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Esraa Elgizawy

on 8 May 2014

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Complement System
1. Definition and Functions
2. Activation Pathways
3. Regulators of Activation
4. Role in Diseases
5. Defects of Complement System and Their Effects
6. Conclusion

Group of serum
that activate one another, named C1,2,...

Helps the abilities of antibodies to
clear pathogens
from an organism.

Considered as an important part of the
innate immune system
It has many biological functions as:
 Classical
– Immune complexes
– Apoptotic cells
– Viruses + GN bacteria

 Lectin
– Mannose groups – terminal ends of microbes

 Alternative
– Bacteria, fungi, viruses, tumour cells etc

The complement system has the potential to be extremely damaging to host tissues. So, its activation must be tightly regulated.

The complement system is regulated by complement control proteins, which are present at a higher concentration in the blood plasma than the complement proteins themselves.
Pathways of Complement Activation

There are three pathways to complement activation
• Classical • Alternative • Lectin
They all end up forming a C3 convertase complex which activates C3
1. Classical Pathway
• It's triggered by activation of the C1-complex

• This occurs when C1 binds to IgM or IgG complexed with antigens or when C1 binds directly to the surface of the pathogen.

2. Alternative pathway
The complement system can also be triggered without antigen-antibody complexes.
Even in their absence, there is a spontaneous conversion of C3 to C3b.
3. Lectin pathway
The lectin pathway is homologous to the classical pathway, but with mannose-binding lectin (MBL) instead of C1.

It's activated by binding of MBL to mannose residues on the pathogen surface
Membrane attack complex
Enzymatic cleavage of
by the C3/C5 convertase, produces:
C5a &C5b

, released into the fluid surroundings where it is a potent anaphylatoxin.

, serves as the anchor for sequential binding of
 The resulting complex
guides the polymerization of
into a tube inserted into the lipid bilayer of the plasma membrane.
 This tube forms a channel allowing the passage of ions and small molecules. Water enters the cell by osmosis and the cell lyses.
1. Cell lysis of organisms
By membrane attack complex: C5b-C9.
2. Opsonization
By binding of C3b to complement receptors and enhanced phagocytosis by neutrophils and macrophages
3. Chemotaxis
By C5a attracts phagocytic cells to the site of damage.

This is aided by the increased permeability of the capillary beds mediated by C3a and C5a.

4. Clearance of circulating immune complexes
By solubilizing them and assisting in their catabolism and elimination from the body.

Failure of this function can lead to immune complex disorders.

5. Lysis of antibody-coated cells
In some cases, this causes such serious disorders as

- Rh disease
- immune hemolytic anemia
- immune thrombocytopenic purpura

6. Promoting antibody formation
Breakdown of C3b generates a fragment (C3d) that binds to antigens enhancing their uptake by dendritic cells and B cells.
of complement activation pathways
C1 inhibitor
Binds and Inactivates C1r and C1s
Inhibition of formation of C3 convertase enzyme- C4b2a
By ongoing catabolization of C4b by Factor I and C4 binding protein
CD59 (protectin)
Inhibits C9 polymerisation during the formation of the membrane attack complex
Other complement control factors
Inhibit complement binding to host cell surfaces
– DAF: (Decay accelerating factor)
– CD55
– MCP: Membrane co-factor protein
Role In Diseases
Complement System has an important role in host defense against infection, and also it is a mediator in both the pathogenesis and prevention of immune complex diseases by its main functions mentioned before as:
Inflammation - Cell lysis - Opsonization
- Clearance of immune complex

It has a protective effect when functioning in moderation against pathogens; at the same time, the inflammation promoted by complement activation can result in cellular damage when not kept in check.
Defects of Complement System and Relation with Diseases
Due to the important role of the complement system, any defect of its activation is associated with specific diseases as follow:
1. Complement deficiency
Increased susceptibility to pyogenic infections

 Contributing factors
– Deficient opsonisation
– Deficiency compromising lytic activity
– Deficient manose-binding lectin pathway

A. Deficient opsonisation
 Opsonization is the process of coating a pathogenic organism so that it is more easily ingested by the macrophage system.

is a potent agent of opsonization
 So, decreased production of C3b results in inadequate opsonization ability and Increase liability to Pyogenic infections.
 absolute deficiencies of C3 itself leads
to defective opsonization and also
deficient leukocyte chemotaxis
because of decreased C3a concentrations.
2. Impaired Cell Lysis
 The terminal complement proteins
are the proteins that form the MAC.
 These proteins are responsible for bactericidal killing of organisms such as N meningitidis.
 Complement deficiencies of them predispose patients to infection
 Frequency rate of meningococcal infection in these patients is 66%, and
also rate of recurrence with the same
organism is as high as 50%.
3. Deficient Lectin
 Deficiency occurs due to mutations – reduced levels.
 It's associated with higher risk of infection in children – whilst losing passive immunity.
 Protective against mycobacterial infections.
2. Glomerulonephritis
C3b regulation is caused by
Factor B
binding to C3b

 If C3 regulation is defective:- often associated with GN.
– Due to C3 nephritic factor – increases stability of C3 convertase enzymes – association with membranoproliferative GN
– Reduced function of Factor H or I Associations atypical Hemolytic Uremic Syndrome. (+/- low level of C3).
 Mutations in the C1 inhibitor gene – inadequate production of physiologically adequate C1 inhibitor

 Inhibits – C1r and C1s, activated FXI and XII

 Consumed by plasmin – trigger for hereditary angioedema.

4. Complement deficiency + SLE
 The complement helps in the prevention of immune complex disease by decreasing the number of circulating immune complexes.
 Inverse correlation with position of deficient protein in activation sequence of the classical pathway
– Homozygous Deficiency of
– strongly association with SLE (93%, 57%, 75%)
– Deficiency of
– 10% prevalence.
 Protective role exists for those in whom activation of classical pathway up to C4 cleavage occurs.
5. Paroxysmal Nocturnal Hemoglobinuria
 Acquired stem cell disorder
 Glycosyl Phosphatidyl-Inositol (GPI) is important anchorage of proteins to cell membranes.
 In PNH – lack of GPI (Glycosyl Phosphatidyl-Inositol) -linked proteins (including complement-regulating surface proteins) - eg DAF (i.e CD55) which regulates formation of C3 convertase and CD 59 – restricts formation of MAC.

6. Complement system + sepsis
 C5a is anaphylatoxin and strong chemoattractant.
 In case of Sepsis, there is excessive early production of C5a which upregulat proinflammatory response.
 Role for blockade of C5a with antibodies – shown to improve survival of septic mice.
 Use in IHD (Ischemic Heart Diseases) to assist cardiac reperfusion.

Complement system:
Group of proteins

Activate one another

Has a role in inflammatory and immune diseases by many functions

-Cell Lysis -Opsonization
-Clear Immune complexes
Activation Bathways
There are 3 pathways of complement activation

-Classical -Alternative -Lectin

Each of them end by formation of C3 convertase enzyme

Then, Formation of Membrane Attack Complex
Role in Diseases
Complement System has a defense mechanism in inflammatory and immunological diseases

Deficiency of some components may lead to serious diseases as GN, PNH, Infective diseases and others
Esraa Sameh

Israa Sami

Esraa Omar

Esraa ElSotohy

Esraa Elgizawy
It's made by complement control proteins

Inhibit the extremely damaging

C1 inhibitor
Inhibition of C3 convertase formation
Full transcript