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Disease Progression in Chronic Relapsing Experimental Allergic Encephalomyelitis Is Associated with Reduced Inflammation-Driven Production of Corticosterone

Max Planck Institute of Psychiatry (A.S., T.P., F.H., J.M.H.M.R.), Section of Neuropsychopharmacology, D-80804 Munich, Germany; Max Planck Institute of Neurobiology (A.S., C.L.), Department of Neuroimmunology, D-82152 Martinsried, Germany; University of Vienna (A.S., M.K.S., C.S., H.L.), Brain Research Institute, A-1090 Vienna, Austria; Department Of Neurology (M.K.S.), University of Graz, A-8010 Graz, Austria; and Department of Pharmacology (F.J.H.T.), Faculty of Medicine, Free University, 1081 BT Amsterdam, The Netherlands

Address all correspondence and requests for reprints to: Dr. J. M. H. M. Reul, Max Planck Institute of Psychiatry, Section of Neuropsychopharmacology, Kraepelinstrasse 2–16, D-80804 Munich, Germany. E-mail: reul{at}mpipsykl.mpg.de

In this study, we demonstrate that disruption of neuroendocrine signaling is a major factor driving disease progression in myelin oligodendrocyte glycoprotein-induced chronic relapsing experimental autoimmune encephalomyelitis, an animal model of multiple sclerosis. Although the initial episode of chronic relapsing experimental autoimmune encephalomyelitis is associated with a robust hypothalamic-pituitary-adrenocortical axis response, we show that subsequent disease progression is associated with a selective desensitization of hypothalamic-pituitary-adrenocortical responsiveness to inflammatory mediators. Inflammatory activity in the central nervous system during relapse is therefore unable to produce an endogenous immunosuppressive corticosterone 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. The effect of hypothalamic-pituitary-adrenocortical axis desensitization on the clinical course of experimental autoimmune encephalomyelitis is aggravated by a marked reduction in proinflammatory cytokine synthesis in the central 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 immune-endocrine effects play a decisive role in determining disease progression in multiple sclerosis, a concept supported by reports that a subpopulation of multiple sclerosis patients shows evidence of hypothalamic-pituitary-adrenocortical axis desensitization.

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