Complement system
(complements i.e. assists functions of antibody)
Jules Bordet
(1870-1961)
1919.
Nobel prize
For complement-mediated
bacteriolysis
Discovery of Complement
1890s Jules Bordet (Institut Pasteur in Paris)
observed:
1. Sheep antiserum to the bacterium Vibrio cholerae
caused lysis of the bacteria.
2. Heating the antiserum destroyed its bacteriolytic
activity.
3. Addition of fresh normal serum, that contained no
Abs against the bacterium and was unable to kill
the bacterium by itself, restored the ability to lyse
the bacteria by the heated antiserum.
Q1: If you were Bordet, what
would
you hypothesize?
A1: Bacteriolytic activity requires 2 different
substances.
a. the specific antibacterial Abs, which
are resistant to the heating process
b. heat-sensitive component responsible
for the lytic activity
c. 56˚C, 30 min will inactivate
complement
Complement system
Consists of serum and cell surface proteins
involved in defense against pathogens and
tissue damage mediated by antibodies
Effector mechanism of both innate and
adaptive humoral immunity
Complement system
Over 30 serum and cell surface proteins:
- Complement components
(in serum inactive, activated sequentially as a cascade)
- Complement receptors
(cell surface, recognize activated components)
- Regulatory proteins of complement
(both in serum and cell surface, inhibit activated components)
Complement system
Pathways of activation
- Classical
- Alternative
- Lectin
Activation and
functions of
complement
(overview)
Activation
pathway Early steps Late steps
Classical C1, C4, C2 C3, C5, C6, C7, C8, C9
Lectin MBL, C4, C2 C3, C5, C6, C7, C8, C9
Alternatve C3, B, D (P) C3, C5, C6, C7, C8, C9
MEMBRANE
ATTACK
COMPLEX
C6 C7 C8 C9
IgG
C5-C9 Lysis
C5a C5b Bacterium
MAC IgM
C5
Activated
C1 C1
C3 CONVERTASE C4 C2
C4b2b3b C4b2b C4a C4b C2b C2a
C5 CONVERTASE
C3
C3b C3a
MEMBRANE
ATTACK
COMPLEX
C6 C7 C8 C9
C5-C9 Lysis
Bacterium
C5a C5b
MAC
C5
MBL
MASP
C3 CONVERTASE C4 C2
C4b2b3b C4b2b C4a C4b C2b C2a
C5 CONVERTASE
C3
C3b C3a
C3a C3b
C3
Alternative C5
Ba Bb convertase
C3 C3b C3bB C3bBb C3bBb3b
Alternative C3
convertase
Bacterium Factor B Factor D Properdin
Lysis
C5-C9 C5b
MAC C5
C5a
MEMBRANE
ATTACK
C9 C8 C7 C6
COMPLEX
C3a
C3
C3b
Anaphylatoxin C3
C5
Alternative
Pathway
C3-Convertase
C5-Convertase C3a C3b
C5b C5aD
C7
C8 BBa
Bb
C9 C6
Effector functions of activated complement
- Cytolysis (MAC)
- Opsonization (C3b, C4b)
- Stimulation of inflammation (C5a, C3a, C4a)
- Stimulation of humoral response (C3d)
- Immune complex clearance (C3b)
Regulatory proteins of complement
CLINICAL ASPECTS OF
COMPLEMENT
(1) Inherited (or acquired) deficiency of C5–C8, greatly
enhancessusceptibility to Neisseria bacteremia and
other infections
A deficiency of MBL also predisposes to severe
Neisseria infections.
A deficiency of C3 leads to severe, recurrent pyogenic
sinus and respiratory tract infections.
(2) Inherited deficiency of C1 esterase inhibitor
resultsin angioedema.
(3) Acquired deficiency of decay-accelerating factor on
the surface of cells results in an increase
incomplement mediated hemolysis (paroxysmal
nocturnal hemoglobinuria).
(4) In transfusion mismatches a large
amounts of anaphylatoxins and membrane attack
complexes are generated.
(5) Immune complexes bind complement, and thus
complement levels are low in immune complex
diseases (e.g., acute glomerulonephritis and systemic
lupus erythematosus).
Binding (activating) complement attracts
polymorphonuclear leukocytes, which release
enzymes that damage tissue.
(6) Patients with severe liver disease cannot synthesize
sufficient complement proteins, are predisposed to
infections caused by pyogenic bacteria.
Complement system
(animation)
http://highered.mcgraw-hill.com/sites/0072556781/student_view0/chapter31/animation_quiz_1.html