The Innate Immune System: The Complement System

I. THE INNATE IMMUNE SYSTEM

E. THE COMPLEMENT SYSTEM: AN OVERVIEW

The overall purpose of this Learning Object is:
1) to introduce the complement system and its role in innate immune defenses; and
2) to introduce how products of the complement system function 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 3 pathways of the complement system.

E. The Complement System (def)

The complement system refers to a series of proteins circulating in the blood and bathing the fluids surrounding tissues. The proteins circulate in an inactive form, but in response to the recognition of molecular components of microorganism, they become sequentially actived, working in a cascade where in the binding of one protein promotes the binding of the next protein in the cascade.

There are 3 complement pathways that make up the complement system: the classical complement pathway, the lectin pathway, and the alternative complement pathway. The pathways differ in the manner in which they are activated and ultimately produce a key enzyme called C3 convertase:

1. The classical complement pathway is activated by antigen-antibody complexes.

2. The lectin pathway is activated by the interaction of microbial carbohydrates with mannose-binding lectin (MBL) in the plasma and tissue fluids.

3. The alternative complement pathway is activated by C3b binding to microbial surfaces and to antibody molecules .

The end results and defense benefits of each pathway, however, are the same. All complement pathways carry out 6 beneficial innate defense functions. Proteins produced by the complement pathways:

1. trigger inflammation (def);

2. chemotactically attract phagocytes to the infection site;

3. promote the attachment of antigens (def) to phagocytes (enhanced attachment or opsonization (def));

4. cause lysis of gram-negative bacteria and human cells displaying foreign epitopes (def);

5. plays a role in the activation of naive B-lymphocytes (def); and

6. remove harmful immune complexes from the body.

We will now look at each of these complement pathways and see how they function to protect the body.

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