Complement: Introduction

The complement system consists of

approximately 20 proteins that are present
in normal human (and other animal)
serum. The term "complement" refers to
the ability of these proteins to
complement, i.e., augment, the effects of
other components of the immune system,
e.g., antibody. Complement is an important
component of our innate host defenses.
• There are three main effects of complement: (1)
lysis of cells such as bacteria, allografts, and
tumor cells; (2) generation of mediators that
participate in inflammation and attract
neutrophils; and (3) opsonization, i.e.,
enhancement of phagocytosis. Complement
proteins are synthesized mainly by the liver.
Complement is heat-labile, i.e., it is inactivated by
heating serum at 56°C for 30 minutes.
Immunoglobulins are not inactivated at this
temperature.
 Activation of Complement

• Several complement components are proenzymes,

which must be cleaved to form active enzymes.
Activation of the complement system can be
initiated either by antigen–antibody complexes or by
a variety of nonimmunologic molecules, e.g.,
endotoxin.
• Sequential activation of complement components
occurs via one of three pathways: the classic
pathway, the lectin pathway, and the alternative
pathway
• Of these pathways, the lectin and the
alternative pathways are more important at
the first time we are infected by a
microorganism because the antibody required
to trigger the classic pathway is not present.
The lectin pathway and the alternative
pathway are, therefore, participants in the
innate arm of the immune system
• All three pathways lead to the production of C3b,
the central molecule of the complement cascade.
The presence of C3b on the surface of a microbe
marks it as foreign and targets it for destruction.
C3b has two important functions: (1) It combines
with other complement components to generate C5
convertase, the enzyme that leads to the
production of the membrane attack complex. (2) It
opsonizes bacteria because phagocytes have
receptors for C3b on their surface
• In the classic pathway, antigen–antibody complexes
activate C1 to form a protease, which cleaves C2 and
C4 to form a C4b,2b complex. The latter is C3
convertase, which cleaves C3 molecules into two
fragments, C3a and C3b. C3a, an anaphylatoxin, is
discussed below. C3b forms a complex with C4b,2b,
producing a new enzyme, C5 convertase (C4b,2b,3b),
which cleaves C5 to form C5a and C5b. C5a is an
anaphylatoxin and a chemotactic factor. C5b binds to
C6 and C7 to form a complex that interacts with C8
and C9 to produce the membrane attack complex
(C5b,6,7,8,9), which causes cytolysis. Note that the "b"
fragment continues in the main pathway, whereas the
"a" fragment is split off and has other activities.
• In the lectin pathway, mannan-binding lectin
(MBL) (also known as mannose-binding
protein) binds to the surface of microbes
bearing mannan (a polymer of the sugar,
mannose). This activates proteases associated
with MBL that cleave C2 and C4 components
of complement and activate the classic
pathway. Note that this process bypasses the
antibody-requiring step and so is protective
early in infection before antibody is formed.
• In the alternative pathway, many unrelated
cell surface substances, e.g., bacterial
lipopolysaccharides (endotoxin), fungal cell
walls, and viral envelopes, can initiate the
process by binding C3(H2O) and factor B. This
complex is cleaved by a protease, factor D, to
produce C3b,Bb. This acts as a C3 convertase
to generate more C3b.
 Regulation of the Complement System
• The first regulatory step in the classic pathway is at
the level of the antibody itself. The complement-
binding site on the heavy chain of IgM and IgG is
unavailable to the C1 component of complement if
antigen is not bound to these antibodies. This
means that complement is not activated by IgM and
IgG despite being present in the blood at all times.
However, when antigen binds to its specific
antibody, a conformational shift occurs and the C1
component can bind and initiate the cascade.
• Several serum proteins regulate the
complement system at different stages.
• C1 inhibitor is an important regulator of the
classic pathway. It inactivates the protease
activity of C1. Activation of the classic pathway
proceeds past this point by generating
sufficient C1 to overwhelm the inhibitor.
• Regulation of the alternative pathway is mediated
by the binding of factor H to C3b and cleavage of
this complex by factor I, a protease. This reduces
the amount of C5 convertase available. The
alternative pathway can proceed past this
regulatory point if sufficient C3b attaches to cell
membranes. Attachment of C3b to cell membranes
protects it from degradation by factors H and I.
Another component that enhances activation of
the alternative pathway is properdin, which
protects C3b and stabilizes the C3 convertase.
• Protection of human cells from lysis by the
membrane attack complex of complement is
mediated by decay-accelerating factor (DAF,
CD55)—a glycoprotein located on the surface
of human cells. DAF acts by binding to C3b and
C4b and limiting the formation of C3
convertase and C5 convertase. This prevents
the formation of the membrane attack
complex.
 Clinical Aspects of Complement

• Inherited (or acquired) deficiency of some complement

components, especially C5–C8, greatly enhances
susceptibility to Neisseria bacteremia and other
infections. A deficiency of MBL also predisposes to severe
Neisseria infections. A deficiency of C3 leads to severe,
recurrent pyogenic sinus and respiratory tract infections.
• Inherited deficiency of C1 esterase inhibitor results in
angioedema. When the amount of inhibitor is reduced, an
overproduction of esterase occurs. This leads to an
increase in anaphylatoxins, which cause capillary
permeability and edema.
• Acquired deficiency of decay-accelerating factor on the
surface of cells results in an increase in complement-
mediated hemolysis. Clinically, this appears as the
disorder paroxysmal nocturnal hemoglobinuria
• In transfusion mismatches, e.g., when type A blood is
given by mistake to a person who has type B blood,
antibody to the A antigen in the recipient binds to A
antigen on the donor red cells, complement is
activated, and large amounts of anaphylatoxins and
membrane attack complexes are generated. The
anaphylatoxins cause shock, and the membrane attack
complexes cause red cell hemolysis.
• Immune complexes bind complement, and thus
complement levels are low in immune complex
diseases, e.g., acute glomerulonephritis and systemic
lupus erythematosus. Binding (activating) complement
attracts polymorphonuclear leukocytes, which release
enzymes that damage tissue.
• Patients with severe liver disease, e.g., alcoholic
cirrhosis or chronic hepatitis B, who have lost
significant liver function and therefore cannot
synthesize sufficient complement proteins, are
predisposed to infections caused by pyogenic bacteria.