B cells in central nervous system disease: diversity, locations and pathophysiology

Abstract

B cells represent a relatively minor cell population within both the healthy and diseased central nervous system (CNS), yet they can have profound effects. This is emphasized in multiple sclerosis, in which B cell-depleting therapies are arguably the most efficacious treatment for the condition. In this Review, we discuss how B cells enter and persist in the CNS and how, in many neurological conditions, B cells concentrate within CNS barriers but are rarely found in the parenchyma. We highlight how B cells can contribute to CNS pathology through antibody secretion, antigen presentation and secretion of neurotoxic molecules, using examples from CNS tumours, CNS infections and autoimmune conditions such as neuromyelitis optica and, in particular, multiple sclerosis. Overall, understanding common and divergent principles of B cell accumulation and their effects within the CNS could offer new insights into treating these devastating neurological conditions.

Epstein-Barr virus promotes T cell dysregulation in a humanized mouse model of multiple sclerosis

“…Though relatively few B cells engraft and infiltrate the CNS compared to T cells, the possibility remains that engrafted EBV-specific or latently infected B cells may play a role through regulatory or non-antibody responses, such as cytokine production 62 and antigen presentation 63 . Engrafted B cells of varying specificities and functionalities, which can act both protectively and pathogenically in EAE 64,65 , may also contribute to the enhancement of disease and the increased CNS inflammation observed in RRMS recipient mice compared to HD groups. Clinical post-mortem evidence has suggested that EBV could contribute to the development and/or progression of MS through infection of CNS-infiltrating B cells and tertiary lymphoid structures, leading to local inflammation [66][67][68] .…”

Immunological defense of CNS barriers against infections

“…B cells represent another important immune cell population that resides in the healthy meninges. B cells represent up to 30% of resident immune cells in the dura mater ( Brioschi et al., 2021 ; Cugurra et al., 2021 ; Fitzpatrick et al., 2020 ; Jain and Yong, 2021 ; Korin et al., 2017 ; Schafflick et al., 2021 ; Wang et al., 2021 ). Resident meningeal B cells exist in multiple stages of development, similar to those found in the bone marrow (e.g., mature naive B cells, immature B cells, pre-B cells, pro-B cells, and mitotic B cells) ( Brioschi et al., 2021 ; Schafflick et al., 2021 ; Wang et al., 2021 ).…”

Changes in Brain Neuroimmunology Following Injury and Disease

“…To recapitulate these observations in pre-clinical mice models, experimental autoimmune encephalitis (EAE) evoked by an injection of myelin proteins is commonly used. Both T and B cells are strongly implicated in MS (Chastain et al, 2011 ; van Langelaar et al, 2020 ; Jain and Yong, 2021 ). Self-reactive T cells in the choroid plexus support neuroimmune homeostasis in the CNS, but in MS and EAE, cerebrospinal fluid T cells skew toward a pathogenic T helper 17 (Th17) phenotype (Mundt et al, 2019 ) that are detrimental for brain function.…”

“…In the cerebrovasculature, endothelial cells are also capable of antigen presentation in EAE and other chronic inflammatory conditions (Pinheiro et al, 2016 ). B cells in the dural meninges are also efficient APCs, and they accumulate and skew toward a pro-inflammatory phenotype in EAE (Jain and Yong, 2021 ). The diversity of cells that can serve as APCs (Chastain et al, 2011 ) highlight the complicated signaling cascades that underlie neuroinflammation in MS, but also serve as opportunities for therapeutic intervention.…”