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5 Complement System

The document discusses the complement system, which consists of over 20 plasma proteins that interact in a cascade to assist in resolving microbial infections. It describes the three pathways of complement activation (classical, lectin, and alternative), the components involved in each pathway, and the consequences of activation such as lysis of cells, inflammatory response, opsonization, virus neutralization, and clearing of immune complexes. Complement activation is regulated to prevent harm to normal tissues. Deficiencies in the complement system can cause diseases like paroxysmal nocturnal hemoglobinuria.

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Usman Suraj
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28 views

5 Complement System

The document discusses the complement system, which consists of over 20 plasma proteins that interact in a cascade to assist in resolving microbial infections. It describes the three pathways of complement activation (classical, lectin, and alternative), the components involved in each pathway, and the consequences of activation such as lysis of cells, inflammatory response, opsonization, virus neutralization, and clearing of immune complexes. Complement activation is regulated to prevent harm to normal tissues. Deficiencies in the complement system can cause diseases like paroxysmal nocturnal hemoglobinuria.

Uploaded by

Usman Suraj
Copyright
© © All Rights Reserved
We take content rights seriously. If you suspect this is your content, claim it here.
Available Formats
Download as PDF, TXT or read online on Scribd
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The

 Complement  System  

Dr.  Aws  Alshamsan  


Department  of  Pharmaceu5cs  
Office:  AA87  
Tel:  4677363  
[email protected]    
Learning  Objec8ves  
By the end of this lecture you will be
able to:

① Recognize the biological functions of the
complement cascade

② Identify the components of the complement
system

③ Describe the three pathways of complement
activation

The  Complement  System  
• A family of more than 20 plasma proteins that
include enzymes, proenzymes (zymogens),
enzyme inhibitors, and glycoproteins

• They interact in cascade and assist in


resolution of microbial infection

• The name was coined because they were


thought to “complement” the antibacterial
activity of antibody

Complement  Func5ons  
The  Complement  System  
• Synthesized mainly by liver hepatocytes and
other cell types (monocyte, macrophage, GI
epithelial cells)

• Circulate as inactive proenzymes


• Proteolytic cleavage removes inhibitory


fragment and exposes the active site of the
complement molecule

Complement  Nomenclature  
① Designated by numerals (C1-C9), letter
symbols (factor D), or trivial names
(homologus restriction factor)

② Peptide fragments made by activation of a


component are denoted:

• For example, activation of C4 results in

• “a” for smaller fragment – C4a

• “b” for larger fragment – C4b

• Exception: C2a fragment is larger than C2b

Complement  Nomenclature  
• Larger fragments bind to the target near the site
of activation, while smaller fragments diffuse from
the site of activation and can initiate localized
inflammatory response


③ Complexes with enzymatic activity have bar
over the number or symbol



C4b2a

Complement  Ac5va5on  
The  Classical  Pathway  
• Begins with the formation of antigen-antibody
complex (immune complex) or by binding of Ab
on bacterial surface

• IgM and IgG can activate the classical


complement pathway

• Early stage involves C1, C4, C2, and C3



The  Classical  Pathway  
The  Classical  Pathway  
The  Classical  Pathway  
The  Classical  Pathway  
The  Classical  Pathway  
Membrane  AKack  Complex  (MAC)  
The  Lec5n  Pathway  
• Lectins such as mannose-binding lectin (MBL)
binds to mannose residues on the surface of
microorgnisms

• Early stage involve MASP1, MASP2, MBL, C2,


C4, and C3

• Sugars recognized by MBL in human cells are


covered with sialic acid

The  Lec5n  Pathway  
C1 MBL
The  Alterna5ve  Pathway  
• It generates active products similar to those of
the classical pathway but without antigen-
antibody complex

• Early stage involve C3, factor B, factor D, and


properdin

• Gram negative and gram positive bacterial cell


wall can activate the alternative pathway

Ac5va5on  Consequences  
Lysis  
• MAC can lyse broad spectrum of cells

• Gram positive bacteria are generally


more resistant to MAC because of their
thick peptidoglycan layer

• Some cells have developed ways to evade


MAC such as cancer cells

Lysis  

Scanning electron micrograph of E. coli before and after


complement lysis

Some microbes develop mechanisms to evade complement lysis


Inflammatory  Response  
• C3a and C5a (anaphylatoxins) bind to
basophils and mast cells

Inflammatory  Response  
• C3a and C5a increase vascular
permeability

• C3a and C5a mediate chemotaxis by


inducing monocytes and neutrophils to
adhere to vascular endothelium,
extravasation, and migration to the site
of complement activation in the tissue
i.e. inflammation

Opsoniza5on  
• C3b and C4b binding facilitates
phagocytosis

• Phagocytic cells express complement


receptors CR1, CR3, and CR4

• Activation of phagocytic cells increase


the number of expressed complement
receptors

Opsoniza5on  
Virus  Neutraliza5on  
• Binding of Ab to viral structures causes:

• Complement fixation (classical, alternative,
and lectin pathways)

• Viral neutralization and aggregation by
complement components e.g. C3b

• Formation of thick protein coat around the
virus

• These mechanisms blocks attachment to
susceptible host cells

Clearing  Immune  Complexes  
• Immune complexes can
damage tissues

• C3b coats immune complexes


• RBC have capability of


binding C3b coated
complexes and carrying
them to liver and spleen to
be cleared

Ac5vated  Complement  Regula5on  
• Activated complement components are
able to harm normal tissues. Therefore,
they get spontaneously inactivated if
they are not stabilized by other
components

• C3 convertase is a central amplification


step in all pathways. Regulatory proteins
control C3 convertase activity

Complement  Deficiencies  
• Paroxysmal Nocturnal Hemoglobinuria
(PNH)

• Somatic mutation in the pig-A gene that
synthesizes GPI proteins

• Mutated GPI cannot bind to DAF and CD59

• This results in hemolytic anemia, iron
deficiency, and thrombosis

Complement  Deficiencies  
• Paroxysmal Nocturnal Hemoglobinuria
(PNH) - Treatment

Problem   Management  
Lack  of  RBC   RBC  transfusion  
Deficient  erythropoie5n   Recombinant  erythropoie5n    
Increased  thrombosis   Heparin  and  an5coagulants  
Loss  of  iron   Iron  supplementa5on  
Persistent  complement   Eculizumab  to  block  C5  
ac5va5on  
You are now able to:

ü Recognize the biological functions of the
complement cascade

ü Identify the components of the complement
system

ü Describe the three pathways of complement
activation

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