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
