B‐cell activation influences T‐cell polarization and outcome of anti‐CD20 B‐cell depletion in central nervous system autoimmunity

Abstract

Objective Clinical studies indicate that anti-CD20 B cell depletion may be an effective multiple sclerosis therapy. We investigated mechanisms of its immune modulation using two paradigms of experimental autoimmune encephalomyelitis (EAE). Methods Murine EAE was induced by either recombinant myelin oligodendrocyte glycoprotein (rMOG), a model in which B cells are considered to contribute pathogenically, or MOG peptide (p)35–55, a model that does not require B cells. Results In EAE induced by rMOG, B cells became activated and, when serving as antigen presenting cells (APC), 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 CNS inflammation, elimination of meningeal B cells, and reduction of MOG-specific Th1 and Th17 cells. In contrast, in EAE induced by MOG p35–55, B cells did not become activated or efficiently polarize proinflammatory MOG-specific T cells, similar to naïve B cells. In this EAE 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 regulatory T cells, and increased the capacity of remaining APC to promote development of encephalitogenic T cells. Interpretation Our study highlights distinct roles for B cells in pathogenesis and regulation of CNS autoimmune disease. Clinical benefit from depletion of antigen-activated B cells may relate primarily to abrogation of proinflammatory B cell APC function. However, in certain clinical settings, elimination of unactivated B cells, which participate in regulation of T cells and other APC, may be undesirable.

Interleukin 6 signaling promotes anti-aquaporin 4 autoantibody production from plasmablasts in neuromyelitis optica

“…Because the level of B-cell depletion appears to correlate with the suppressive effects of anti-CD20 in NMO (39), it has been argued that B cells are essential for the pathogenesis of NMO, either via acting as antigen-presenting cells or as autoantibody producers. Weber et al recently reported that activated antigen-specific B cells serve as antigen-presenting cells and polarize proinflammatory T cells in EAE (40), supporting the view that the therapeutic effects of anti-CD20 might be attributable to the depletion of antigen-presenting B cells. Notably, they also cautioned that elimination of CD20 + cells might deplete nonactivated cells as well as regulatory B cells possessing anti-inflammatory potentials.…”

SLAM–SAP Signaling Promotes Differentiation of IL-17–Producing T Cells and Progression of Experimental Autoimmune Encephalomyelitis

“…Moreover, decreased EAE disease in Sh2d1a 2/2 mice may be a consequence of defective Ag priming or homing, leading to reduced numbers of pathogenic Th1 or Th17 cells at the target site. T-B cell cooperation likely promotes pathogenesis of MS as the depletion of B cells from MS patients has been found to reduce inflammation and myelin loss (68,69). Given the established importance of SAP functioning in lymphocyte-lymphocyte communication (25), our findings documenting roles for SAP in FIGURE 7.…”

B Cell Receptor Recognition of Glatiramer Acetate is Required for Efficacy through Antigen Presentation and Cytokine Production

“…In the MOG 35-55 model, B cell depletion prior to disease onset enhances disease severity, while therapeutic depletion significantly decreases disease severity [12]. In the rMOG 1-125 model, B cell depletion prior to disease onset and therapeutic dosing significantly reduces disease severity [13]. These data suggest that the role of B cells is dependent on the model, the time of dosing, and suggests protective and pathogenic functions.…”