Inflammatory Immune Response
Inflammation is the local response of a tissue to damage or infection.
The aim of the inflammatory response is to recruit cells and other factors from the
bloodstream into tissue to aid in the removal of pathogens and dead cells or tissue.
Four main events occur during an inflammation response to promote these aims.
1. Vasodilatation causes increased blood flow to the area, increasing the supply of
cells and factors.
2. Activation of endothelial cell lining the blood vessels makes them more sticky to
white blood cells so that blood cells can adhere more strongly to endothelium.
3. Increased vascular permeability make it easier for cells and proteins to pass through
the blood vessels walls and enter the tissue.
4. Chemotactic factors are produced; these are molecules that attract cells into the
tissue from the bloodstream.
A. The first stage in the inflammatory response following infection is recognition of
the pathogen by macrophages which have receptors to recognize the antigen, this will
be followed by activation of these tissue macrophages. The activated macrophages
will result in activation of many cells and protein pathway and recruitment of
phagocytes to site of inflammation. These phagocytes can remove pathogens and
damage tissue (figure 1a & 1B).
B. If the inflammatory responses is severe it will affect brain and trigger the liver to
produce a number of proteins known as acute phase proteins. Some of acute phase
proteins can act as opsonins which help phagocytic cell to kill the antigens.
C. Natural killer cells and interferons are other important components of the innate
immune system and contribute to the inflammatory response to protect against virus.
Activation of macrophages.
The activated macrophages produce a number of factors including prostaglandins,
platelet- activating factor (PAF) and cytokines.
Prostaglandins are a group of small biologically active lipid molecules derived from
arachidonic acid and involve in controlling of inflammation. Both of PAF and
Prostaglandins act directly on the endothelium to increase vascular permeability.
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Three of cytokines produced by the macrophages, interlukin-1 (IL-1), interlukin-8
(IL-8) and tumor necrosis factor-α (TNF-α), are important in the inflammatory
response. These factors have a number of effects.
TNF-α, PAF and the prostaglandins act directly on the endothelium to increase
vascular permeability. PAF also causes platelets to release histamine which is another
potent agent at increasing vascular permeability.
IL-1 and TNF-α activate endothelial cells lining the blood vessels at site of infection
to express a number of adhesion molecules on their cell surface such as E-Selectin
and P-selectin. These adhesion molecules will facilitate the binding of circulating
neutrophils to endothelial blood vessels, enabling the neutrophils to leave the
bloodstream and enter the tissue (figure 2). Neutrophils and macrophages ingest and
kill bacteria and other microorganisms. The recruitment of neutrophils is also
promoted by IL-8, which is chemotactic for neutrophils.
Activation of other pathways during inflammatory responses.
A number of other cell types and biochemical pathways can also be activated during
an inflammatory response. They can all cause the increase in blood flow, increase in
vascular permeability and chemotactic activity that result in the accumulation of
granulocytes and monocytes at the site of inflammation . The activated macrophages
and granulocytes can then begin to remove the pathogenic organisms by the process
of phagocytosis.
A. Mast cells.
Mast cells are distributed throughout the body. They contain many large granules and
have similar properties to basophils, which are a type of white blood cell. There are
two types of mast cells, mucosal mast cells and connective tissue mast cells, which,
although sharing most properties do have some differences.
When they are activated mast cells release the contents of their granules in a process
known as mast cell degranulation. The contents of the granules include histamine,
heparin and proteolytic enzymes. These factors result in vasodilation and increased
vascular permeability. Activated mast cells also start to synthesize new products,
especially prostaglandins and leukotreines which are products of arachidonic acid
pathway. These new products also cause vasodialation, increased vascular
permeability and attract neutrophils to the site (figure 3).
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B. Clotting system.
Activation of the clotting system leads to the cleavage of fibrinogen to generate fibrin
threads which form blood clots and fibrinopeptides which are chemotactic for
phagocytes. Formation of a blood clot is important if there has been damage to blood
vessels because the clot can limit the entry of pathogens into bloodstream and
therefore the spread of pathogenic organisms.
C. Complement system.
The complement system is made up of a number of different plasma proteins that play
many roles in resistance to infection. During inflammatory responses, a complement
component C5a is produced, which cause increased vascular permeability. Other
complement components, C3a and C5a, can cause mast cell degranulation thereby
amplifying the inflammatory process.
D. Kinin system.
Kinins are small polypeptides of 9-11 amino acids. They are cleaved from larger
plasma proteins called kininogens by specific esterase. The most important kinin in
inflammation is bradykinin which causes pain and vasodilation and increases vascular
permeability.
Acute phase response.
If the pathogen is not eliminated by continued recruitment and stimulation of
macrophages will result in a rise in the concentration of macrophage-derived
cytokines in the plasma. These cytokines can affect other organs, particularly the
brain and the liver, leading to a systemic response known as acute phase response.
A. Cytokines and the brain.
IL-1 affects the brain causing fever, anorexia. Fever is known to have a protective
effect in infection and the replication of some pathogens is inhibited at a higher
temperatures (figure 4).
B. cytokines and the liver (figure 5).
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IL-6 has a potent effect on hepatocytes, stimulating them to produce a series of
proteins called acute phase proteins. Acute phase proteins are found in the serum at
basal in healthy normal individuals but rise in concentration following stimulation of
the liver.
Fibrinogen. Is involved in clotting and generation of fibrinopeptides.
Haptoglobulin. This protein binds to iron containing haemoglobin and reduces the
concentration of iron that many bacteria require for their metabolism, thereby
reducing bacterial growth.
Complement component C3. this can cleaved to generate C3a, which activate mast
cells and C3b which helps phagocytes recognize pathogens.
Mannose binding protein (MBP). MBP is able to bind to mannose containing sugars
on the surface of pathogens and also helps phagocytes recognize pathogens.
C-reactive protein (CRP). CRP binds to phosphoryl choline which is found on the
surface of a variety of bacteria, fungi and parasites and is exposed in damaged cells.
The increased serum concentration of the acute phase proteins results in their
increased accumulation; this is also aided by the increases in blood flow and vascular
permeability caused by mediators of inflammatory response. The acute phase proteins
provide additional factors that help in the elimination of infectious agents, as CRP,
C3b and MBP acts as opsonins to help phagocytes to recognize pathogens.
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Figure 1a.
Figure 1B. Phagocytosis
Figure 2. effect of cytokines on adhesion molecules.
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Figure 3. mediator of mast cell activation.
Figure 4. effect of cytokines on brain.
Figure 5. acute phase Response
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