Complement
Complement Pathways: General Features
1. family of proteins made by liver
2. many found as zymogens
3. proteolytic fragments can function as effector molecules to:
a. facilitate interaction of phagocytes to induce opsonin-mediated
phagocytosis
b. induce osmotic lysis of microbes (MAC)
c. enhance vascular permeability by inducing degranulation of mast
cells/basophils
d. induce chemotaxis of neutrophils
e. facilitate immune complex elimination
4. Two pathways: classical and alternative generate common fragment “C3b” and
converge into a common pathway
Alternative complement pathway: Activation
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involved in innate immunity
spontaneously generated C3b by tickover binds to microbe
Factor B binds to microbe
Factor D cleaves Factor B  Ba, Bb
C3bBb = alternative pathway C3 convertase
a. stabilized by properdin
C3bBb cleaves C3  C3a, C3b
C3bBbC3b = alternative pathway C5 convertase
C3bBbC3b cleaves C5  C5a, C5b
terminal pathway  membrane attack complex
Classical complement pathway: Activation
1. immune complex formation with either IgG or IgM (IgM more effective)
2. C1 binds to Fc region of antibody
3. C1 cleaves C4  C4a, C4b
4. C2 binds next to C4b
5. C2 cleaved by C1  C2a, C2b
6. C4b2a = classical pathway C3 convertase
7. C4b2a cleaves C3  C3a, C3b
8. C4b2a3b = classical pathway C5 convertase
9. C4b2a3b cleaves C5  C5a, C5b
10. terminal pathway  membrane attack complex
Terminal complement pathway: Activation
1. activation of alternate or classical pathway  C5b  formation of MAC 
insertion of MAC into target membrane  osmotic lysis and death of microbe
Complement Biological Activities
C3a and C5a
1. anaphylatoxins
2. bind to receptors on mast cells and basophils  degranulation  histamine 
increases vascular permeability  cells migrate from blood into tissues
3. C5a is chemotactic for neutrophils
4. histamine + chemotaxis of neutrophils  inflammatory response
5. C4a is only generated by classical pathway
C3b
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opsonin if put on surface of microbe
if put on immune complexes facilitates their elimination
amplifies complement activity via alternative pathway
required for formation of C5 convertase of alternative and classical pathways
C5b
1. stimulus for formation of membrane attack complex (C5b, C6, C7, C8, C9)
C2b
1. weak kinin  increase vascular permeability  contributes to inflammation
Complement Regulation
1. complement proteins are species specific
2. Factor I – inactivates C3b and C4b  iC3b, iC4b
3. Factor H – binds fluid phase C3b preventing its attachment to cells
a. dissociates alternative pathway C3 convertase by binding C3b
competitively
4. DAF – binds membrane bound C4b and C3b  prevent formation of C3
convertases
a. promote dissociation of convertases by binding C4b and C3b
competitively
5. C4bp – binds fluid phase C4b preventing its attachment to cells
a. dissociates classical C3 convertase by binding C4b competitively
6. CR1 – binds membrane bound C4b and C3b  prevent formation of C3
convertases
7. MCP – cofactor for Factor I
8. AI – binds to C3a, C4a, C5a preventing their binding to mast cell receptors
9. C1 INH – inhibits C1  prevents spontaneous activation of classical pathway
a. inactivates kallikrein
10. MAC INH incluce HRF, S-protein, CD59
Complement and Coagulation Pathways are Linked Via Kallikrein
Intrinsic coagulation pathway generates kallikrein
Factor XII –– tissue damage  Factor XIIa
prekallikrein –– Factor XIIa  kallikrein
Factor XII –– kallikrein  Factor XIIa [amplification]
C5 –– kallikrein  C5a + C5b
kininogen –– kallikrein  kininogen(a) + bradykinin (vasodilator, increases
vascular permeability)
6. kallikrein is inhibited by C1 INH
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Complement Genetic Deficiencies
C1 esterase inhibitor deficiency (C1 INH)
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associated with the disease hereditary angioedema (HAE)
recurrent facial/tongue and laryngeal edema
edema of GI tract  colic or diarrhea
overproduction of C4a (weak anaphylotoxin) and C2b (weak kinin) causing
histamine release and vasodilation respectively
5. C5a and bradykinin produced  vasodilation
6. vasodilation  edema
Deficiencies in glycosylphosphatidylinositol (GPI) anchors
1. DAF, CD59 and HRF are attached to cell membrane by GPI anchors
2. DAF – decay of C3 convertases  blocks amplication of alternative and classical
pathways
3. CD59, HRF – block formation of MAC
4. GPI deficiency  DAF, CD59, HRF not anchored  cells susceptible to lysis by
complement
5. paroxysmal nocturnal hemoglobulinuria (PNH)
6. only affects RBCs  hemolytic anemia
C3 protein deficiency
1. severe recurrent pyogenic infections
2. C3 required for:
a. C3b – opsonization
b. Immune complex elimination
c. Formation of C5 convertases
Terminal pathway protein deficiencies
1. MAC is required for elimination of Neisseria species
2. MAC not formed  recurrent meningococcal and gonococcal Neisserial
infections
Xenotransplantation: Complement is Deleterious
1. hyperacute rejection – minutes to hours after graft transplantation
a. humans have IgM antibodies that react with 1,3 galactosyl linkage of
porcine carbs on endothelial lining of graft blood vessels
b. immune complex formation
c. classical pathway activated
d. destruction of endothelial cells lining graft blood vessels
e. graft thrombosis
2. How does damage to the endothelial cells occur?
a. anaphylatoxins (C3a, C4a, C5a) made
b. anaphylatoxins bind to receptors on mast cells and basophils
c. degranulation and histamine release
d. histamine increases vascular permeability
e. C5a is chemotactic for phagocytes. It also activates phagocytes
f. Phagocytes try to eat immune complexes and release inflammatory
mediators that damage the endothelial cells
g. Cell damage activates intrinsic coagulation pathway, thrombosis and
activation of kallikrein  bradykinin
h. MAC formation on porcine endothelial cells
i. Osmotic lysis.
Activated macs  fibroleukin or fgl2  fibrin deposition and thrombosis