Cytokine-Defined B Cell Responses as Therapeutic Targets in Multiple Sclerosis

Abstract

Important antibody-independent pathogenic roles of B cells are emerging in autoimmune diseases, including multiple sclerosis (MS). The contrasting results of different treatments targeting B cells in patients (in spite of predictions of therapeutic benefits from animal models) call for a better understanding of the multiple roles that distinct human B cell responses likely play in MS. In recent years, both murine and human B cells have been identified with distinct functional properties related to their expression of particular cytokines. These have included regulatory (Breg) B cells (secreting interleukin (IL)-10 or IL-35) and pro-inflammatory B cells (secreting tumor necrosis factor α, LTα, IL-6, and granulocyte macrophage colony-stimulating factor). Better understanding of human cytokine-defined B cell responses is necessary in both health and diseases, such as MS. Investigation of their surface phenotype, distinct functions, and the mechanisms of regulation (both cell intrinsic and cell extrinsic) may help develop effective treatments that are more selective and safe. In this review, we focus on mechanisms by which cytokine-defined B cells contribute to the peripheral immune cascades that are thought to underlie MS relapses, and the impact of B cell-directed therapies on these mechanisms.

Keywords: B cell modulation; B-cell depletion; B-lymphocytes; cytokine-defined responses; immune modulation; multiple sclerosis.

Figure 1

Multifaceted functions of B cells and their implications in the pathogenesis of MS. In addition to their potential to differentiate into antibody-secreting plasmablasts and plasma cells, B cells can present antigen to T cells, as well as up- or down-regulate local immune responses through elaboration of pro- or anti-inflammatory cytokine, respectively. Plasma cells can also secrete pro- and anti-inflammatory cytokines that could modulate T cell and myeloid-cell responses. Abnormal B cell responses of potential relevance to MS include aberrant production of autoreactive antibodies, exaggerated activation of T cells through antigen presentation, and induction of pro-inflammatory T cell and myeloid-cell responses through abnormal secretion of pro-inflammatory B cell cytokines and/or insufficient secretion of B cell regulatory cytokines.