Introduction

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.

 

Complement activation

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:

 

  • The classical pathway: this is stimulated by antibody bound to antigen in immune complexes. A single IgM, or multiple IgG are required to initiate the pathway. C1q binds to the complex, and C1s and C1r bind to C1q. C1q activates C1r, which then activates C1s. C1s cleaves C4, producing C4b, which then cleaves C2. C4b and C2b (the active cleavage product from C2) then form a complex- C4bC2b, which is a C3 convertase.

 

  • The lectin pathway: soluble carbohydrate-binding innate immune components (collectins, such as mannose-binding lectin or ficolins) bind to foreign polysaccharides. These are already bound to proteases, MASPs (mannose-binding-lectin-associated serine proteases), which are activated by a conformational change when the collectin binds to antigen. MASPs then cleave C4 and C2, forming C4bC2b.

 

  • The alternative pathway: this may be initiated independently of the other two pathways, although the major role is in amplification of the complement cascade after C3 is cleaved by the classical or lectin pathway. C3b is produced by a low level reaction with water continuously in plasma (C3 is mildly unstable in an aqueous environment), and is then deposited on cell surfaces. Factor B binds to C3b, and is then cleaved by Factor D, producing C3bBb, a C3 convertase. This is then able to convert multiple molecules of C3, producing C3b (close to the cell surface, where it is able to bind), resulting in amplification of the response).

 

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 2007

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. 

Overview of complement activating pathways



Effector functions of complement

The main effector functions are

 

1. Anaphylatoxins:

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:

  • Opsonisation: opsonins are molecules that help bind pathogens to phagocytes, stimulating phagocytosis. C3b attached to a cell surface encourages phagocytosis through various complement receptors on phagocytes.
  • B cell stimulation: C3 binds to CR2 (complement receptor 2) on B cells, providing co-stimulation for B cell activation
  • Immune complex clearance: activated C3 interrupts the lattice of immune complexes, making them more soluble. C4 and C3 present in immune complexes can bind CR1 on red blood cells, which then transport immune complexes to organs with large numbers of phagocytes, such as the liver and spleen, where phagocytes remove immune complexes from the circulation

 

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 deficiency

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. 

References

Nairn R, Helbert M. Immunology for Medical Students. Mosby 2007.

DeFranco A, Locksley R, Robertson M. Immunity. OUP Oxford 2007.

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