What is Complement System?

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In 1896, Jules Bordet, a young Belgian scientist at Pasteur Institute analyzed the heat-stable and a heat-labile components of blood serum.

The heat-stable components are found to provide immunity against specific microorganisms, whereas the heat-labile components are found to be responsible for the non-specific antimicrobial activity and are capable of killing bacteria. He referred these heat-labile components as “alexia”.

Paul Ehrlich introduced the term “complement” to the same components /enzymes to suit their characteristic function.

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Since components/enzymes are activated immediately in the presence of pathogens, and not specific to any antigen, they are considered as a part of innate immunity.

However, antibody activates some of the complement proteins, so complement activation is also a part of humoral immunity.

Complement enzymes stimulates inflammation, facilitates antigen phagocytosis, and also destroy some cells directly. About 20 serum and membrane enzymes or proteins are identified to have a complementary role in immune response.

Most of the complement enzymes are inactive, until they are cleaved by a protease. The cleaved complement enzyme in turn becomes protease to activate the remaining enzymes of the complement system.

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Thus many components of the complement system serve as the substrate of a prior component and then as an enzyme to activate a subsequent component. Their activity remains for a very short time. If they fail to react with next enzyme they become inactive again.

This pattern of sequential activation produces an expanding cascade of activity (reminiscent of the operation of the blood clotting system).

Complement components are numbered 1 to 9 with a prefix C e.g. CI, C2…. C9, in the order in which they are discovered.

Fortunately numbering is almost the same as the order in which they function in the activation cascade. CI is composed of three subcomponents Clq, Clr, and Cls. Components C3 and C5 are involved in the generation of anaphylotoxis and in the promotion of leukocyte chemotaxis, the result of these two activities begin the inflammatory response.

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CI and C4 are involved in the neutralization of viruses. The components also combine in various sequences to participate in other biological activities, including antibody-mediated cell lysis, phagocytosis, opsonization and anaphylaxis. The complement system is known to be activated by the immunoglobulins IgM and IgG.

During activation, some complement components split into two parts. The larger fragment of the molecule is usually referred as “b” and the smaller fragment is referred as “a”.

Fragment b remains attached to the pathogen; while the smaller fragment ‘a’ having other biological activities diffuse away. The b fragment which participates further in the complement cascade is usually larger than the other fragment “a”. Activated complement fragments with enzymatic activity may be indicated by placing a bar over their numbers for e.g. active C3 can be represented as C3 and inactive complement is indicated as Ci.

Convertase is the general name used for a complement enzyme that converts an inactive complement protein into an active one. For example, active C3 convertase converts inactive C3 to active C3a and C3b.

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Fragments released from individual components during activation of complement system, operate by a non-cytolytic mechanism through specific receptors present on various cell types.

The direction and intensity of the biological response depends on the state of the receptors (affinity and density) and on the function of cells bearing the receptors.

From the functional standpoint, complement receptors can be divided into two types. Receptors of the first type are adherent in nature.

The adherent receptors mediate adherence of cells and other particles with membrane bound C3b or C4b fragments and are known as “complement receptors” in short they are represented as CRs.

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Adherence reaction mediated through the CR receptors on phagocytes lead to stimulation of phagocytosis, activation of metabolism, secretary function and movement of phagocytes towards the site of inflammation. The complement receptors, present on the other cells of the immune system are involved in a variety of immunoregulatory reactions.

For example CR1 on erythrocytes may bind circulating immune complexes (that had activated complement) and transport them to the liver where the immune complexes are partially degraded and thus become more soluble.

The second type of receptors reacts with small fragments of components of complement system, such as C4a, C3a, C5a etc., as well as with Clq, Ba, and factor H. Stimulation of these receptors results in various biological reactions such as chemotaxis, anaphylactic reaction, secretion of vasoactive amines, mediators of the inflammatory reactions etc.

Synthesis of components of complement system takes place at various sites of the body. For example Hepatic parenchymal cells synthesize C3, C6, C8 and B components. CI is synthesized by columnar epithelial cells of gut. C4 and C2 are produced by macrophages in primary organs.

Fetal lung, liver and intestine produce C5, and C2. C3, C4, C5, B, D, P are synthesized in intestinal epithelium. The levels of complement enzymes are regulated by genes.

Chromosome 1 contains the genes for Clq, C8, C4b, factor H, CR1, CR2, and DAF, and chromosome 12 contains the genes for Clr and Cls. The gene for C3 has been localised to chromosome 19, factor I to chromosome 4 and CI (IA) to chromosome 11. Four complement proteins, the C4A isotype, the C4B isotype, C2 and factor B, are encoded by genes within the major histocompatibility complex (MHC) on chromosome 6.

Activation of Complement system takes place through three different pathways; they are “classical complement pathway”, “lectin pathway”, and “alternative complement pathway”. The pathways differ in the manner in which they are activated and ultimately produce a key enzyme called C3 convertase, but all the three pathways share a common terminal reaction, i.e. formation of membrane attack complex (MAC).

C3 cleavage in each pathway leads to activation of C5-C9 and MAC formation. MAC causes destruction of target cell. Nucleated cells in general are relatively resistant to lysis by complement system, due to their ability to remove MAC by endocytosis or through repair mechanism.

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