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Part 1 - The Thymus Gland
In presenting my article on tin, the possibility that tin is involved in
thymus gland function was mentioned. Deficiencies of tin, zinc, magnesium
and other minerals due to malabsorption from celiac disease could adversely
affect the thymus gland. I wanted to include a citation of a good website
article on the thymus gland. There are literally thousands of papers
listed on PubMed presenting various aspects of the thymus gland and thymic
function. Yet I can find not one single comprehensive article on the
internet providing a clear and thorough overview of the thymus gland and
its function. Perhaps this is due to historical misconceptions of thymic
function in adults. Those views are changing as new and recent studies
advance the understanding of the thymus. Scientists are now actively
pursuing ways to take advantage of thymic function to treat illness,
autoimmune disease, prevent transplant rejection, and maintain our health
and immune system as we age.
The thymus gland is a pinkish-gray organ located behind the breastbone in
humans. It is relatively large in infants and reaches a maximum size by
puberty when it begins to shrink through a process called "involution",
becoming much reduced in size as we age. For centuries the thymus was an
enigma to medical science, its function unknown. Not until 1961 did
scientists begin to understand the crucial role the thymus has in the
establishment and development of a normal immune system. Once thought
vestigal after puberty, only quite recently have scientists recognized that
the thymus is still very much active beyond puberty and continues to play
an important immunological role in adults. It is alarming that "large
thymuses appearing on children's x-rays were intentionally reduced by high-
dose radiation and many cardiac surgeons still routinely excise the thymus
during open heart surgery." [Ref 1]
Understanding the thymus requires an understanding of lymphocytes. The
precursors of lymphocytes (white blood cells) are stem cells produced in
the bone marrow. Some lymphocytes mature in the bone marrow before
entering the blood circulation and are called "B cells" (B, as in Bone).
Some stem cells migrate from the bone marrow to the thymus where they
proliferate and mature into "T cells" (T, as in Thymus). T cells are key
to immunity and tolerance. When a naive T cell encounters and recognizes a
foreign body or antigen, it becomes activated and begins to divide and
differentiate, proliferating into some 1000 clones consisting of
various "helper", "regulatory" and "cytotoxic" T cells. Helper T cells
travel to inflammation sites where they encounter and bind to B cells
causing B cells to divide and differentiate into plasma cells which, in
turn, produce and secrete antibodies. Cytotoxic T cells bind to and
destroy cells which express foreign antigens. Regulatory T cells have a
role in tolerance.
There are actually 2 groups of T cells distinguished by receptors on their
surface encoded by 2 different sets of gene segments, alpha/beta and
gamma/delta. Both develop in the thymus. The majority of T cells are
alpha/beta. Little is understood about gamma/delta T cells except that
they migrate from the thymus to various body tissues, including epithelia
of the intestine where they may play a role preserving the integrity of
damaged epithelial surfaces by delivering an epithelial cell growth
factor. In addition, gamma/delta T cells have regulatory roles influencing
B cell and other T cell activity. From hereon, the discussion only
concerns alpha/beta T cells.
In the thymus, the stem cells give rise to large numbers of immature T
cells or "thymocytes". A critical selection and elimination process occurs
within the thymus. To survive this process, a thymocyte must have
receptors which can recognize certain molecules that identify "self".
These are called major histocompatibility complex (MHC) molecules, or, in
humans, human leukocyte antigen (HLA) molecules. If a thymocyte
successfully interacts with MHC molecules expressed on the surface of
epithelial cells within the cortex of the thymus, it survives. Some 95% of
thymocytes fail this test and die. Some of the surviving thymocytes, in
addition to recognizing self MHC molecules, also have a high affinity for a
complex of a self-peptide which can pose a danger of triggering autoimmune
disease. Many, but not all, of these autoimmune thymocytes are eliminated
in medulla of the thymus through interactions with dendritic cells or
macrophages (central tolerance). Mechanisms elsewhere in the body act
further to eliminate autoimmune T cells (peripheral tolerance). MHC
molecules are either Class I or Class II. Class I molecules are found on
the surface of nearly all cells of the body and identify "self". Class II
molecules are found only on the surface of antigen presenting cells such as
dendritic cells. Thymocytes initially are capable of recognizing both MHC
Class I and II molecules, and are thus referred to as being "double
positive" CD4CD8 T cells. Further education of thymocytes in the thymus
results in mature naive T cells which recognize only MHC Class I (CD8 T
cells) or Class II (CD4 T Cells) molecules.
