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Cells
of the innate immune system
Inevitably some pathogens penetrate our barrier mechanisms of
protection. In this scenario we require a force to repulse the
threat and protect our integrity and function. This introduces
the second part of our innate defense system where individual
cells are uniquely programmed to defend and protect other tissue
cells. The cells of the innate immune system are our rapid deployment
force. They migrate to wherever they are required to shore up
any breach in the barrier defense system. For vertebrates they
also act as the holding force until the adaptive immune system
cells can muster for the counter attack.
Phagocytes
Phagocytes are our first line of internal defense. As the name
suggests they eat foreign particles or cellular debris from our
own dead cells. We know that phagocytosis as a form of defense has
been around for a long time and can be found in both vertebrates
and invertebrates.
There are several different types of phagocyte. Some are specialized
and limit their activity to a specific organ. Others move around
the body. Those that migrate through our system are monocytes and
macrophages. Actually they are one and the same cell. When a phagocyte
is in a blood vessel it is called a monocyte but when it migrates
through a blood vessel wall and into tissue it is called a macrophage.
Specialized phagocytes include; microglial cells in the brain; alveolar
macrophages in the lungs; liver Kupffer cells; splenic macrophages;
kidney mesangial phagocytes; resident macrophages in lymph nodes;
synovial A cells in the joints; peritoneal macrophages and all of
these cells are sourced from stem cell precursors in the bone marrow.
They can live for several months to several years in the blood stream.
There are so many different names for macrophages because in the
process of their discovery they were originally regarded as distinct
entities. Only later did we realize they were all the same cell
type. They have some minor immune functions including production
of complement factors which we will discuss at a later date. They
make an iron binding protein, transferrin; a fever inducing protein
or "pyrogen"; various cytokines chemical signals including
interferons which can act directly as antiviral agents, several
enzymes and blood clotting factors.
Their key immune function is to clean up cellular debris that
is produced when our own cells die at the end of their useful life
as well as to remove pathogens. For example, liver Kupffer cells
clean up the blood by engulfing dead and damaged red blood cells
and also phagocytose pathogens that have been targeted by antibodies.
Generally, anything that doesn't look healthy the Kupffer cells
will eat. When an infectious agent invades the body the body responds
with three key events. First there is and increased blood supply
to the affected region. The blood vessels receive a chemical message
from cells that have been infected or damaged by the invader. These
then vasodilate - simply get larger to increase blood flow to the
area. Second, The blood capillary walls become more permeable again
in response to the cytokine signals damaged cells give off. The
endothelial cells which make up the blood vessels become more "loose"
they retract to make holes where large molecules can pass through.
This allows antibodies to get in to the tissue. Third, the retracted
endothelial cells produce markers on their cell surface which phagocytes
have receptors for. Phagocytes/monocytes floating along in the blood
stream pass through a section of blood vessel that has gone through
these changes and has these markers on the blood vessel wall. As
soon as the monocytes see these markers they become activated. They
attach to the blood vessel wall and then force their way through
the small holes in between the endothelial cells. They become pseudopodial-like
and squeeze themselves into an elongated shape to push through into
the tissue (Hmm, wasn't there something like that on the X-files?).
Once through the blood vessel wall they migrate the short distance
to the site of infection by "chemotaxis". The damaged
cells are still producing their chemical signals as these chemicals
diffuse out from the source they become more and more diluted. Phagocytes
(now called macrophages because they are in the tissue) are able
to recognize concentration levels of the chemical signals (called
chemotactic molecules) and they will feel their way along the concentration
gradient towards the source. Once the macrophages have arrived they
set to work. Phagocytes are able to recognize a large number of
infectious agents without any help from other parts of the immune
system. This harks back to the properties of phagocytes as the central
defense mechanism in simple invertebrates. Although phagocytes are
now only one part of the vertebrate immune system they have lost
none of their ability to act independently in our defense. As well
as having receptors to bind to various microorganisms they also
bind to surfaces that have been covered (we say "opsonized")
in antibodies or complement. After attachment, the macrophages proceed
to surround the microorganism with pseudopodia to engulf the pathogen.
As with invertebrate phagocytes, the internalized microorganism
is rapidly broken down with enzymes. We will go on to describe these
events in much more detail later. For now I just want to explain
basic functions of different immune cell types.
Granulocytes
Polymorphonuclear granulocytes is the umbrella term given for
cells that are neutrophils, basophils or eosinophils. The name describes
what they look like. Most cells have nice round nuclei in them,
but these cells have irregular shaped nuclei. If you did not look
at them too closely you would think the cells had several small
nuclei in them. They don't, the nuclei are "lobular" they
bulge out in different places but the nodules are all linked together.
