Stress, glucocorticoids and the susceptibility to develop autoimmune disorders of the central nervous system

Alterations of the immunoendocrine circuit along the hypothalamic-pituitary -adrenocortical (HPA) axis in various autoimmune diseases have recently bee n observed, suggesting a modulatory role of this feedback regulation in the pathogenesis of autoimmune diseases. Susceptibility to experimental autoim mune encephalomyelitis (EAE) may be influenced by variations in the product ion of endogenous glucocorticoid hormones (GC). The adrenocortical response is central to recovery from EAE in the Lewis rat, as reflected by increase d severity of the disease in adrenalectomized animals. The key role of GC i n modifying the induction and progression of EAE is also emphasized by a re versal of corticoid-mediated effects through treatment with glucocorticoid receptor (GR) antagonists. We studied the relationship between defective GR function and susceptibility to EAE in transgenic (Tg) mice expressing GR a ntisense RNA. EAE was induced with the encephalitogenic myelin oligodendroc yte peptide (pMOG 36-50) in wild type (Wt) and transgenic (Tg) female mice bearing GR antisense RNA. pMOG 36-50 induced typical EAE in Wt mice but not in Tg mice. Histological examination of brains and spinal cords of Wt mice showed the presence of inflammation and/or demyelination, whereas in Tg mi ce neither were present. Although the mechanisms underlying the resistance of Tg mice to EAE induction are not yet clarified, compensatory changes at different levels of the HPA-immune axis in response to the potent immunogen ic challenge are likely to participate in the observed effects. This work u nderlies the plasticity of the HPA-immune axis and suggests that pharmacolo gical manipulation of neuroendocrine-immune networks may be a therapy of mu ltiple sclerosis.