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Complement System

by Peter J. Delves, PhD

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

  • Augmenting antibody (Ab) responses and immunologic memory

  • Lysing foreign cells

  • Clearing immune complexes and apoptotic cells

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 (see Figure: Complement activation pathways.):

  • Classical

  • Lectin

  • Alternative

Complement activation pathways.

The classical, lectin, and alternative pathways converge into a final common pathway when C3 convertase (C3 con) cleaves C3 into C3a and C3b. Ab = antibody; Ag = antigen; C1-INH = C1 inhibitor; MAC = membrane attack complex; MASP = MBL-associated serine protease; MBL = mannose-binding lectin. Overbar indicates activation.

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 (see Figure: 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.

Biologic activities

Complement components have other immune functions that are mediated by complement receptors (CR) on various cells.

  • CR1 (CD35) promotes phagocytosis and helps clear immune complexes.

  • CR2 (CD21) regulates Ab production by B cells and is the Epstein-Barr virus receptor.

  • CR3 (CD11b/CD18), CR4 (CD11c/CD18), and C1q receptors play a role in phagocytosis.

  • C3a, C5a, and C4a (weakly) have anaphylatoxin activity: They cause mast cell degranulation, leading to increased vascular permeability and smooth muscle contraction.

  • C3b acts as an opsonin by coating microorganisms and thereby enhancing their phagocytosis.

  • C3d enhances Ab production by B cells.

  • C5a is a neutrophil chemoattractant; it regulates neutrophil and monocyte activities and may cause augmented adherence of cells, degranulation and release of intracellular enzymes from granulocytes, production of toxic oxygen metabolites, and initiation of other cellular metabolic events.

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