The Immune System which Adversely Alter Thyroid Functions: A Review on the Concept of Autoimmunity
Azad Reza Mansourian
The immune system protect individual from many pathogens exists within our environment and in human body, by destroying them through molecular and cellular mechanism of B and T cells of immune system. Autoimmunity is an adverse relation of immune system against non- foreign substances leaving behind either alters the normal function or destroying the tissue involved. Autoimmunity occur in genetically predispose persons with familial connections. The autoimmunity to the thyroid gland mainly consists of Hashimato thyroiditis and Grave's disease, the two end of spectrum in thyroid function of hypo and hyperactivity, respectively. The thyroid stimulating hormone receptor, thyroglobuline, enzymes of thyroid hormones synthesis are targeted by autoantibodies and cell- mediated reactions. The aim of this review is to explore the studies reported on the autoimmunity to the thyroid gland.
July 15, 2010; Accepted: July 23, 2010;
Published: August 18, 2010
The immune system play an important role in destroying many human pathogens
existed in our environment and within the human body, otherwise these pathogen
causes pathological damages, which hurt the various organism within the body.
The immune system does its responsibility through the two mechanisms which are
called innate and adaptive immunity. In practice the innate immune system face
antigen first and the various pathogens are meeting the innate immune system.
Prior to face adaptive immunity. Within the body when the adaptive immune system
is activated through a pathogen the tatter, antigen mostly is destroyed through
a complex reactions which happen within the immune system on meeting an antigen
(Jiang and Chess, 2006; Nelson,
2004; Kroneberg et al., 1986).
The above mentioned two systems do their function through many biochemical
molecules and different cells existed in the immune systems the soluble molecules
are lysozyme, complement, acute phase proteins, interferon and different antibody
and the participated cells immune systems are phagocytes, natural killer cells
and T- lymphocytes respectively. On condition an antigen enter the first line
of barrier the body which is the epithelial surface of various organs, the phagocyte
cells encounter the antigens and subsequently the pathogen can be destroyed,
through a complex reaction within the immune system (Schwarz
and Bhandoola, 2006).
The cells within the immune system contains of lymphoid and myeloid sub-division
producing lymphocytes and phagocytes. The lymphocytes also contain B and T-cells.
The T and B come from Thymus and Bone marrow respectively and either of B and
T cells have their own specific antigen receptor and on binding antigen to these
receptors, cellular activation occur within the immune system, to destroy the
encountering antigens, with the coordination exist between T and B cells of
immune system (Weigle, 1975; Li
et al., 2006).
Autoimmunity: Also it is absolutely clear the immune deficiency in human
leave the individual defenseless against many antigen present in our environment
which can be a topic for other study, but the other undesired upper end of spectrum
which is the main subject behind this present review and it is the activity
of immune system against body own tissues which causes tremendous problems,
through the unwanted reaction of both B and T-cells by producing various antibodies
by B-cells and many reactive T-cells against its own tissues (Sakaguchi,
2005; Weetman et al., 1990; Misaki
et al., 1984) which many diseases and abnormalities can be produced
by the unwanted immune reactions, with are called autoimmune diseases. In such
disease the immune system are activated, producing many antibodies and activated
T-cells which can be targeted at various part of the cells organelles, such
as different enzymes, key macromolecules, hormone receptors and cell nucleus
(Holborow, 1960; Mansourian et
al., 2007; Chiovato et al., 1993; Mariorri
et al., 1987). These damages can be either specific or non-specific.
The thyroid autoimmunity are specific autoimmune diseases and the thyroid gland
various cells and organelles are targeted by the individual immune systems and
the thyroid function seriously affected leaving the patients with hypothyroidism
in Hashimato and hyperthyroidism in Grave's disease (Okita
et al., 1980; Aoki and Degroot, 1979).
Genetic in autoimmunity: The base for autoimmunity is genetic and there
are many studies indicating the development of autoimmune disease originating
from evidence of association with human lymphocyte antigens. Other studies indicated
that there are few genetic factors associated with developing autoimmunity whether
it is either organ or non- organ specific. The autoimmunity to the thyroid diseases
proved to be familial (Kite and Witebsky, 1968;
Bartel, 1941; Brix et al., 1998a; Brix
et al., 2000; Nagayama et al., 1989).
