B Cells Are Multifunctional Players in Multiple Sclerosis Pathogenesis: Insights from Therapeutic Interventions

Abstract

Multiple sclerosis (MS) is a severe disease of the central nervous system (CNS) characterized by autoimmune inflammation and neurodegeneration. Historically, damage to the CNS was thought to be mediated predominantly by activated pro-inflammatory T cells. B cell involvement in the pathogenesis of MS was solely attributed to autoantibody production. The first clues for the involvement of antibody-independent B cell functions in MS pathology came from positive results in clinical trials of the B cell-depleting treatment rituximab in patients with relapsing-remitting (RR) MS. The survival of antibody-secreting plasma cells and decrease in T cell numbers indicated the importance of other B cell functions in MS such as antigen presentation, costimulation, and cytokine production. Rituximab provided us with an example of how clinical trials can lead to new research opportunities concerning B cell biology. Moreover, analysis of the antibody-independent B cell functions in MS has gained interest since these trials. Limited information is present on the effects of current immunomodulatory therapies on B cell functions, although effects of both first-line (interferon, glatiramer acetate, dimethyl fumarate, and teriflunomide), second-line (fingolimod, natalizumab), and even third-line (monoclonal antibody therapies) treatments on B cell subtype distribution, expression of functional surface markers, and secretion of different cytokines by B cells have been studied to some extent. In this review, we summarize the effects of different MS-related treatments on B cell functions that have been described up to now in order to find new research opportunities and contribute to the understanding of the pathogenesis of MS.

Keywords: B cell subtypes; antibodies; antigen presentation; costimulation; cytokines; multiple sclerosis; therapy.

Figure 1

B cell development. B cells develop in the bone marrow and enter the circulation as transitional B cells. B cells remain naive until they encounter an antigen after which they differentiate into plasma blasts, short-lived plasma cells, or further mature into class-switched or non-class-switched memory B cells in a GC response. However, non-class-switched memory B cells can also be formed independent of a GC. A proportion of the memory B cells further develops into plasma blasts and/or plasma cells. Regulatory B cells are characterized within the transitional, naive, memory, and plasma blast or plasma cell population. Potential developmental routes are indicated with the dotted lines.

Figure 2

B cell effector functions. B cells exert different effector functions. B cells evolve into plasma blasts or plasma cells and produce antibodies (1). B cells produce different pro-inflammatory cytokines (lymphotoxin (LT)-α, tumor necrosis factor (TNF)-α, interleukin (IL)-6 or regulatory cytokines (IL-10, IL-35)) that influence other immune cells (2). B cells present antigens to T cells and provide costimulatory signals in order to induce appropriate T cell responses (3). B cells form ectopic lymphoid follicles that support the inflammatory responses (4). CD, cluster of differentiation; CD40L, CD40 ligand; APRIL, a proliferation-inducing ligand; BAFF, B cell activating factor; TCR, T cell receptor; BCR, B cell receptor.

Figure 3

Effects of immunomodulatory therapy on B cell subtype distribution and function. B cell development in the bone marrow and periphery (A), antigen presentation and costimulatory molecules expressed on the B cell surface (B) and B cell cytokine production (C) are shown together with the effects of treatment on the different B cell subtypes and functions. CD, cluster of differentiation; IFN-β, interferon-β; FTY, fingolimod; GA, glatiramer acetate; NA, natalizumab; DMF, dimethyl fumarate; TFL, teriflunomide; RTX, rituximab; IL, interleukin; TGF, transforming growth factor; TNF, tumor necrosis factor; Th, T helper.