Immunology
Complement Cascade
30+ plasma proteins that lyse pathogens, opsonize, and amplify inflammation
The complement system is a cascade of ~30 plasma proteins (synthesized by the liver) that "complement" antibodies in destroying pathogens. Three activation pathways converge on C3 convertase: classical (antibody-antigen via C1q), lectin (mannose-binding lectin recognizes microbial sugars), alternative (spontaneous C3 hydrolysis amplified on microbe surfaces). Functions: cytolysis via the membrane attack complex (MAC, C5b-9); opsonization (C3b coats pathogens for phagocytosis); anaphylatoxins (C3a, C5a) drive inflammation. Defects cause recurrent infections (Neisseria with terminal pathway deficiency) or hemolytic disease (PNH lacks decay-accelerating factors). Eculizumab (anti-C5) revolutionized treatment of PNH and aHUS.
- Number of proteins~30 plasma + cell-surface regulators
- SourceLiver (most), monocytes, macrophages
- PathwaysClassical, lectin, alternative
- Convergence pointC3 convertase → C3b + C3a
- Membrane attack complexC5b-6-7-8-9 pore in membrane
- Anti-C5 drugEculizumab (Soliris) — PNH, aHUS, gMG
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Why complement matters
- Bacterial defense. Critical against encapsulated and Gram-negative bacteria.
- Antibody amplification. Multiplies effect of bound IgG/IgM.
- Inflammation. Anaphylatoxins drive vascular and chemotactic effects.
- Immune complex clearance. Prevents deposition and autoimmunity.
- Drug targets. Eculizumab, ravulizumab, pegcetacoplan transformed PNH and aHUS.
- Diagnostic value. Low C3/C4 indicates active SLE, glomerulonephritis.
- Vaccine adjuvant biology. Some adjuvants act via complement.
Common misconceptions
- Complement is one protein. ~30 — cascading proteolytic activations.
- Only triggered by antibodies. Lectin and alternative pathways are antibody-independent.
- Complement is adaptive immunity. Innate — present at birth, no memory.
- MAC kills all bacteria. Mainly Gram-negative; Gram-positive resistant.
- Higher C3/C4 = stronger immunity. Levels are consumption markers; low signals active disease.
- Eculizumab is harmless. Mandatory meningococcal vaccination — fatal infections reported without it.
Frequently asked questions
What are the three complement pathways?
Classical — triggered by IgM or IgG bound to antigen; C1q binds Fc; C1r/C1s activate C4 and C2 → C4b2a (C3 convertase). Lectin — mannose-binding lectin (MBL) binds mannose on microbes; MASPs cleave C4 and C2 same as classical. Alternative — C3 spontaneously hydrolyzes (~1%/hour, "tickover"); on microbial surface (lacking host inhibitors), factor B and D form C3bBb convertase. All three converge on cleaving C3.
What's the membrane attack complex?
Terminal step. C5 cleaved to C5a (released) and C5b. C5b binds C6, then C7 (membrane insertion), C8 (initiates pore), and 10-16 C9 molecules forming a ring pore (~10 nm diameter) in the lipid bilayer. Water and ions flood in, lysing the cell. Effective on Gram-negative bacteria (especially Neisseria) and enveloped viruses; Gram-positive resistant due to thick peptidoglycan.
What does C3b do?
Opsonization — coats pathogens; phagocytes (neutrophils, macrophages) recognize via CR1, CR3 receptors and engulf. C3b is the most important opsonin alongside IgG. Also forms C5 convertase (C3bBb3b or C4b2a3b) cleaving C5 to launch MAC. Inactivated C3b (iC3b) still tags for phagocytosis. Bound C3b is cleaved by factor I in presence of cofactors (factor H on host cells).
What are anaphylatoxins?
C3a, C4a, C5a — small peptides cleaved off during cascade. Bind G-protein-coupled receptors on mast cells (release histamine), neutrophils (chemotaxis), endothelium (vasodilation). C5a most potent — recruits neutrophils to infection site, primes oxidative burst. Excess in sepsis contributes to shock and DIC. C3a/C5a inhibitors are investigated for COVID-19 and ARDS.
How do host cells avoid complement attack?
Multiple regulators. Decay-accelerating factor (DAF/CD55) and MCP (CD46) on cell surface dissociate or inactivate C3 convertases. CD59 prevents MAC assembly by blocking C9 polymerization. Factor H in plasma binds host sialic acids and accelerates C3b decay. PNH (paroxysmal nocturnal hemoglobinuria) — GPI-anchor defect strips DAF and CD59 from RBCs; chronic intravascular hemolysis ensues.
What's eculizumab?
Humanized monoclonal antibody against C5 — blocks cleavage to C5a and C5b, preventing MAC and C5a-driven inflammation. Approved for PNH (paroxysmal nocturnal hemoglobinuria), aHUS (atypical hemolytic uremic syndrome), generalized myasthenia gravis, NMO. Patients require meningococcal vaccination — terminal pathway blockade markedly increases Neisseria meningitidis risk. Annual cost historically ~$500,000.
What infections occur with complement deficiency?
Pattern depends on which component is deficient. Early classical (C1, C2, C4): SLE-like autoimmunity (impaired immune complex clearance), pyogenic infections. C3 deficiency: severe recurrent pyogenic infection, glomerulonephritis. Terminal (C5-C9): recurrent Neisseria infections (gonorrhea, meningitis) — disproportionate because MAC is the main defense against this genus. MBL deficiency mild — common in 5% population, increased infection risk in young children only.