2. THE COMPLEMENT
SYSTEM
1st discovered by Jules Bordet
in 1896 as a heat labile
component of serum.
So named because of its
ability to complement the
antibacterial properties of
Ab’s in the heat labile
fraction of serum.
3. WHAT IS COMPLEMENT SYSTEM?
Complement is a system of ̴40 proteins in the plasma & on cell
surfaces amounting to >3g/L & constituting >15% of globular fraction of
plasma.
Arranged in a hierarchy of proteolytic cascades that starts with
identification of the pathogenic surface and leads to-
Generation of potent proinflammatory mediators
Opsonisation
Targeted lysis of pathogenic surface through assembly of MAC.
Functions in both innate and adaptive immunity.
5. COMPLEMENT ACTIVATION
Complement proteins are present in
inactive state in plasma
Activated to become proteolytic
enzymes that degrade other
complement proteins
Forming a cascade capable of
tremendous amplification.
EARLY
REACTINGLATE
REACTING
6. Conversion of C₃ into C₃ₐ and C₃ by C₃ convertase is the
point at which all complement activation cascades converge.
b
7. Proteolysis of C₃ (most abundant component)
It can occur via 3 pathways
Classic
al
pathwa
y
Alternate
pathway
Lectin
pathway
Triggered
by fixation
of C₁ To
Ag-Ab
complex
Triggered by
microbial
surface
molecules,
complex
polysaccharide
PMBL binds to
carbohydrates of
microbes & directly
activates C₁
1. ACTIVATION
2. AMPLIFICATIO
N
3. LYSIS
8. CLASSICAL PATHWAY-
C1qrs complex made of
1 molecule of C1q , 2
molecules of C1r and 2
molecules of C1s.
Can bind to Fc region of
complement fixing
antibody.
19. NOVEL PATHWAYS OF
COMPLEMENT ACTIVATION-
1. Kallikrein & Thrombin - C3 & C5 can be directly
cleaved by proteases unrelated to the complement
cascade like kallikrein and thrombin leading to
generation of anaphylotoxins (C3a & C5a).
2. C2 bypass pathway – direct cleavage of C3 by
MBL/MASP2
3. Properdin pathway - Properdin can promote de-
novo C3 convertase assembly when immobilized on
an inert surface & initiate C3 convertase formation
on microbial surface( eg Neisseria gonorrheae ).
20. IMPORTANCE OF C3
C
3
C3a + C3b
C3 Convertase
ANAPHYLOTOXI
N
AMPLIFICATION
OF ALTERNATE
PATHWAYC5
Convertase
OPSONISATIO
N
31. C4b2b is the active C3
convertase cleaving C3 to
C3a & C3b
DAF, C4BP & CR1 displace
C2b from C4b2b complex.
C4b bound to C4BP, CR1 or
DAF is cleaved by factor I into
inactive C4d and C4c.
32. On the host cell,
complement control
protein CR1, H, MCP &
DAF bind to C3b &
displace Bb
C3b bound to H, CR1 & MCP is
cleaved by factor I into iC3b.
Thus there is no complement
activation on host cell surface.
33. C5 convertase cleaves C5
into C5a and C5b
CR1 and H displace C3b.
CR1 & H act as cofactors
in the cleavage of C3b by
I
34. The terminal proteins of
complement form a
membrane pore, the MAC
CD59 prevents final assembly
of MAC at the C8-C9 stage.
MIRL blocks MAC by
preventing C9 assembly.
37. INVESTIGATIONS -
1. Quantification of individual complement
components
2. Quantification of activation products
3. Quantification of complement function
4. Quantification of autoantibodies to complement
components.
41. HYPOCOMPLEMENTIC URTICARIAL
VASCULITIS-
•HUVS is a severe systemic form of urticarial
vasculitis.
•Aka McDuffie syndrome.
•Female : male = 2:1
•Peak incidence 5th decade. Also seen in
children.
42. PATHOPHYSIOLOGY-IgG Ab to collagen
similar region of C1q
form immune
complex & start the
cascade.
Activate classical
complement pathway
into and around blood
vessels
Mast cell
degranulation.
Urticaria,
angioedema, ↑ed
vascular permeability
Leucoclastic
vasculitis
43. CRITERIA FOR DIAGNOSIS
(SCHWARTZ)-
MAJOR
1. Chronic urticarial
exanthema
2. hypocomplementemia
MINOR
1. Leucoclastic vasculitis
by biopsy
2. Arthralgia or arthritis
3. Uveitis or episcleritis
4. Glomerulonephritis
5. Recurrent Abdominal
pain
6. Positive C1q Ab
46. LAB DIAGNOSIS-
1. ↑ed ESR
2. Hypocomplementemia with low C1q, C3, C4
3. C1q Ab- not specific
4. ANA Ab without anti-dsDNA
5. Skin biopsy - Diagnostic