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Adult
bone marrow
Bone marrow is not a jumbled up mass of cells, it has a structure
and system if its own. If you cut a collar bone in half lengthways
you would notice distinct changes in color throughout the tissue.
Some areas would be very red and these areas would be the site
of erythrocyte production as well as white blood cell production.
Other patches would be yellow in color as a result of adipose
fat cell accumulation. The yellow areas are relatively inactive
in healthy people but when an individuals blood system is stressed
in some way these yellow patches convert into blood cell forming
tissue, so yellow regions are our emergency reserve.
Different bones have different accumulations of red and yellow
tissue at different times in our lives. Embryos will have almost
all red marrow as they concentrate on producing as many blood
cells as they can for their rapidly growing bodies. Yellow adipose
tissue develops later and for healthy adults red marrow is eventually
restricted to a presence in just the breast bone, spinal vertebrae,
ribs, collar bones, pelvis and skull.
Even within the red marrow there is a loose structure but it
can normally only be observed through fixing and staining the
tissue to reveal accumulations of different cell types in different
areas. Bone marrow cells need a scaffolding to help them organize
and be systematic in the production and release of cells into
the blood stream. This scaffold is provided through three main
structures, the blood capillary network, venous sinuses and a
reticular fiber framework.
In many bones the capillary network stems from a single artery
which enters the bone close to its center. Inside the bone it
subdivides and continues to subdivide along the length of the
bone. Small capillary branches radiate off the larger blood vessels
to reach the extremities of the bone marrow. These capillaries
connect up with a second system of vessels called venous sinuses
(sinus is Latin for cavity). In effect the connection between
venous sinuses and blood capillaries is continuous. Blood from
these sinuses is collected by venules and veins which merge together
to leave the bone via a single vein. So the blood system of a
bone is closed, one entry and one exit.
We make the distinction of a venous sinus network from the standard
blood capillary network because venous sinuses have some special
properties that blood capillaries/arteries/veins don't. Venous
sinuses are the vessels into which blood cells are released after
being produced from the marrow cells. These sinuses are barrel
shaped and expand and contract to accommodate the variable production
and release rate of blood cells (you make more blood cells when
you are sleeping than when you are awake). The sinuses either
have perforated walls or don't have walls at all, they may just
be passageways between marrow cells. Blood cells that are ready
to leave the bone migrate to these sinuses and release themselves
into the passageways. If there is a vessel wall present, the new
blood cells find a perforation and squeeze themselves through
the opening. Usually the hole is too small for easy passage of
cells so blood cells have to force their way through. The small
hole size ensures blood cells already in the vessel don't readily
get back into the bone marrow.
Finally we have a reticular cell and fiber meshwork which forms
the underlying scaffold for supporting the bone marrow cells and
helping keep the blood capillaries in position. This "reticular
framework" basically stops the marrow cells from sloshing
around and getting damaged when we move.
Different bone marrow cell types will roughly organize themselves
into collectives. Undifferentiated stem cells are found away from
the capillary and sinus network. The daughter cells that come
from the stem cells move towards the sinuses. As they do they
mature and differentiate so the most mature blood cells are found
congregated around the capillary/sinus network. Lymphocytes seem
to favor associating close to radial arteries whereas erythrocytes
head for the venous sinuses. Megakaryocytes are also found congregating
close to the venous sinus so they can break down and release their
platelets we described in chapter 3.
General changes in the color of the red marrow can sometimes
be observed. If an individual is under challenge from a chronic
infection the red marrow changes to pale pink. The marrow switches
from producing red blood cells to concentrating on making white
blood cells. This may result in anemia as a side effect of combating
infection.
Adult
thymus
The thymus, would you believe, in evolutionary terms is the ultimate
derivation of fish gills. To compare a fish embryo to a human one
in early stages of development we see a very close similarity in
the development. Both look as though they are developing gill clefts.
