Fever 2

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Pathogenesis of fever

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pyrogens, pyrogenic cytokines, elevation of hypothalamic set point by cytokines, production of cytokines in the CNS.

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pyrogen

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any substance that causes fever.

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Exogenous pyrogens

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derived from outside the patient; most are microbial products, microbial toxins, or whole microorganisms.

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The classic example of an exogenous pyrogen

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lipopolysaccharide (endotoxin) produced by all gram-negative bacteria.

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Pyrogenic products of gram-positive organisms include

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enterotoxins of Staphylococcus aureus and the group A and B streptococcal toxins, also called superantigens.

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One superantigen of clinical importance is

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isolates of S. aureus from patients with toxic shock syndrome.

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Endotoxin is a highly pyrogenic molecule in humans:

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When it is injected intravenously into volunteers, a dose of 2–3 ng/kg produces fever, leukocytosis, acute-phase proteins, and generalized symptoms of malaise.

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Cytokines

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are small proteins (molecular mass, 10,000–20,000 Da) that regulate immune, inflammatory, and hematopoietic processes.

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Example of the manifestation of cytokines IL-1 and IL-6

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elevated leukocytosis seen in several infections with an absolute neutrophilia.

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Some cytokines also cause fever; formerly referred to as endogenous pyrogens, they are now called pyrogenic cytokines.

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IL-1, IL-6, tumor necrosis factor (TNF), ciliary neurotropic factor (CNTF), and interferon (IFN) .

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Isn't a pyrogenic cytokine

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IL-18, a member of the IL-1 family

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Each cytokine is encoded by

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a separate gene,

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Inducers of IL-1, IL-6, TNF which—individually or in combination—trigger the hypothalamus to raise the set point to febrile levels.

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Bacterial, fungal, viral infection, inflammatory processes, trauma, tissue necrosis and antigen-antibody complexes

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Elevation of the Hypothalamic Set Point by

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Cytokines

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During fever, levels of prostaglandin E2 (PGE2 ) are

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elevated in hypothalamic tissue and the third cerebral ventricle.

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The concentrations of PGE2 are highest

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near the circumventricular vascular organs (organum vasculosum of lamina terminalis)

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organum vasculosum of lamina terminalis

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—networks of enlarged capillaries surrounding the hypothalamic regulatory centers. Destruction of these organs reduces the ability of pyrogens to produce fever.

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it appears that both exogenous and endogenous pyrogens interact with the endothelium of these capillaries and that

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this interaction is the first step in initiating fever—i.e., in raising the set point to febrile levels.

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Pyrogenic cytokines such as IL-1, IL-6, and TNF are released from the cells and enter the systemic circulation. Although the systemic effects of these circulating cytokines lead to fever by inducing the synthesis of PGE2 , they also induce PGE2 in peripheral tissues. The increase in PGE2 in the periphery accounts for the nonspecific myalgias and arthralgias that often accompany fever. It is thought that some systemic PGE2 escapes destruction by the lung and gains access to the hypothalamus via the internal carotid. However, it is the elevation of PGE2 in the brain that starts the process of raising the hypothalamic set point for core temperature

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How many PGE2 receptors ?

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4 and each signals the cell in different ways.

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Of the four receptors, the third (EP-3) is

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Essential PGE2 receptor for fever

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PGE2 released from the hypothalamic endothelium triggering PGE2 receptor on glial cells

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it is not a neurotransmitter in fever.

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cyclic AMP rapid release from glial cells

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is a neurotransmitter in fever genesis.

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the release of cyclic AMP from the glial cells activates

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activates neuronal endings from the thermoregulatory center that extend into the area.

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The elevation of cyclic AMP is thought to account for

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changes in the hypothalamic set point either directly or indirectly (by inducing the release of neurotransmitters).

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Distinct receptors for microbial products are located on the hypothalamic endothelium. These receptors are called

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Toll-like receptors and are similar in many ways to IL-1 receptors.

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The direct activation of Toll-like receptors also

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also results in PGE2 production and fever.

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Cytokines produced in the brain may account for

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caused by hyperpyrexia of CNS hemorrhage, trauma, or infection.

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Viral infections of the CNS induce

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induce microglial and possibly neuronal production of IL-1, TNF, and IL-6. In experimental animals, the concentration of a cytokine required to cause fever is several orders of magnitude lower with direct injection into the brain substance or brain ventricles than with systemic injection.

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cytokines produced in the CNS can

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raise the hypothalamic set point, bypassing the circumventricular organs.

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CNS cytokines probably account for the

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caused by hyperpyrexia of CNS hemorrhage, trauma, or infection.