Neuroimmunoregulation and natural immunity.

The development and function of the immune system is regulated by neuroendocrine factors. Immune function may be divided into adaptive and natural immunity. Adaptive immune responses are driven by specific determinants of the antigen (epitopes), require 5-10 d to fully develop, and show an accelerated or memory response after repeated exposure to the same antigen. Natural immunity may be divided into host defense mediated by non-immune factors (e.g., antimicrobial proteins, enzymes, mucus etc.) and polyspecific responses of the immune system. This polyspecific response relies on natural antibodies and on some other serum proteins (e.g., lipopolysaccharide-binding protein-LBP, C-reactive protein-CRP), and on surface receptors of macrophages, natural killer cells and B and T lymphocytes for activation. Highly conserved homologous (crossreactive) epitopes, or homotopes for short, are recognized by the natural immune system. Natural antibodies, LBP, and CRP are capable of activating the entire immune system after combination with the appropriate homotope. During febrile illness natural immune host defense is promptly elevated because of the rapid rise of natural antibodies, LBP, and CRP in the serum. This is known as the acute phase response (APR), which is initiated by a sudden rise of cytokines in the circulation, such as IL-1, IL-6, and TNF-alpha. The cytokines act on the brain, the neuroendocrine system, and on other tissues and organs, which leads to fever and profound hormonal and metabolic changes. The hypothalamus-pituitary adrenal axis is activated and serves as the primary regulator of immune and inflammatory reactions. Insulin, glucagon, and catecholeamine levels are also raised. Bone marrow activity and leukocyte function are high and the liver is converted to the rapid production of acute-phase proteins (APP). APP include LBP, CRP, fibrinogen, some complement components, enzyme inhibitors, and anti-inflammatory proteins, which may rise in the serum from several hundred to a thousand times within 24-48 hr. Therefore, natural immunity is a polyspecific response to homotopes, which functions as an instantaneous defense mechanism in health and which is rapidly boosted by cytokines and hormones during febrile illness. This is a highly successful defense reaction, as in the overwhelming majority of cases, febrile illness leads to recovery and the development of adaptive immunity in man and higher animals.