The development comes from four pouches of tissue in the pharyngeal
area just below the mouth. In fish these tissue pouches develop
into gills but for mammals the pouches eventually become the inner
ear, tonsils, parathyroid and the thymus.
Development of the human embryonic thymus begins at around 60
days after fertilization and gradually increases in size and complexity.
This differentiation will only continue for a certain period of
time and then stop if it does not receive a stimulus to continue
growth. This stimulus must come from the arrival of the first lymphocyte
precursors. Immature lymphocytes begin to congregate at and in the
thymus of human embryos at about 90-100 days after fertilization.
Most of these immature lymphocytes have come from the yolk sac and
fetal liver rather than the bone marrow which is still undergoing
extensive development at this stage.
Lymphocytes arrive via the blood stream at the thymic rudiment
and with the first advance wave of immature lymphocytes there is
an invasion of thymic tissue by an extensive blood vessel system.
This permits penetration of the lymphocytes into the thymus. These
precursor lymphocytes interact with the epithelial cells. The epithelial
cells are stimulated to continue their development of the thymus
structure and they also begin to produce thymic hormones at this
stage. The lymphocytes are in turn promoted to differentiate and
mature.
In the early embryonic stages of development the thymus is just
a mush of cells in a bag. Eventually, with successive waves of immature
lymphocytes arriving and continued stimulus from them for the thymus
to differentiate it becomes a highly ordered structure. By birth
the thymus is a bilobed pouch in humans with the lobes only just
connected to each other. The pouches are in effect separate thymuses
but closely associated with each other. In birds the lobes entirely
separate into long nodular sacs one on each side of the jugular
veins. For humans and most mammals the thymus nestles at the top
of the heart at the vertical midline of the body in the thoracic
cavity (where your lungs are). The lower parts of the lobes rest
over the front of the heart and the top of the thymus sort of wraps
around the wind pipe.
Each of the two lobes are enclosed in a capsule. Within each thymic
lobe is a structured organization of lymphocytes and reticular cells.
The lobe is divided up in a rough honeycomb appearance by membranes
called "trabeculae" or sometimes "septa" which
extend from the outer capsule into the thymic lobe. Each division
of the tissue by the septa is a "lobule". Each lobule,
when histologically stained can be seen to have an outer layer of
darkly staining cells called the "cortex" consisting of
cells which turn out to be lymphocyte cells mixed in with many blood
vessels, and an inner core called the "medulla" consisting
of some lymphocytes but predominantly epithelial cells (epithelial
cells and reticular cells are essentially one and the same thing).
Immature lymphocytes arrive in the thymus through a single artery.
Similar to the bone marrow the thymus has a closed circulatory blood
system, one entry and exit point. The blood vessels have several
physical layers surrounding them called the "blood-thymus barrier".
This barrier consists of membranes, connective tissue and cells
which play an important part in restricting which cells are allowed
to cross into the medulla of thymic lobules and which cells are
flushed straight through the thymus. The blood thymus barrier is
known to be much weaker where the vessels pass through the medulla
of thymic lobules and cells crossing to and from the vessels can
be observed in this region. Cells do not apparently cross from or
to blood vessels in any other area of the thymus. Just how the blood-thymus
barrier selects which cells to allow passage and which to keep in
the vessels is not known. Clearly though only immature lymphocytes
are allowed to pass from the vessels into the medulla tissue and
only mature lymphocytes are allowed to pass back into the blood
vessels.
Once the immature lymphocytes have passed the blood-thymus barrier
they are called "thymocytes". Over 90% of all thymocytes
are found densely packed into the cortex regions of lobules with
just 10% of thymocytes found in the medulla regions. These cells
are at different stages of maturation. cortex thymocytes are the
most immature and medulla thymocytes are close to complete maturation
and preparing for release back into the blood stream. The thymus
is something of a black hole for thymocytes. Of all the immature
lymphocytes that enter the thymus only 10% leave as fully differentiated
cells. The rest die at some stage during the maturation process
in the cortex or medulla of thymic lobules. Clearly vast numbers
of immature Thymus dependant cells (T cells) must be produced by
the bone marrow to ensure that enough cells leave the thymus to
maintain the adult immune system.
