Role of IL-12/IL-23 in the Pathogenesis of Multiple Sclerosis

Multiple sclerosis (MS) is a T-cell-mediated autoimmune disease of the central nervous system (CNS) with a complex genetic background. It is generally accepted that MS begins with the formation of acute inflammatory lesions that were mediated by autoreactive T cells and B cells because of the breakdown of the blood-brain barrier (BBB). The demyelinating plaques were dominated by activated T cells and macrophages associated with oligodendrocyte destruction. IL-12 and IL-23 are two heterodimeric cytokines belonging to the p40 family, which plays an important role in regulating T-cell responses. They both are heterodimers of two subunits. IL-12 is a heterodimer of p35 and p40, whereas IL-23 is a heterodimer of p19 and p40. They share a common subunit, p40. Both IL-12 and IL-23 were mainly produced by antigen-presenting cells (APCs), including macrophages, dendritic cells, and B cells, and exerted their biologic functions on CD4 T cells. IL-12 receptor and IL-23 receptor are heterodimeric receptors. They share a common receptor subunit, the IL-12 receptor â1 chain. IL-12 receptor consists of the IL-12 receptor â1 chain and IL-12 receptor â2 chain, while the IL-23 receptor consists of the IL-12 receptor â1 chain and a second chain called the IL-23 receptor. IL-12 drives naïve CD4? T cells to differentiate into the IFN-ã- producing Th-1 lineage, while IL-23 promotes the IL-17-producing Th-17 lineage. Both IL-12-driven Th-1 cells and IL-23-driven Th-17 cells are believed to contribute significantly to the pathogenesis of MS and EAE.