Surviving thymocytes eventually leave the thymus to become part of a
repertoire of mature T cells entering the blood circulation and lymph
nodes, some migrating to body tissues such as the intestinal epithelia.
Some immature and "double positive" thymocytes also escape from the thymus,
migrating to other tissues where they complete their development
peripherally. Intraepithelial lymphocytes (IEL) are of special interest to
celiac disease research because their numbers appear to increase as the
disease progresses. However, a recent study demonstrated that the apparent
increase in IEL is likely due to a decrease in the number of epithelial
cells. [Ref 2] In celiac disease, IEL may increase in number within
individual epithelia, but overall, the number of IEL in the gut remains the
same. Research has asked the question whether IEL originate within the
thymus or extrathymically. It appears that most IEL originate and develop
in the thymus, the remainder completing their development under thymic
influence extrathymically after migration from the thymus. In animal
studies where the thymus has been removed, some IEL of limited number and
repertoire may develop from bone marrow stem cells. The presence of the
thymus is necessary for normal IEL repertoire and population.
The thymus is responsible for the generation of a repertoire of some 25 to
100 million naive T cells (in adults) which have never encountered an
antigen. However, for each specific antigen, there are at most no more
than several thousand T cells possessing receptors capable of recognizing
it. After a T cell encounters an antigen and proliferates, most of these T
cell clones eventually die off after the immune system clears the antigen.
A few T cells with memory of the specific antigen remain to stand guard.
But T cells have a finite ability to proliferate, and eventually they can
no longer divide and die. Therefore, to maintain the repertoire of naive T
cells and remain healthy as we age, it is necessary for the thymus to
continue to produce T cells. The recent recognition that the thymus
continues to be active in adults has placed new emphasis on thymus
research, and efforts are being made to find ways to rejuvenate the thymus
and return its function to a pre-puberty level. These efforts have
beneficial implications for patients undergoing transplant procedures, for
autoimmune disease, and within the discipline of anti-aging research.
The thymus also produces a number of hormones and peptides. These thymic
hormones are critical to the proliferation and differention of T cells. A
group of thymic peptides, called thymosin, have been getting a great deal
of attention and have been found to enhance and facilitate immune response
and other functions such as wound repair. Another peptide, thymolin has
been found to be very beneficial in maintaining a number of the body's
basic functions including the cardiovascular, endocrine, immune and nervous
systems. One study of thymolin, combined with a study of the pineal gland
peptide, epithalamin, administered to elderly patients, showed significant
decreases in clinical manifestions of numerous diseases and a decrease in
mortality rate. [Ref 3]
The thymus is particularly sensitive to malnutrition. Studies have shown
zinc and magnesium deficiencies adversely affect the thymus. I have
mentioned the possibility that tin may be involved in thymus function as
studies have shown tin is most concentrated in the thymus. Malnutrition
during infancy and childhood could severely impact thymus development and
its ability to produce a complete and normal repertoire of T cells. The
normal thymus produces the majority, if not all, CD25+CD4+ regulatory T
cells crucial to tolerance and the prevention of autoimmune disease. A
malnourished thymus may also be impaired in its ability to destroy
autoimmune thymocytes, further setting the stage for the development of
autoimmune disease. Malabsorption and mineral deficiencies from untreated
celiac disease could impair thymic function resulting in the possible
initiation of the many autoimmune diseases associated with celiac disease.
One study found, "The proportional and absolute numbers of circulating
thymus dependent lymphocytes (T cells) were reduced in untreated patients
with coeliac disease but were normal after treatment with a gluten free
diet." [Ref 4] Another study found, "In active coeliac patients, CD4CD8 T
cell percentages were significantly decreased in both the epithelial layer
and lamina propria. Levels of CD8 expression by CD4CD8 T cells in the
epithelial layer were decreased significantly in patients with active
coeliac disease. CD4CD8 T cell proportions did not return to normal in
treated coeliac patients whose villous architecture had responded to gluten
withdrawal." [Ref 2]
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(Continued in Part 2 of 2)
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