The complement system is a critical part of the immune response, consisting of over 20 proteins that help eliminate pathogens through various mechanisms, including opsonization, inflammation, and cell lysis. It operates through three pathways: classical, alternative, and lectin, which converge to form complexes that activate the membrane attack complex to destroy targeted cells. Major functions include cell lysis, opsonization, chemotaxis, and enhancing antibody production to improve the immune defense against infections.

1. 4/30/2019 Complement
System
Immunology
Muhammad Yousaf
M.SC, SELF, ROLL NO; 24

2. Complement System | Muhammad Yousaf
Complement System
Complement system , a part of immune system, is biological cascade of reactions due to the
more than 20 proteins mainly formed by the liver cells and always found in blood circulation by reacting
with each other in an order or manner, on the surface of the pathogens. These proteins are also present
inside the body and get activated when stimulated by some triggers by an antigen when it is bound to
antigen. This complement system helps the immune system to eliminate the outsider and invader
bacteria, viruses and pathogens by helping macrophages and mast cells. The proteins in complement
system are called “Complements, Zymogens and Proenzymes”. Complement system helps the immune
system by means of opsonization, apoptosis, inflammation, phagocytosis and chemotoxicity.
These complements were first identified by Jules Bordet in 1895 as heat sensitive components
in blood that causes the opsonization and killing of bacteria. These proteins are actually the precursors
of some enzymes in inactive form. Complements are simply denoted by capital letter C with numbers
are they were discovered like C1, C2, C3 and so on. Others are represented by alphabets like B, D. Some
are simply represented by names like homologous restriction factor. Some of the proteins have further
subunits like C1 has three subunits which are C1q, C1r and C1s. C2 and C5 have two components i.e. a
and b. Larger subunits are denoted by b while smaller are denoted by a except in case of C2a which is
larger than its C1b.
Activation of Complement System & Cell Lysis
Activation of complement system is done by three pathways.
• Classical Pathway – activated by antibody-antigen reaction.
• Alternative Pathway – activated on microbial surface
• Lectin Pathway – activated by plasma lectin that binds to mannose residues on microbes.
In these pathways, as they have different various steps, but all form the complexes like C3 Convertase
which cleaves the C3 into C3a and C3b, C5 Convertase which similarly cleaves the C5 into C5a and C5b.
When C5 convertase is formed, it activates the late components of complement system to form the
Membrane Attacking Complex (MAC) and kills the pathogens.
CLASSICAL PATHWAY
Classical pathway begins when antigen-antibody complex is formed. Only IgM or IgG are responsible for
triggering the attachment of proteases. After attachment with antigen, some of the conformational
changes are produced in Fc region of antibodies exposing the binding site for C1 proteins. For the
activation of complement system, it is necessary that antibody should binds with an antigen.
As C1 is a large protein, composed of five molecules, in which one molecule of C1q and two molecules of
each C1r and C1s subunits are present. Binding of C1 occurs by means of C1q at Fc region of protein
while C1r and C1s are involved in cleavage of C4 and C2.

3. Complement System | Muhammad Yousaf
Immune complex attached with C1 also cleaves the C4 when C4 contacts with this whole complex and
converted into C4a and C4b. C4b becomes activated and attached with target surface while C4a goes
away to performs its own function, involve in calling macrophages and also in chemotoxicity. C2 is
attracted by C4b cleaves the C2 into two subunits which are C2a and C2b. Similarly, the larger subunit
C2a binds with C4b while C2b goes away as it have smaller size and performs functions like C4a. Now,
the complex of C4bC2a is called as C3 Convertase and activates the C3 by cleaving it into C3a and C3b. A
single complex of C3 Convertase can cleave a lot of numbers of C3 molecules. C3b, now has two options,
either attached with target’s surface or attached with C3 Convertase. When C3 binds with C3
Convertase, the complex is now called as C5 Convertase.
Same like C3 Convertase, C5 Convertase also activates the C5 by cleaving it into C5a and C5b. C5a goes
away but C5b stabilize itself by successively binding with C6 and C7. This C5bC6C7 complex is injected
into the membrane of target cell and binds C8 with itself. This complex also binds with a number of C9
proteins to form a hole in membrane which is called membrane attack complex (MAC). MAC allows the
intracellular fluids to come outside of the cell and unwanted substances to get into the cell also with
some water leading to the lysis of the pathogenic cell. The formation of MAC is easier in Gram negatives
bacteria as compared to Gram positives because Gram positives have rigid thick layer of peptidoglycan.
As mentioned above, C3b also cover the target’s cell surface and work like opsonin and increases the
chances of phagocytosis which is also called opsonization.
ALTERNATIVE PATHWAY
The alternative pathway is initiated without any antigen-antibody complex formation. It is initiated by
the cell surface molecules or constituents of foreign cells or pathogens like lipopolysaccharides.
Entrance of any foreign pathogen like bacteria leads to inflammation and complements reach to that
site. C3 molecules, in this case, are activated by directly contacting with antigen. Hydrolysis of C3 occurs
which cleaves the C3 into its two subunits C3a and C3b. C3b attaches with target cell surface and binds
with another serum protein called factor B. The factor B is cleaved into Ba and Bb by means of
enzymatically active serum protein known as factor D because after attaching with C3b, factor B
exposes a site which acts as substrate to factor D. The cleaved Bb remains attached with C3b to form a
complex of C3bBb also known as C3 Convertase. So, as like in classical pathway, C3 Convertase leads to
the formation of C5 Convertase which ultimately forms the MAC and kills the pathogen’s cell.
MANNOSE BINDING LECTIN (MBL) PATHWAY
Some microorganisms like bacteria, such as Salmonella, Listeria and Neisseria strains, some fungi and
some viruses including HIV-1, can activate complement system without antibody and endotoxin. This
pathway works when circulating lectin (MBL) attaches with some mannose residue on glycoproteins and
carbohydrates on the surface of target cell. The concentration of MBL increases during inflammation
and also an acute phase protein.

4. Complement System | Muhammad Yousaf
As MBL gets attached with cell’s surface carbohydrates residues, it is bounded with two other
components which are MASP-1 and MASP-2 where MASP stands for MBL-associated serine proteases.
This leads to the formation of tetrameric complex same like C1s and C1r and also cleaves the C4 and C2
and form the C3 Convertase. This pathway also resembles with classical pathway as it further continues
to form C5 Convertase and MAC and finally killing of cells.
Functions of Complement System
Some of the major functions performs by the complement system are given below:
Cell Lysis:
Cell membrane of the pathogens is ruptured by the complex C5b6789 which ultimately leads to the
death of that organism.
Opsonization:
Surface of target cell is coated by C3b protein molecules, act like opsonin and enhances the chances of
opsonization or phagocytosis.
Chemotaxis:
Protein molecules which were gone away as they formed like C5a, C3a attracts the neutrophils, mast
cells and macrophages towards antigen and cause inflammation, i.e. chemotaxis.
Antibodies Production:
B cells also produce more antibodies as they have receptors for C3b which is an antibody producing
amplifier and form an effective defense mechanism to destroy pathogens.