Complement 2

Dr. Dalia Wehedi

– The alternative pathway was first described by Pillemer in 1954.

1. The C3b binds with factor B to form C3bB complex. The interaction between C3b and factor B
is stabilized by Mg2, which is the only ion required for functional activation of the alternative
pathway.
2. The C3bB is split into two fragments, Ba and Bb, by another serum protein called factor D or
C3 proactive convertase. The Ba is released into the medium and the Bb binds to C3b forming
the C3bBb complex, which possesses the C3 convertase activity.
3. The C3bBb complex activates more C3, leading to the formation of more C3bBb, which in
turn is capable of activating C5 and the MAC. The C3bBb complex has a half-life of only 5
minutes, but by binding with properdin it forms PC3bBb complex, which is relatively heat
stable.
4. The alternative pathway then proceeds from C3 to produce finally the MAC, in the same way
as occurs in the classical pathway.
Lectin pathway of complement
activation
– The lectin pathway, as the name suggests, is triggered by lectins. Lectins are the proteins
that recognize and bind to specific carbohydrate targets.
– The mannose-binding lectin (MBL) is one such protein that takes part in the lectin
pathway of
complement activation. MBL is a large serum protein that binds to nonreduced mannose,
fructose, and glucosamine on bacterial.
– The binding of MBL to a pathogen results in the secretion of two MBL-associated serine
proteases: MASP-1 and MASP-2. MASP-1 and MASP-2 are similar to C1r and C1s,
respectively, and MBL is similar to C1q. Formation of the MBL/MASP-1/ MASP-2
trimolecular complex results in activation of MASPs and subsequent cleavage of C4 into
C4a and C4b. Subsequently, it proceeds to produce MAC in the same way as that occurs
in the classical and alternative pathways.
Regulation of complement system

1. Level of antibody
2. C1 inhibitors
3. Other inhibitory substances.
4. Decay-accelerating factor (DAF)
5. Regulation of alternative pathway.
The biological effect of a
complement
1. 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.
– 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.
The biological effect of a
complement
2. Opsonization:
Complement plays an important role in opsonization of pathogenic bacteria and viruses.
Bacteria and viruses are easily phagocytosed by phagocytic cells in the presence of
complement component C3b.
This is because the receptors for the C3b component are present on the surface of many
phagocytes.
The biological effect of a
complement
3. 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.
The release of histamine into the tissues results in increased capillary permeability and smooth muscle
contraction. Fluid is released into the tissue, thereby causing edema and swelling.
There is some evidence that C3a and C5a may also act directly on endothelial cells, causing increased
vascular permeability.
The end result is very similar to the classical anaphylactic reaction that takes place when IgE antibodies
bound to the membranes of mast cells and basophils react with the corresponding antigens. For this
reason, C3a and C5a are called as anaphylatoxins.
The biological effect of a
complement
4. 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.
5. 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

Complement plays an important role in the well-being of humans. Deficiency of various components may result
in many
diseases as follows:
1. 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.
2. Acquired deficiency of DAF results in an increase in complement-mediated hemolysis. The condition
manifests clinically as paroxysmal nocturnal hemoglobinuria.
3. 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.
4. 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, therefore, are highly susceptible to infections caused
by pyogenic bacteria.
Biosynthesis of complement

– Various components of the complement are synthesized at various sites of the body. For
example, C1 is synthesized in the intestinal epithelium, both C2 and C4 in the
macrophages, C5 and C8 in the spleen, and C3, C6, and C9 in the liver.
– There is an increase in the level of C3, C4, C5, and C6 in the acute phase of
inflammation. Complement along with some other plasma proteins known as acute phase
reactants show a rise in acute inflammation.