BSN/BN
Kantipur Academy of Health Science
MSc Microbiology
MSc Biochemistry
• It is a system consisting of group of （ approximately 30 ） plasma and cell
membrane proteins involved in the effector role of the host defense process.
• It is the major effectors of humoral branch of immune system.
• It is include serum and membrane bound proteins that function in both
adaptive and innate host defense system, these proteins are highly regulated
and interact via a series of proteolytic cascades.
• Complement proteins are Synthesized in the liver and by cells involved in the
inflammatory response hepatocytes, monocytes, macrophage and epithelial
cells of gastrointestinal tract.
• The term "Complement" refers to the ability of these proteins to complement
(augment) the effects of other components of the immune system.
History
• In the late 19th century Hans Ernst found that serum contains a
"factor" capable of killing bacteria.
• In 1896 Jules Bordet in Paris at the Pasteur Institute, demonstrated
this principle has two components one that maintains this effect after
being heated (heat – stable) responsible for the immunity against
specific microorganisms and one that loses this effect after being
heated (heat – liable) responsible for the immunity against non-
specific microorganisms.
History of Complement system
In the late 1890s the term "
complement" was introduced by Paul
Ehrlich as a part of his larger theory of
the immune system.
In the early half of the 1930s Stanley's
team proved the role of complement
in both the innate and the cell-
mediated immune response upon the
important opsonisation mediated
effect of C3b.
History of Complement system
• Complement was discovered by Jules Bordet as a heat-labile
component of normal plasma that causes the opsonisation and killing
of bacteria.
The basic functions of Complement system:
• After initial activation, the various complement component interact in
highly regulated cascade to carry out a number of basic functions
including:
1. Cell lysis: rupturing membranes of foreign cells.
2. Opsonization: enhancing phagocytosis of antigens.
3. Chemotaxis: attracting macrophages and neutrophils.
4. Agglutination: clustering and binding of pathogens together (sticking)
The components of Complement
• 30+ components – 20 are soluble, rest attached to membranes.
• They form about 5% of serum globulins and circulated in blood
functionally inactivated as proenzyme.
• The complement components are designated by numerals (C1…..C9),
• the smaller fragment resulting from cleavage of component is
designated "a" and the largest fragment "b" (e.g. C3a, C3b) exception
in C2 cleavage C2a is the largest fragment designated.
• The complement fragments interact with one another to form
functional complexes which have enzymatic activity and designated
by a bar over the number or symbol (e.g. C4b2a).
Biochemical pathways that activate the
complement system:
• Sequential activation of complement components occurs via three
main pathways:
• Classical complement pathway
• Alternative complement pathway
• Manose lectin pathway (MLP).
• By interaction of one of the initial components with bacterial cell
surface substances (“Lectin pathway”), bacterial products (the
“Alternative pathway”), or by antibodies that have bound to antigens
(the “Classical pathway”).
Complement activation
• There is a “recognition unit”, made up of some of the initial
components.
• The early steps in the complement activation is the formation of C5b
which can be occur by one of the mentioned ways, the final step
leading to the formation of the “membrane attack complex”. or MAC
which are identical in all three pathways.
Classical complement pathway
• It is activated by the formation of soluble antigen – antibody complex.
IgM and certain subclasses of IgG (IgG1, IgG2 and IgG3 but not IgG4) can
activate this pathway.
• Steps of Classical pathway:
• Ag – Ab complex induce conformational changes in IgM that expose a
binding site for the C1 component of the complement system. C1 in
serum is a macromolecular complex consist of C1q and two molecules of
C1r and C1s held together to form complex (C1qr2S2) which stabilized
by Ca+2 ions....
Steps of Classical pathway:
• C1qr2S2 cleave C4 into C4a and C4b, and cleave C2 into C2a and C2b
then form (C4b2a) complex which is called C3 convertase.
• C3 convertase cleave C3 into C3a and C3b leading to the formation of
(C4b2a3b) complex which is called C5 convertase. C5 will cleave into
C5a and C5b.
• C5b will bind to C6 to form C5b6789 and initiate the formation of
MAC (membrane attack complex) which form a large pore in the
membrane of microbial cell.
Membrane attack complex:
• It is the cytolytic end product of the complement cascade, this
complex forms a large channel through the membrane of the target
cell, enabling ions and small molecules to diffuse freely across the
membrane, consisting of C5b, C6, C7, C8 and polymeric C9.
Alternative complement pathway
• The alternative pathway is continuously activated at low level.
• It is not rely on pathogen- binding antibodies like classical pathway for
initiation, so it's a component of innate immune system.
• It is activation involves four serum proteins (C3, factor B, factor D and
properdin).
• Some initiators required for this pathway activation may be
pathogens like (gram positive, gram negative, Fungal, parasites,
viruses and some tumors cells) or non pathogens like (Cobra venom
factor, dextran sulfate, agarose and heterologous erythrocyte of
mouse and rabbit)
Steps of Alternative pathway:
• Spontaneously cleavage of C3 into C3a and C3b, C3b will bind to the
surface of cell wall of microbial cell.
• C3b will bind with B factor in the presence of D factor cleavage into
Ba and Bb to form C3bBb which has C3 convertase activity.
• C3 will cleave into C3a and C3b to form C3bBb3b binding with
properdin stabilizes.
• C3bBb3bp has C5 convertase activity cleave C5 and form C5b6789
which leading to form MAC.
Lectin complement pathway
• Or Mannose – binding lectin pathway (MBL pathway) because lectin
activates complement binds to mannose residues, like the alternative
pathway dose not depend on antibody for it is activation.
• The lectin pathway is homologous to classical pathway but with
opsonization.
• Lectins are proteins in serum that recognize and binding to specific
carbohydrate target mannose residues on the surface of
microorganisms …leading to:
1. Activation of C1 which cleave C4 into C4a andC4b also C2 into C2a
and C2b and form C4b2a complex
2. C4b2a complex has C3 convertase activity to cleavage C3 into C3a
and C3b and form C4b2a3b complex.
3. C4b2a3b complex has C5 convertase activity to cleave C5 into C5a
and C5b, C5b bind and form C5b6789 and form MAC.
Summary of 3 pathways
All three pathways converge at the cleavage of C3, leading to:
• Formation of the C5 convertase.
• Activation of the Membrane Attack Complex (MAC), which creates
pores in the target cell membrane, resulting in lysis.