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Introduction
From our look at the evolutionary development of the immune
system we can see that our defense is based on a complex network
of cells and organs. We saw how the immune system was built and
why and we remarked upon the many interlocking layers that have
developed in mammals. It is important to realize that our immune
system was not built from scratch. It has been modified and added
to through evolution. We still have some of the invertebrate defense
mechanisms available to us, they have simply been incorporated
into the larger system.
These layers of evolutionary development allow us to subdivide
the immune system into two main parts; The innate immune system
which can be identified as primarily related to invertebrate defense
systems, and the adaptive immune system that we see develop through
vertebrate evolution. The key difference between the two systems
is that resistance to infection is not improved by repeated infection
in the innate immune system. In contrast, the adaptive immune
system will increase the ferocity of its defense to a pathogen
with repeated infection. We saw the adaptive immune system at
the core of our review of human medical history. It was the adaptive
immune system that was conferring disease resistance against further
infection by smallpox after inoculation by variolation or Edward
Jenner's vaccination.
The
innate immune system
The innate immune system is our first line of defense. This obstacle
is what invading pathogens first encounter and must circumnavigate
to have any chance of successful colonization. The adaptive immune
system is only activated if the pathogen successfully penetrates
the innate immune system.
The innate immune system can be further subdivided into passive
and active mechanisms of defense. Passive forms of defense primarily
consist of barrier mechanisms which may be biochemical or physical
in nature. They resist invasion by opportunistic pathogens by restricting
their access and ability to penetrate into our bodies. These barriers
are permanently present. They do not normally increase in concentration
or respond to specific pathogens.
Barrier
mechanisms
The most obvious barrier is our skin. The skin has many different
properties that contribute to our defense. Before we describe them
it is worth remembering that one requirement of a defense system
is to distinguish self from non-self and protect against assimilation.
The skin is our outer limits. It is a containment system to ensure
that I am me and you are you. When you rub up against someone (!)
you don't lose any of your DNA nor do you gain any of theirs. This
applies to protection against invading pathogens regardless of size.
The requirement is to stop contamination of your DNA with the DNA
of a another individual of the same or different species.
I want to make clear the two key roles of a defense system. To
keep an individual's DNA intact and to ensure survival of the individual
so that the DNA can be passed on and ensure the survival of the
species. It's a subtle but important distinction. People remark
that the skin is the largest of our organs. Actually not strictly
true, it is the largest of our mid sized organs. Our skeletal system
is the largest organ. However, the skin, as our exterior is clearly
our very first line of defense against infection.
1) The skin's physical properties include a heavily keratinized
layer of dead cells that is repeatedly replenished by the epidermis.
The build up of tightly packed dead cells and the high concentrations
of keratin reduce increase the hydrophilic (resists water) properties
of the skin. This, the cornified layer, protects through limiting
fluid penetration. It is not perfect, water and other chemicals
will slowly penetrate through but when you take a shower 99.9% of
the water goes down the plug hole and not into you. Considering
many pathogens require water for survival and may be water borne,
this is an important property. Of course this works both ways. We
need water for survival and since our evolutionary development from
aquatic life to life on land we now have a clear need to reduce
our loss of water. The skin is an effective containment vessel.
Hence, we get back to our need to protect our own DNA from contamination
and cross over with other individuals.
2) The sebaceous glands provide an important protective barrier.
The oils produced are also hydrophilic and reduce penetration or
loss of water. Our outer layer is comprised of dead skin cells.
Because it is dead, it does not have the ability of self maintenance
that living structures do. The structure and integrity of the cornified
layer rapidly degrades especially with exposure to the harsh outside
world with nasty chemicals, polluted air and UV light. Sebaceous
gland oils help maintain the cornified layer by keeping it supple
and flexible. You might say that the skin barrier has its own protective
support system. You can see where the idea of the immune system
as a multi-layered structure comes from.
3) Hair also has a protective influence and provides its own loose
barrier which pathogens must navigate before they arrive at the
skin surface. Hair protects some of the more sensitive and exposed
body orifices. It restricts air borne pathogens and particles in
the nasal cavity, ears and around the eyes. Hair may cushion against
cuts and grazes which reduce the integrity of the skin. Hair, in
conjunction with melanin in the skin will also help maintain skin
integrity by reducing exposure to UV light.
4) Before we leave the exterior barrier mechanisms we should quickly
comment on the physical structure and conformation of the body.
