The general meaning of the systemic response in inflammatory diseases is not well understood. Nor do we know whether the systemic response has any unfavorable role when inflammatory diseases become chronic. We call chronic inflammatory diseases (CIDs) “systemic in nature”, but the significance of these systemic signs and symptoms is not known. In order to understand the role of the systemic response a conceptual framework was developed over the last decade.
1) The evolutionary principle of replication with variation and selection is undeniably fundamental and it has history. It was a successful history of positive selection, which can only happen under circumstances of unrestricted gene transfer to the progeny.
Genes that might play a specific role in CIDs were evolutionarily not conserved because unrestricted gene transfer in the context of CIDs was not possible (negative selection pressure).
The regulatory mechanisms of the neuroendocrine and immune systems evolved to cope with non-life-threatening transient inflammatory episodes but not with serious life–threatening CIDs. No prolonged adaptive program exists in CIDs.
2) Organisms evolved under conditions that favored the development of complex mechanisms for obtaining food, and for storage and allocation of energy-rich fuels. Energy regulation and cellular bioenergetics take the highest position in the hierarchy of homeostatic control. The main supporters of energy-rich fuel storage in liver, muscle, and adipose tissue are insulin, insulin–like growth factor 1, androgens/estrogens, and the parasympathetic nervous system (storing factors).
The neuroendocrine systems are important regulators of energy storage and provision
Pathways of the immune and the neuroendocrine systems including energy regulation were evolutionarily conserved for transient non–life–threatening inflammatory episodes. Thus, no specific neuroendocrine program and energy regulation program have been conserved for CIDs.
Since the immune system is one of the major energy consumers, particularly in the activated phase, the stimulated systemic response must be viewed as an “energy appeal reaction”, which leads to re–allocation of energy–rich substrates to the immune system.
However, the long–standing re–allocation program leads to disease sequelae such as depressive symptoms & fatigue, anorexia, malnutrition, muscle wasting & cachectic obesity, insulin (IGF–1) resistance with hyperinsulinemia, dyslipidemia, increase of adipose tissue in the proximity of inflammatory lesions, alterations of steroid hormone axes (e.g., hypoandrogenism), elevated sympathetic tone and local sympathetic nerve fiber loss, decreased parasympathetic tone, inflammation–related anemia, and osteopenia. The pathophysiological links are described in J Intern Med, 2010, 267: 543.
The framework explains that CID sequelae are a consequence of a continuous “energy appeal reaction”. The systemic response of the body, the energy appeal reaction, is important to support the immune system during short–lived inflammatory episodes but its continuous use in CIDs is highly unfavorable. Since the aging process of a normal subject has similarities with a long–term low level inflammatory disease, the concept also explains age–related diseases.