Complement
Complement system is a cascade (group or system of proteins) present in blood serum.
An array of approximately 20 types of soluble proteins, called a complement system,
functions to destroy extracellular pathogens.
Cells of the liver and macrophages synthesize complement proteins continuously; these
proteins are abundant in the blood serum and are capable of responding immediately to
infecting microorganisms.
The first activity that led to discovery of existence of this cascade was bacteriolysis.
Jules Bordat demonstrated in 1896 that factor or principle found in blood serum was
capable of killing bacteria and could be analyzed into two components-A heat stable
and heat labile component.
Heat stable component confers immunity against specific antigens wheras heat labile
component is non specific in nature.
Paul Ehrlich in the late 1890’s named this as complement because it is something in
blood that complements the cells of immue system.
The complement system is so named because it is complementary to the antibody
response of the adaptive immune system.
Complement proteins bind to the surfaces of microorganisms and are particularly
attracted to pathogens that are already bound by antibodies.
Binding of complement proteins occurs in a specific and highly regulated sequence, with
each successive protein being activated by cleavage and/or structural changes induced
upon binding of the preceding protein(s).
After the first few complement proteins bind, a cascade of sequential binding events
follows in which the pathogen rapidly becomes coated in complement proteins.
Complement proteins perform several functions
The proteins serve as a marker to indicate the presence of a pathogen to phagocytic
cells, such as macrophages and B cells, and enhance engulfment; this process is
called opsonization. Opsonization refers to an immune process where particles such
as bacteria are targeted for destruction by an immune cell known as a phagocyte.
Certain complement proteins can combine to form attack complexes that open pores in
microbial cell membranes. These structures destroy pathogens by causing their
contents to leak
The complement system helps antibodies and phagocytic cells clear pathogens
from an organism.
There are three different pathways by which the complement system may occur.
The classical complement pathway starts with antibody binding, which causes a
cascade reaction of complement proteins that gradually form a membrane attack
complex.
The alternative complement pathway is usually stimulated by pathogen antigens
or toxins rather than antibodies, and cleaves C3 until there is enough to continue
the steps of the classical complement pathway from the C5 convertase step.
The lectin pathway is homologous to the classical pathway, but with the opsonin,
mannose-binding lectin (MBL), instead of C1 from the antibody. This pathway
uses proteases on the MBL to form C3 convertase, which continues the steps of
the classical complement pathway from the C3 convertase step.
The complement system is regulated by complement control proteins, such as
decay accelerating pathway, which prevent complement proteins from forming
MAC on the body’s cells.
Classical Complement Pathway
The classical complement pathway is the main pathway by which the complement
system occurs. It is comprised of a cascade of many steps with complement proteins
cleaving one another in a sequential order:
1. The antibody binds to an antigen on the surface of a pathogen, activating the C1
complement protein.
2. C1 acts a protease and cleaves C2 and C4 to form C4b2b.
3. C42b converts C3 into C3a and C3b, which forms a C5 convertase.
4. C5 convertase cleaves C5 into C5a and C5b.
5. C5b forms a complex with C6, C7, and then C8, and C9, which becomes the
membrane attack complex that lyses the pathogen.
Note that C5a has a number of other functions in the immune system, such as causing
vasodilation during inflammation and stimulating neutrophil chemotaxis. Additionally,
the body’s cells express a glycoprotein called decay accelerating factor, which decays
C3 and C5 convertase on the body’s cells. This factor prevents membrane attack
complexes from forming on the body’s cells under normal conditions.
The Classical and Alternative Complement Pathways: The classical and
alternative complement pathways start off differently, but end in the same cascade of
complement proteins that combine to form a membrane attack complex.
The Alternative Complement Pathway
The alternative pathway may be a leftover evolutionary precursor to the classical
pathway. Unlike the classical pathway, the alternative pathway is generally activated by
microbial inflammatory mediators instead of antibodies. For example,
lipopolysaccharide, the toxin of gram-negative bacteria, may activate this pathway. The
steps for the alternative pathway are:
1. The pathogenic antigen (such as LPS) activates C3 so it creates a C3B complex
2. Factor D cleaves the C3B complex so that C3bBb is created.
3. C3bBb is a C3 convertase, which converts more C3 into C3a and C3b.
4. Similarly to the classical pathway, C3b forms a C42b complex, and the rest of the
steps are essentially the same as the classical pathway, ending with C5b forming
a membrane attack complex with C6, C7, C8, and C9.
Lectin Pathway
The lectin pathway is not caused by antibody binding, but by a carbohydrate -binding-
protein called mannan-binding-lectin (MBL). It is an acute phase reactant produced in
the liver and binds to the carbohydrates on the surfaces of many pathogens. The steps
for the lectin pathway are:
1. MBL binds to the carbohydrates on a pathogen.
2. Proteases bound on the other side of the MBL cleaves C4 into C4a and C4b.
3. C4b creates C3 convertase, and the rest of the steps happen identically to the
classical pathway from the C3 convertase step.