Neuroendocrine Influences on Experimental Autoimmune Encephalomyelitis

Abstract

Experimental autoimmune encephalomyelitis (EAE), a model for human multiple sclerosis, is an inflammatory disease of the CNS mediated by autoreactive T lymphocytes directed against the neuroantigen, myelin basic protein (MBP). EAE is inducible in the Lewis rat, which exhibits an acute monophasic disease, and in selected mouse strains, which show a remitting-relapsing or chronic course of paralysis. We examined the effects of neuroendocrine modulation by restraint stress on these models of EAE. In Lewis rats, daily cycles of restraint resulted in significant suppression of both clinical and histopathologic changes of EAE. Suppression of EAE was more pronounced in the female than in the male rat, which follows from the higher endogenous corticosterone levels in the female. Mechanistic studies suggested that stress affected the processing of MBP or the T-cell idiotype. In the relapsing murine model of EAE, B10.PL mice were restrained beginning either before MBP challenge or after the establishment of relapsing disease. We observed a striking inhibition of EAE clinical signs in mice stressed before challenge relative to nonstressed controls. Interestingly, approximately 10 days after termination of the stress period, clinical signs returned and were as severe or more severe than in control nonstressed animals. Stress administered after relapsing EAE was established had no protective effect. In vitro parameters revealed that only stress initiated before disease induction significantly reduced the frequency of MBP-specific lymphocytes in the spleen and lymph nodes. Both Th1 and Th2 cytokine responses were suppressed in stressed mice. T-cell receptor transgenic mice exposed to restraint showed a marked decreased in the number and functional activity of transgene-positive lymphocytes. In summary, elevated levels of endogenous neuroendocrine hormones exert a profoundly suppressive effect on both acute and chronic models of autoimmune CNS injury.

Cutting Edge: Macrophage Migration Inhibitory Factor Is Necessary for Progression of Experimental Autoimmune Encephalomyelitis

“…First, increased levels of steroid hormones, whether produced endogenously or introduced exogenously, can lead to amelioration of disease flares (5,18). Because MIF has been shown to be a potent antagonist of glucocorticoid activity, it is possible that the absence of MIF in MIF Ϫ/Ϫ animals allows for elevations in glucocorticoid hormones contributing to protection from disease.…”

Geschlechtsspezifische Unterschiede der schlafendokrinen Regulation und deren Bedeutung für die Pathophysiologie der Major Depression

“…Tierexperimentelle Arbeiten haben gezeigt, dass eine verminderte Stimulierbarkeit der HPA Achse die Vulnerabilität erhöht an einer experimentellen autoimmunen Enzephalitis, dem Tiermodell für MS, zu erkranken (Huitinga et al 2000). Auch haben tierexperimentelle Daten gezeigt, dass wiederholter Stress einen erneuten Krankheitsschub verhindern kann (Levine and Saltzman 1987;Whitacre et al 1998 Parameter und eine Verminderung des Tiefschlaf-Quotienten und der 'delta sleep ratio'), für die eine Erhöhung der CRH Sekretion und eine unzureichende negativer Rückkopplung durch Kortisol verantwortlich gemacht werden [ (Antonijevic et al 2000a;Antonijevic et al 2000b;Armitage et al 2001;Buysse et al 1997;Kupfer et al 1990 Episode zu entwickeln assoziiert Kupfer et al 1990;Murck et al 2003;Steiger et al 1989;Zobel et al 1999 Erst in den letzten Jahren haben einige Arbeiten aufgezeigt, dass das Geschlecht eine wichtige Rolle für die schlafendokrine Regulation spielt, sowohl bei jungen Probanden, aber auch im Alterungsprozess (Armitage 1995;Dijk et al 1989;Ehlers and Kupfer 1997).…”

“…Dieser Befund wird unterstützt durch tierexperimentelle Studien, die einen protektiven Effekt einer HPA Aktivierung auf inflammatorische Schübe gezeigt haben (Levine and Saltzman 1987;Whitacre et al 1998 (Sapolsky 1987;Sheline et al 1996;Sheline et al 1999 Keck ME, Wigger A, Welt T, Muller MB, Gesing A, Reul JM, et al (2002) …”

Stress and Disease Progression in Multiple Sclerosis and Its Animal Models

“…This effect was not observed when the stressor was administered after EAE induction. Interestingly, Whitacre et al [12] reported that 10 days after termination of the stress period, clinical signs returned and were as severe or more severe than in control nonstressed animals. Correa et al [13] showed that the application of varied chronic stressors (swimming, water deprivation, restraint, crowding, sound for 14 days) before EAE induction with myelin basic protein suppressed EAE in Wistar rats.…”

“…Several studies have supported the notion that chronic stressor may have a protective effect on EAE only when administered before disease induction [10][11][12] . This effect was not observed when the stressor was administered after EAE induction.…”