Complement System

The term “complement” was coined by Paul Ehrlich to describe the activity in serum, which could “complement” the ability of specific antibody to cause lysis of bacteria. Complement historically refers to fresh serum capable of lysing antibody-coated cells.

Complement system is composed of over 20 different proteins produced by hepatocytes,macrophages and intestinal epithelial cells. Fibroblasts and intestinal epithelial cells make C1, while the liver makes C3, C6, and C9. They are present in the circulation as inactive molecules.

Though some components are resistant to heat, heating serum at 56oC for 30 minutes destroys complement’s activity and thus they are not able to kill the microbes or pathogens present in the blood. Thus complement system are heat labile.  Serum complement levels, especially C3, often drop during infection as complement is activated faster than it is produced.

Several complement proteins are zymogens (proenzymes). Which means they are an inactive substance which is converted into an enzyme when activated by another enzyme. They get activated when infected with pathogen. When activated, they become proteases that cut peptide bonds in other complement proteins to activate them by the process called proteolysis. Proteolysis removes an inhibitory fragment exposing an active site. Complement proteins work in a cascade, where the binding of one protein promotes the binding of the next protein in the cascade.

The compliment components are named in various ways e.g. by numerals (C1- C9), by alphabetical symbols (factor D) and by common trivial names (homologus restriction factor). Complement components named by numerals are numbered in the order in which they were discovered. During activation, some complement components are cleaved into two unequal fragments. The larger part of the molecule is designated “b” while the smaller fragment “a”.

Small fragment,known as Anaphylotoxins, may diffuse away into the micro-environment to produce other effects (they act as chemotactic agents) while in most cases it is the “b” fragment that participates in the cascade reaction sequence or in other words binds to the surface of the cell to be lysed (the fragments of C2 are an exception to this rule: C2a binds to the membrane while C2b is freed into serum or tissue spaces).

Inactivated fragments are indicated by a small “i”. Enzymatically active forms are symbolized by a bar over the letter or number.

Activation of complement results in the production of several biologically active molecules such as MAC, which contribute to nonspecific immunity and inflammation. Complement is not antigen-specific and it is activated immediately in the presence of pathogen, so it is considered part of innate immunity. Since antibody also activates some complement proteins, complement activation is also part of humoral immunity. Their activation proceeds via different pathways in a cascade fashion leading to lysis.

A polymeric membrane attack complex (MAC) is formed following the activation of complement system. MACs breakdown the cell membrane leading to “pore” formation. Movement of ions and fluid into cell through these pores leads to cell lysis. Complement products opsonize the antigen which is then easily phagocytosed. Immune complexes also require complement products for their removal from the body. Also byproducts of complements, cascade induce inflammation which again augments the overall cellular response in the affected area. Beside all these, complements play important role in viral neutralization in several ways.

Complement proteins can be quantified directly by ELISA, and complement activity can be measured by the complement fixation test.