Neuroendocrine regulation of natural immunity

Abstract

ABSTRACT Natural killer (NK) cells, γδ T lymphocytes and CD5 + B lymphocytes are key effector cells in the natural immune system. These cells utilize germ-line coded receptors that recognize highly conserved, homologous epitopes (homotopes). Cytokines, hormones and neurotransmitters regulate natural immunity. Under physiological conditions the natural immune system is regulated similarly to the adaptive immune system: growth and lactogenic hormones (GLH), insulin-like growth factor-I (IGF-I), insulin, leptin, some steroid (glucocorticoid at physiological concentrations, dehydroepiandrosterone and some of its derivatives) and thyroid hormones are stimulatory. The peptides of the hypothalamus-pituitary-adrenal axis (CRF, AVR ACTH, αMSH, βEND) exert an immunosuppressive, anti-inflammatory and anti-pyretic effect. Opioid peptides and estradiol are immunomodulators that promote some immune activities while inhibiting others. High (pathophysiological) levels of glucocorticoids, progesterone and testosterone act as immunosuppressive hormones. Beta-adrenergic agents are immunosuppressive and antiinflammatory, whereas cholinergic agents promote immunity and inflammation. Substance P and calcitonin-gene related peptide are pro-inflammatory and promote immunity, whereas somatostatin is an antagonoist of these neuropeptides. Mild infection or a sublethal dose of endotoxin elicits a brief elevation of GH and PRL in the serum. Severe trauma, sepsis and shock results in the elevation of TNFα, IL-1 and IL-6 in the blood stream, the GLH-IGF-I axis is suppressed, whereas the hypothalamus-pituitary-adrenal axis is activated. LH, FSH, estrogens, androgens, progesterone, and thyroid hormones all decline during infection and endotoxin shock, as a rule. Leptin, insulin, glucagon, α-MSH, endorphin, and arginine vasopressin are increased during endotoxemia. A “sympathetic outflow” leads to elevated blood levels of catecholamines. Fever and catabolism prevails, whereas acute phase proteins in the liver, cell proliferation in the bone marrow, and protein synthesis by leukocytes are increased. This is an acute emergency reaction to save the organism after the adaptive immune system has failed to contain and eliminate the pathogenic agent. During sepsis and endotoxin shock, glucocorticoids potentiate the production of acute phase proteins and regulate pro-inflammatory cytokine production. Catecholamines also inhibit inflammatory responses and promote, even initiate, the acute phase response. Leptin regulates energy metabolism and it is a major stimulator of the immune system. If the acute phase reaction fails to protect the host, shock will develop and death will follow. The acute phase response leads to immunoconversion, which involves the suppression of the T-cell regulated adaptive immune system and the amplification of natural immunity. Natural antibodies, C-reactive -, endotoxin binding- and mannose binding proteins are boosted and serve as polyspecific recognition molecules for leukocytes. The natural immune system provides the first and the last line of host defence and its functional integrity and massive activation is largely dependent on the neuroendocrine system.