Complement system

Joules Bordet and Gengou octave

The term complement refers to

 system of factors

 found in normal serum

 activated characteristically by antigen-antibody interaction and

which subsequently mediates a number of biologically

significant consequences.
GENERAL PROPERTIES:-

 Complement is present in the sera of all mammals

 It is a non-specific serological reagent because complement

from one species can react with antibodies from other species

 Complement constitutes about 5 per cent of normal serum

protein and is not increased as a result of immunization.

 Effect of temperature on complement

 complement as a whole is heat labile but some of its

components are heat stable.

 its cytolytic activity undergoing spontaneous denaturation slowly

at room temperature and being destroyed in 30 minutes at 56°C.

A serum, deprived of its complement activity by heating at 56°C for

30 minutes, is then said to be 'inactivated'.

Components
The complement system consists of at least 30 chemically
and immunologically distinct serum proteins which make up
the complement components.

Fractions:
 Complement is a complex of nine different fractions, C 1
to C9.
 The fraction C 1 occurs in serum as a calcium ion-
dependent complex, which on chelation with EDTA yields
three protein subunits called C 1 q, r and s
 Thus Complement is made up of a total of 11 different
proteins.
 Complement fractions are named C 1 to C9 in the sequence of

the cascading reaction, except that C4 comes after C1 and

before C2.

 c1-c4-c2-c3-c5-c6-c7-c8-c9
 The model traditionally used to explain Complement activity

in immune cytolysis is the lysis of erythrocyte sensitized by

its antibody.

 The erythrocyte (E) antibody (A) complex is called EA

 when Complement components are attached to EA, the

product is called EAC

 followed by the components that have reacted

example:- EAC 14235 or EAC 1-5

 Complement component acquires enzymatic or other

demonstrable biological activity, indicated by a bar over the

component number

 enzymatically activated C 1 is shown as CT.

 Fragments cleaved from Complement components during the

cascade --indicated by small letters ( C3a, C3b).

 Inactivated forms of C components are indicated by the prefix 'i'

(iC3b).
Complement (C) ordinarily does not bind to

 free antigens or free antibodies

 only to antibodies that have combined with their antigens

( Antigen-Antibody Complex)

 Various terms such as fixation, binding and consumption

have been used to refer to the combination of C with bound

immunoglobulin, leading to the activation of the classical C

pathway.
The site of Complement binding :- located on the Fc piece of the Ig
molecule (CH2 domain on Ig G, CH4 on Ig M), and is expressed only when
Immunoglobulin is combined with its antigen.
 All classes of Immunoglobulin do not fix Complement . Only Ig

M, Ig G3, 1 and 2 (in that order) fix Complement , but not Ig G4,

Ig A, Ig D or Ig E.

 The fixation of Complement is not influenced by the nature of

antigens, but only by the class of immunoglobulins.

Biosynthesis of Complement
Complement components are synthesized at various sites in the
body.
 intestinal epithelium C1
 macrophages C2, C4
 spleen C5, C8)
 liver C3, C6, C9
 Complement is an 'acute phase substance' and a rise in
Complement levels C4, C3, C5 and C6 during the acute phase
of inflammation.
Acute-phase proteins (APPs)
 class of proteins
 whose concentrations in blood plasma either increase or decrease
in response to inflammation. This response is called the acute-
phase reaction (acute-phase response).
1.Positive acute-phase protein :- plasma concentration increase
during inflammation
2. Negative acute-phase proteins:-plasma concentration decrease
during inflammation
Positive acute phase protein Negative acute phase protein
 Fibrinogen  Albumin
 C-RP  Transferrin
 Lectin  Anti- thrombin
 Hepcidin  Transthyretin
 Ferritin
 SAA protein
COMPLEMENT ACTIVATION

 Complement is present in the body in an inactive form .

 when complement activity is induced by antigen antibody combination or

other stimuli, Complement components react in a specific sequence as a

cascade i. e c1-c4-c2-c3-c4-c5-c6-c7-c8-c9

 the Complement cascade is a series of reactions in which the preceding

components act as enzymes on the succeeding components, cleaving them

into dissimilar fragments.

 The larger fragments usually join the cascade. The smaller fragments which

are released often possess biological effects which contribute to defence

mechanisms by various basic effector mechanisms.

Effector Mechanism including:-
 Lysis of cells and bacteria
 Promoting virus neutralisation
 Opsonisation, which promotes phagocytosis of particulate
antigens
 Immune clearance, which removes immune complexes from
circulation and deposits them in the spleen and liver
 Amplifying the inflammatory process, increasing vascular
permeability, inducing smooth muscle con traction and effecting
the release of histamine from mast cells
Biological effect of complement activation
Complement Pathway

1.classical Complement pathway:-first one to identified identified

2.alternative or properdin pathway

3.Lectin pathway.
Classical complement patway
Alternate complement pathway
Overview Pathway of Complement Activation
Regulation of complement activation
Several inbuilt control mechanisms regulate the complement
cascade at different steps.
These are mainly of two kinds: Inhibitors and Inactivators
1.inhibitors:- bind to complement components and halt their further
function
Examples:-
 C1 esterase inhibitors ( Berinert , Cinryze, Kalbitor)
 S-Protein

2. inactivators:-are enzymes that destroy complement proteins.

 1.Inhibitors:
A. C1 esterase inhibitors

 Heat labile
alpha Neuramino-glycoprotein

This does not prevent the normal progress of the complement cascade
but checks its autocatalytic prolongation.
B. S protein
 present in normal serum
 Binds to C67 and modulates the cytolytic action of the membrane
attack complex MAC
2.Inactivators:-
A) serum beta-globulin,called Factor-I (known as C3b, C4b INAC,
conglutinogen activating factor or KAF) , provides homeostatic
control of C3 activation, particularly by the alternative pathway.
B) Another beta globulin Factor H acts in concert with Factor I,
modulating C3 activation.
C) Anaphylatoxin in-activator is an alpha-globulin that
enzymatically degrades C3a, C4a and C5a which are
anaphylatoxins released during the C cascade.
D) The C4 binding protein controls the activity of cell bound C4b.
Biological Effects Of Complements
1.Phagocytosis
2. Inflammatory response
3. Hypersensitivity reactions
4. Autoimmune diseases
5.Endotoxic shock
6. Immune adherence
7. Conglutination
Clinical syndromes associated with genetic deficiencies of
complement components

 C1 inhibitor Heriditary Angioedema

 C1 C2 C3 Deficiency SLE and other Collagen vascular
disease
 C3 Deficiency severe recurrent pyogenic infections
 C5 to C8 Deficiency Bacteremia mainly with
gram- negative Diplococci , Toxoplasmosis
 C9 Deficiency No Disease
Hereditary Angioedema
 Deficiency of the C 1 inhibitor

 associated with hereditary angioneurotic edema

 characterized by episodic angioedema of the subcutaneous tissues

or mucosa of the respiratory or alimentary tracts.

 It may be fatal when the larynx and trachea are affected.

 The attack is precipitated by local exhaustion of the reduced

amount of the C1 inhibitor, leading to the autocatalytic activation

of C1 and the unrestrained breakdown of C4 and C2.

Teatment of Heriditary Angioedema

 infusion of fresh plasma as a source of the inhibitor.

 Prophylactic administration of epsilon amino-caproic acid (or its
analogues) is useful.
 They are believed to inhibit the activation of plasma enzymes,
thus sparing the small amounts of the C 1 inhibitor present.
 SLE Malar Rash and Discoid
complement Defect C1, C2 and C3
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