Abstract
While the contribution of autoreactive CD4+ T cells to the pathogenesis of Multiple Sclerosis (MS) is widely accepted, the advent of B cell-depleting monoclonal antibody (mAb) therapies has shed new light on the complex cellular mechanisms underlying MS pathogenesis. Evidence supports the involvement of B cells in both antibody-dependent and -independent capacities. T cell-dependent B cell responses originate and take shape in germinal centers (GCs), specialized microenvironments that regulate B cell activation and subsequent differentiation into antibody-secreting cells (ASCs) or memory B cells, a process for which CD4+ T cells, namely follicular T helper (TFH) cells, are indispensable. ASCs carry out their effector function primarily via secreted Ig but also through the secretion of both pro- and anti-inflammatory cytokines. Memory B cells, in addition to being capable of rapidly differentiating into ASCs, can function as potent antigen-presenting cells (APCs) to cognate memory CD4+ T cells. Aberrant B cell responses are prevented, at least in part, by follicular regulatory T (TFR) cells, which are key suppressors of GC-derived autoreactive B cell responses through the expression of inhibitory receptors and cytokines, such as CTLA4 and IL-10, respectively. Therefore, GCs represent a critical site of peripheral B cell tolerance, and their dysregulation has been implicated in the pathogenesis of several autoimmune diseases. In MS patients, the presence of GC-like leptomeningeal ectopic lymphoid follicles (eLFs) has prompted their investigation as potential sources of pathogenic B and T cell responses. This hypothesis is supported by elevated levels of CXCL13 and circulating TFH cells in the cerebrospinal fluid (CSF) of MS patients, both of which are required to initiate and maintain GC reactions. Additionally, eLFs in post-mortem MS patient samples are notably devoid of TFR cells. The ability of GCs to generate and perpetuate, but also regulate autoreactive B and T cell responses driving MS pathology makes them an attractive target for therapeutic intervention. In this review, we will summarize the evidence from both humans and animal models supporting B cells as drivers of MS, the role of GC-like eLFs in the pathogenesis of MS, and mechanisms controlling GC-derived autoreactive B cell responses in MS.
Highlights
THE GERMINAL CENTER REACTIONMultiple sclerosis (MS) is a neuroinflammatory autoimmune disease affecting nearly 2.3 million people globally [1]
The evidence supporting the interconnectedness of TH17, TFH, and B cells and the remarkable plasticity of each lineage could offer a possible inroad for unraveling the puzzle of the factors that induce and promote Multiple Sclerosis (MS)
Ample evidence suggests that memory B cells in MS patients are ideally equipped for the reactivation of encephalitogenic CD4+ T cells, a process which can occur in the central nervous system (CNS) or in the deep cervical lymph nodes (dCLN)
Summary
Multiple sclerosis (MS) is a neuroinflammatory autoimmune disease affecting nearly 2.3 million people globally [1]. The remarkable clinical success of Rituximab (RTX), a B cell-depleting monoclonal antibody (mAb) targeting CD20, challenged this long-held assumption, demonstrating that the role of B cells in MS may have been underappreciated [3] This proposition is further supported by studies showing that B cells are a major target of previously established disease-modifying therapies (DMTs), and that positive therapeutic responses are strongly associated with the elimination of pathogenic B cell subsets. Following resolution of the primary response, circulating and resident memory T and B cells are on stand-by for secondary antigen encounters, upon which they can undergo rapid differentiation and restoration of effector function These encounters can result in the development of new GCs. MS has long been thought to be primarily mediated by autoreactive CD4+ T cells directed against central nervous system (CNS) antigens, such as myelin basic protein (MBP), myelin oligodendrocyte glycoprotein (MOG), or aquaporin-4 (AQP4) [23, 24]. Experimental evidence from human MS patients and experimental animal studies have led to a proposed mechanism in which an unknown trigger results in the aberrant activation of autoreactive CD4+ T cells in the immune periphery, after which these encephalitogenic CD4+ T cells enter the CNS from the choroid plexus (CP), are reactivated by local APCs in the CNS, and initiate a proinflammatory cascade that results in increased permeability of the blood-brain barrier (BBB), subsequent recruitment of proinflammatory immune cells, and subpial cortical damage [40]
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