The Innate Immune System: Fever

I. THE INNATE IMMUNE SYSTEM

J. FEVER

The overall purpose of this Learning Object is to learn how fever functions in innate immune defenses.

LEARNING OBJECTIVES FOR THIS SECTION

Innate immunity refers to antigen-nonspecific defense mechanisms that a host uses immediately or within several hours after exposure to an antigen (def). This is the immunity one is born with and is the initial response by the body to eliminate microbes and prevent infection.

Unlike adaptive immunity, innate immunity does not recognize every possible antigen. Instead, it is designed to recognize molecules shared by groups of related microbes that are essential for the survival of those organisms and are not found associated with mammalian cells. These unique microbial molecules are called pathogen-associated molecular patterns or PAMPS and include LPS from the gram-negative cell wall, peptidoglycan and lipotechoic acids from the gram-positive cell wall, the sugar mannose (a terminal sugar common in microbial glycolipids and glycoproteins but rare in those of humans), bacterial and viral unmethylated CpG DNA, bacterial flagellin, the amino acid N-formylmethionine found in bacterial proteins, double-stranded and single-stranded RNA from viruses, and glucans from fungal cell walls. In addition, unique molecules displayed on stressed, injured, infected, or transformed human cells also act as PAMPS. (Because all microbes, not just pathogenic microbes, possess PAMPs, pathogen-associated molecular patterns are sometimes referred to as microbe-associated molecular patterns or MAMPs.)

Most body defense cells have pattern-recognition receptors for these common PAMPSand so there is an immediate response against the invading microorganism. Pathogen-associated molecular patterns can also be recognized by a series of soluble pattern-recognition receptors in the blood that function as opsonins and initiate the complement pathways. In all, the innate immune system is thought to recognize approximately 10³ of these microbial molecular patterns.

The innate immune responses do not improve with repeated exposure to a given infection and involve the following:

phagocytic cells (neutrophils, monocytes, and macrophages);
cells that release inflammatory mediators (basophils, mast cells, and eosinophils);
natural killer cells (NK cells); and
molecules such as complement proteins, acute phase proteins, and cytokines.

Examples of innate immunity include anatomical barriers, mechanical removal, bacterial antagonism, pattern-recognition receptors, antigen-nonspecific defense chemicals, the complement pathways, phagocytosis, inflammation, and fever.

We will now take a closer look at fever.

J. Fever

Activated macrophages and other leukocytes release inflammatory cytokines such as TNF-alpha and IL-1 when their pattern-recognition receptors (PRRs) bind pathogen associated molecular patterns or PAMPs (def) - molecular components associated with microorganisms but not found as a part of eukaryotic cells. These include bacterial molecules such as peptidoglycan, teichoic acids, lipopolysaccharide, mannans, flagellin, pilin, and bacterial DNA. There are also pattern-recognition molecules for viral double-stranded RNA (dsRNA) and fungal cell walls components such as lipoteichoic acids, glycolipids, mannans, and zymosan.

For More Information: Pathogen-Associated Molecular Patterns (PAMPs) from Unit 4

For More Information: Pattern-Recognition Receptors (PRRs) from Unit 4

For More Information: Cytokines from Unit 4

These cytokines stimulate the anterior hypothalamus of the brain, the part of the brain that regulates body temperature, to produce prostaglandins (def) that lead to an increase in body temperature. Up to a certain point, fever is beneficial:

1. Fever increases the environmental temperature above the optimum growth temperature for many microorganisms. If the microorganisms are growing more slowly, the body's defenses have a better chance of removing them all.

2. Fever leads to the production of heat shock proteins that are recognized by some intraepithelial T-lymphocytes (def) called delta gamma T-cells, resulting in the production of inflammation-promoting cytokines.

3. Fever elevates the temperature of the body increasing the rate of enzyme reactions, and speeding up metabolism within the body. An elevation in the rate of metabolism can increase the production and activity of phagocytes, speed up the multiplication of lymphocytes, increase the rate of antibody and cytokine production, increase the rate at which leukocytes are released from the bone marrow into the bloodstream, and speed up tissue repair. Too high of a body temperature, however, may cause damage by denaturing the body's enzymes.

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