Download IMMUNE DEFENCE - ASAB-NUST

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There are many molecules of the innate immune system which are
important in mediating protection against microbes during the period
before the development of adaptive immunity.
Although these molecules react with particular structures associated with
microbes, they are nonspecific in that they can react with many different
microbes that express these structures.
The major molecules are those of the complement system, acute phase
proteins and cytokines, especially the interferons.
The complement system can be activated by antibodies, and cytokines
are involved in activation of antigen presenting cells critical to triggering
T lymphocyte response.
Cytokines released by macrophages also play a role n acute
inflammation
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The complement system is a protective system common to all
vertebrates.
In man it consists of set of over 20 soluble glycoproteins, many of which
are produced by hepatocytes and monocytes.
They are constitutively present in blood and other body fluids and may
be present in quite large amounts.
For example C3, the pivotal molecule of the complement system, is
present at about 1g in serum. On appropriate triggering, these
components interact sequentially with each other like.
This “cascade” of molecular events involves cleavage of some
complement components into active fragments which contribute to
activation of the next component, ultimately leading to lysis of, and / or
protection against, a variety of microbes.
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Complement can be “activated” directly by certain molecules associated with
microbes (alternative pathway), or by antibodies bound to a microbe or any
other antigen (classical pathway), C3 present at high concentration in the
serum, is critical to both of these pathways and its cleavage into C3a and C3b is
the single most important event in the activation of the complement system.
Alternative pathway
(microbe alone)
Classical pathway
(antibodies-mediated)
C3
Activation leads to
Inflammation
Lysis
Enhanced Phagocytes
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This may be achieved by two different cleavage enzymes, C3 convertases – one as
a component of the alternative pathway, the other a part of the classical pathway.
In the absence of antibody mediate immunity, the alternative pathway is activated
by interaction of C3 with certain types of molecules on microbes or by self
molecules which react with the microbes.
More specifically the alternative pathway depends on the normal continuous low
level breakdown of C3. One of the fragments, C3b , is very reactive and can
covalently bind to virtually any molecules or cell. If C3b binds to a self cell,
regulatory molecules associated with this cell inactive it, protecting the cell form
complement mediated damage. However, if C3b binds to a microbe, factor B is
usually activated and its cleavage product Bb binds to C3b on the microbe. This
C3Bb complex is enzymatically active and amplifies the breakdown of additional
C3 to C3b.
The major functions of the complement system are:
a. Initiation of inflammation by direct activation of
mast cells.
b. Attraction of neutrophils to the site of microbial
attack.
c. Enhancement of the attachment of the microbe to
the phagocyte.
d. Killing of the microbe activating the membrane
attack complex.
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The complement system is a powerful mediator of inflammation and
destructions and could cause extensive damage to host cells if
uncontrolled. However, complement components rapidly lose binding
capacity after activation, limiting their membrane-damaging ability to the
immediate vicinity of the activation site. This system is also tightly
regulated by inhibitory / regulatory proteins.
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It is important to note that, since the activated complement components
are unstable, activation of complement components are depressed
complement levels in an individual may indicate that complement is being
used up faster than it is being produced, suggesting chronic activation of
complement perhaps resulting from continuous in vivo formation of
antigen-antibody complexes.
Acute phase proteins are important in innate defense against microbes
and in limiting tissue damage caused by microbial infection, trauma,
malignancy and other diseases e.g. rheumatoid arthritis.
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They are also important in tissue repair.
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These molecules include C-reactive proteins, complement components,
opsonic proteins such as a mannose binding protein, metal binding
protein and protease inhibitors.
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The major acute phase proteins and serum amyloid protein A have
similar structures and are termed pentraxins, based on the pentagonal
association of their subunits.
2. CRP, which was named based on its ability to react with the C-protein of
pneumococcus, is composed of five identical polypeptides associated by
glycolipids expressed by microbes in a form different from that on
mammalian cells. Its binding properties permit it to interact with a variety
of pathogens.
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These proteins, mainly produced by the liver, or are present at low levels
and rapidly increase following infection.
They are produced by hepatocytes in the liver in response to the
cytokines
IL-1,
IL-6,
TNFa and
IFNy released by activated macrophages and NK cells.
IL-6 appears to be the major cytokine of importance in enhancing
production of acute phase proteins.
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Proteins
Functions
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C-reactive protein (CRP)
Binds to bacterial phosphoryl choline, activates
complement, acts as an opsonin.
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Serum amyloid A(SAA)
Activates complement, acts as an opsonin.
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Mannose binding protein (MBP)
Binds to mannose on bacterial surface, attaches to
phagocyte MBP receptors, activates complement via
classical pathway.
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Complement components e.g.
C2, C3, C4, C5 & C9
Chemotaxis, opsonization and lysis.
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Metal binding proteins
Removal of essential metal ions required for bacterial
growth.
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Fibrinogen
Coagulation factor.
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Interferons are important molecules which can mediate protection against
virus infection, and are thus particularly important in limiting infection
during the period when specific humoral and cellular immunity is
developing.
However, they do not simply function by interfering with virus replication
but also act as communication molecules between cells.
Type I interferons, a and b, are cytokines produced by many different cells
in response to a virus and protect adjacent cells form viral infection.
Type II IFN, IFNy, is produced by specialist cell of the immune system
and is important not only for antiviral cytokines.
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Their synthesis is induced by viral or bacterial infections and in particular
by intracellular microbes.
At least 12 different, highly homologous species of IFNα are produced,
primarily by infected leukocytes as well as by epithelial cells and
fibroblasts.
In contrast, a single species of IFN β is produced, normally by fibroblasts
and epithelial cells.
The proinflammatory cytokines IL-1 and TNF α are potent inducers of
IFN-α/ β secretion, as are endotoxins derived form the cell wall of gram
negative bacteria.
These IFNs play an important role in innate defense against viral
infections.
Both IFNα and IFNβ inhibit protein synthesis in virally infected cells
preventing mRNA translation and DNA replication.
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IFNr is a multi-functional cytokines produced by Th 1 cells and NK cells.
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It enhances the phagocytic function of these cells.
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IFN-α/ β
IFN gamma
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Chromosomal
location
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12
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Origin
All nucleated cells, especially fibroblasts,
macrophages and dendritic cells
NK cell s and Th 1 ,
and CD8 T cells
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Induced by
Intracellular bacteria and protozoans
Antigen stimulated T
cells
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Functions
Antiviral, increases MHC class I
expression, inhibits cell proliferation
Antiviral, increases
MHC I & II
expression, activates
macrophages
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Collectins are a group of carbohydrate binding proteins.
These molecules act as opsonins and are probably important in the innate
immune response to infections.
They include mannose binding protein, an acute phase protein, and
conglutinin.
A family of small peptides, peptide antibiotics, have potent antibacterial
activities. These molecules include cecropins, magainins and defensins
and are part of the body’s innate defense mechanisms against microbial
infection. In general, they are basic peptides with molecular weights of 35 kDa and are effective against both gram positive and gram negative
bacteria.
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