VI. THE INNATE IMMUNE SYSTEM
E. THE COMPLEMENT SYSTEM
1. The Classical Complement Pathway
The overall purpose of this Learning Object is:
1) to learn how the classical complement pathway is activated; and
2) to learn how products of the classical 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:
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.
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 classical complement pathway.
E. THE COMPLEMENT SYSTEM
1. The Classical Complement Pathway (def)
Although at least 21 different serum proteins have thus far been identified as part of the classical complement pathway, one can look at it as a pathway that is primarily activated by antibody molecules (def) of either the IgG or IgM isotypes binding to an antigen (def) and involves 11 major serum protein components.
IgG and IgM are classes of antibody molecules that will be discussed in greater detail in Unit 5, but as mentioned previously, one of the major defenses against microbes is the immune defenses' production of antibody molecules against that microbe. The "tips" of the antibody (the Fab portion; see Fig. 1) have shapes that are complementary to epitopes (def) - portions of microbial proteins and glycoproteins found on the surface of the microbe. The Fc portion of IgG and IgM can activate the classical complement pathway by enabling the first enzyme in the pathway, C1, to assemble.
The reactions are as follows:
a. Typically to activate the classical complement pathway, IgG or IgM is made in response to an antigen. The Fab (def) portion of IgG (2 molecules) or IgM (1 molecule) reacts with epitopes of that antigen. A protein called C1q first binds to the Fc (def) portion of antigen-bound IgG or IgM after which C1r and C1s attach to form C1, the first enzyme of the pathway (see Fig. 2).
b. The activated C1 (def) now enzymatically cleaves C4 into C4a and C4b (see Fig. 3). The C4b then binds to adjacent proteins and carbohydrates on the surface of the antigen and then binds C2. The activated C1 cleaves C2 into C2a and C2b forming C4b2a, the C3 convertase (see Fig. 4). Now the classical complement pathway is activated. C3 convertase can now cleave hundreds of molecules of C3 into C3a and C3b (see Fig. 5).
c. Some molecules of C3b bind to C4b2a, the C3 convertase, to form C4b2a3b (see Fig. 6), a C5 convertase that cleaves C5 into C5a and C5b (see Fig. 7).
d. C5b binds to the surface of the target cell and subsequently binds C6, C7, C8, and a number of monomers of C9 to form C5b6789n, the Membrane Attack Complex (MAC) (see Fig. 8).
As mentioned above, components of the complement pathways carry out 6 beneficial innate defense functions. These include:
a. triggering inflammation (def)
- C5a is the most potent complement protein triggering inflammation. It causes mast cells to release vasodilators such as histamine (def) so that blood vessels become more permeable; it increases the expression of adhesion molecules on leukocytes and the vascular endothelium so that leukocytes can squeeze out of the blood vessels and enter the tissue (diapedesis); it causes neutrophils to release toxic oxygen radicals for extracellular killing; and it induces fever. To a lesser extent C3a and C4a also promote inflammation. As we will see later in this unit, inflammation is a process in which blood vessels dilate and become more permeable, thus enabling body defense cells and defense chemicals to leave the blood and enter the tissues.
b. chemotactically attracting phagocytes to the infection site
- C5a also functions as a chemoattractant (def) for phagocytes. Phagocytes will move towards increasing concentrations of C5a and subsequently attach, via their CR1 receptors to the C3b molecules attached to the antigen. This will be discussed in greater detail later in this unit under phagocytosis.
c. promoting the attachment of antigens (def) to phagocytes (enhanced attachment or opsonization (def))
- C3b and to a lesser extent, C4b can function as opsonins, that is, they can attach antigens to phagocytes. One portion of the C3b binds to proteins and polysaccharides on microbial surfaces; another portion attaches to CR1 receptors on phagocytes, B-lymphocytes, and dendritic cells for enhanced phagocytosis. (see Fig. 10). Actually, C3b molecule can bind to pretty much any protein or polysaccharide. Human cells, however, produce Factor H that binds to C3b and allows Factor I to inactivate the C3b. On the other hand, substances such as LPS on bacterial cells facilitate the binding of Factor B to C3b and this protects the C3b from inactivation by Factor I. In this way, C3b does not interact with our own cells but is able to interact with microbial cells. C3a and C5a increase the expression of C3b receptors on phagocytes and increase their metabolic activity.
d. causing lysis of gram-negative bacteria and human cells displaying foreign epitopes (def); and
- C5b6789n, functions as a Membrane Attack Complex (MAC) (def). This helps to destroy gram-negative bacteria as well as human cells displaying foreign antigens (virus-infected cells, tumor cells, etc.) by causing their lysis; see Fig. 8 and Fig. 9. It can also damage the envelope of enveloped viruses.
e. serving as a second signal for activating naive B-lymphocytes (def);
- Some C3b is converted to C3d. C3d binds to CR2 receptors on B-lymphocytes. This serves as a second signal for the activation of B-lymphocytes whose B-cell receptors have just interacted with their corresponding antigen.
f. removing harmful immune complexes from the body
- C3b and to a lesser extent, C4b help to remove harmful immune complexes from the body. The C3b and C4b attach the immune complexes to CR1 receptors on erythrocytes. The erythrocytes then deliver the complexes to fixed macrophages within the spleen and liver for destruction. Immune complexes can lead to a harmful Type III hypersensitivity, as will be discussed later in Unit 3 under Hypersensitivities.
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