From humoral fever to neuroimmunological control of fever

Fever is a part of the acute phase response to infection or systemic inflammation. It is thus a part of a complex physiological defence strategy against 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 by immune cells activated by contacts with foreign molecules (exogenous pyrogens). These fever-inducing mediators, produced by the host cells (endogenous pyrogens), were originally thought to be distributed by means of the bloodstream (similarly to hormones) to different tissues of the body. Although the details of their transport across the blood–brain-barrier have not been clarified, it has been assumed that they activate the local production of inflammatory mediators within the brain, inducing a change in the thermoregulatory set-range and resulting in fever (humoral theory of fever). This concept has apparently changed in the past few years. Evidence has recently been presented supporting the possibility of the transport of immune signals to the brain via vegetative and peripheral nerves. In this review an attempt is made to describe the events leading to a fever response accompanying the systemic inflammation against a background of microbiological, immunological and physiological data. The experimental evidence published during the last five years has been reviewed, and a new concept of neuroimmunological control of fever is presented. This concept suggests that the host immune defence is coordinated through an integration of the neural, immune, hemopoietic 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-monitoring system, and this information is confirmed by immune signals delivered by the humoral transport. The combination of these signals would allow the brain to recognize the nature of the challenge, and to activate an appropriate defence strategy. Fever as a part of many successful defence strategies against infections may thus be beneficial.     

Neurophysiology of fever

Fever is a primary disorder of thermoregulation and a common clinical sign in many diseases. It is characterized by an upward displacement in the level at which body temperature is regulated. Early attempts to study hypothalamic neuronal activity in relation to fever described the behavior of isolated single units after intravenous injections of endotoxin pyrogen. It was concluded that the thermosensitivity of many warm-sensitive units was depressed after pyrogen injections, but due to the indirect technique employed, it is not possible to distinguish whether this observation is the cause or result of fever. A decrease in hypothalamic thermosensitivity is contrary to observations made during fever in conscious animals. More specific applications of pyrogenic stimuli such as prostaglandin E1 onto individual hypothalamic neurons using the technique of microelectrophoresis have not borne out these earlier observations. A major obstacle to studying the neurophysiology of thermoregulation and fever is the absence of any obvious correlation between neuroanatomy and function in the hypothalamus. Present methods of identifying and classifying hypothalamic cells as participants in thermoregulation are patently inadequate. Until a more specific correlation between anatomy and function is established, the neurophysiological mechanisms of fever will remain obscure.     

Yellow fever

With the infestation by Aedes aegypti, urban yellow fever might already exist. This did not occur because of either the lacking of a sufficient contact between the diseased individual and the A. aegypti or perhaps because this, after sixty years without transmitting the virus, needs an adaptation phase to infecting again.     

基孔肯雅热

基孔肯雅热(Chikungunya fever,CHIK)是由基孔肯雅病毒(Chikungunya virus,CHIKV)病毒引起的,伊蚊叮咬传播的,以发热、关节疼痛等为主要特征的自限性传染性疾病。1952年在坦桑尼亚发生的暴发流行中首次分离CHIKV[1-2],亚洲地区于