There are studies indicating the Graves disease and Hashimato's thyroiditis
are thyroid disorder with genetic predisposition (Epstein,
1999; Klavinskis et al., 1988; Nagasaka
et al., 2000; Brix et al., 2001;
Ringold et al., 2002), the high level of serum
antibodies was found in serums belongs to the patients relatives, with a documented
thyroid diseases (Hall et al., 1960;
Zeitlin et al., 2007; Stenszky et al.,
There are also reports of simultaneous incidence of autoimmune thyroid disorder
and other autoimmune diseases. Examples of such a diseases are the existence
thyroid and stomach antibodies in first degree relatives with Hashimato thyroiditis
(Bartel, 1941; Brix et al.,
2001; Philips et al., 1991, 1993;
Ringold et al., 2002; Hall
et al., 1960; Zeitlin et al., 2008;
Pop et al., 1998; Weetman
and McGregor, 1994; Parkes et al., 1996;
Yanagawa et al., 1993; Stenszky et al.,
Also nearly all types autoimmune diseases demonstrate some correlation with
human lymphocyte antigen specificity,but it should be mentioned ethnicity also
play a role on the level of autoimmunity (Chen et al.,
1999; Weetman and McGrgor, 1994; Tomer
et al., 1997; Shields et al., 1994).
Diagnostic role of autoimmunity: There are three indications for the
presence of autoantibodies and other autoimmunity determinants with individual
serum which can be summarized as follow: (1) The raising autoantibodies which
are the main determinant factors for disease onset. (2) There may be an abnormality
in which through its process and the damages predispose the individual to produce
autoantibodies and finally. (3) There may be an pathogen which cause the disease
and the production of antibodies as well. In clinical practice all of above
three possibilities are routinely should be investigated for the management
and treatment of patients. The elevation of antibodies in various autoimmune
disorder and antibodies raised secondary to some diseases such as myocardial
infraction is now an instrumental to diagnose, treat and manage the cardiovascular
patients (Crile, 1954; Hubble, 1959;
Buchanan et al., 1961; Mulhern
et al., 1996; Jenkins and Weetman, 2002;
Irvine et al., 1965; Doniach
et al., 1963; Hjort et al., 1963).
Thyroid autoimmune diseases: Various type of auto immune diseases in
the thyroid gland can be sub-divided as follow: (1) Grave's disease, with thyroid
enlargement, resulting with hyperthyroidism and its subsequent clinical consequence
(Sanders et al., 2003; Chazenbalk
et al., 2002, 2004; Chen
et al., 2003). (2) Hashimato's thyroiditis accompanied with goiter,
resulting in hypothyroidism or thyroid function remain with normal range and
euthyroid state (Suzuki et al., 1980; Blanchin
et al., 2007; Weetman et al., 1989;
Beierwaltes et al., 1968)
Also the autoimmunities to the thyroid gland are well documented and categorized,
but there are still some thyroid dysfunctions which can be labeled as transient
thyroid dysfunction which can happen, on its own, or may be occurred during
a particular physiological state, such as pregnancy and depression (Hidaka
et al., 1992; Bogner et al., 1995;
Weetman, 2001; Poppe et al.,
2003; Pratt et al., 1993;
Kong et al., 2009; Holmes et al., 1977;
Rapopott et al., 1998; Woolner
et al., 1959). In our study of thyroid function in pregnancy, we
found there is a high prevalence of thyroid dysfunction during pregnancy although
we did not measure the thyroid antibodies in pregnant womens, but the
growing fetus can be an antigenic determinant in production of antibody within
the thyroid gland during the pregnancy, which has been reported by other studies,
(Mansourian, 2010b; Mansourian et
al., 2010; Shahmohammadi et al., 2008;
Brix et al., 1998b). It is indicated in some pregnancies, postpartum
women and in either neonatal by hyperthyroidism or hypothyroidism the elevation
of auto antibodies were observed (Mansourian et al.,
2010; Pratt et al., 1993; Poppe
et al., 2003; Gribetz et al., 1954;
Jansson et al., 1984; Kajantie
et al., 2006; Radetti et al., 2007).
