Identification of a possible therapeutic target through pathogenic T cell analysis of multiple sclerosis

Abstract

Multiple sclerosis is an autoimmune disease affecting the central nervous system (CNS), in which Th17 and Th1 cells are involved. Comprehensive gene expression profiling analysis employing DNA microarray showed that NR4A2, an orphan nuclear receptor, is strongly upregulated in the peripheral blood T cells derived from MS patients. Further analysis revealed that NR4A2 plays a pivotal role for mediating production of inflammatory cytokines from pathogenic T cells. In experimental autoimmune encephalomyelitis (EAE), an animal model of MS, NR4A2 was selectively upregulated in the CNS-infiltrating T cells and the peripheral blood T cells. Intriguingly, a forced expression of NR4A2 augmented promoter activities of IL-17 and IFN-gamma genes, leading to an excessive production of these cytokines by splenic T cells. In contrast, treatment with siRNA specific for NR4A2 resulted in a significant reduction in the production of IL-17 and IFN-gamma. Furthermore, treatment with NR4A2-specific siRNA reduced the ability of encephalitogenic T cells to adoptively transfer EAE in recipient mice. These results imply that NR4A2 is an essential transcription factor for triggering the inflammatory cascade in MS/EAE and may serve as a novel therapeutic target of the diseases.