Dual Role of B Cells in Multiple Sclerosis

Abstract

B cells have emerged as an important immune cell type that can be targeted for therapy in multiple sclerosis (MS). Depleting B cells with anti-CD20 antibodies is effective in treating MS. Yet, atacicept treatment, which blocks B-cell Activating Factor (BAFF) and A Proliferation-Inducing Ligand (APRIL), two cytokines important for B cell development and function, paradoxically increases disease activity in MS patients. The reason behind the failure of atacicept is not well understood. The stark differences in clinical outcomes with these therapies demonstrate that B cells have both inflammatory and anti-inflammatory functions in MS. In this review, we summarize the importance of B cells in MS and discuss the different B cell subsets that perform inflammatory and anti-inflammatory functions and how therapies modulate B cell functions in MS patients. Additionally, we discuss the potential anti-inflammatory functions of BAFF and APRIL on MS disease.

Keywords: B cells; disease-modifying therapies; multiple sclerosis.

Figure 1

B cell activating factor (BAFF) and a proliferation-inducing ligand (APRIL) are cytokines that bind to BAFF receptor (BAFFR), transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI), and B cell maturation antigen (BCMA) expressed on the surface of B cell subsets. BAFF and APRIL signal through the receptors to affect B cell subset development, survival, and function. Recombinant TACI-Ig (atacicept) inhibits BAFF and APRIL function by blocking binding to their receptors.

Figure 2

BAFFR, TACI, and BCMA are expressed at different stages of B cell development. After exiting the bone marrow, B cell precursors (pre-B cells) differentiate into immature transitional B cells that have anti-inflammatory functions. Transitional B cells then give rise to mature naïve and mature anti-inflammatory B cell subsets. Mature naïve B cells can become activated and further differentiate into short-lived plasma cells, memory B cells, and plasmablasts, which finally become long-lived plasma cells. All three BAFF and APRIL receptors are expressed at various levels on B cell subsets. BAFFR is highly expressed from the transitional B cells to the mature naïve B-cell stage. TACI is highly expressed from the mature naïve B cells to the activated and memory B cell stages. BCMA is most highly expressed by plasmablasts and short- and long-lived plasma cells.