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The complement system 

The complement system

Chapter:
The complement system
Author(s):

Marina Botto

and Mark J. Walport

DOI:
10.1093/med/9780199204854.003.050102
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date: 28 April 2017

The complement system consists of over 20 distinct proteins and is an essential component of the innate immune system. It is a major effector mechanism of host defence against infection and inflammatory responses, has an important role in the physiological removal of immune complexes and dying cells, and plays an accessory role in the induction of antibody responses.

Complement activation and regulation

This occurs through three distinct pathways, each generating C3 convertases that cleave native C3 to form the active product C3b, which can deposit on foreign surfaces acting as opsonin or generate complexes capable of binding and cleaving C5. This culminates in the formation of the membrane attack complex, which disrupts target cell membrane integrity and can result in cell lysis.

Classical pathway of complement activation—plays a role in both innate and adaptive immunity; begins by the binding of C1q to (a) the Fc portion of antibodies complexed with antigens, or (b) directly to the surface of certain pathogens or host ligands such C-reactive protein complexed to its phospholipids; activated C1 complex then acts on the next two components of the classical pathway, cleaving C4 and then C2 to generate the classical pathway C3 convertase.

Alternative pathway of complement activation—is in a constant state of activation or ‘tick-over’; activates through an amplification loop that can proceed efficiently on the surface of a pathogen or on abnormal host tissues (including virus-infected cells or tumour cells) but not on a host cell.

Lectin pathway of complement activation—mainly triggered following the binding of mannose-binding lectin (MBL) and ficolin proteins to carbohydrate residues on the surface of pathogens, leading to the activation of MBL associated serine protease (MASPs), one of which cleaves C4 and C2 sequentially to form C3 convertase.

Complement regulatory proteins—these tightly regulate complement activation, in the fluid-phase and on cell surfaces, preventing both depletion of complement proteins and limiting complement-mediated host cell damage.

Complement in disease

Hereditary or acquired abnormalities of complement activation components or of complement regulatory proteins can result in disease, including the following conditions.

Hereditary complement deficiency—(1) immunodeficiency—e.g. hereditary C3 deficiency leads to increased susceptibility to pyogenic infections; patients lacking one of the proteins of the membrane attach complex (MAC) display complex susceptibility to neisserial infection. (2) Autoimmune disease—e.g. homozygous hereditary deficiency of one of the early classical pathway components (C1q, C1r, C1s, C4, and C2) is associated with a markedly increased susceptibility to systemic lupus erythematosus (SLE). (3) Abnormalities of complement regulation—e.g. hereditary angio-oedema caused by deficiency of C1 inhibitor.

Acquired complement deficiency—(1) excessive classical pathway activation (C4 low, C3 normal or low)—e.g. SLE, mixed essential cryoglobulinaemia, rheumatoid vasculitis; (2) excessive alternative pathway activation (C3 low, normal C4)—e.g. caused by C3 nephritic factor (see below).

Abnormal complement regulation—(1) autoantibodies to complement proteins—e.g. C3 nephritic factor, an IgG autoantibody that binds to and stabilizes the fluid phase and cell-bound alternative pathway C3 convertase, is associated with partial lipodystrophy, membranoproliferative glomerulonephritis type 2, recurrent infections, and retinal abnormalities. (2) Paroxysmal nocturnal haemoglobinuria—caused by the loss through somatic mutation of expression of two membrane-bound regulators (CD59 and CD55) that prevent the formation and assembly of membrane attack complex in cell membranes and thereby inhibit the lysis by complement of autologous cells.

Measurement of complement in clinical practice

Diagnosis—measurement of complement activity in serum is required in the context of patients with possible (1) immunodeficiency—particularly recurrent pyogenic infections; (2) vasculitis and glomerulonephritis; (3) chronic infections—e.g. bacterial endocarditis, hepatitis C; or with (4) conditions specifically associated with abnormalities of the complement system.

Monitoring—there are very few diseases in which the repeated monitoring of complement levels is useful, but it may have a role in some patients with SLE.

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