Complement system

The complement system is a biochemical cascade of the immune system that helps clear pathogens from an organism. It is derived from many small plasma proteins work together to form the primary end result of cytolysis by disrupting the target cell's plasma membrane.

The actions of the complement system affect both innate immunity and acquired immunity.

Activation of this system leads to cytolysis, chemotaxis, opsonization, immune clearance, and inflammation, as well as the marking of pathogens for phagocytosis. The complement system consists of more than 35 soluble and cell-bound proteins, 12 of which are directly involved in the complement pathways. The proteins account for 5% of the serum globulin fraction. Most of these proteins circulate as zymogens, which are inactive until proteolytic cleavage. The complement proteins are synthesized mainly by hepatocytes; however, significant amounts are also produced by monocytes, macrophages, and epithelial cells in the gastrointestinal and genitourinary tracts.

Three biochemical pathways activate the complement system: the classical complement pathway, the alternate complement pathway, and the mannose-binding lectin pathway. Antibodies, in particular the IgG1 class, can also "fix" complement.

Outline

The three pathways all generate homologous variants of the protease C3-convertase. C3-convertase cleaves and activates component C3, creating C3a and C3b and causing a cascade of further cleavage and activation events. C3b binds to the surface of pathogens leading to greater internalization by phagocytic cells. C5a is an important chemokine, helping recruit inflammatory cells. C5b initiates the membrane attack pathway, which results in the membrane attack complex (MAC), consisting of C5b, C6, C7, C8, and polymeric C9. MAC is the cytolytic endproduct of the complement cascade; it forms a transmembrane channel, which causes osmotic lysis of the target cell. Kupffer cells help clear complement-coated pathogens. As part of the innate immune system, elements of the complement cascade can be found in species earlier than vertebrates; most recently in the protostome horseshoe crab species, putting the origins of the system back further than was previously thought.

Classical pathway

The classical pathway is triggered by activation of the C1-complex (which consists of one molecule C1q and two molecules C1r and C1s), either by C1q's binding to antibodies from classes M and G, complexed with antigens, or by its binding C1q to the surface of the pathogen. This binding leads to conformational changes in C1q molecule, which leads to the activation of two C1r (serine protease) molecules. Then they cleave C1s (another serine protease). The C1-complex now binds to and splits C2 and C4, producing C2b and C4b. The inhibition of C1r and C1s is controlled by C1-inhibitor. C4b and C2a bind to form C3-convertase (C4b2a complex: NB the 2a is actually the larger fragment of the two, contrary to conventional nomenclature designating 'b' fragments as the larger). Production of C3-convertase signals the end of the Classical Pathway, but cleavage of C3 by this enzyme brings us to the start of the Alternative Pathway.

Alternative pathway

The alternative pathway is triggered by C3 hydrolysis directly on the surface of a pathogen. It does not rely on a pathogen-binding protein like the other pathways. In the alternative pathway, the protein C3 is produced in the liver, and is then cleaved into C3a and C3b by enzymes in the blood. If there is no pathogen in the blood, the C3a and C3b protein fragments will be deactivated. However, if there is a nearby pathogen, some of the C3b is bound to the plasma membrane of the pathogen. Then, it will bind to factor B. This complex will then be cleaved by factor D into Ba and the alternative pathway C3-convertase, Bb.

The C3Bb complex, which is "hooked" onto the surface of the pathogen, will then act like a "chain saw", catalyzing the hydrolysis of C3 in the blood into C3a and C3b, which positively effects the number of C3Bb hooked onto a pathogen.

After hydrolysis of C3, C3b complexes to become C3bBb3b, which cleaves C5 into C5a and C5b. C5a and C3a are known to trigger mast cell degranulation. C5b with C6, C7, C8, and C9 (C5b6789) complex to form the membrane attack complex, also known as MAC, which is inserted into the cell membrane, "punches a hole", and initiates cell lysis.

Furthermore, products of C3 and C5 enhance neutrophil phagocytosis, that is, they are chemokines. C3a also starts chemotaxis.

Lectin pathway

The lectin pathway is homologous to the classical pathway, but with the opsonin, mannan-binding lectin (MBL) and ficolins, instead of C1q. This pathway is activated by binding mannan-binding lectin to mannose residues on the pathogen surface, which activates the MBL-associated serine proteases, MASP-1, MASP-2, MASP-3, which can then split C4 and C2 into C4b and C2b. C4b and C2b then bind together to form C3-convertase, as in the classical pathway. Ficolins are homologous to MBL and function via MASP in a similar way. In non-vertebrates without an adaptive immune system, ficolins are expanded and their binding specificities diversified to compensate for the lack of pathogen-specific recognition molecules.

Regulation of the Complement System

The complement system is regulated by complement regularity proteins. These Proteins are present at high concentration in the blood plasma than the complement proteins. The complement regularity proteins are found on self-cells' surfaces, to prevent self-cells from being targeted by complement proteins (complement system is part of the non-specific immunity)

Role in disease

It is thought that the complement system might play a role in many diseases with an immune component, such as Alzheimer's disease, asthma, lupus erythematosus, various forms of arthritis, autoimmune heart disease and multiple sclerosis.

Deficiencies of the terminal pathway predispose to both autoimmune disease and infections (particularly meningitis).

References