From humoral fever to neuroimmunological control of fever

Fever is a part of the acute phase response to infection or systemic inflam mation. It is thus a part of a complex physiological defence strategy again st micro-organisms invading the body of the host, or against non-microbial agents recognized as foreign by mobile immune cells of the body. The fever is induced by inflammatory mediators (prostaglandins, cytokines) released b y immune cells activated by contacts with foreign molecules (exogenous pyro gens). These fever-inducing mediators, produced by the host cells (endogeno us pyrogens), were originally thought to be distributed by means of the blo odstream (similarly to hormones) to different tissues of the body. Although the details of their transport across the blood-brain-barrier have not bee n clarified, it has been assumed that they activate the local production of inflammatory mediators within the brain, inducing a change in the thermore gulatory set-range and resulting in fever (humoral theory of fever). This c oncept has apparently changed in the past few years. Evidence has recently been presented supporting the possibility of the transport of immune signal s to the brain via vegetative and peripheral nerves. In this review an atte mpt is made to describe the events leading to a fever response accompanying the systemic inflammation against a background of microbiological, immunol ogical and physiological data. The experimental evidence published during t he last five years has been reviewed, and a new concept of neuroimmunologic al control of fever is presented. This concept suggests that the host immun e defence is coordinated through an integration of the neural, immune, hemo poietic and endocrine systems. The brain seems to be informed of any damage or antigenic challenge in the periphery of the body by a sensory host-moni toring system, and this information is confirmed by immune signals delivere d by the humoral transport. The combination of these signals would allow th e brain to recognize the nature of the challenge, and to activate an approp riate defence strategy. Fever as a part of many successful defence strategi es against infections may thus be beneficial. (C) 2000 Elsevier Science Ltd . All rights reserved.