The pathogenic role for B cells in the context of relapsing remitting multiple sclerosis (MS) is incompletely defined. Although classically considered a T cell-mediated disease, B cell-depleting therapies showed efficacy in treating the clinical symptoms of RRMS without decreasing plasma cells or total immunoglobulin (Ig) levels. Here, we discuss the potential implications of antibody-independent B cell effector functions that could contribute to autoimmunity with particular focus on antigen presentation, cytokine secretion, and stimulation of T cell subsets. We highlight differences between memory and naïve B cells from MS patients such as our recent findings of hyper-proliferation from MS memory B cells in response to CD40 engagement. We discuss the implications of IL6 overproduction in contrast to limited IL10 production by B cells from MS patients and comment on the impact of these functions on yet unexplored aspects of B cells in autoimmune disease. Finally, we contextualize B cell effector functions with respect to current immunomodulatory therapies for MS and show that glatiramer acetate (GA) does not directly modulate B cell proliferation or cytokine secretion.

Plasma cells and the autoreactive Abs they produce are suspected to contribute to the pathogenesis of multiple sclerosis, but recent attempts to target these components of humoral immunity have failed. MEDI551, an anti-CD19 Ab that depletes mature B cells including plasma cells may offer a compelling alternative that reduces pathogenic adaptive immune responses while sparing regulatory mechanisms. Indeed, our data demonstrate that a single dose of MEDI551, given before or during ongoing experimental autoimmune encephalomyelitis, disrupts development of the disease. Leukocyte infiltration into the spinal cord is significantly reduced, as well as short-lived and long-lived autoreactive CD138+ plasma cells in the spleen and bone marrow, respectively. In addition, potentially protective CD1dhiCD5+ regulatory B cells show resistance to depletion, and myelin-specific Foxp3+ regulatory T cells are expanded. Taken together, these results demonstrate that MEDI551 disrupts experimental autoimmune encephalomyelitis by inhibiting multiple proinflammatory components whereas preserving regulatory populations.

Plasma cells and the autoreactive antibodies they produce are suspected to contribute to the pathogenesis of Multiple Sclerosis, but recent attempts to target these components of humoral immunity have failed. Recently we reported that MEDI551, an anti-CD19 antibody, disrupts development of EAE, the mouse model of MS. Leukocyte infiltration into the spinal cord is significantly reduced as well as short- and long-lived autoreactive CD138+ plasma cells in the spleen and bone marrow. In addition, potentially protective CD1dhiCD5+ regulatory B cells show resistance to depletion, and myelin-specific FoxP3+ regulatory T cells are expanded. Thus, MEDI551 may offer a compelling alternative that reduces pathogenic adaptive immune responses while preserving regulatory mechanisms. The sparing of long-lived plasma cells by anti-CD20 therapies and targeting of this population by MEDI551 prompted us to compare the efficacy of anti-CD19 Ab and anti-CD20 Ab in our EAE model. Our data demonstrated that anti-CD19 depletion is more effective than anti-CD20 depletion to ameliorate EAE. In fact, the frequency of residual antibody-producing cells correlated with residual disease severity in both the anti-CD19 and anti-CD20 treatment groups. No other correlations with residual EAE severity were found. We conclude that CD19+ plasma cells remaining after B cell depletion therapy contribute to residual EAE severity by producing autoreactive antibodies and pro-inflammatory factors.