The most obvious example is the presence of eyelids which physically
sweep clean the eye surface. Tear draining ducts from the eyes are
also important. The ducts (you can see them in the corner of your
eye) drain to the rear of the nose and allow removal of old and
contaminated fluid from the eye surface. If the ducts are blocked
through incomplete development or sometimes infection then maintenance
of the constant flow of fluid over the eye is disrupted. This can
lead to a build up of opportunist organisms over the eye surface.
The length of the ear canal (eustachian tubes) also has an influence
on the ability of pathogens to penetrate inside. If the ear canals
are too short as may occur in genetic conditions such as ectodermal
dysplasias. It makes for easy penetration by pathogens. People with
ectodermal dysplasia have repeated infections by meningitis for
this simple reason. Internally we have cilia which line the trachea
connecting the mouth to the lungs. Cells lining the trachea have
projections (cilia) which help to catch and then move any foreign
particles away from the delicate lungs.
5) Secretions. So far we have described the physical properties
that resist pathogens. We also have our biochemical defenses to
consider. We mentioned the sebaceous gland secretions maintaining
skin integrity. Oils also contribute to the skins exterior pH value.
At around pH 5.5 the skin is slightly acidic which is not a favorable
environment for a number of air borne pathogens. Sweat secretion
will also contribute to pH as will the presence of skin flora.
Semen contains spermine and the enzyme lysozyme can be found in
most secretions including tears. Lysozyme is able to cut through
chemical bonds of proteoglycans as may be found in the cell walls
of many bacteria such as Staphylococcus. We produce wax in our ears
and mucus for our nose and throat both of which help to bind foreign
particles and stop them from penetrating to more sensitive areas.
Acid in the stomach helps to break down food but also makes the
stomach a less desirable place for colonization by other organisms.
The intestines and vagina do contain many colonies of commensal
organisms. The presence of benign organisms is favorable as they
resist and defend themselves against more dangerous pathogens. In
protecting themselves, these organisms protect us.
Production,
development, and differentiation of immunological cells
All the above are exterior defense mechanisms. Yes, the intestines,
lungs etc. are our exterior as they are open to the air. They are
merely modified "invaginations". These innate defense
mechanisms are very effective but they do not give total protection.
Consequently we need internal defense systems. This requires the
use of individual cells performing specialist functions of the immune
system. All the cells of the immune system come from a single source
in the bone marrow called "hematopoietic stem cells".
These cells are undifferentiated, to look at them you would not
recognize that they were any cell of the immune system. These stem
cells divide and multiply at a rapid rate to produce offspring called
"progenitor cells". These cells will then divide and start
to develop into the different cells of the immune system. These
immature cells are called "differentiating cells". There
are six types of differentiating cells, erythrocytic, granulocytic,
thrombocytic, monocytic, T-lymphocytic and B-lymphocytic. They change
and mature into fully functioning immune cells under the guidance
of cytokine chemical signals which we will look at later. Those
unique stem cells in our bone marrow ultimately produce;
- 1) erythrocytes (red blood cells) from the erythrocytic
line. These cells do not have an immune system function.
- 2) Neutrophils from the granulocytic line
- 3) Basophils from the granulocytic line
- 4) Eosinophils from the granulocytic line
- 5) Thrombocytes (also known as blood platelets) from
the thrombocytic line.
- 6) Monocytes/macrophages from the monocytic line
- 7) T lymphocytes from the T-lymphocytic line
- 8) B lymphocytes from the B-lymphocytic line
We will just briefly comment on the erythrocyte cells here. Red
blood cells do not have a protective function in the immune system.
They operate to carry oxygen and carbon dioxide around the body.
Stem cells in the bone marrow give rise to progenitor cells. These
cells in turn produce offspring called "proerythroblasts".
At this stage synthesis of the iron rich hemoglobin molecules starts.
These cells are about 20micrometers in diameter, which is about
3-4 times the diameter of mature red blood cells. The proerythroblasts
each divide to produce 16 daughter cells. With each division the
cells become smaller and the nucleus condenses. Shortly before maturation
is complete the nucleus is expelled from the cell in humans and
most mammals (note, some mammals such as chickens, camels and many
lower vertebrates have mature red blood cells that keep the nucleus).
Once the cells are fully mature they are released from the bone
marrow into the blood stream. They are now around 6-8micrometers
in diameter and donut shaped. Without a nucleus human erythrocytes
only last around 120 days before they become so damaged that they
are no longer functional. At this time they are phagocytosed by
the liver Kupffer cells.
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