Fever Producing Substances: Pyrogens

Fever Producing Substances

Fever causing Pyrogen is usually derived from microorganisms. 

Keywords: Pyrogens, Cytokines, Interleukin, Endogenous, PGF2, Exogenous, Lipopolysaccharides (LPS), LPB- LPS, Tumor necrosis factor – α, Arachidonic -acid, PGE2.

What is pyrogen?

The fever-producing substance is pyrogen. The pyrogen is usually derived from microorganisms such as bacteria, viruses, viroids, etc. When present in large amount may lead to severe inflammation when not treated, it may lead to shock, multi-organ failure, and even death.

   Exogenous Pyrogens

   Microbial: Virus, Bacteria, Yeast, Fungus, Malarial parasites

                    Lipopolysaccharide in gram-negative bacteria wall.

                    Lipoteichoic in gram-positive bacteria.

   Non–microbial:                                                      

   Nonself: Some drugs, e.g.,  Colchicin

                 Environment pollution

   Self: Antigen-antibody complexes

            Metabolic products of steroids

   Endogenous Pyrogens are synthesized from phagocytic cells.

O antigen

Outer core

Inner core

Lipid-A

Cytokines combine with the receptor of macrophage

   Endotoxins: The most common pyrogens are endotoxins produced by gram-negative bacteria. T They are chemically lipopolysaccharides (LPS). The structure of endotoxin is as follows:

1. Lipid –A,

2. Polysaccharide core inner core and outer core, then

3. O-antigen.

LPS molecules are present in the outer membrane of gram-negative bacteria. Lipid-A is the toxic part of lipopolysaccharide, and it is the same in all gram-negative bacteria. It is strongly pathogenic but not immunogenic. Lipid-A is responsible for the disease –cause severe shock and, if not appropriately treated, may cause death. Lipid-A is identical in all, but polysaccharide varies in gram-negative bacteria. Polysaccharide is highly immunogenic but not pathogenic.

What is an immunogenic substance –The immunogenic substance stimulates the immune system of the body.

What is a pathogenic substance –The pathogenic substance causes disease.

Non-endotoxins: Substances usually derived from microorganisms other than gram-negative bacteria and other chemical substances.

Type of Pyrogens:

Internal pyrogens: Endogenous substances are synthesized by body cells.

External pyrogens: Exogenous substances are not produced by the body cells, and they enter into the body by any route.

Endogenous pyrogens are low molecular-weight proteins produced in response to stimulation by exogenous pyrogens and released into the circulation, causing fever by acting on the preoptic area of the hypothalamic thermostat.

Two different groups of pyrogens are formed :

1. One by Neutrophils and

2. Another by Monocytes

Pyrogens secreted from the monocytes are not identical to those produced by neutrophils. The monocytes produce many pyrogens for a more extended period than those produced by neutrophils.

Major endogenous pyrogens are interleukin- 1 and -6(IL-6).

Minor endogenous pyrogens are interleukin-8, macrophage inflammatory protein-α, and β, interferon α,β and γ, tumor necrosis factor- α(TNF α), etc. These cytokines are absorbed into general circulation, migrate to the brain's circumventricular organs. Here the cytokines bind to endothelial receptors on vessel walls to receptors on microglial cells resulting in activation of the arachidonic acid pathway. In addition, these proteins produce a cyclooxygenase which induces the formation of PGF2 from the hypothalamus. PGF2 then stimulates the release of neurotransmitters –cyclic adenosine monophosphate causing the increase in body temperature.

The cells of the immune system, especially macrophages and monocytes, engulf the invading bacteria.  The bacteria release their metabolite into the surrounding. When the immune system kills the bacteria, the structural part of the bacteria's cell wall is destroyed, and its products diffuse into the surroundings. These metabolic products of living pathogens and products of dead pathogens are exogenous pyrogens.

Exogenous pyrogens are not able to raise fever, and they act through endogenous pyrogens. Exogenous pyrogens, when they enter the body, they stimulate the immune system of the body. The cells of the immune system, especially neutrophils, monocytes, and macrophages, produce endogenous pyrogens.

Exogenous pyrogens attach with CD14 on the cells of the immune system, especially macrophages and monocytes, and trigger the cellular synthesis of endogenous pyrogens. The cytokines are endogenous pyrogens. IL-1, . IL-6, TNFα, etc., are cytokines. They act on the hypothalamus and cause an increase in temperature.

 

Exogenous pyrogens: The first known use of exotoxin was in 1920. They are toxic so- soluble substances produced during the growth of a microorganism and released into the surrounding. Usually, these pyrogens, along with products of the bacterial cell wall, act on  o toll-like receptors in the hypothalamus and elevate the thermoregulatory set point in the hypothalamus.

Mode of action:  The bacterial lipopolysaccharides (LPS) present in the cell wall of gram-    negative bacteria bind to a lipopolysaccharide-binding protein (LPB). LPB- LPS complex then  bind to CD14 receptors on a macrophage. The LPB- LPS binding to CD14 results in cellular    synthesis and release of various endogenous cytokines, e.g., interleukin- 1 and -6(IL-6) tumor necrosis factor- α (TNFα). These endogenous cytokines activate the arachidonic acid pathway to synthesis and release of PGE2 -the ultimate mediator of the febrile response. The arachidonic acid pathway is mediated by the enzymes phospholipase A2, cyclooxygenase -2, and prostaglandin E2 synthase.

Methods used for detection of pyrogenic materials:-
1. The Limulus amoebocyte lysate (LAL) test detects endotoxins.
2. The recombinant factor C assay test and
3. Rabbit pyrogen test.