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COMPLEMENT SYTEM

Immune system
a. Adaptive immune system
b. Innate immune system- complement
Definition:
Is a group of serum proteins atleast 20 in number which
normally remain in active form and when activated they act
in concert in an orderly sequence to exert biological effects
Functions:
Provides actual protection from the response
Antibodies point out the target, complement destroys it

Production of complement components:
Components are synthesized by the liver, spleen,
macrophage and intestinal epithelial cells

Inactive complement
C1, NH1, factor 1, C4, Bb (first to
be activated)
Bacterial invasion
Activation of complement

Components of the complement system
20 components
o C1,2,3,4,5,6,7,8,9
o Factor B, factor D, factor H, factor I
o Properdin, C4-binding protein, S-protein
o C1 inhibitor

COMPONENTS
C1
-exist in blood serum as molecular complex containing
>6 molecules of C1q
>2 molecules of C1r
>2 molecules of C1s
>Mu chains (IgM and IgG contains binding site of C1q)
C3
-abundant proteins of the complement system (1.3mg/dl)
and has the ability to active self
C5
-unique terminal complement pathway
-Plasma at 70 ug/l; together with the other proteins of the
terminal pathway, C5b forms the MAC
Properdin
-normal serum with concentration of approximately
5-15 ug/ml
-stabilaize C3 convertase
Factor D
-plasma protein that circulates in active enzyme formation
-cleaves factor B
FLUID PHASE REGULATORS
1. C1 INHIBITOR/ C1NH
- MW: 150,000
- Inactivated C1 by binding to the active site of C1r

2. Factor H
- MW: 160,000
- Prevents binding of factor B by binding to C3b
- Allows factor 1 to break down C3b


3. Factor I
-a serine protease that inactivate C3b and C4b when they are
associated with factor H
4. C4 binding protein/ C4BP
- cofactor for factor I in the activation of C4b
- Abundant in plasma
- Cause cessation of the classical pathway
5. S-Protein
- Control protein that act at a further level complement
activation
- Aka VITRONECTIN

CLASSICAL PATHWAY
Complement involved: C1 to 9
Stimulus: Ag-Ab complex
Immunologic activator: IgM/ IgG (1, 2, 3)
Non-immunologic activator: apoptotic cells, staphylococcal
proteins A, C-reactive protein, Gram (-) bacteria, viruses, and
parasites

IgG- needs 2 molecules to activate the pathway and binds to CH
2

IgM- needs one molecule to activate the pathway and binds to
CH
3

STAGES OF CLASSICAL PATHWAY
1. Recognition unit
a. C1 is the first to bind (750,000 D)
b. C1s requires Ca
++
for stabilization
C1q
-One subunit
-410,000 D
-6 strand that form 6 globular heads with a collagen like
tail portion
-recognize the fc region of the 2 adjacent Ab molecules
-bind to the antibody
-atleast 2 of the globular heads
C1r and C1s
-2 subunits each
-C1r, C1s (2 complex) - s-shaped structure
-C1s-C1r-C1r-C1s- generate enzyme activity to begin
the pathway
-serine protease proenzymes
- Binding of C1q- activation of C1r and C1s activated
C1rs substrate C1s substrate: C4 and C2
*substate- are chemical component activated by enzymes
2. Activation Unit
a. C1s cleaves C4 to slpit off C4a
b. Splitting off the C4a
c. C4b binds to the antigen
d. C2 is cleaved by C1s
e. C2b is released
f. C4bC2a/ C3 convertase is formed (enzyme)
g. C3 cleaves to the C4bC2a complex
h. C3 is cleaved into C3a and C3b
i. C3b are activated and formed near the C4bC2a complex
j. C3b is formed to C4b and C2a to form C5 convertase
(C4bC2aC3b)
3. Membrane attack complex
a. C5a splits off
b. C5b attaches to the cell membrane
c. C6 then C7 binds to C5b
d. C8 binds and forms small hole in the membrane
e. C9 forms a tubule (pore)
ALTERNATIVE PATHWAY

MW CONCENTRATION FUNCTION
FACTOR B 43 200 C3b to form C3
convertase
FACTOR D 24 1-2 Cleaves factor B
PROPERDIN 53 25 Stabilizeds
C3bBb/ C3
convertase

Aka:Incomplete pathway/ Properdin pathway
Immunologic activators: aggregated IgA; in some instances
IgG4 and IgE
Non-immunologic activators: bacterial and plant
polysaccharides, LPS, cobra factor, viruses, tumor cells,
zymosan and inulin

a. C3 in plasma is cleaved (have the capacity to self-
activate)
b. C3b is cleaved until becomes stable
c. Either it is activated in hydrolysis
d. Factor B binds to C3b
e. Factor D binds to the complex and Ba is cleaved off
while C3bBb is formed (active C3 convertase)
f. Properdin stabilizes C3 convertase
g. C3b is formed continuously
h. C5 convertase (C3bBbC3b)
i. C5 binds to C5 convertase
j. C5 splits into C5a and C5b
k. The remainder of the pathway continue in the classic
pathway
Membrane attack complex
C5a splits off
C5b attaches to the cell membrane
C6 then C7 binds to C5b
C8 binds and forms small hole in the membrane
C9 forms a tubule (pore)

MANNOSE BINDING LECTIN PATHWAY
Belongs to the family of calcium dependent lectin called
COLLECTINS
Homologous in structure to C1q
Lectin binds mannose or related sugars to initiate the
pathway
Present in serum
Increased during an initial inflammatory response

MBL binds to the surface of the cell
2 MBL associated serine proteases (MASP-1,
MASP-2) becomes activated
MASP-1 and MASP-2 cleaves C4 and C2
C3 convertase is formed

Functions of the following
C4a- minor anaphylatoxin
C2b- kinin like activity
C3a- anaphylatoxin
C5a- anaphylatoxin and chemotactic factor
C5ba- membrane attack complex
C3b- stabilized by polysaccharides
C5b, C5b6, C5b7, C5b8, C5b9- terminal components

Final effect of activation
All component pathways results in the formation of
membrane attack complex (MAC) leading to lysis of target
cells

Biological activities
1. Anaphylatoxin
-C3a, C4a, C5a-cayses degradation of mast cells,
basophils, and release mediators such as histamine
(increase capillary permeability, contraction of smooth
muscle)
2. Opsonization
-C3b promote the attachment of antigen to phagocytes
3. Chemotaxis
-C5a, C5, C6, C7 complex attracts phagocyte to the
infected site

Function of complement

C3
activation
C3a, C5a inflammation
C56789 cell lysis
C3b

opsonization, IC clearance, Bcell
activation

Alterations in complement level
May occur
o Due to persistent infection
o Autoantibody response to self-antigen
May contribute to the pathology of the disease
Activation is related intravascular thomobosis which leads
to schemic injury tissues

Elevated complement
Trauma
Inflammatory conditions
Acute illness
Common and non-specific

Decrease complement
Excessive activation
Being consumes
Genetic defect
*HYPOCOMPLEMENTEMIA
- Due to thecomplexity of IgG/ IgM capable of
activating complement