Update on the Autoimmune Pathology of Multiple Sclerosis: B-Cells as Disease-Drivers and Therapeutic Targets

Abstract

Background: Collectively, research on the role of B-cells in the pathogenesis of multiple sclerosis (MS) illustrates how translational medicine has given rise to promising therapeutic approaches for one of the most debilitating chronic neurological diseases in young adults. First described in 1935, the experimental autoimmune/allergic encephalomyelitis model is a key animal model that has provided the foundation for important developments in targeted therapeutics. Summary: While additional B-cell therapies for MS are presently being developed by the pharmaceutical industry, much remains to be understood about the role played by B-cells in MS. The goal of this review is to summarize how B-cells may contribute to MS pathogenesis and thereby provide a basis for understanding why B-cell depletion is so effective in the treatment of this disease. Key Messages: B-cells are key players in the pathogenesis of MS, and their depletion via B-cell-targeted therapy ameliorates disease activity. Clinical Implications: In 2008, data from the first CD20-targeting B-cell depleting therapeutic trials using rituximab in MS were published. Since then, there has been a large body of evidence demonstrating the effectiveness of B-cell depletion mediated via anti-CD20 antibodies. Intense research efforts focusing on the immunopathological relevance of B-cells has gained significant momentum and given rise to a constellation of promising therapeutic agents for this complex B-cell-driven disease, including novel anti-CD20 antibodies, as well as agents targeting CD19 and BAFF-R.

Transcriptome profiling of peripheral blood immune cell populations in multiple sclerosis patients before and during treatment with a sphingosine‐1‐phosphate receptor modulator

“…T helper cells and memory B cells are mediating the destructive processes by presenting antigens and secreting proinflammatory cytokines to costimulate immune responses . The intrathecal formation of antibody‐producing plasma cells and plasmablasts is another hallmark of the pathophysiology of MS …”

High-Density Peptide Microarray Analysis of IgG Autoantibody Reactivities in Serum and Cerebrospinal Fluid of Multiple Sclerosis Patients

“…B cells have regulatory and antigen-presenting functions, and the activation of antigen-specific B cells (usually dependent on helper T cells) results in their proliferation and differentiation, culminating in the generation of memory B cells and antibody-secreting plasmablasts and plasma cells. A role of B cells in MS is supported by studies, in which effector B cells as well as antibodies were found in CNS lesions and in cerebrospinal fluid (CSF) of MS patients (7,8), and by clinical trials, which showed that B-cell depletion is effective in the treatment of this disease (9). Recently, a genetic fine-mapping revealed that active cis-regulatory elements of B cells are enriched of MS-associated single-nucleotide polymorphisms (10).…”

Increased B�cell activating factor is associated with B�cell class switching in patients with tuberculous pleural effusion

“…Early researches on BAFF focused more on autoimmune diseases. It has been reported that up-regulated BAFF is involved in autoimmune disorders such as rheumatoid arthritis, systemic lupus erythematosus, and autoimmune encephalomyelitis (15,16,22). In human active pulmonary TB, the levels of BAFF and a proliferation-inducing ligand (APRIL) were markedly increased.…”