Developmental consequences of hypothalamic-pituitary-adrenocortical system disruption: Impact on thymus gland maturation and the susceptibility to develop neuroimmune diseases

Glucocorticoid hormones (GCs) exert a negative feedback action on the hypothalamic-pituitary-adrenocortical (HPA) axis activity at the pituitary, hypothalamic and extrahypothalamic levels. Activation of the HPA axis is one of the major responses to stressful stimuli, including infectious diseases. The neuroendocrine response to stress displays profound gender-specific differences, largely dependent on the presence of gonadal steroids. Such marked 'sensitivity' of the HPA axis to the sex steroid hormonal milieu is reflected at the immune system level with the known immunological sexual dimorphism and increased vulnerability of the female sex to autoimmune diseases. Transgenic mice with impaired glucocorticoid receptor (GR) function were created to serve as an animal model for the study of neuroendocrine changes occurring in stress-related disorders, such as major depression. These mice have increased plasma concentrations of adrenocorticotropic hormone, as well as a reduction of GR binding capacity. We have recently used this animal model to further our knowledge on the role of GC feedback during the developmental maturation of HPA-immune functions. The dysregulation of the HPA axis in transgenic mice was accompanied by a number of abnormalities, including: an abnormal developmental pattern of adrenal secretory activity, a reduced GC feedback action at the thymus gland level, alterations in thymocyte trafficking leading to a higher helper/suppressor (CD4+:CD8-) ratio and abnormal immune reactivity. In another experimental approach, the impact of reduced GC tone on thymus ontogenic development was studied in the progeny of adrenalectomized pregnant rats. In this animal model, the accelerated maturation of T cells suggests that absence of GCs during fetal life may determine an earlier colonization of the thymic primordium by T cell precursors. Altering the glucocorticoid influence during embryonic development may have different long-term effects on the responsiveness of the HPA axis. The GCs differentially regulate cytokine production of antigen- presenting cells by shifting the generation of T-helper subsets from naive T cells (Th0 cells) to T-helper 1 (Th1) or the T-helper 2 (Th2) type. In line with the effects of GCs on Th cytokine profile, GCs suppress the Th1-type- mediated delayed type of hypersensitivity (DTH) reactions like experimental allergic encephalomyelitis (EAE), a model for human multiple sclerosis. Such concepts are discussed in the light of experimental and animal studies, as well as literary information generated in humans, suggesting that susceptibility to autoimmune disorders of the CNS like multiple sclerosis may be linked to a defective response of the HPA axis. Transgenic mice (B6C3F1) expressing a GR antisense RNA appear resistant, while intact (B6C3F1) mice are vulnerable to EAE induction, indicating that the neuroendocrine-immune status of the transgenic mice markedly affects the development and progression of the disease. Together, the present findings clearly support a vital role for type II GR gene expression in the development of the HPA- immune regulatory loop, and underline the potential modulatory role of this feedback regulation in the pathogenesis of autoimmune diseases of the CNS.