It has also been recommended by many studies, that the maternal serum concentration
of autoantibodies should be measured during the clinical investigation of thyroid
function test in routine thyroid function assessment of suspected subjects,
pregnancies and in newborns in addition to other thyroid function test, such
as thyroid stimulating hormone and thyroxin and triiodothyronine, (Mansourian,
2010b; Radetti et al., 2007;
Kajantie et al., 2006).
In addition either of hyperthyrodism and hypothyroidism have many other metabolic
disorder. dyslipidemia is among such abnormalities. It has been shown that in
hypothyroidism, the cholesterol and low density lipoprotein level are increased
(Mansourian, 2010a; Mansourian et
It should be noted, in thyroid disorder caused by autoimmunity and subsequent
dyslipidemia which can be its adverse effect, should be taken into account,
due to the cardiovascular abnormalities and particularly the atherosclerosis,
which many he accompanied by cholesterol elevation (Galesanu
et al., 2004; Vala, 2001; Mansourian,
2010b) In a study and review by author it was stated that lipid disorder
among thyroid patients and thyroid hormone alteration frequently seen during
pregnancy (Mansourian, 2010b; Pratt
et al., 1993; Poppe et al., 2003)
but on the same time as thyroid hormones assessments is carried out, thyroid
auto antibodies, iodine, lipid profile, assessment of pregnant women in particular
and other suspected individuals should be evaluated for any thyroid disorder
and possible side effect of dyslipidemia resulted from thyroid malfunctions.
(Mansourian, 2010a, b; Marjani
et al., 2008; Mansourian et al., 2008).
There are also some experimental studies on the induction of autoimmunity by
thyroid injury, which can be a topic for studies in humans (Bagchi
et al., 1995; Flynn et al., 2007).
Autoimmunity to the thyroid gland
Thyroid gland: Thyroid gland is the largest of endocrine glands in
human weighted approximately about 20 g located in front of the neck. This gland
produces the two most important hormones required for bodys metabolism
namely thyroxin (T4) and tridiothyronin (T3) in addition to latter hormones,
the thyroid produce Calcitonin, responsible for calcium and bone metabolism.
The reactions, which finally produce T4 and T3, begin with the absorption and
maintains of iodine and preparation of this element to participate in the structure
of organic molecules on the thyroglobulin macromolecule, there for the first
step in synthesis of T4 and T4 is the absorption and transferring the iodine
on the thyroids residue on the thyroglobulin.
The topic of iodine deficiency in human have been the corner stone of many
research about thyroid disorder, in fact one of the first primary tool to diagnose
the hypothyroidism is the assessment of iodine status. In our earlier study,
we found that iodine deficiency can be manifested the base for some thyroid
disorder, the findings which have been reported by many other studies (Mansourian
et al., 2007). It was already mentioned in experimental studies the
elevated iodine itself which can be observed in thyroid injury can be a base
for autoimmunity to the thyroid gland (Bagchi et al.,
1995; Flynn et al., 2007; Zois
et al., 2006).
Thyroglobulin (Tg) is produced when iodine added on the thyrosil residue of
this latter macroprotien within the thyroid gland. All these reaction leading
to production of T4 and T3 do take place by the action of thyroid stimulation
hormone (TSH), not only TSH facilitate the thyroid hormone synthesis, through
the activation of, many enzymes with the thyroid gland such as thyroxine peroxidase
and other enzymes of iodine oxidation, but the thyroid enlargement also carried
out by TSH. This latter hormone does all these physiological and biochemical
functions through cAMP. When TSH binds to the THS receptor on the thyroid gland
the sequence of event happen, on the receptor which located on the membrane,
leading to the production of cAMP, a second messenger responsible for all the
events in the thyroid gland and TSH functions. Therefore, it is the TSH receptor
which locate in the center of thyroid function and any unwanted stimulation
TSH or blocking of TSH receptor, result in over activation or suppression of
thyroid hormone production due to the alteration happen in the level of c AMP
concentration in the thyroid gland (Tonacchera et al.,
1996; Prabhakar et al., 1997). Autoimmunity
to the thyroid genetically, predisposes individuals; finally leave the patients
with the consequence of thyroid disorders. It should be mentioned also that
it is not only the TSH receptor, which can be targeted by the immune system,
but also as it was mentioned earlier T-cell mediated responses and cell destruction
can be associated with thyroid autoimmunity (Collins and
Gough, 2002; Metcalfer et al., 1997; Weetman
et al., 1982).