However they look (morph) multi (poly) nuclear. The granulocyte
bit comes from the look of the cytoplasm surrounding the nucleus.
These cells contain a lot of granules, they look like a bag of marbles.
The granules contain various chemicals the cells use in defense.
Granulocyte cells are very short lived. They may last up to 3 days
but rarely longer. Because of their limited survival there is rapid
turnover of cell production. Around 80 million granulocytes are
made in the bone marrow each minute. Granulocytes are the dominant
white blood cell in the blood stream accounting for 50-70% of total
numbers.
Neutrophils
Neutrophils are 10-20micrometers in diameter and are the most
common polymorphonuclear granulocyte cell to be found in the blood
constituting 90% of all granulocytes. Neutrophils function in a
similar fashion to phagocytes. They too float around in the blood
stream until they enter a section of vessel that expresses markers
and changes indicating that tissue close by is under attack by some
pathogen. Neutrophils squeeze through the blood capillaries and
in to the tissue. They also migrate along a concentration gradient
of chemotactic chemicals to the site of cell damage send out their
distress signals. Neutrophils engulf microorganisms or damaged tissue
like phagocytes. Activated neutrophils then release the contents
of their granules against the engulfed particles. The granules that
neutrophils produce contain enzymes and bactericidal chemicals.
There are two types of granules that neutrophils produce. Primary
granules are called "azurophilic". azure means blue and
this is the color the granules stain using giemsa dye (giemsa was
a popular dye used by immunology pioneers to stain cells to make
them easier to see using a microscope). The azurophilic granules
contain;
- 1) Hydrolase enzymes such as nuclease, lipase, phospholipase,
alpha-amylase, elastase and collagenase. These enzymes will break
down bacterial cell walls in to amino acids, sugars and nucleotides.
- 2) Lysozyme. This will break down glycosides in bacterial
cell walls.
- 3) Myeloperoxidase. This enzyme binds to hydrogen peroxide
produced by other cells such as phagocytes producing oxygen radicals.
These radicals are very unstable molecules they have an urgent
need to bind to something. They will bind to anything, cell walls
of bacteria or even our own cells, they are very non-specific
in their action but very potent. In binding to a cell wall they
rip apart the molecular structure and consequently punch holes
in the cell wall. This enzyme binds to hydrogen peroxide produced
by other cells such as phagocytes producing oxygen radicals. These
radicals are very unstable molecules they have an urgent need
to bind to something. They will bind to anything, cell walls of
bacteria or even our own cells, they are very non-specific in
their action but very potent. In binding to a cell wall they rip
apart the molecular structure and consequently punch holes in
the cell wall.
- 4) Cationic proteins. Composed of positively charged
amino acids arginine and lysine. These proteins have a mild bactericidal
action. The positive charge help bind the proteins to other molecules
altering their shape and breaking down structural integrity. Neutrophils
also produce secondary granules (which stain pink with giemsa
dye). These granules are 2micrometers in size and are the most
commonly produced granule constituting 70% of a neutrophil's granule
population. They contain more lysozyme and lactoferrin, an iron
containing protein first found in milk. Lactoferrin is an antibacterial.
It binds iron making it unaccessible to bacteria. Bacteria need
a supply of iron for their normal physiology and functioning.
So, the main function of neutrophils is to kill pathogenic organisms
by phagocytosis and cell wall breakdown.
Eosinophils
Of all white blood cells, eosinophils constitute between 2 and
5% in people who do not have allergies. This figure rises considerably
for those of us with some form of atopic reaction be it asthma,
eczema and/or hayfever. Although they are mainly found in the blood
stream they can also be seen in large concentrations under epithelium
with high bacterial concentrations such as the intestines, vagina,
nasal passages and lung passages for those with asthma. Their size
is around 11-15micrometers in diameter. They have a nucleus with
just two lobes and their cytoplasm is filled with granules that
will bind the red dye eosin, hence the name eosinophil. Their granules
contain several products including enzymes like acid phosphatase,
glucuronidase, cathepsins, ribonuclease, histaminase, arylsulphatase
and peroxidase. They also produce "major basic protein"
which is toxic. Eosinophils are able to migrate to an area of inflammation
by chemotaxis in response to chemicals released by T cells, mast
cells and basophils. They have the ability to damp down an immune
response from mast cells (below) by releasing histaminase which
inactivates the mast cell product histamine. Arylsulphatase will
break down the slow reactive substance of anaphylaxis (SRS-A) also
produced by mast cells.
