The complement system is an enzyme cascade that helps defend against infection. Many complement proteins occur in serum as inactive enzyme precursors (zymogens); others reside on cell surfaces. The complement system bridges innate and acquired immunity by
Complement components have many biologic functions (eg, stimulation of chemotaxis, triggering of mast cell degranulation independent of IgE).
Complement activation: There are 3 pathways of complement activation (Fig. 3: Complement activation pathways.):
Classical pathway components are labeled with a C and a number (eg, C1, C3), based on the order in which they were identified. Alternative pathway components are often lettered (eg, factor B, factor D) or named (eg, properdin).
Classical pathway activation is Ab-dependent, occurring when C1 interacts with Ag-IgM or aggregated Ag-IgG complexes, or Ab-independent, occurring when polyanions (eg, heparin, protamine, DNA and RNA from apoptotic cells), gram-negative bacteria, or bound C-reactive protein reacts directly with C1. This pathway is regulated by C1 inhibitor (C1-INH). Hereditary angioedema is due to a genetic deficiency of C1-INH.
Lectin pathway activation is Ab-independent; it occurs when mannose-binding lectin (MBL), a serum protein, binds to mannose, fructose, or N-acetylglucosamine groups on bacterial cell walls, yeast walls, or viruses. This pathway otherwise resembles the classical pathway structurally and functionally.
Alternate pathway activation occurs when components of microbial cell surfaces (eg, yeast walls, bacterial cell wall lipopolysaccharide [endotoxin]) or Ig (eg, nephritic factor, aggregated IgA) cleave small amounts of C3. This pathway is regulated by properdin, factor H, and decay-accelerating factor (CD55).
The 3 activation pathways converge into a final common pathway when C3 convertase cleaves C3 into C3a and C3b (Fig. 3: Complement activation pathways.). C3 cleavage may result in formation of the membrane attack complex (MAC), the cytotoxic component of the complement system. MAC causes lysis of foreign cells.
Factor I, with cofactors including membrane cofactor protein (CD46), inactivates C3b and C4b.
Patients deficient in complement components C1, C2, C3, MBL, MASP-2, factor H, factor I, or complement receptor 2 (CR2) are susceptible to recurrent bacterial infections. Deficiency of C5, C9, factor B, factor D, or properdin are specifically associated with susceptibility to neisserial infections.
Defects in C1, C4, and C5 are associated with SLE; defects in CR2 are associated with common variable immunodeficiency, and defects of CR3 are associated with leukocyte adhesion deficiency type 1.
Mutations in the genes for factor B, factor H, factor I, membrane cofactor protein (CD46), or C3 have been linked to the development of the atypical variant of hemolytic uremic syndrome.
Complement components have other immune functions that are mediated by complement receptors (CR) on various cells.
Last full review/revision November 2014 by Peter J. Delves, PhD
Content last modified December 2014