Proinflammatory GM-CSF–producing B cells in multiple sclerosis and B cell depletion therapy

Abstract

B cells are not limited to producing protective antibodies; they also perform additional functions relevant to both health and disease. However, the relative contribution of functionally distinct B cell subsets in human disease, the signals that regulate the balance between such subsets, and which of these subsets underlie the benefits of B cell depletion therapy (BCDT) are only partially elucidated. We describe a proinflammatory, granulocyte macrophage-colony stimulating factor (GM-CSF)-expressing human memory B cell subset that is increased in frequency and more readily induced in multiple sclerosis (MS) patients compared to healthy controls. In vitro, GM-CSF-expressing B cells efficiently activated myeloid cells in a GM-CSF-dependent manner, and in vivo, BCDT resulted in a GM-CSF-dependent decrease in proinflammatory myeloid responses of MS patients. A signal transducer and activator of transcription 5 (STAT5)- and STAT6-dependent mechanism was required for B cell GM-CSF production and reciprocally regulated the generation of regulatory IL-10-expressing B cells. STAT5/6 signaling was enhanced in B cells of untreated MS patients compared with healthy controls, and B cells reemerging in patients after BCDT normalized their STAT5/6 signaling as well as their GM-CSF/IL-10 cytokine secretion ratios. The diminished proinflammatory myeloid cell responses observed after BCDT persisted even as new B cells reconstituted. These data implicate a proinflammatory B cell/myeloid cell axis in disease and underscore the rationale for selective targeting of distinct B cell populations in MS and other human autoimmune diseases.

Targeting B cells in relapsing–remitting multiple sclerosis: from pathophysiology to optimal clinical management

“…Recent studies also elaborated the importance of antibody-independent functions of B cells in MS. In a recent study, a subtype of memory B cells that produces the proinflammatory cytokine granulocyte macrophage colony-stimulating factor (GM-CSF) was found to be more frequent and active in the blood of MS patients compared with controls [Li et al 2015b]. These B cells were especially able to switch myeloid cells (and subsequently T cells) to a proinflammatory phenotype.…”

Insights into the Role of Neuroinflammation in the Pathogenesis of Multiple Sclerosis

“…Research conducted by Egwuagu and Yu reported that B cells also contribute to the overall inflammatory milieu in MS by co-stimulating T cells to produce and release inflammatory factors and of course, by promoting the production of monoclonal immunoglobulins, whose identification in the CSF still represents one of the hallmarks of the disease [48,49]. A research group showed that B cells in the peripheral blood from MS patients exhibit higher expression levels of GM-CSF receptors compared to controls, supporting the involvement of these cells in disease pathogenesis, in addition to T cells and natural killer cells (NK), which are also augmented in MS sufferers [50,51]. Nonetheless, B cells seem to play an active part in triggering the auto-inflammatory cascades of MS by stimulating the production of IL-6, tumor necrosis factor alpha (TNFα) and interferon gamma (IFN Ɣ ) as well as by acting as APCs and promoting the production of autoantibodies [45,[49][50][51][52][53].…”

Mapping the effects of vitamin D in multiple sclerosis

“…As already mentioned, the subset of IL-10-producing B cells (Breg cells) seems to be reduced in number or functionally impaired in MS [155][156] 159] . Vitamin D is thought to have regulatory capacities, raising high expectations for effects on Breg cells.…”

“…This balance seems to be disturbed towards more pro-inflammatory cytokines in patients with MS. Indeed, B cells from patients with RRMS, compared to healthy controls, secrete more lymphotoxin, tumour necrosis factor-α, and granulocyte-macrophage colonystimulating factor [154][155] . Also, B cells of patients with MS were less capable of producing the regulatory cytokine Interleukin-10 (IL-10) [154, 156] .…”

“…However, a widely accepted phenotypical definition in humans is still lacking. When looking at IL-10-producing B cells, we and others have demonstrated that IL-10 + Breg cell numbers are reduced in patients with RRMS [155, 159] , although a preserved Breg cell frequency, as well as function, in MS also has been reported [160] . Breg cells have an important function in suppressing disease activity, possibly through inhibition of Th1 and Th17 differentiation [161] or the induction and/or maintenance of regulatory T cells [23,[162][163] .…”