Integrated evolutionary, immunological, and neuroendocrine framework for the pathogenesis of chronic disabling inflammatory diseases.

The pathogenesis of chronic disabling inflammatory diseases (CDIDs) is poorly understood. Current concepts that focus on abnormalities of the immune system are, in our view, incomplete. Here we propose that chronic disruption of homeostasis through abnormal neuronal and endocrine host responses to transient inflammatory reactions contributes to the appearance of CDIDs. Coordinated reactions of the supersystems (immune, nervous, endocrine, and reproductive) that maintain homeostasis have been evolutionarily conserved to respond to and eliminate foreign agents over a period of days to a few weeks. If the responses of these supersystems fail to return to normal after elimination of the pathogen, a continuous aggressive immune response is created; this situation can trigger development of CDIDs. Maladaptation of the supersystems during CDIDs has not been evolutionarily conserved but is nevertheless still prevalent because a large proportion of these diseases tend to appear after the reproductive phase. We propose that this integrated systems hypothesis may permit better identification of a patient at risk or in the early stages of developing a CDID such as rheumatoid arthritis and enable more coordinated intervention than is presently attempted.