Hypothalamo-pituitary-adrenal axis and chronic immune activation.

Corticosteroids have potent immunosuppressive and anti-inflammatory effects. Although corticosteroids are an important weapon in the clinical arsenal for treating inflammatory episodes, the mechanisms underlying the actions and regulation of endogenous corticosteroids remain obscure. In the late 1980s and early 1990s, a hypothesis was proposed that suggested that susceptibility to autoimmune disease was linked to a hypoactive hypothalamo-pituitary-adrenal (HPA) axis. It was further suggested that this defect in regulation of the HPA axis was situated at the level of the hypothalamus. This compelling hypothesis directly linked control of the HPA axis with susceptibility to disease rather than just severity of inflammation. The initial findings acted as a stimulus to further research, and over the next decade the hypothesis was tested. Recent studies suggest that the original hypothesis is in need of modification and that susceptibility is more complex and requires the involvement of more than a single parameter. These data are discussed together with recent developments concerning regulation of the HPA in disease in preclinical models and patients with rheumatoid arthritis. The latter studies in patients with rheumatoid arthritis provide evidence for the existence of a subpopulation of these patients with altered negative feedback regulation of the HPA axis.