Complement is a part of the innate immune system, and assists phagocytes and antibody in the clearance of pathogens. The complement system mediates a variety of immune responses such as triggering inflammation, attracting phagocytes (chemotaxis), promoting phagocytosis of pathogens through opsonisation, stimulating antibody production and directly attacking infected cells or enveloped viruses.
Complement consists of around 30 serum and membrane proteins, and can be activated by antibody bound to antigen, or several innate triggers. These triggers generate the active components of complement from inactive precursors, stimulating a cascade of proteolytic reactions, which activate further complement components.
The inactive precursors are named C plus their number, for example C3. The large fragment produced after cleavage is named C3b, and the small fragment C3a. The large fragments have enzyme activity, and cleave the next component in the pathway. The small fragments of C3 and C5 (C3a and C5a) are active (see below), whereas most others are not.
There are three pathways by which complement is activated. All three produce a C3 convertase, and after this point the effector functions are derived from a common pathway:
In the bloodstream C3b is inactivated by Factor H and I; it must attach to a cell surface to prevent inactivation. Host cell membranes are protected by other specific inhibitors.
Diagram adapted from Nairn and Helbert Immunology for Medical Students 2008
All three pathways produce C3 convertases, which cleave C3 producing C3a and C3b. C3b is a central component in the amplification loop through the alternative pathway, as described above, and is critical to the effector functions of complement. C3b attached to a microbial surface acts as a tag for phagocytosis of the microbe. If C3b attaches close to a C3 convertase, the C3 convertase cleaves C5, producing C5a and C5b. C5b recruits C6, C7, C8 and multiple molecules of C9, which together form the membrane attack complex.
The main effector functions are
The small cleavage fragments of C5 and C3, C5a and C3a, are anaphylatoxins- they promote inflammation through their action on endothelial cells, mast cells and phagocytes. C5a is the major inflammatory mediator of complement, and is chemoattractant for neutrophils and monocytes. When these cells reach the affected tissue, phagocytosis and degranulation is stimulated by anaphylatoxins. C3a shares these functions, but is far less potent.
2. Complement receptor mediated functions:
3. Cell lysis:
The membrane attack complex forms a transmembrane pore, which promotes leakage of intracellular components out of the cell, and allows entry of immune mediators. The MAC results in osmotic lysis of the target cell. This is effective primarily against enveloped viruses and gram negative bacteria; gram positive bacteria are relatively protected by their thick peptidoglycan layer. Protectin (CD59) on mammalian cell surfaces binds C7 and C8, preventing the formation of the membrane attack complex.
Complement deficiencies are rare, and commonly undiagnosed as there are redundancies in the system; a deficiency in one component can be compensated for by use of alternative mechanisms. The symptoms depend on which component if affected. Deficiencies in the early lectin and classical pathways cause type III hypersensitivity (immune complex diseases) because the removal of immune complexes is impaired. Deficiencies in these early components have been found to cause SLE. Deficiencies in early components also cause recurrent bacterial infection, due to impaired opsonisation of the bacteria and impaired triggering of antibody production.
Deficiencies in the late complement components, involved in the formation of the MAC, increase susceptibility to Neisseria infections specifically. Recurrent and atypical infections with Neisseria meningitides and Neisseria gonococcus are seen.
Nairn R, Helbert M. Immunology for Medical Students. Mosby 2007.
DeFranco A, Locksley R, Robertson M. Immunity. OUP Oxford 2007.
Fastbleep © 2019.