Clinical studies indicate that anti‐CD20 B‐cell depletion may be an effective multiple sclerosis (MS) therapy. We investigated mechanisms of anti‐CD20‐mediated immune modulation using 2 paradigms of experimental autoimmune encephalomyelitis (EAE).

Murine EAE was induced by recombinant myelin oligodendrocyte glycoprotein (rMOG), a model in which B cells are considered to contribute pathogenically, or MOG peptide (p)35‐55, which does not require B cells.

In EAE induced by rMOG, B cells became activated and, when serving as antigen‐presenting cells (APCs), promoted differentiation of proinflammatory MOG‐specific Th1 and Th17 cells. B‐cell depletion prevented or reversed established rMOG‐induced EAE, which was associated with less central nervous system (CNS) inflammation, elimination of meningeal B cells, and reduction of MOG‐specific Th1 and Th17 cells. In contrast, in MOG p35‐55‐induced EAE, B cells did not become activated or efficiently polarize proinflammatory MOG‐specific T cells, similar to naive B cells. In this setting, anti‐CD20 treatment exacerbated EAE, and did not impede development of Th1 or Th17 cells. Irrespective of the EAE model used, B‐cell depletion reduced the frequency of CD4⁺CD25⁺Foxp3⁺ regulatory T cells (Treg), and increased the proinflammatory polarizing capacity of remaining myeloid APCs.

Our study highlights distinct roles for B cells in CNS autoimmunity. Clinical benefit from anti‐CD20 treatment may relate to inhibition of proinflammatory B cell APC function. In certain clinical settings, however, elimination of unactivated B cells, which participate in regulation of T cells and other APC, may be undesirable. Differences in immune responses to MOG protein and peptide may be important considerations when choosing an EAE model for testing novel B cell‐targeting agents for MS. ANN NEUROL 2010