9/1/2022

Do not confuse between two words:

Complement and Compliment

Complement
To help
To augment

Compliment
To honour

To praise

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Complement
Defination
An important member of innate immune system

Complement are a group of proteins normally These are a group of heat labile Proteins(20)
found in serum inactive form, but when (Inactivated at 560C for 30 min)
activated they augment the immune response Present in blood in inactive form
in sequential manner.
Activation process occurs in sequential
manner.
Important member of innate immune system.
Constitue about 5% of normal serum proteins. (Like sequential reactions found in
activation of clotting factors)
Antigen non-specific.
Species nonspecific.
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Can be activated by both

innate and acquired immune system Complements are produced in

When activated: perform some important

1.Mainly Liver (Hepatocyte)
biological functions

2. Macrophage

3. Epithelial cells of
GIT and Genitourinary system

4.Spleen.

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Nomenclature of Components
When activated,complement is broken into
two components as a and b:
(such as: C2a, C2b ; C3a, C3b ; C4a, C4b ; C5a, C5b)

Designated by numerals as: C1, C2, C3………..C9

inactive form
activation b + a

Also designated as alphabets as:

factor B, D, H, I

Also designated as name such as: Properdin

b binds with the site of action

Most of the a diffuse out from

the site and initiate local inflammatory reaction

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Complement activation
Whatever is the pathway, ultimately they produce
3 pathways an enzyme, C5 convertase

C5 convertase cuts C5 to form C5a and C5b

1. Classical pathway and finally C5b6789
(acquired immunity involved,antigen-antibody complex mediated)

C5b6789 is a tube like structure called

2. Alternative pathway Membrane attack complex (MAC)
(innate immunity)

MAC insert into the membrane and creates hole in

3. Lectin activation pathways the cell membrane leads to loss of osmotic integrity
(innate immunity) and rupture of microbe or cell. (Allow free water pa
ssage across the cellmembrane)

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Classical pathway Alternate pathway MB lectin pathway

Stages of complement Activation
There are four main stages of complement
activation
Production of
C5 convertase 1)Initiation of pathway.
C5 2) Formation of C3 convertase.
C5a + C5b 3)Formation of C5 convertase.
C5b + C5a 4)Formation of membrane attack complex.
C5b – 9
Membrane attack complex

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In this pathway complement is activated when

complement proteins bound to an antigen
antibody complex . (Antibody dependent
pathway )

IgM is the best complement activator

IgG (IgG1, IgG2, IgG3) also activate complement

IgA, IgD, IgE and IgG4 do not activate complement

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when antigen-antibody complex bind C1 and is

cleaved to form

Activated C1q activate C1r activate C1s(act as C4b2b + C3b C4b2b3b (C5 convertase)
Protease)
C4
activated C1s C4b
C4a(anaphylatoxin)
C5
C4b2b3b C5b
C2
C4b C4b2b C5a

C2a
C6, C7, C8, C9
(C4b2b is an enzyme. Expressed as C4b2b) C5b C5b6789(MAC)

C4b2b is the C3 convertase of classical pathway

C5b6789 is the final product of complement activation.
C3 It is also called Membrane attack complex(MAC)
C4b2b C3b

C3a(anaphylotaxin)

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Why IgM is better complement activator?

Immunoglobulins have complement receptors
on its Fc fragment (CH2)
C1 is composed of
Receptor remains in hidden state one C1q, two C1r and two C1s q

s r
Receptor is exposed when it
combines with antigen C1q has 6 heads and a common stem
(six tulip heads together)

Complement
binding site
C1q is activated when

2 heads of C1q bind with

Hidden receptor in resting state 2 Fc of

immunoglobulins
Exposed receptor when binds with antigen

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q q

s r s r

No activation Activation
of complement of complement

Because 2 heads of C1q binds with 2 Fc

Diagram of C1

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Comparison between IgG and IgM

Since IgM is pentamer and IgG is monomer

IgM is better (1000 times) complement activator

No activation at Lower Activation at Lower

concentration of IgG concentration of IgM

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Inducers of C3
alternative pathway Plays the central role

C3(H2O) in blood and tissue is spontaneously being

Bacterial LPS
Hydrolysis into C3a and C3b
Teichoeic acid
Fungal cell wall
Viral envelop In blood
Cobra venom and C3 C3b C3a
Inulin tissue
Agarose
Aggregated IgA
If C3b can immediately (60 micro seconds) bind with
certain inducers (foreign substances)

Complement activation starts

Otherwise, C3b will be destroyed

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Once C3b binds with any of those inducers, then : C3bBbC3b is the C5 convertase
for alternate pathway
Factor B binds with C3b = C3bB
C5
Factor D cleaves the C3b bound factor B release C3bBbC3b C5b
Small fragment (Ba) which diffuses away and gen C5a
erates =C3bBb
C3bBb is the C3 convertase of alternate pathway C5b combines with C6, C7, C8, C9

It is an enzyme, Denoted as C3bBb C5b6789

Which cleaves C3 molecules into (Membrane attack complex (MAC)
two fragments. C3a and C3b.

