Disease progression in chronic relapsing experimental allergic encephalomyelitis is associated with reduced inflammation-driven production of corticosterone

In this study, we demonstrate that disruption of neuroendocrine signaling i s a major factor driving disease progression in myelin oligodendrocyte glyc oprotein-induced chronic relapsing experimental autoimmune encephalomyeliti s, an animal model of multiple sclerosis. Although the initial episode of c hronic relapsing experimental autoimmune encephalomyelitis is associated wi th a robust hypothalamic-pituitary-adrenocortical axis response, we show th at subsequent disease progression is associated with a selective desensitiz ation of hypothalamic-pituitary-adrenocortical responsiveness to inflammato ry mediators. Inflammatory activity in the central nervous system during re lapse is therefore unable to produce an endogenous immunosuppressive cortic osterone response, and disease progresses into an ultimately lethal phase. However, disease progression is inhibited if the circulating corticosterone level is maintained at levels seen during the initial phase of disease. Th e effect of hypothalamic-pituitary-adrenocortical axis desensitization on t he clinical course of experimental autoimmune encephalomyelitis is aggravat ed by a marked reduction in proinflammatory cytokine synthesis in the centr al nervous system in the later stages of disease, reflecting an increasing involvement of antibody, rather than T cell-dependent effector mechanisms, in disease pathogenesis, with time. Thus, our data indicate that distinct i mmune-endocrine effects play a decisive role in determining disease progres sion in multiple sclerosis, a concept supported by reports that a subpopula tion of multiple sclerosis patients shows evidence of hypothalamic-pituitar y-adrenocortical axis desensitization.