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Question continued: I’ve read somewhere that when the body is infected by viral or  bacterial pathogens, the immune system raises the body temperature to help fight the spread of infection. How does the immune system know how to do such a thing? It almost sounds as if the immune system has a brain of its own. I mean it  may sound silly, but – does it? Who designed it to be able to fight off infections or even know what an infection is or when it’s inside the body?

Answer by Tirumalai Kamala:

Fever results not from the immune system alone but from immune system plus hypothalamus.

Infections typically target specific cells, tissues and organs. This is called Tissue tropism. Some pathogens have a broad range, others narrow. Since infections can target every organ from skin, GI tract and lungs to heart and brain, it stands to reason that every cell in the body is immunocompetent enough to signal its distress to its surroundings. How do non-immune cells raise this alarm call? Some approaches are ubiquitous, others are cell- or tissue-specific.  What they have in common is that a ripple effect ensues and brings to the site professional immune system cells such as neutrophils, monocytes, macrophages and lymphocytes to name just a few (Inflammation). Once at the site, these immune cells get activated locally, responding to by-products of the infection.

When immune cells such as monocytes and macrophages are activated, they release a bunch of chemical messengers, aka cytokines such as interleukin-1, -6, tumor necrosis factor and others. These are collectively called endogenous pyrogens (1) because they influence the thermoregulatory set point. This is the first step necessary for the fever response. What’s the thermoregulatory set point? How do endogenous pyrogens influence it? How does fever start and stop?

The thermoregulatory set point
The hypothalamus has thermoregulatory neurons (2). The thermoregulatory set or reference point is established by the firing rate of these neurons.

How endogenous pyrogens influence the thermoregulatory set point
Once released at the site of infection, endogenous pyrogens travel through the blood stream and enter the hypothalamus after crossing the blood-brain barrier with the help of either specialized transporters or at specialized locations. In the hypothalamus they trigger the production of other chemical messengers such as prostaglandin E2 for example, which alter the firing rate of the thermoregulatory neurons. This in turn increases the thermoregulatory set point (1)

The simplified cartoon below summarizes the entire process (3).

  • Infection causes local cells to trigger their distress.
  • Local cell distress brings immune cells to the site.
  • Immune cells get activated by by-products of the infection.
  • Activated immune cells locally secrete among other things, endogenous pyrogens.
  • Endogenous pyrogens travel to the hypothalamus.
  • In the hypothalamus, they cause increase of the thermoregulatory set point.
  • But core temperature is lower than the thermoregulatory set point (shiver, feel cold, seek warmth, etc.).
  • Body adjusts to increase core temperature (blood vessels constrict, metabolic heat rises as does body temperature).
  • Now body core temperature equals the thermoregulatory set point.
  • When infection’s cleared, immune cells stop endogenous pyrogen production.
  • Thermoregulatory set point reverts back to normal.
  • But now core temperature is higher than thermoregulatory set point
  • Body adjusts (sweat, feel hot, seek cool, etc.) until core temperature equals thermoregulatory set point.


  1. Dinarello, Charles A. “Cytokines as endogenous pyrogens.” Journal of Infectious Diseases 179.Supplement 2 (1999): S294-S304.

    Cytokines as Endogenous Pyrogens

  2. Boulant, Jack A. “Role of the preoptic-anterior hypothalamus in thermoregulation and fever.” Clinical infectious diseases 31.Supplement 5 (2000): S157-S161. Role of the Preoptic-Anterior Hypothalamus in Thermoregulation and Fever
  3. Cannon, Joseph G. “Perspective on fever: the basic science and conventional medicine.” Complementary therapies in medicine 21 (2013): S54-S60.