From birth until puberty the thymus increases in size but after
puberty it gradually declines in size losing up to 50% of its weight
by the time we reach our 70s. This loss of weight is called "involution".
Inevitably the loss of weight also indicates a similar reduction
in activity. The lobules simply get smaller and contain fewer thymocyte
cells. Contrary to popular belief the thymus does not disappear
or become inactive. The thymus remains our only source of mature
T cells and there is no other proven mechanism of producing this
cell type. The thymus does however considerably slow down its release
rate of mature T cells as it involutes. This comes back to comments
in chapter 2 where we indicated the immune system was not designed
to last 70 years or more. It was only meant to keep us alive until
reproductive age. The increasing disruption to T cell production
has been suggested as one factor in death from old age.
I guess after all that you want to know about thymus function.
The problem is that while we understand the thymus is involved in
T cell education and maturation we don't really understand the mechanisms
in detail. There are a lot of gaps in the hypothesis. However, in
essence the thymus takes naive lymphocytes from the bone marrow
and trains them to react and defend only against non-self antigens.
The bone marrow produces lymphocytes that collectively can attack
a very wide range of antigens including antigens on our own cells.
The Bone marrow makes no distinction between those lymphocytes that
will benefit us and those that could harm us. Immature lymphocytes
are unable to respond to any antigenic challenge so their migration
from the bone marrow to the thymus is uneventful and of no consequence,
good or bad, to us.
This rabble of cells is then educated by cells of the thymus.
Right now there is an argument over which cells in the thymus are
the instructors and educators. Some say it is the epithelial (reticular)
cells. Others say the education comes from a population of dendritic
cells found in the thymus that are possibly a subgroup of phagocyte
cells produced in the bone marrow. I would say probably both cell
types can be thymocyte educators. There is much duplicity in the
immune system to ensure continued protection even if areas of the
immune system are inactivated and there is no reason to think the
thymic education is any different.
The educating cells present our antigens to the immature thymocytes.
Those that are able to respond to the presented antigens die. Those
that don't respond are assumed to be protective and beneficial for
us and will mature to leave the thymus. All thymocytes are primed
to die, they have to be told to live by the educating cells. Not
what you would expect right? Normally we would believe the process
would be reversed and that thymocytes live until they are instructed
to die by the educating cells. The inbuilt self destruct mechanism
is supposedly a failsafe. If a potentially damaging thymocyte escapes
education it should die and never leave the thymus.
There are some problems however. The cells in the thymus do not
have all our antigens available to use in educating thymocytes.
Some antigens from specialized organs such as the brain and, yes,
hair follicles are not present in the thymus. There are also other
flaws in thymic education but I want to discuss all this in detail
when we get to looking at T cell education and autoimmune disease
development. In summary then, the thymus is the educator of T cells
into a viable defense force and removes recalcitrant and dangerous
self reactive immature T lymphocyte precursors.
Secondary
organs of the immune system
The secondary organs could be seen in part as storage organs,
the immune systems barracks where immune cells rest and prepare
for future defense of the body. These organs permit swift communication
between a large number of immune cells allowing presentation of
antigens and mobilization of a large immune response. The secondary
organs include numerous lymph nodes, the spleen, tonsils, adenoids
and Peyers patches. Some of these items are readily identifiable
organs, highly organized and encapsulated. Such examples include
the spleen and lymph nodes. Other lymphoid "organs" are
not organs at all they are merely accumulations of immune cells
in other tissue. Such accumulations include mostly mucosa-associated
lymphoid tissue (MALT) such as Peyers patches found in gut tissue.
Non-encapsulated lymphoid tissue is less organized and might be
described as a more primitive part of the defense system closer
to the accumulations of defense cells seen in primitive vertebrates
and higher invertebrates.
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