Dr. Pratiwi S Gunawan, drg.,MKes.

,PAH(K)

Definition : series of heat-labile serum proteins

Site

: serum and all tissue fluids except urine and CSF

Synthesis : in liver appear in fetal circulation during 1st 13 W

Function

: Responsible for certain aspects of

immune response and inflammatory response

Activation : antigen-antibody complex or endotoxin, capsule

series of proteins activated sequentially
Inactivation: inhibitors in plasma (short lived)
Biological effects: either beneficial or harmful to host

 Complement was discovered by Jules Bordet as a

heat-labile component of normal plasma that

causes the opsonisation and killing of bacteria.
The complement system refers to a series of >20
proteins, circulating in the blood and tissue fluids.

 Most of the proteins are normally inactive, but in response

to the recognition of molecular components of

microorganisms they become sequentially activated in an
enzyme cascade the activation of one protein
enzymatically cleaves and activates the next protein in the
cascade.

 Complement can be activated via three different pathways

(Figure 1), which can each cause the activation of C3,

cleaving it into a large fragment, C3b, that acts as an
opsonin, and a small fragment C3a (anaphylatoxin) that
promotes inflammation. Activated C3 can trigger the lytic
pathway, which can damage the plasma membranes of
cells and some bacteria. C5a, produced by this process,
attracts macrophages and neutrophils and also activates
mast cells.

Classical Pathway

Mannose Binding Lectin (MBL)

Pathway

Alternative Pathway

Antigen-Antibody complex

Activating surfaces

C1

C3b

Pathogen surfaces

C4

Factor D
Factor H
Factor I

C4
Factor B

MBL
MASP-1
MASP-2

C2

C2

C3 Convertase

C3a
C3
C3b
C3b
C5 Convertase

C5

Lytic Pathway

C5b
C6
C7
C8
C9

C5b-9

C5a

Anaphylatoxin
Activates mast cells
Chemotactic

Continued next page

Membrane attack complex (MAC)

 There are 3 major pathways

1. Classical pathway triggered when IgM or certain

subclassed of IgG ( IgG1 & IgG3 )
2. Alternative pathway triggered when a
breakdown product of C3 hydrolis ( C3b ) is
deposited on the surface of microbe
3. Lectin pathway initiated in the absence of
antibody by the attachment of plasma mannosebinding lectin ( MBL ) to microba

A) Classical pathway:
- Complement is activated by antigen antibody
complex (IgM or IgG)
- Fc portion of the antibody form a binding site for C1q
- The numerical sequence of the complement factors in the
classic pathway is:
C1q,r,s , C4, C2, C3, C5, C6, C7, C8, C9

The reaction sequence divided into three

stages:
1) Recognition stage:
- C1q act as the recognition element
- It binds to Fc portion of IgM or IgG
- The activated C1 molecule can cleave many C4
molec.
2) Activation stage:
The complement components C4, C2, C3, C5, C6,
C7,
C8, C9 participate in that order
3) Membrane attack stage:
Complement components C5, C6, C7, C8, C9
participate where cell membrane damage and cell
lysis occur

This pathway is initiated by:

* Bacterial endotoxin, polysaccharide capsule,
aggregates of IgE and properdin
* It starts at C3 then C5, C6, C7, C8, C9
* The complement compon. C1, C4, C2 are bypassed
* Antibodies are not required to initiate
activation of
this pathway
* This pathway provides a means of nonspecific
resistance

Classical Pathway

C1
C4

C2

C3
C5
C6
C7
C8
C9

Membrane damage

Alternative pathway

Classic Pathway
* Specific acquired immunity
* Initiated by antibody

Alternative pathway
* Non-specific innate immunity
* Bacterial endotoxin, capsule

* Interaction of all components

* C1, C4, C2 are by-passed

* Properdin system not involved

* Properdin system is involved

Beneficial effects:
1) Cytolysis:
- activated complement proteins polymerize on cell
surfaces of bacteria or erythrocyte to form pores
in its membrane (killing by osmotic lysis)

2) Opsonization:
- binding of complement proteins opsonin (C3b)
to surfaces of foreign organisms or particles
- Phagocytic cells express specific receptors for
opsonins, so promote phagocytosis

3) Inflammatory response :
Small fragments released during complement
activation have several inflammatory actions:
a) C5a is chemotactic and attract neutrophiles and
macrophages
b) C5a activate phagocytes and neutrophils
C) C3,C4 and C5 are anaphylatoxins
Cause degranulation of mast cells and release of
histamine and other inflammatory mediators

4) Immune complex clearance:

- C3b facilitate binding of immune complex to several
surfaces (erythrocytes) and enhance removal by liver
and spleen

- binds erythrocytes to blood vessels , make them as

easy prey for phagocytosis
- C3 deficiency associated with Immunocomplex
disease and susceptibility to recurrent infections

5-Enhancement of antibody production:

- Binding of C3b to its receptors on activated B cells
(CR2) greatly enhances antibody production
- Patient who are deficient in C3b produce
much less antibody than normal individuals and
more susceptible to pyogenic infection

Harmful effects:
- If complement activate systematically on a large
scale (Cm ve bacilli)
- If activated by an autoimmune response to host cells

 The complement system plays a critical role in

inflammation and defence against some bacterial

infections. Complement may also be activated
during reactions against incompatible blood
transfusions, and during the damaging immune
responses that accompany autoimmune disease.
Deficiencies
of
individual
complement
components or inhibitors of the system can lead to
a variety of diseases (Table ), which gives some
indication of their role in protection against
disease

Complement Deficiency

Disease

C3 and Factor B

Severe bacterial infections

C3b-INA, C6 and C8

Severe Neisseria infections

Deficiencies of early C components C1, C4, C2.

Systemic lupus erythematosus (SLE),

glomerulonephritis and polymyositis

C1-inhibitor

Hereditary angioedema

The Complement System

i.

the binding of antibodies to antigen performs no useful

function until and unless it can activate an effector
mechanism.
ii. The complement system serves several effector roles.
iii. So, the complement system provides the actual protection
from the response while the interaction of antibodies and
antigen provides the specificity of the response.
iv. Put another way, antibodies "finger" the target, complement
destroys it.

Thanks