The role of B cells in multiple sclerosis: Current and future therapies

Abstract

While it was long held that T cells were the primary mediators of multiple sclerosis (MS) pathogenesis, the beneficial effects observed in response to treatment with Rituximab, a monoclonal antibody (mAb) targeting CD20, shed light on a key contributor to MS that had been previously underappreciated: B cells. This has been reaffirmed by results from clinical trials testing the efficacy of subsequently developed B cell-depleting mAbs targeting CD20 as well as studies revisiting the effects of previous disease-modifying therapies (DMTs) on B cell subsets thought to modulate disease severity. In this review, we summarize current knowledge regarding the complex roles of B cells in MS pathogenesis and current and potential future B cell-directed therapies.

Transcription cofactor GRIP1 differentially affects myeloid cell–driven neuroinflammation and response to IFN-β therapy

“…Clinically, four types of MS have been described: primary progressive MS; secondary progressive MS; progressive relapsing; and, the most common, relapsing-remitting MS (RRMS; Milo and Miller, 2014 ). For all types, autoimmune demyelination is the hallmark of the disease, which prompted much work dissecting the roles of T cells ( Jäger et al, 2009 ; Kaskow and Baecher-Allan, 2018 ; Liu et al, 2008 ; McGinley et al, 2018 ; Merrill et al, 1992 ) and B cells ( Negron et al, 2019 ; Staun-Ram and Miller, 2017 ; Weber et al, 2010 ) in MS. However, recent accumulating evidence demonstrates the pivotal role of myeloid cells such as microglia (MG) in MS pathogenesis ( Croxford et al, 2015 ; Mahad and Ransohoff, 2003 ; Mishra and Yong, 2016 ; Sominsky et al, 2018 ; Yamasaki, 2014 ).…”

Therapies for multiple sclerosis targeting B cells

“…Several recombinant antibodies and fusion proteins targeting components of the BAFF/APRIL system have been developed, however, none have progressed past phase-II trials (57). Of particular interest is atacicept (TACI-Ig), a fusion protein comprised of the extracellular domain of the naturally occurring TACI receptor and the Fc domain of human IgG.…”

“…In addition, receptors for BAFF and APRIL also expressed on some T cells and regulatory cells were found to have more pleiotropic roles, which may include protective pathways that may be disrupted by their blockade. There is also evidence that suggests that APRIL is a negative regulator of autoimmunity and that atacicept preferentially targets naive B cells, plasmablasts, and plasma cells but has a lesser effect on memory-B cells, which are the relevant disease-promoting subset, resulting in a relative increase in memory-B cells after depletion of soluble BAFF and APRIL (57,60). Overall, the experience with atacicept suggests that the roles of B cells and humoral immunity in MS are complex and not fully understood, therefore calling for caution when testing new agents.…”

“…The complex, multi-player immune pathogenesis of MS, which provides multiple sites for therapeutic intervention on one hand, and the various mechanisms by which B cells contribute to the pathogenesis of MS along with the success of anti-CD20 therapies in MS, on the other hand, propelled studies on the effects of other MS drugs on B cells. Indeed, essentially all other approved therapies for MS, some of which have been designed to target T cells, were found to have some effects on the frequency, phenotype, trafficking, function, or responses of B cells, which may contribute to their therapeutic activity (11,32,57,65-67) (Table 2).…”

Vitamin D Supplementation in Multiple Sclerosis: A Critical Analysis of Potentials and Threats

“…Over time, when entering the progressive phase of the disease, these mechanisms go into reverse [4]. Inflammation in MS is considered to be mostly driven by T-cells; however, with the introduction of B-cell depleting therapeutic agents, there is increasing evidence for CD20-expressing T-and B-cells as the second pillar in the pathogenesis of MS [5,6]. Immunotherapies have been widely used in MS, as they have been shown to reduce the relapse rate and the accumulation of new brain lesions in patients with relapsing-remitting MS (RRMS) [7,8].…”