Similarly, the loss of adrenal and gonadal hormones belongs to an adaptive program because reproduction is switched off at the expense of immune defense mechanisms.27,28 The whole reproductive program, including courtship behavior, is too energy consuming. In addition, the loss of androgens is an important factor to increase muscle wasting and, thus, re-allocation of muscle proteins to gluconeogenesis.
Elevated Sympathetic Tone
Increased sympathetic activity has been described in CIDs, although the meaning is unclear.1,29 Increased sympathetic activity leads to gluconeogenesis and, more importantly, to β2‑adrenergically mediated lipolysis. In this situation, both pathways may be switched on to support an activated immune system, but its continuous operation is unfavorable in CIDs. The loss of sympathetic nerve fibers described in inflammatory lesions is another hallmark of tissue inflammation. Importantly, sympathetic nerve fibers appear in high density in the fat tissue surrounding inflammatory lesions and activated lymph nodes in arthritis.26 This development supports lipolysis in neighboring fat tissue.
Decreased Parasympathetic Tone
Consistent with an increased activity of the SNS, decreased activity of the parasympathetic nervous system can occur during CIDs.30 The SNS is switched on at the expense of the parasympathetic system, which is linked to reduced gastrointestinal activity, decreased nutrient uptake, and diminished glucose uptake into the liver. As in the case of other systemic events described, the program may have been evolutionarily conserved for transient inflammatory episodes but becomes unfavorable in CIDs because the antiinflammatory cholinergic pathway is not active.31
Table 2: Etiological Factors in CIDs
- Genetic susceptibility (gene polymorphisms, polygenic)
- Complex environmental priming (microbes, toxins, drugs, injuries, radiation, cultural background, and geography)
- Immune response (exaggerated and continuous immune response against harmless self or foreign antigen)
- Tissue destruction (continuous wound response without proper healing but fibrotic scarring)
- Systemic response (support of the immune and wound response by redirection of energy-rich fuels leading to unwanted disease sequelae)
Point 5 of this list becomes comprehensible in the context of a continuous energy allocation to the immune system. It is the hope of the author that this framework leads to new therapeutic developments for CIDs that focus on energy allocation to and energy expenditure by the activated immune system.
Inflammation-Related Anemia
The following causes of anemia have been described in disease pathology: 1) allocation of iron to macrophages and other cells of the reticuloendothelial system stimulated by hepcidin; 2) reduced intestinal iron resorption initiated by hepcidin; 3) disturbed erythropoiesis due to proinflammatory cytokines and reduced half-life of erythrocytes (phagocytosis by macrophages); and 4) reduced influence of erythropoietin on erythropoiesis (little production or resistance). Circulating cytokines stimulate these pathophysiological elements.
