Therapeutic potential of regulatory cytokines that target B cells

Abstract

Autoreactive B cells play a crucial role in the pathogenesis of autoimmune diseases by producing auto-antibodies and presenting antigens. Regulatory cytokines that simultaneously suppress multiple pathways have the potential to control autoreactive B cells. The generally inhibitory cytokine IL-10 may have a stimulatory effect on human B-cell survival and antibody production. TGF-β family cytokines can decrease or increase antibody production and can suppress B-cell proliferation and differentiation. In contrast to TGF-β1, which induces extensive fibrosis, TGF-β3 and bone morphogenetic protein 6 (BMP-6)/BMP-7 induce non-scarring wound healing and counteract tissue fibrosis. Therefore, TGF-β3 and BMP-6/BMP-7 may be clinically applicable as therapeutic cytokines that target B cells. Recent progress in protein engineering may enable us to generate novel biologic therapies based on TGF-β family cytokines.

Keywords: B cell; BMP; TGF-beta; regulatory T cell.

Fig. 1.

A schematic illustration on the signaling of TGF-βs and BMPs. TGF-β family molecules bind to specific type II and type I receptors. In most cells, TGF-β binds to TGFBR2 and ALK5 (also known as TGF-β receptor-1; TGFBR1), and BMPs bind to the BMP type II receptor (BMPR2), and ALK1, ALK2, ALK3 and ALK6. Activated type I receptors induce the phosphorylation of specific receptor-regulated (R-) SMADs. In general, a TGF-β signal results in SMAD2/3 phosphorylation and a BMP signal induces SMAD1/5/8 phosphorylation. Activated R-SMADs form complexes with SMAD4 that accumulate in the nucleus to regulate the expression of target genes. SMAD6 and SMAD7 are recognized as inhibitory SMADs and antagonize the TGF-β signal by inhibiting the activation of R-SMADs.