Research ArticleMultiple Sclerosis

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

Science Translational Medicine  21 Oct 2015:
Vol. 7, Issue 310, pp. 310ra166
DOI: 10.1126/scitranslmed.aab4176

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Eclipsing multiple sclerosis

B cell depletion therapy (BCDT) has been shown to limit inflammation in some cases of multiple sclerosis (MS); however, how exactly BCDT works has remained unclear. Now, Li et al. report that a subset of B cells that produce the cytokine granulocyte macrophage–colony stimulating factor (GM-CSF) contributes to MS pathogenesis. These cells are more frequent in MS patients than in healthy controls and increase proinflammatory myeloid responses. Moreover, production of these cells counterbalances the generation of interleukin-10 (IL-10)–producing regulatory B cells, which are thought to be protective in disease. After BCDT, the ratio of GM-CSF/IL-10–producing B cells is normalized, suggesting that BCDT may work in part by decreasing the number of pathogenic GM-CSF–producing B cells.

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.

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