B Cell Maturation Antigen impacts the efficacy of B-cell targeting therapies in neuro-inflammation.

Abstract

Abstract B cells have emerged as a therapeutic target for multiple sclerosis (MS). Depleting B cells with anti-CD20 antibodies are effective in treating MS. Yet, blockade of BAFF and APRIL, two cytokines important for B cell development and function, paradoxically increased disease activity in MS patients. The stark differences in clinical outcomes with these therapies demonstrate that B cells have both inflammatory and regulatory effects in MS. B cell Maturation Antigen (BCMA), a receptor that binds both BAFF and APRIL, plays a prominent role in B cell function. The role BCMA plays in MS remains enigmatic and therefore we designed this study to explore the impact BCMA deficiency has on the development and progression of experimental autoimmune encephalomyelitis (EAE), a rodent model of MS. We found that EAE induced with MOG35–55 was more severe in BCMA−/− mice compared to BCMA+/+ mice. The increased disease was associated with increased CNS inflammation and a skewing of B-cells toward a mature/inflammatory phenotype. Using bone marrow chimera strategies, we found that BCMA deficiency in B-cells was responsible for the increase in disease severity. Next, we found that anti-CD20 treatment significantly reduced EAE in BCMA−/− mice but had no effects on BCMA+/+ mice. Conversely, we found that TACI-Ig treatment had no effect on BCMA−/− mice but did reduce EAE in BCMA+/+ mice. Our data demonstrate that BAFF and APRIL constrains the development and function of inflammatory B-cells through BCMA. Furthermore, our data provide clues into the paradoxical results of clinical trials with anti-CD20 and TACI-Ig in MS.