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By
Kimberly Pryor A more
detailed discussion of estrogen's effects on the thymus and
indole-3-carbinol's ability to halt those effects provides an interesting
glimpse into estrogen's harmful grasp on the body's immune system. The
Enigmatic Gland Researchers
now understand that the thymus regulates the immune system, and they are
beginning to observe the way sex hormones take their toll on this gland, but
for centuries the thymus remained a mystery among physicians. It first
attracted attention in the second century A.D. when the Greek physician Galen
published reports that the thymus, which is located in the upper chest just
above the heart, was the seat of courage. By the 1890s,
many physicians were convinced that the thymus could be blamed for the sudden
deaths of children, especially what today is known as sudden infant death
syndrome. Because the thymus remained large in newborns and experienced a
gradual involution (shrinkage) throughout life, these unenlightened doctors
believed that the thymus could swell to an unhealthy size, crushing the
trachea and asphyxiating the infant. Some physicians even subjected the
infants to x-ray irradiation of the thymus as a way to prevent the gland's
enlargement. As the thymus shrank, so too did the baby's immune systems, and
studies determined that these same babies experienced an increased risk of
developing thyroid cancer and possibly breast cancer later in life.(1) Amazingly, as
recently as 1950, the thymus still remained an enigma. Many physicians
believed that it oversaw an undetermined function of embryonic and fetal
development and that by the time a mother gave birth, the gland had served
its purpose and remained unfunctional in the body. The mystery
of the thymus was finally unveiled in the late 1950s. Researchers identified
the thymus as a lymphoid organ essential to the resistance of infection, a
function supported by one 1960s study examining the effects of the removal of
the thymus (thymectomy) from newborn mice. The thymectomized animals lost
their resistance to skin grafts from other strains of mice, experienced
decreased antibody responses and an increase in some cancers, and started to
waste away, most likely due to an increased susceptibility to infection. Transplants
of thymus from other mice reversed the animal's decline in immunity.
Thymectomy in older mice, on the other hand, had little effect on immunity,
supporting the theory that the thymus protects the immune system early in
life but is less effective in later years.(2) The Thymus
and T Cells To understand
estrogen's ability to cause involution (shrinkage) of the thymus, it's
important to observe the way this essential gland regulates the immune
system. The process begins in the bone marrow and in the fetal liver where
precursors of lymphocytes are born. Lymphocytes are divided into two main
groups: the B cells that form antibodies and T cells which develop in the
thymus (Fig. 1). Primitive T cell precursors migrate from the bone marrow to
the thymus, where the cells undergo a series of stages to become a mature T
cell. In the late
1970s, scientists began to understand precisely how the thymus helps
orchestrate the immune response by providing a home for these primitive
cells, otherwise known as T cell precursors, to reach maturity. Developing T
cells carry T cell receptors (TCRs) similar to the antibodies within B cells.
Both the antibodies on the B cells and the TCRs on the T cells are capable of
recognizing antigens. However, these antibodies and TCRs are not infallible.
Some of them experience what amounts to a case of mistaken identity,
interpreting themselves as an antigen. To prevent these confused cells from
entering the bloodstream and to ensure that the immune system does not self
destruct, immature B cells undergo a filtering process. Each T cell precursor
which emerges from the bone marrow must pass through a much more complex
filtering process within the thymus. This process detects and destroys the
cells unable to distinguish between self and antigen. Only mature T cells
capable of this differentiation are released into the bloodstream to patrol
for antigens. Once T cells
mature they are classified into two main groups: "killer" or
cytotoxic T cells (Tc) are involved in skin graft rejection, the destruction
of cells infected with virus and protection against cancers; and
"helper" T cells (Th), which are mandatory for B and Tc cells to
launch their defense against antigens. When the immature T cells enter the
thymus from the bone marrow or fetal liver prior to the filtering process,
the surface proteins that differentiate these two main classes of T cells are
absent. But once gene rearrangements occur, the two classes of T cells are
distinguished by two distinct markers, CD4 markers on helper cells and CD8 on
the "killer" cells. During their stay in the thymus, these cells
are called thymocytes.(3) The HIV virus
sets siege on the body by not only damaging developing T cells, but also
targeting those mature T cell surfaces marked with the CD(4) molecule. As
AIDS disrupts the function of the thymus, the body becomes less capable of
replacing the CD4 cells destroyed by the HIV virus. Without CD4 T cells, the
immune system has no direction for activation.4 As the thymus
teaches the cells how to detect antigens and as it selects only those cells
capable of destroying antigens, the CD4-CD8- double-negative (DN) thymocytes