These cells are also able to phagocytose microorganisms but this
is only a secondary function. These cells are primarily employed
to combat antigenic challenges that are too big to be phagocytosed.
This traditionally this includes the threat from parasitic worms
or "helminths". They readily bind to parasites that are
covered in IgE type antibody. Once activated they release all their
granular products against the parasite. So in comparison to macrophages,
rather than phagocytosing the microorganism and than breaking it
down with enzymes in a form of internal digestion, the eosinophil
works by releasing its enzymes to externally digest the parasite.
This method is less specific than internal digestion. The enzymes,
once released from the cells, will act on anything including our
own tissue.
Basophils
Basophils are quite small cells at only 10-12 micrometers in diameter
and only constitute about 0.2-1% of all white blood cells present
in us. Basophil granules contain heparin, histamine, decarboxylase,
histidine, dehydrogenase and diaphorase. Heparin is well known for
its anti blood clotting ability and it also causes muscle contraction.
Histamine you probably have heard of before and has a potent ability
to make blood vessels more permeable. We don't know much about basophils
but they seem to play a minor role in anaphylactic, allergic reactions
and parasitic defense. They have a very high affinity for antibody
type IgE and usually we see basophils coated and bound by IgE in
tissue. This binding of IgE may induce a cascade of events involving
other immune cells responding to the high concentrations of IgE.
Basophils may act as marker beacons in an immune response and particularly
allergies. By increasing blood vessel permeability for cells and
antibodies to get in to tissue, and binding IgE, they may help reinforce
and concentrate an immune response against a parasite.
Mast
cells
Mast cells are vary similar in structure and function to basophils.
They are closely related but we are not sure exactly what the relationship
is. For many years they were thought to be actually one and the
same cell but subtly switch their function depending on the circumstances
the cell finds itself in. However, we can confidently say they are
distinct populations of cells but very closely related. Mast cells,
like basophils, have granules containing heparin and histamine.
Mast cells are found in lymph nodes, spleen, bone marrow around
blood vessels, nerves, glands and found throughout the skin. However
it is extremely rare to find one in the blood. Like basophils they
have a very high affinity for antibody type IgE. The cell surface
receptors for these antibodies are the triggers for release of histamine
and other products and release results in anaphylactic and allergic
reactions.
Thrombocytes
/ blood platelets
Blood platelets or thrombocytes can be found throughout the blood
system. They are very small, about 2-3 micrometers long, are oval
shaped and do not have a nucleus. Without a nucleus they don't last
very long. After around ten days in the blood stream they die. They
are actually pieces of a much larger cell that has been pinched
into small chunks.
Platelets are derived from cells called "megakaryocytes"
in the bone marrow. As the name suggests these cells are huge. Normally
cells multiply by first replicating their chromosomes into two duplicate
sets. These two sets then move to opposite sides of a cell and the
cell then pinches in two to produce two daughter cells. However
a megakaryocyte doesn't do this, rather it goes through a process
called "endoreduplication". In this process the chromosomes
of the cell multiply as normal, but the duplicate sets produced
do not separate two to permit the cell to pinch into two daughter
cells. Instead the chromosomes continue to duplicate but stay in
the same single cell. The resulting cell eventually has 16 times
the number of chromosomes present in normal cells. After reaching
this stage the cell cytoplasm produces numerous granules and then
starts to divide into about 4000 small membrane-enveloped chunks.
The nucleus is phagocytosed by bone marrow macrophages. The cytoplasmic
chunks, or platelets are released from the bone marrow into the
blood stream.
Platelets are involved in several minor processes. Their key role
is in blood clotting after a wound. Any wound attracts a large numbers
of platelets to the scene. The platelets release clotting factors
from their granules to help seal off damaged blood capillaries and
they also release permeability factors and chemoattractants to pull
in leukocytes to destroy any infective organism that might take
advantage of the tissue damage. The platelets themselves get lodged
in between a structure of fibrous material called fibrinogen. Fibrinogen
develops as a scaffold framework at the site of any tissue injury.
The platelets have receptors to bind fibrinogen and something called
"Von Willebrand factor" to literally fill in and plug
up the gaps in the scaffold. Very much a finger in the dyke scenario.
Platelets have a whole range of receptors to help bind to any area
of injury. They can latch on to antibody types IgG and IgE and have
receptors for factor VIII.
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