University of Juba

School of Veterinary Medicine

Course: SVM -32 -Immunology Class: 3rd Year

Complement activation pathways

Lecture 8 Date: 23rd Nov. 2023

 Complement system
• The term complement refers to the ability of a
system of some nonspecific proteins in normal
human serum to complement, i.e., augment the
effects of other components of immune system,
such as antibody.
• It is an important component of the human innate
host defense system, consists of approximately 20
proteins that are present in normal human serum.
 Properties of the Complement System
• It is present in sera of all mammals including
humans and in lower animals including birds,
amphibians, and fishes.

• These are heat-labile substances that are

inactivated by heating serum at 560C for 30
minutes.
 Cont.
• These are glycoproteins and are synthesized
primarily by liver cells and to a very less extent by
macrophages and many other cell types
• The complement usually does not bind to the
antigen or antibody but only to antigen - antibody
complex.
• The importance of the complement lies in the fact
that it contributes to both the acquired and innate
immunity of an individual
 Complement Activation Pathways
In the innate immune system , complement can
be activated in two ways:

• Alternative pathway, in which antigen is

recognized by particular characteristics of its
surface, or

• Mannan-binding lectin ( MBL) pathway

 Cont.
In the adaptive immune system complement is
activated via;

• Classical pathway that begins with antigen-

antibody complexes
 Functions of the complement systems
Functions of complement include;

• Lysis of bacteria, and fungal cells, viruses, etc.

• Promotion of phagocytosis (opsonization)

• Triggering of inflammation

• Secretion of immunoregulatory molecules

 Cont.
• Clearance of immune complexes from
circulation

• Producing chemotactic substances

• Increasing vascular permeability

• Stimulate the smooth muscle contraction

promoting mast cell degranulation

 Complement nomenclature

• Components C1 through C9, B, D, and P are

native complement (protein) components.

• Fragments of native complement components

are indicted by lowercase letter (e. g . , C4a,
C5b, Bb). Smaller cleavage fragments are
assigned the letter "a,'' and major (larger)
fragments are assigned the letter "b."
 Cont.

• A horizontal bar above a component or

complex indicates enzymatic activity (e. g . ,
C4bC2b) .
 Alternative pathway
• The alternative pathway is initiated by cell-
surface constituents that are recognized as
foreign to the host, such as LPS.

• Various enzymes (e.g . , kallikrein , plasmin ,

elastase) cleave C3, the most abundant serum
complement component into C3a and C3b.
 Cont.
• Unstable C3b fragment, is the major opsonin
of the complement system and readily
attaches to receptors on microbial cell
surfaces.
• C3b binds Factor B .
• Factor B in the complex is cleaved by Factor D
to produce C3bBb, an unstable C3 convertase
Alternative pathway of complement activation.
Beginning with the binding of C3b to a microbial
surface, this pathway results in an amplified
production of C3b and formation of a C5
convertase
Alternative pathway of activation of the complement
 Cont.
• Two proteins, C3b inactivator (I) and β1 H-
globulin (H), function as important negative
regulators, making an inactive form of C3b to
prevent the unchecked over amplification of
the alternative pathway.

• Alternatively, C3bBb binds properdin (Factor P)

to produce stabilized C3 convertase, C3bBbP.
 Cont.
• Additional, C3b fragments join the complex to
make C3bBbP3b, also known as C5 convertase.
C5 convertase cleaves C5 into C5a and C5b.

• C5b inserts into the cell membrane and is the

necessary step leading to formation of the
membrane attack complex (MAC) and cell lysis.
 Cont.
• The membrane-bound C5b–6–7 complex acts
as a receptor for C8 and C9. C8, on binding to
the complex, stabilizes the attachment of the
complex to the foreign cell membrane.
• The C5b–8 complex acts as a catalyst for C9,
which is a single chain glycoprotein with a
tendency to polymerize spontaneously
 Cont.
• The C5b-8 complex on binding to C9 molecules
undergoes polymerization, which finally ends in
the formation of C5b-9 complex also known as
MAC.
• The MAC forms a trans-membrane channel of
100 Å diameter in the cell. This trans-membrane
channel allows the free exchange of ions between
the cell and the surrounding medium.
 Cont.
• This influx of water, swelling of the cell, and,
for certain cell types, rupture of the cell
membrane and finally lysis.
 Biological Effects of Complement
• Chemotaxis

• Opsonization

• Hypersensitivity reaction

• Cytolysis

• Enhancement of Antibody Production

 Chemotaxis
• C5a is a chemotactic molecule specifically
recognized by polymorphonuclear leukocytes or
phagocytic cells.

• This substance causes leukocytes to migrate to a

tissue in which an antigen-antibody reaction is
taking place. At that site, a phagocytic cell
recognizes opsonized particles and ingests them
 Cont.
• C5a not only has a chemotactic effect on
neutrophils, but also activates these cells
causing their reversible aggregation and
release of stored enzymes, including
proteases.
• •
C5a also enhances the adhesiveness of
neutrophils to the endothelium
 Opsonizaton
• Complement plays an important role in
opsonization of pathogenic bacteria and viruses.
these pathogrns are easily phagocytosed in the
presence of complement component C3b.

• This is because the receptors for the C3b

component are present on the surface of many
phagocytes.
 Hypersensitivity Reaction
• Complement participates in type II (cytotoxic) and
type III (immune-complex) hypersensitivity
reactions.
• The C3a, C4a, and C5a components stimulate
degranulation of mast cells with release of
mediators, such as histamine.
• The C3a fragments bind to receptors on basophils
and mast cells and induce the release of stored
vasoactive amines (e.g., histamine) and heparin.
 Cytolysis
• Complement mediates cytolysis. Insertion of
C5b–9 complex (MAC) into the cell membrane
leads to killing or lysis of erythrocytes,
bacteria, and tumor cells.
• The insertion of the MAC complex results in
disruption of the membrane, there by leading
to entry of water and electrolytes into the cell.
 Enhancement of antibody production
• The binding of C3b to the surface receptors on the
activated B cells markedly enhances the
production of antibodies in comparison to that of B
cells activated by antigen alone.
• Hence, deficiency of C3b leads to reduced
production of antibodies. Therefore, low
concentration of both C3b and antibodies affects
host defense, resulting in severe pyogenic
infections.
 Deficiency of complement
Deficiency of various components may result in
many diseases as follows:
• Inherited deficiency of C1 esterase inhibitors
causes angioedema. The low level of C1 esterase
inhibitors leads to overproduction of esterase.
This leads to an increase in release of
anaphylatoxins, which cause capillary
permeability and edema.
 Cont.
• Acquired deficiency of DAF results in an increase
in complement- mediated hemolysis. The
condition manifests clinically as paroxysmal
nocturnal hemoglobinuria.
• Inherited or acquired deficiency of C5–8
components greatly enhances susceptibility to
Neisseria bacteremia and other infections.
Deficiency of C3 leads to severe recurrent
pyogenic sinusitis and respiratory infections
 Cont.
• The synthesis of sufficient quantities of
complement is reduced in the patients with
severe liver disease, such as chronic hepatitis
or alcoholic cirrhosis.

• These patients are highly susceptible to

infections caused by pyogenic bacteria.