The Innate Immune System: The Acute Phase Response

I. THE INNATE IMMUNE SYSTEM

K. THE ACUTE PHASE RESPONSE

The overall purpose of this Learning Object is to learn what is meant by the acute phase response and how it 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 the acute phase response.

K. Acute Phase Response

The acute phase response is an innate body defense seen during acute illnesses and involves the increased production of certain blood proteins termed acute phase proteins (def).

Activated macrophages and other leukocytes release inflammatory cytokines such as tumor necrosis factor-alpha (TNF-alpha), interleukin-1 (IL-1), and interleukin-6 (IL-6) 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 travel through the blood and stimulate hepatocytes in the liver to synthesize and secrete acute phase proteins (def). This response provides an early defense and enables the body to recognize foreign substances early on in the infection process prior to the full activation and implementation of the immune responses. Two important acute phase proteins are C-reactive protein and mannose-binding protein. They function as soluble pattern-recognition receptors.

1. C-reactive protein (CRP) binds to membrane phospholipids in microbial membranes (phosphorylcholine in bacterial membranes and phosphatidylethenolamine in fungal membranes). It functions as an opsonin, sticking the microorganism to phagocytes, and activates the classical complement pathway.

For More Information: The Classical Complement Pathways from Unit 4

2. Mannan-binding lectin (MBL) - also known as mannan-binding protein or MBP - binds to mannose-rich glycans (short carbohydrate chains with the sugar mannose or fructose as the terminal sugar). These are common in microbial glycoproteins and glycolipids but rare in those of humans. It functions as an opsonin, sticking the microorganism to phagocytes, and activates the lectin pathway.

Flash animation showing activation of the lectin pathway, formation of C3 convertase, and formation of C5 convertase.

For More Information: The Lectin Complement Pathways from Unit 4

Products of the complement pathways, in turn, promote inflammation, attach microbes to phagocytes, cause to MAC cytolysis, and chemotactically attract phagocytes to the infected area.

For More Information: The Benefits of the Complement Pathways from Unit 4

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