Interleukin-23 And Multiple Sclerosis

Multiple sclerosis(MS) is a chronic inflammatory autoimmune disease of the central nervous system(CNS), characterized by recurrent and multifocal demyelination. The clinical manifestations of multiple sclerosis ,which include loss of visual ,sensorimotor , autonomic, and cognitive functions, frequently have a profound effect on activities of daily life. The mechanism of MS is not clear now, while a recognized opinion is that the gene susceptibility and environmental stimulating factor both contribute to the disease.Experimental autoimmune encephalomyelitis(EAE), a T cell-mediated inflammatory disease of the CNS, is a rodent model of human multiple sclerosis. It can be induced in susceptible animals by immunization with myelin proteins or peptides or by adoptive transfer of myelin-specific cells. EAE shares many clinical and histopathological features with multiple sclerosis(MS)and is a commonly used animal model of this human autoimmune disease.Early investigations suggested that the disease is mediated by CD4+effector cells specific to myelin antigens and associated with numerous cytokines like Interleukin-12(IL-12). Interleukin-23(IL-23), a newly discovered proinflammatory cytokine which is belong to the IL-12 family, is a heterodimeric cytokine composed of a unique p19 subunit and a common p40 subunit shared with IL-12. IL-23 is produced predominantly by macrophages and dendritic cells, and shows activity on the differentiation of native T cells and production of IFNγ,IL-17 and other novel factors. As a novel composite factor closely related to IL-12 in structure, IL-23 shows similar as well as distinct biological activities from IL-12 , concerned with the stabilization of internal environment and stimulation of the immune system in pathological conditions.Although numerous studies have concluded that IL-12 is essential for the onset and development of MS, these investigations were based on the IL-12p40 subunit through the use of IL-12p40 gene-targeted mice and neutralizing antibodies against p40. As the discovery of IL-23 sharing the IL-12p40 and binding to IL-12Rβ1, it's clear now previous studies based on p40 do not discriminate between IL-12 and IL-23. The effect of blocking p40 or IL-12Rβ1 is concerned with the absence of both IL-12 and IL-23. The perceived central role for IL-12 in autoimmune inflammation, specially in the brain , has been misinterpreted.Current studies shows that the functions previously attributed to IL-12 for EAE are induced by two distinct cytokines: IL-12 promotes the development of native T cells and the infiltration of inflammatory cells into CNS; and IL-23 acts as a key factor, inducing the IL-17 production, promoting the recruitment and reactivation of inflammatory cells and mediating late-stage Th17 inflammation. Activated macrophages/microglia and mature DCs(dendritic cells) are the cellular sources of IL-23p19 in MS lesions. The presence of mature DCs in the perivascular cuff raised the possibility that IL-23-producing DCs are involved in the pathogenesis of relapsing multiple sclerosis. DCs from patients with MS secret increased amounts of IL-23 compared to healthy donors upon the CD46 activation because of the genetic variance which results the dysregulation of IL-23/Th17 inflammatory axis and the onset of CNS autoimmune reaction.