CorpusHuman Anatomy
Lymphatic & ImmuneMolecule

Complement system

Also known as: complement, complement cascade, classical pathway, alternative pathway, lectin pathway, membrane attack complex, MAC, C3, C5a, anaphylatoxins

A cascade of more than 30 plasma and membrane proteins, mostly made by the liver, that are activated on microbial surfaces by three pathways (classical, lectin, alternative) converging on C3, and that opsonise, inflame, lyse microbes via the membrane attack complex and clear immune complexes.

Overview

Number of proteins> 30
Most abundant componentC3 (≈ 1–1.5 g/L)
Main site of synthesisLiver (many are acute-phase proteins)

Complement proteins circulate as inactive precursors. Activation is a proteolytic cascade in which each enzyme cleaves the next component into a small soluble fragment (usually "a") and a larger fragment (usually "b") that binds the activating surface. All three activation pathways generate a C3 convertase, which cleaves C3 — the most abundant component (≈ 1–1.5 g/L) — into C3a and C3b, and then a C5 convertase.

The classical pathway starts when C1q binds the Fc regions of antigen-bound IgM (one pentamer suffices) or IgG (several molecules close together; IgG3 and IgG1 best), or binds CRP or apoptotic cells. Activated C1r and C1s cleave C4 and C2, forming the classical C3 convertase C4b2a (in some newer texts the large C2 fragment is called C2b, giving C4b2b). The lectin pathway is triggered antibody-independently when mannose-binding lectin (MBL) or ficolins bind carbohydrate patterns on microbes; associated serine proteases (MASP-1/2) then cleave C4 and C2, producing the same convertase. The alternative pathway starts from spontaneous low-level hydrolysis of C3 ("tick-over"); C3b deposited on a surface lacking host regulators binds factor B, which is cleaved by factor D to form C3bBb, stabilised by properdin — an amplification loop that also magnifies the other two pathways. Adding C3b to either C3 convertase creates the C5 convertase (C4b2a3b or C3bBb3b).

C5 cleavage starts the terminal pathway: C5b binds C6, C7, C8 and multiple C9 molecules to form the membrane attack complex (MAC, C5b–9), a pore that lyses thin-walled microbes — notably Neisseria. Host cells are protected by regulators: C1 inhibitor, factor H and factor I (inactivate C3b), decay-accelerating factor (DAF, CD55), membrane cofactor protein (CD46) and CD59 (protectin), which blocks MAC assembly.

Location

Plasma and interstitial fluid; most components synthesised by hepatocytes (some by macrophages and epithelium); regulators on host cell membranes.

Parts & subdivisions

  1. Classical pathway
    C1q binds antigen–antibody complexes (IgM, IgG) → C1r/C1s → C4, C2 → C3 convertase C4b2a.
  2. Lectin pathway
    Mannose-binding lectin or ficolins bind microbial sugars → MASPs → C4, C2 → C4b2a.
  3. Alternative pathway
    Spontaneous C3 hydrolysis; C3b + factor B, cleaved by factor D → C3bBb (stabilised by properdin); amplification loop.
  4. C3b and iC3b (opsonins)
    Coat microbes and immune complexes for uptake through complement receptors CR1 and CR3; C3d binds CR2 (CD21) on B cells and lowers their activation threshold.
  5. Anaphylatoxins (C3a, C4a, C5a)
    Trigger mast-cell degranulation, increase vascular permeability and smooth-muscle contraction; C5a is also a potent neutrophil chemoattractant.
  6. Membrane attack complex (C5b–9)
    Pore formed by C5b, C6, C7, C8 and polymerised C9 that causes osmotic lysis.
  7. Regulators
    C1 inhibitor, factor H, factor I, C4-binding protein, DAF (CD55), MCP (CD46), CD59.

Function

  • Opsonisation of microbes (C3b) for phagocytosis.
  • Inflammation and leukocyte recruitment (C3a, C5a).
  • Lysis of microbes, especially Neisseria (MAC).
  • Clearance of immune complexes and apoptotic cells (C1q, C3b, CR1 on red cells).
  • Enhancement of B-cell responses (C3d–CR2) and links to coagulation.

Clinical significance

Complement deficiencies

Early classical components (C1q, C2, C4) → SLE-like immune-complex disease (C2 deficiency is the commonest inherited classical-pathway deficiency in white populations). C3 → severe recurrent pyogenic infections with encapsulated bacteria and glomerulonephritis. Terminal components (C5–C9) or properdin → recurrent or fulminant neisserial infection. MBL deficiency → infections in infancy. Factor H/I abnormalities → atypical haemolytic uraemic syndrome and C3 glomerulopathy.

Hereditary angioedema

Autosomal dominant C1-inhibitor deficiency causes recurrent, non-itchy, non-pitting swelling of the face, lips, larynx and bowel without urticaria, mediated by excess bradykinin (C1-INH also inhibits kallikrein); low C4 even between attacks. Antihistamines and adrenaline are ineffective; treat with C1-INH concentrate or icatibant (bradykinin B2-receptor antagonist). ACE inhibitors (which reduce bradykinin breakdown) must be avoided.

Paroxysmal nocturnal haemoglobinuria

Acquired PIGA mutation in a stem cell prevents synthesis of GPI anchors, so red cells lack CD55 and CD59 and undergo complement-mediated intravascular haemolysis (dark morning urine), with thrombosis and marrow failure. Treated with the anti-C5 antibody eculizumab — which, by blocking MAC formation, requires meningococcal vaccination.

Complement levels as disease markers

Low C3 and C4 indicate classical-pathway consumption (active SLE, cryoglobulinaemia); low C3 with normal C4 indicates alternative-pathway activation (post-streptococcal glomerulonephritis, C3 glomerulopathy with C3 nephritic factor).

Mnemonics

Complement fragments

C3b binds bacteria (opsonin); C3a, C4a, C5a cause anaphylaxis-like effects (anaphylatoxins); C5a = chemotaxis; C5b–9 = MAC; deficiency of C5–C9 = recurrent Neisseria ("N**ine").

Test yourself

Which antibody is a pentamer, is produced first in a primary response and is the most efficient activator of the classical complement pathway?
  1. IgM
  2. IgG
  3. IgD
  4. Secretory IgA

Answer: IgM

Pentameric IgM (joined by a J chain) has 10 antigen-binding sites, so it agglutinates well and a single molecule bound to a surface can activate C1q. It dominates the primary response before class switching.

Recurrent Neisseria meningitidis infections are characteristic of deficiency of…
  1. C1 esterase inhibitor
  2. C3
  3. C5–C9 (terminal complement)
  4. Decay-accelerating factor (CD55)

Answer: C5–C9 (terminal complement)

Neisseria are particularly susceptible to lysis by the membrane attack complex (C5b–9). Terminal complement deficiency — or therapeutic C5 blockade with eculizumab — predisposes to recurrent neisserial infection. C1-INH deficiency causes hereditary angioedema; CD55/CD59 loss causes PNH.

More lymphatic & immune system questions

Compiled from standard anatomy and physiology references — see the Lymphatic & Immune System sources. For education only; not medical advice.