that arise from the bone marrow transform into CD4+CD8+ double-positive (DP)
thymocytes. Next DP thymocytes are transformed into single positive (SP)
immunocompetent T cells capable of recognizing foreign antigens. Those SP
cells are sent off into the bloodstream to patrol the body.5 It was in
observing these double negative and double positive T cells that researchers
began to recognize estrogen's ability to shrink the thymus. Estrogen
and the Thymus Female sex
hormones affect the body by binding to a specific nuclear protein, the
estrogen receptor, which in turn binds to specific estrogen response elements
in estrogen regulated genes. Two types of estrogen receptors exist: ERalpha
and the recently discovered ERß (beta). Due to the presence of ERalpha in
both the thymus and thymocytes, the thymus is a prime target of estrogen, and
the binding process in the thymus becomes similar to estrogen binding in the
uterus.(6-7) This is why administered estrogens have profound effects on the
thymus, causing an increased rate of thymic atrophy. The fact that sex
hormone receptors exist on immune cells indicates that the effects of
estrogen on these cells are mediated by those receptors.(8) Growing
evidence suggests that estrogen's effect on the thymus is one reason females
are more susceptible to autoimmune diseases. Estrogen decreases the number of
double positive T cells generated in the thymus but increases the number of T
cells in the liver. Because these extrathymic T cells have not learned how to
differentiate between antigens and particles which belong in the body they
experience autoreactivity-i.e. they recognize themselves as an antigen-one
reason why scientists are now starting to name estrogen as a culprit in
autoimmune diseases.(9) Oral
contraceptives' ability to alter the estrogen levels in the body and reduce
the risk of rheumatoid arthritis is another argument for the hypothesis that
estrogen influences autoimmune diseases. Estro-gen has the ability to delay
the body's allograft rejection while castration has been found to increase
allograft rejection in mice, further supporting the evidence that estrogen
affects the immune system.(10) Researchers
are beginning to understand why estrogen has such a detrimental effect on the
thymus. Allen Silverstone, professor of microbiology and immunology at the
State University of New York Health Science Center in Syracuse, and his
colleagues, determined that thymic atrophy induced by the estrogenic
compounds estradiol (E2), diethylstibestrol (DES) and
2,3,7,8-Tetrachloro-dibenzo-p-dioxin significantly depleted CD4+CD8+ and SP
thymocyte distribution, with DN cells becoming more than 40 percent of the
remaining population. In other words, immature thymocytes increased while
mature thymocytes decreased.(11) In another
study, Silverstone and colleagues administered estradiol, to a group of male
mice with the Estrogen Receptor alpha knocked out (ERKO) and to a control
group with the ER alpha intact. The control group showed significant
alterations in their CD4/CD8 ratio while the percentage of double positive
CD4+CD8+ cells, which are capable of recognizing antigens, declined. By
contrast, the ERKO mice did not undergo any significant alterations in the
CD4/CD8 ratio after estradiol treatment, demonstrating that the estrogen
receptor plays a key role in how the thymus educates the T cells. The presence
of ER alpha controlled the decline in double positive cells in the control
group, but surprisingly it only was responsible for some, but not all, of the
estrogen-caused thymic atrophy. ERKO mice given estradiol still experienced
some thymic atrophy, although not to the extent of the mice still possessing
the alpha receptor. The results also suggested that the ER alpha was
essential in certain cells and that a moderate level of estrogens is
necessary to develop a full-sized thymus.(12) Originally,
researchers believed that thymic atrophy induced by estrogenic compounds was
the result of apoptosis (cell death) of immature thymocytes or estrogen
targeted double-positive T cells. Silverstone presents evidence to the
contrary, demonstrating that estrogen exerts its effects early in the
cell-generation process. In mice given Dexamethasone (Dex), estradiol (E2),
and 2,3,7,8-tetracholorodibenzo-p-dioxin (TCDD), estradiol and dioxin halted
the cell cycle, slowing down the pace in which stem cells, the precursors to
T cells, are formed in the bone marrow and/or the fetal liver. The estrogenic
compounds did not kill cells, but rather activated signals that told the cell
not to divide as frequently.(13) Thymic
Atrophy and Pregnancy The thymus
atrophies in humans after puberty and shrinks to a small remnant in old age,
although even in very old humans the thymus continues to produce a limited
number of T cells. During pregnancy, the thymus shrivels from a healthy,
large active organ to a considerably reduced size. In pregnant women with
autoimmune diseases, one result of this involution is the disappearance of
the disease. After pregnancy, and especially after lactating, the mother
experiences thymus growth until it returns to its normal size. Immunologist
Thomas Waldschmidt of the University of Iowa Department of Obstetrics and
Gynecology proposes the reason for this involution during pregnancy is due to
the fact that a pregnant mother is holding within her uterus what amounts to
a foreign graft, i.e. a fetus with tissue that doesn't belong to the mother.
