The complement system is a cascade of plasma proteins that forms a major component of innate immunity, recognizing and eliminating pathogens through opsonization, inflammation, and direct cell lysis via the membrane attack complex (MAC). It consists of over 30 proteins that can be activated by three pathways: classical, alternative, and lectin.
Complement activation proceeds through sequential proteolytic cleavage cascades. The alternative pathway (most ancient) is spontaneously active at low levels and amplifies on pathogen surfaces. The classical pathway is triggered by antibody-antigen complexes. The lectin pathway recognizes carbohydrate patterns (mannose-binding lectin). All three converge on C3 convertase formation, which cleaves C3 into C3a (anaphylatoxin, mast cell activator) and C3b (opsonin). C5 convertase then produces C5a (powerful chemoattractant, neutrophil recruiter) and C5b, which initiates MAC formation (C5b-9). Complement fragments (C3a, C5a) act as DAMPs during tissue injury, recruiting neutrophils and activating mast cells. C1q also recognizes apoptotic cells for clearance.
Complement plays a dual role: essential for pathogen clearance but also drives inflammation in sterile injury, autoimmune disease, and chronic conditions. Excessive complement activation contributes to rheumatoid arthritis, lupus, asthma, ARDS, and ischemia-reperfusion injury. C5a is a key driver of neutrophil recruitment and tissue damage. Complement deficiencies increase infection risk (especially Neisseria). Therapeutic complement inhibition is used in specific conditions (e.g., eculizumab for paroxysmal nocturnal hemoglobinuria).
- Over 30 proteins form the complement cascade
- Three activation pathways: classical, alternative, lectin
- C3a and C5a are anaphylatoxins that activate mast cells
- C5a is a powerful neutrophil chemoattractant
- C3b opsonizes pathogens for phagocytosis
- MAC (C5b-9) directly lyses bacteria and cells
- Spontaneous low-level alternative pathway activation on surfaces
- Complement fragments act as DAMPs during sterile inflammation
- neutrophils — C5a is a powerful chemoattractant recruiting neutrophils to injury sites
- mast cells — C3a and C5a activate mast cells causing degranulation
- opsonization — C3b opsonizes pathogens for enhanced phagocytosis
- membrane attack complex — terminal complement pathway forms MAC (C5b-9) for cell lysis
- DAMPs — complement fragments act as DAMPs during tissue injury
- macrophages — macrophages express complement receptors for opsonized pathogen recognition
- Substance P — complement activation and substance P work together in neurogenic inflammation
- bradykinin — bradykinin and complement fragments synergize to increase vascular permeability
- histamine — complement anaphylatoxins trigger histamine release from mast cells
- prostaglandins — complement activation enhances prostaglandin production
- chemokines — complement fragments act as chemotactic signals like chemokines
- endothelial cells — complement fragments activate endothelial cells to upregulate adhesion molecules
- acute phase response — complement proteins are acute phase proteins upregulated during inflammation
- antibodies — antibodies activate the classical complement pathway
- Systemic lupus erythematosus — complement deficiency increases SLE risk; complement also drives SLE pathology
- rheumatoid arthritis — excessive complement activation contributes to joint inflammation in RA
- ARDS — complement activation drives acute respiratory distress syndrome
- atherosclerosis — complement contributes to atherosclerotic plaque inflammation
- ischemia-reperfusion injury — complement activation during reperfusion causes tissue damage
- bacteria — complement is essential for bacterial clearance but can be evaded by pathogens
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