Complement System

By Peter J. Delves, PhD, University College London, London, UK

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Biology of the Immune System
Overview of the Immune System
Cellular Components of the Immune System
Molecular Components of the Immune System
Human Leukocyte Antigen (HLA) System
Complement System
Immunotherapeutics

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 either

Ab-dependent, occurring when C1 interacts with Ag-IgM or aggregated Ag-IgG complexes
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, fuctose, 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.

Complement deficiencies and defects

Deficiencies or defects in specific complement components have been linked to specific disorders; the following are examples:

Deficiency in C1, C2, C3, MBL, MASP-2, factor H, factor I, or complement receptor 2 (CR2): Susceptibility to recurrent bacterial infections
Deficiency of C5, C9, factor B, factor D, or properdin: Susceptibility to neisserial infections
Defects in C1, C4, and C5: SLE
Defects in CR2: Common variable immunodeficiency
Defects of CR3: Leukocyte adhesion deficiency type 1
Mutations in the genes for factor B, factor H, factor I, membrane cofactor protein (CD46), or C3: Development of the atypical variant of hemolytic uremic syndrome

Biologic activities of complement

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.