complement activation
Summary
Complement activation is a proteolytic cascade of plasma proteins that opsonizes pathogens, promotes inflammation, and forms the membrane attack complex (MAC) to lyse target cells. It occurs via three pathways—classical, alternative, and lectin—all converging on C3 convertase formation and C5-C9 assembly.
Detail
The complement system is part of innate immunity (though it interacts with adaptive immunity) consisting of >30 plasma proteins that act in a proteolytic cascade. Three activation pathways converge on a common terminal pathway:
1. Classical pathway: Activated by antigen-antibody complexes (IgM or IgG) binding C1q, leading to C1r/C1s activation, which cleaves C4 and C2 to form C3 convertase (C4b2a).
2. Alternative pathway: Activated by pathogen surfaces (spontaneous C3 hydrolysis, 'tickover') without antibody involvement; factors B, D, and properdin stabilize C3bBb (C3 convertase).
3. Lectin pathway: Mannose-binding lectin (MBL) binds mannose residues on microbial surfaces, activating MASP proteases that cleave C4 and C2, similar to classical pathway.
All pathways converge at C3 cleavage into C3a and C3b. C3b joins convertases to form C5 convertase, cleaving C5 into C5a and C5b. C5b initiates the membrane attack complex (MAC, C5b-9), which lyses gram-negative bacteria (especially Neisseria) by creating pores in the cell membrane.
Key functions/products: - C3b: opsonization (enhances phagocytosis) - C3a, C5a: anaphylatoxins (mast cell degranulation, chemotaxis of neutrophils, increased vascular permeability) - C5a: potent neutrophil chemoattractant - MAC (C5b-9): cell lysis
Regulatory proteins prevent host cell damage: C1 esterase inhibitor, Decay-accelerating factor (DAF/CD55), CD59 (protects against MAC), Factor H and I.
Clinical correlations: - C1 esterase inhibitor deficiency → hereditary angioedema (unopposed bradykinin activity) - DAF/CD59 deficiency (GPI-anchor defect) → paroxysmal nocturnal hemoglobinuria (PNH), causing complement-mediated hemolysis - Terminal complement deficiencies (C5-C9) → recurrent Neisseria infections (meningitis, gonorrhea) - C3 deficiency → severe recurrent pyogenic infections - Early complement deficiencies (C1, C4, C2) → increased risk of SLE-like autoimmune disease due to impaired immune complex clearance - Low complement levels seen in SLE, post-streptococcal glomerulonephritis, membranoproliferative GN (via activation/consumption) - Eculizumab (anti-C5 antibody) used to treat PNH and atypical hemolytic uremic syndrome by blocking MAC formation.
Sources
- First Aid for the USMLE Step 1
- Kuby Immunology
- Robbins and Cotran Pathologic Basis of Disease
- Janeway's Immunobiology
Reviewed by AnkiBoss editorial — medical student review. Information here is for study reference only and is not medical advice. Spotted an error? Let us know.