The pathogenesis of experimental autoimmune encephalomyelitis

Abstract

Multiple Sclerosis (MS) is a chronic demyelinating disorder of the central nervous system (CNS) mediated by autoantigen-specific T cells. Experimental autoimmune encephalomyelitis (EAE) is an animal model for MS driven by pathogenic, myelinspecific Th1 and Th17 cells. A deeper understanding of the role of T cells in EAE should help to increase our knowledge of the underlying basis of disease in MS patients and assist in the discovery of novel drug targets. This study examined the role of the caspase-1-processed cytokines IL-1β and IL-18 in IL-17A production by T cells and in induction of EAE. IL-1β plays a critical role in promoting IL-17A production by γδ and CD4 T cells, however, IL-l-targeted drugs, although effective against autoinflammatory diseases, are less effective against autoimmune diseases. Caspase-1 dependent secretion of IL-1β and IL-18 from dendritic cells (DCs), in synergy with IL-23, induced the production of IL-17A by T cells. Direct injection of a caspase-1 inhibitor suppressed IL-17A production by CD4 T cells and γδ T cells and attenuated disease in actively induced EAE.