSF), this highly vascularized tissue facilitates migration of peripheral immune cells into the CSF, thereby serving as an immunological niche enabling immunosurveillance [ 81 , 95 , 96 ]. The tight junctions, adherent junctions and gap junctions between the epithelial cells are essential for the regulation of the permeability, integrity and polarity of the BCSFB [ 94 ].…”

Updates of the role of B-cells in ischemic stroke

“…The study also found that migration of such memory B-cells was reduced in multiple sclerosis (MS) patients treated with natalizumab, suggesting an emphasis on the role of BCSFB as an important channel for activated B-cells to enter the cerebrospinal fluid ( Haas et al, 2020 ). The important role of B-cells in diseases of the central nervous system (CNS), particularly in multiple sclerosis, emphasizes the ways in which B-cells contribute to neuropathology by secreting antibodies and neurotoxic molecules as well as presenting antigens ( Rodriguez-Mogeda et al, 2022 ).…”