Abstract
One of the many symptoms that the majority of mammalian diseases have in common is the higher-than-normal body temperature of the patient, a condition commonly known as fever. When it comes to infectious factors, fever is a characteristic response of the host to many bacterial pathogens, and depending on a plethora of variables, it can either be beneficial or harmful to the patient’s body. The great number of attempts to understand and describe pyrogenesis -that is, the induction of fever- in the last century, serve as a reminder of this phenomeno’s great importance to not only human but also animal medicine. In this article, a description of both the immunological and neurological basis of pyrogenesis is presented, in order to unify and aptly summarize existing literature on the subject.
Introduction
Fever from a physiological point of view
Commonly speaking, fever is used to refer to a situation where the body temperature is higher than the normal average (around 37oC / 98.6oF for humans). However, this is not a completely correct use of the term. Fever should be distinguished from a similar condition, called hyperthermia, which is also characterized by elevated temperature. While in both cases an excess production of heat is observed, the key difference is that fever also includes an increase in the “normal reference temperature” of the individual. In other words, during fever the brain thinks that the body is colder than it actually is (Cunningham & Klein, 2013).
The role of fever is to aid the immune system in neutralizing a pathogen, most often a bacterium, that has infected the body. More specifically, the fever-induced higher temperature state promotes the function of cells that comprise the innate immunity such as Natural Killer cells and neutrophils, while also increasing the number of the latter. As per the adaptive immunity (which in broad terms is responsible for antibody production), fever enhances the function of most cells involved in its mechanisms, such as antigen-presenting dendritic cells, macrophages and T-lymphocytes (Tizard, 2018). While a high temperature can inhibit the replication of invading bacteria (Blomqvist & Engblom, 2018), it can prove to be harmful for the organism itself, if it is not well-regulated.
Chemokine signaling in pyrogenesis
The induction of fever, named pyrogenesis (from the Greek pyr = fire and genesis = birth), is a complex phenomenon that encompasses many different cells, substances and mechanisms.
Once the body has recognized the presence of an infectious agent, it begins a multistep cascade of immunological actions and reactions. In broad terms, this cascade begins with the production of the proinflammatory cytokines Tumor Necrosis Factor-alpha (TNFα), Interleukin-1 (IL-1) and subsequently Interleukin-6 (IL-6) by cells of the immune system, all induced by the transcription factor NF-kB and regulated by a series of complex circuitry involving those and other chemokines (Tizard, 2018).
Interleukin-1 (or more accurately, its fragment, IL-1β) is a potent endogenous (produced naturally by the organism) pyrogen, and acts on the thermoregulatory area of the brain in order to induce fever. The region of the brain associated with endogenous pyrogens is the “Organum Vasculosum of the Lamina Terminalis,” or OVLT for simplicity (Cunningham & Klein, 2013). Located on the third ventricle’s rostroventral boundary, it is one of the Circumventricular Organs. The OVLT is closely related to the anterior hypothalamus and is involved in the processing of autonomous functions including measuring blood serum osmolality and, of course, pyrogenesis (Low, 2016).
In their extensive review, Blomgvist and Engblom (Blomqvist & Engblom, 2018) mentioned the existence of TNF-α, IL-1β and IL-6 receptors on the endothelial cells of the vessels passing through the Circumventricular Organs. These receptors facilitate the communication between the immune system and the different cellular types that possess them. It should be noted that the forementioned organs’ vasculature is characterized by the absence of the Blood-Brain Barrier, making them a suitable candidate for the transfer of messages from the peripheral blood to certain areas of the brain. The action of endogenous pyrogens to those receptors comes down to the production of Prostaglandin E2 (Cunningham & Klein, 2013). The synthesis of this prostaglandin happens at the aforementioned endothelial cells, thanks to the presence of an enzyme called microsomal Prostaglandin E Synthase-1 (mPGES-1). Prostaglandin E2 (PGE2) binds to the EP3 receptor expressed in the neurons of the preoptic hypothalamic area (Blomqvist & Engblom, 2018), thus affecting the anterior hypothalamic thermoregulatory center and hereby causing an increase in temperature.
Cation homeostasis and thermoregulation
Although fever induction happens at the level of the anterior hypothalamus, there exists an interesting interplay between the activity in this area and the cationic balance of the posterior hypothalamus. As was shown by Myers et al. (Myers et al., 1976), temperature changes either in the environment or in the anterior hypothalamus caused a shift in the extracellular Ca++ concentration in the posterior hypothalamus, that was absent when neural communication between the two areas was chemically obstructed. More specifically, colder temperatures caused an increase in extracellular Ca++that was associated with a subsequent increase in body temperature. The opposite was demonstrated to be true, when the subject was exposed to warmer temperatures. Proving that this phenomenon was also present in inflammation associated with the rise of temperature, the researchers injected Salmonella typhosa to the rostral hypothalamus and observed the same Ca++ efflux in the caudal hypothalamic area.
The shifts in calcium ion balance described above appear to have an effect unique to the posterior hypothalamus, as experimentally induced changes in the Ca++ concentration of the anterior hypothalamus did not seem to alter the body temperature of the subject (Myers & Veale, 1971). This, however, cannot be said about Na+ions, as in the same paper, the authors demonstrated a temperature change both when Na+ was injected in the anterior and in the posterior hypothalamus, proving this way that Na+ exerts a regulation in both of these areas.
The proposed mechanism for the effect of Ca++imbalance in the temperature shift emphasizes the role of the cation in the stability of neuronal membranes. Considering the transduction of information via a rate code, Myers et al. (Myers et al., 1976) suggest that an increase in intracellular Ca++-and thus a decrease in extracellular- observed in “higher-temperature signaling” lowers the rate of fire of cholinergic heat producing neurons of the posterior hypothalamus, whereas the opposite happens in the case that “lower-temperature signaling” is received. Cholinergic neurons -albeit different ones- are also responsible for the transmission of the appropriate neuronal information from the anterior to the posterior hypothalamus when it comes to temperature modulation (Myers, 1971).
Conclusion
In conclusion, fever is a multisystemic response of the mammalian body to an invading pathogen. It is regulated by the thermoregulatory center in the anterior hypothalamic area of the brain, which interfaces with the rest of the body chemically, via cytokines. Once stimulated, the anterior hypothalamus communicates synaptically with the posterior hypothalamus, where shifts in the Ca++ concentration regulate the activity of heat-producing neurons.
Understanding the mechanisms behind fever is of great importance to health sciences. Knowledge of both the chemical and the neural pathways of pyrogenesis can aid in the advancement of internal medicine with the development of new medicinal compounds
that can affect specific parts of the thermoregulatory mechanism -such as the EP3 receptors- and the optimization of diagnostic/therapeutic clinical protocols.
Written by: Evangelos Panteras
Works Cited
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