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

Identification: Kumar, Gaurav


B Cell Maturation Antigen impacts the efficacy of B-cell targeting therapies in neuro-inflammation
Gaurav Kumar, Rose M Ko, Robert C. Axtell
Oklahoma Medical Research Foundation, Oklahoma City, OK, USA
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, TACI-Ig treatment, which blocks 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 inflammation in the central nervous system (CNS) 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. Also, for the first time we observed that BCMA deficiency directly affects the infiltration of inflammatory myeloid cells during EAE. We next assessed how BCMA-deficiency affected the efficacy of anti-CD20 and TACI-Ig therapies.  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 study demonstrates that BAFF and APRIL constrains the development and function of inflammatory B-cells through BCMA.  Moreover, our data introduce a new paradigm suggesting that BAFF-APRIL signaling through BCMA affects inflammatory myeloid cells during neuro-inflammation. Finally, our data provide clues into the paradoxical results of clinical trials with anti-CD20 and TACI-Ig in MS patients.  


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