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C3b can also be attached to our own tissue but

activation of complement does not occur

Why this happens?

C3b can bind with both self and foreign tissue. Alternative
But our cell surface (mammalian cells) contain pathway
SIALIC ACID which rapidly inactivates C3b

Bacteria, fungus and virus do not contain

sufficient SIALIC ACID to inactivate C3b

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Lectin: it is a protein that can

bind with carbohydrate

During acute inflammation

Some acute phase proteins are produced

Mannan- binding lectin (MBL)

1. It is one type of acute phase protein
2. Produced from liver

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3. It binds with carbohydrates present on Mechanism of complement activation by MBL

surface of:
Mannan-bining lectin ( also known as
Mannose binding protein,acute phase
Salmonella Candida
protein produced in inflammatory
Streptococ Cryptococc
response) binds with surface of
cus us
microbes bearing Mannan.(A polymer
Listeria HIV
of sugar ,mannose) and form
Neisseria Influenza A
tricomplex of MBL with two serine
Leishmania
proteases MASP-1(MBL-associated
serine protease) and MASP-2(MBL-
associated serine protease).This
4. It does not bind with healthy human tissue tricomplex is activated to cleaves C2
and C4 components of complement,
converging with the classical
pathway.

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Classical pathway MB lectin pathway Alternate pathway

Immune complex Microbial surface Microbial surface

Activated C1 MBL C3
Factor B,D
C4 C3 convertase Properdin
C2 C4b2b C3bBb
C3

C3b

C5b

C5b – 9
Membrane attack complex

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Biological or effector 2. Enhancement of phagocytosis (Opsonization)

functions of complement ( C3b)(phagocytized much better in t
1.Cytolysis he presence of complement.)
(Bacteria, fungus, virus (enveloped), Bacteria without opsonin Bacteria with opsonin
RBC, mismatched graft, Tumour
cells.Gram-negative bacteria espesially C3b
Neisseria are very susceptible.)
Insertion of C5b,6,7,8 ,9(MAC) into the cell membrane forms
a pore in the membrane and disruption of the membrane and bacteria
entry of water and electrolytes.
C3b
receptor
membrane attack complex phagocyte

Electrolytes, H2O

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How opsonization occurs

3. Anaphylatoxins C3a, C4a, C5a

Coating of foreign substance or immune complex with

C3b C3a, C4a, C5a can act on mast cells and
basophils and induce degranulation and
release Histamine and other inflammatory
Phagocytic cells have corresponding receptors for
C3b (CR1)
mediators

Through the receptors, phagocytes are attached Vasodilatation, contraction of smooth muscles,
to the antigen increase vascular permeability.
but in excess cause ANAPHYLAXIS

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4)Chemotaxis:It is directed movement of leukocy Enhancement of Antibody Production

tes toward the site of infection.
Attract neutrophil
C5a The binding of C3b derivatives to
C5,6,7 receptors on the surface of activated B
cells greatly enhances antibody
production compared with that by B cells
that are activated by antigen alone.

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Regulation of complement system

and safeguard against 1. C1 inhibitor (C1INH)
self activation of complement system
It inactivates C1 by destroying
activated C1r and C1s
Complement is a dangerous weapon

Potentially, it can damage our own tissue

Activation of classic pathway can only occur
when enough activated C1 is generated to
Our body has got its own mechanism
outnumber action of C1INH.
to avoid self tissue injury by complement.
Person with C1INH deficiency develops
To avoid constant complement activation a regul a disease named as hereditary angioedema
atory network exists to terminate complement
activity.

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3. Decay accelerating factor (DAF,CD55)

2. Factor H, factor I and properdin .
It is a Glycoprotein on our cell surface
Regulation of alternative pathway is mediated
by binding of Factor H to C3b. Decay accelerating factor acts by destabilizing
C3 convertase and C5 convertase in all three pat
hway.
This protects lysis of host cell by
Factor I cleaves C3b and C4b and preventing formation of MAC
reducing the amount of C5
convertase. Factor P(properdin)
protects C3b and stabilizes the C3
convertase of the alternative
pathway.

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Probable questions
1. Define complement
Complement deficiency disorder
2. How they are activated?
• Inherited or acquired deficiency of C5-C9 ,
3. IgM is better complement activator than IgG greatly enhances susceptibility to Neisseria
- explain
bacteremia.
4. What are the functions of complements?
• Deficiency of C3 leads to severe recurrent
5. What is MAC?
pyogenic and respiratorty tract infection
• Inherited or acquired deficiency of C1
6. Mention the role of C3 in formation of MAC estarase inhibitor leads over production of
7. How our body gets away from damaging estarase leads to angioodema. (increase
effect of complement? capillary permeability and odema.)

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The end
• Reduced level of decay-accelerating factor
and CD59 result in increase haemolysis by
MAC , causing paroxysmal nocturnal
hemoglobinuria.

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