Therefore, the impaired, significantly reduced thymus prevents the mother's
immune system from producing the T cells necessary to reject the fetus.
Waldschmidt, together with obstetrician Asha Rijhsinghani, noticed this phenomenon
in pregnant mice during the middle to latter stages of gestation when the
mother's ability to make CD4 and CD8 T cells disappeared.(14) Indole-3-Carbinol’s
Role Silverstone
surmises that one reason Indole-3-Carbinol may be so effective in altering
estrogen's detrimental effects on the body and on the thymus, is through its
ability to affect which genes the ER alpha and ERß receptors are able to
activate. I3C enables those receptors to activate genes that metabolize
estrogen.(15) Additionally,
I3C's ability to alter the way estrogen is metabolized by the body can
diminish the effects of hormonal contraception or estrogen replacement
therapy. Researchers have noticed an altered lymphocyte reactivity in women
participating in these two activities, an observation which indicates altered
immune response.(16) For males,
testosterone also plays a role in thymic atrophy, and age-related involution
of the thymus from the juvenile period through puberty to post-puberty
depends on rising testosterone levels. This age-related involution has been
reversed in male rats exposed to the anti-estrogenic drug Tamoxifen.(17)
Indole-3-Carbinol, which has been shown to produce similar anti-estrogenic
effects, can block testosterone conversion into estrogen, alleviating thymic
atrophy. References 1. Blakeslee,
Dennis. The Thymus and Immunologic Reconstitution. JAMA Newsline, HIV/AIDS
Information Center. February 8, 1999. 2. Blakeslee,
Dennis. The Thymus and Immunologic Reconstitution. JAMA Newsline, HIV/AIDS
Information Center. February 8, 1999. 3. Blakeslee,
Dennis. The Thymus and Immunologic Reconstitution. JAMA Newsline, HIV/AIDS
Information Center. February 8, 1999. 4. Blakeslee,
Dennis. The Thymus and Immunologic Reconstitution. JAMA Newsline, HIV/AIDS
Information Center. February 8, 1999 and Silverstone, Allen. personal
communication. 1999. 5. Blakeslee,
Dennis. The Thymus and Immunologic Reconstitution. JAMA Newsline, HIV/AIDS
Information Center. February 8, 1999 and Staples, J, Gasiewicz, T, Fiore, N,
Lubahn, D, Korach, K, and Silverstone, A. Estrogen Receptor alpha Is
Necessary in Thymic Development and Estradiol-Induced Thymic Alterations.
Journal of Immunology. October 15, 1999. To be published report. 6. Staples,
J, Gasiewicz, T, Fiore, N, Lubahn, D, Korach, K, and Silverstone, A. Estrogen
Receptor alpha Is Necessary in Thymic Development and Estradiol-Induced
Thymic Alterations. Journal of Immunology. October 15, 1999. To be published
report. 7. Bridges,
ED, Greenstein, BD, Khamashta, MA, Hughes, GR. Specificity of estrogen
receptors in rat thymus. Int. J Immunopharmacol. 1993, November, 15:927-32. 8. Chao TC.
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19:95-106. 9. Okuyama,
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Fiore, N, Gasiewicz, T, Silverstone, A. 2,3,7,8-Tetrachlorodibenzo-p-dioxin
and diethylstilbestrol affect thymocytes at different stages of development
in fetal thymus organ culture. Toxicology and Applied Pharmacology. 1998,
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Estrogen Receptor alpha Is Necessary in Thymic Development and
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Silverstone, AE, Frazier, DE Jr., Fiore, NC, Soults JA, Gasiewicz, TA.
Dexamethasone, beta-estradiol, and 2,3,7,8-Tetrachlorodibenzo-p-dioxin elicit
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1994, June, 126: 248-59. 14.
Rijhsinghani, A, Bhatia, SK, Kantamneni, L, Schlueter, A, Waldschmidt, TJ.
Estrogen inhibits fetal thymocyte development in vitro. Am J Reprod Immunol.
1997, May, 37: 384-90 and personal communication with Waldschmidt, TJ, 1999. 15.
Silverstone, A. personal communication. 1999. 16. Helgason,
S, von Schoultz, B. Estrogen replacement therapy and the mixed lymphocyte
reaction. Am J Obstet Gynecol. 1981, 141: 393. 17. Sfikakis,
PP, Kostomitsopoulos, N, Kittas, C, Stathopoulos, J, Karayannacos, P,
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