STEPTRACKERIMMUNOLOGY + HEMATOLOGY | INNATE IMMUNITY | HIGH-YIELD REVIEW

Complement

A cascade of plasma proteins that opsonizes microbes, recruits inflammatory cells and punches holes in membranes — three ways in, one shared core at C3.

FOCUS ON

Activation: classical (IgM or IgG–antigen complexes bind C1q), lectin (mannose-binding lectin on microbial sugars), alternative (spontaneous C3 hydrolysis on microbial surfaces; factors B, D, properdin). All form a C3 convertase → C3a + C3b → C5 convertase → C5a + C5b → C5b–C9 MAC. Functions: C3b = opsonin (with IgG); C3a, C4a, C5a = anaphylatoxins (mast cell degranulation); C5a = neutrophil chemotaxis; MAC = lysis (key for Neisseria); C3b clears immune complexes. Regulators: C1 esterase inhibitor (deficiency → hereditary angioedema, ↑ bradykinin; ACE inhibitors worsen), DAF (CD55) and CD59 (deficient in PNH), factor H and I (aHUS, C3 glomerulopathy).

COMPONENT

ROLE

DEFICIENCY OR EXCESS

CLUE

C1q, C1r, C1s · C4 · C2

Classical pathway; C1q binds Fc of IgM (one) or IgG (two)

Early classical deficiency (C2 most common) → SLE-like disease, encapsulated infections

Poor immune-complex clearance

Mannose-binding lectin

Lectin pathway; cleaves C4 and C2 via MASPs

MBL deficiency → infections in infancy

Common, often mild

Factor B · factor D · properdin

Alternative pathway amplification loop on microbial surfaces

Properdin deficiency (X-linked) → Neisseria

—

Central component; C3b opsonizes and forms convertases

C3 deficiency → severe recurrent pyogenic infections (encapsulated), immune-complex GN

Most severe single deficiency

C3a · C4a · C5a

Anaphylatoxins: mast cell histamine release, vasodilation

—

C5a is also the main chemoattractant

C5b–C9 (MAC)

Pore in membrane → lysis

Terminal deficiency → recurrent Neisseria (meningococcus, disseminated gonococcus)

Eculizumab (anti-C5) mimics it

C1 esterase inhibitor

Blocks C1r/C1s and kallikrein

Hereditary angioedema (AD): recurrent non-itchy swelling of face, airway, gut; ↓ C4

↑ bradykinin · no urticaria · ACE inhibitors contraindicated · C1-INH concentrate, icatibant, ecallantide

DAF (CD55) · CD59

GPI-anchored; disassemble convertase · block MAC on self cells

PNH (acquired PIGA mutation) → intravascular hemolysis, morning hemoglobinuria, thrombosis, pancytopenia

Flow cytometry · eculizumab, ravulizumab

Factor H · factor I · MCP (CD46)

Inactivate C3b on host surfaces

Atypical HUS (non-diarrheal), C3 glomerulopathy, macular degeneration (factor H variants)

Eculizumab for aHUS

CR1 (CD35) · CR2 (CD21) · CR3 (CD11b/CD18)

C3b on RBCs carries immune complexes to spleen · C3d boosts B cells · iC3b phagocytosis

CR3 is defective in LAD

EBV uses CR2

Complement consumption

Immune-complex disease uses up C3, C4

↓ C3 + ↓ C4: SLE, cryoglobulinemia, serum sickness · ↓ C3 only: PSGN, MPGN/C3G, aHUS

CH50 screens classical pathway

Picture it — the complement cascade

Three entries, one coreClassical, lectin and alternative pathways each build a C3 convertase. C3b opsonizes and builds the C5 convertase; C3a and C5a recruit inflammation; C5b starts the membrane attack complex. Host cells are shielded by C1-INH, factors H and I, DAF and CD59.

Schematic diagrams, not to scale.

Mechanism — hereditary angioedema

↓ C1 esterase inhibitor

→

Unchecked kallikrein+ C1 activation (↓ C4)

→

↑ Bradykinin

→

Non-pitting, non-itchy swellingAirway, gut

ACE normally degrades bradykinin — ACE inhibitors cause the same angioedema and are forbidden in HAE.

Three pathways

PATHWAY

TRIGGER

FIRST PROTEINS

Classical

IgM/IgG bound to antigen

C1q, C1r, C1s → C4, C2

Lectin

Mannose on microbes

MBL + MASPs → C4, C2

Alternative

Microbial surface (no antibody)

C3(H₂O), factors B, D, properdin

How it's tested

COMMON CONFUSIONAllergic (histamine) angioedema itches and comes with hives and responds to antihistamines and epinephrine; HAE (bradykinin) has no hives and needs C1-INH or a bradykinin blocker.

THE TRAPLow C4 between attacks is the screening clue for hereditary angioedema — C3 stays normal.

YOUR APPROACHWhich pathway or regulator → what product is missing or excessive (opsonin, chemotaxin, MAC, bradykinin) → infection, autoimmunity or hemolysis pattern.

If you see… think…

Main opsonins → C3b and IgG

Neutrophil chemotaxis → C5a (also IL-8, LTB₄)

Recurrent meningococcal infection → C5–C9 deficiency

Lupus-like rash and nephritis in a child with low CH50 → C2 or C1q deficiency

Facial and laryngeal swelling without hives after a dental visit → hereditary angioedema

Angioedema after starting lisinopril → bradykinin accumulation

Dark morning urine, thrombosis, pancytopenia → PNH (CD55/CD59 loss)

Non-diarrheal HUS with low C3 → factor H or I defect

Low C3 with normal C4 after strep pharyngitis → post-streptococcal GN (alternative pathway)

Required vaccine before eculizumab → meningococcal