The Innate Immune System: The Complement System - The Alternative Complement Pathway

I. THE INNATE IMMUNE SYSTEM

E. THE COMPLEMENT SYSTEM

3. The Alternative Complement Pathway

The overall purpose of this Learning Object is:
1) to learn how the alternative complement pathway is activated; and
2) to learn how products of the alternative complement pathway 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.

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:

We will now take a closer look at the alternative complement pathway.

E. THE COMPLEMENT SYSTEM

3. The Alternative Complement Pathway

The alternative complement pathway is mediated by C3b, produced either by the classical or lectin pathways or from C3 hydrolysis by water. (Water can hydrolize C3 and form C3i, a molecule that functions in a manner similar to C3b.)

Activation of the alternative complement pathway begins when C3b (or C3i) binds to the cell wall and other surface components of microbes. C3b can also bind to IgG antibodies. Alternative pathway protein Factor B then combines with the cell-bound C3b to form C3bB. Factor D then splits the bound Factor B into Bb and Ba, forming C3bBb. A serum protein called properdin then binds to the Bb to form C3bBbP that functions as a C3 convertase (see Fig. 1) capable of enzymatically splitting hundreds of molecules of C3 into C3a and C3b. The alternative complement pathway is now activated.

Some of the C3b subsequently binds to some of the C3bBb to form C3bBb3b, a C5 convertase capable of splitting molecules of C5 into C5a and C5b (see Fig. 2).

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

The beneficial results are the same as in the classical complement pathway above.

trigger inflammation (def): C5a>C3a>c4a;

chemotactically attract phagocytes to the infection site: C5a;

promote the attachment of antigens (def) to phagocytes via enhanced attachment or opsonization (def): C3b>C4b;

serves as a second signal for the activation of naive B-lymphocytes (def)): C3d;

cause lysis of gram-negative bacteria and human cells displaying foreign epitopes (def): MAC; and
remove harmful immune complexes from the body: C3b>C4b.

Flash animation showing the role of C5a in vasodilation, the chemotaxis of phagocytes towards C5a, and their attachment to the opsonin C3b as a result of the complement pathways.

Flash animation showing the formation of the Membrane Attack Complex (MAC) during the complement pathways.

YouTube animation illustrating benefits of the complement pathways.

For More Information: Defense Benefits of the Complement Pathways

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