The molecular bases for autoimmunity to the thyroid gland: T-cell and
B-cell, which mainly originated from Thymus and Bone marrow cell are behaved
to destroy only individual foreign antigens in a complex molecular mechanism
and through other pathways, the immune system, behaved in such way to recognize
the non- foreign antigen, within the thyroid, in other word the bodys
thyroid own cells and tissues are protected by the immune system and it behaved
to recognized the self thyroid antigens. Only on condition that the immune system
does not recognize and discriminate the thyroid non- foreign antigen, only on
that condition the predispose persons thyroid will be attacked by self immune
system, with all its adverse effects, on the thyroid metabolism. Such immunity
against persons own thyroid is called thyroid autoimmunity, it means a molecule
within the person thyroid is considered a foreign molecule and the immune system
begin to react against that molecule (Weetman et al.,
1982; Drehage, 1996; Owen and
Smart, 1985; Benvenga et al., 1987; Sakaguchi,
2005; Shields et al., 1994; Tomer
et al., 1997; Lamki et al., 1973;
McIntosh et al., 1993). In fact that molecule
stimulates all the reactions required by the immune system to destroy the normal
procedures of the thyroid gland molecules and reactions. There are many reports,
indicating the gender play an important role in triggering the autoimmunity.
Thyroid autoimmunity proved to be sex- related and high incidence of autoantibodies
were found among females (Mansourian et al., 2010).
In fact also in our study we did not measure the level of autoantibodies in
our women sample population but incidence of thyroid disorder and in particular
hypothyroidism was more common among females (Mansourian
et al., 2008).
The autoimmunity in thyroid mainly consists of Hashimato thyroiditis and Graves
disease. The two end of thyroid diseases spectrum leaving the patients in hypothyroid
and hyper thyroid conditions, respectively (Endo et
al., 1983; Amino et al., 1982; Bogner
et al., 1984).
Hashimato thyroiditis: Hashimato thyroiditis is an autoimmune thyroid
disease. In this thyroid disorder, the immune system activated against self-
organ and attack, the thyroid gland. The consequence of thyroid attack by the
immune system is the reduction of thyroid hormone synthesis and thyroid gland
in compensation to this latter reaction continue to produce hormone to reach
to the normal level, which the body required for that level of thyroid hormone,
by doing so the thyroid gland enlarged and it is developed into goiter, this
type of goiter which the body gain normal level of thyroid hormones is called
simple goiter, it means, it is only the enlargement of thyroid gland without
any toxicity due to the enhanced production and the hyperplasia of the gland,
but the thyroid finally enter into hyperthyroid state (Buchanan
et al., 1961; Fatourechi et al., 1971;
Eason, 1928; Suzuki et al.,
1980; Benvenga and Trinarchi, 2008; Pearce
et al., 2003).
The side- effects of Hashimatos d sease includes: fatigue weight gain,
depression, gastrointestinal, abnormality, intolerance to cold constipation,
dry skin and hair, speech and vision abnormalities. Those Hashimatos patients
without any successful treatment, eventually face, reduction in their heart
rate, drop in their body temperature and their eye become puffy around their
eyes. If the Hashimatos disease remain untreated and in advance cases,
it will end up with heart failure.. the molecular and cellular mechanism behind
cell destruction with the thyroid gland, is a combination of T-cell autoimmunity
activity in the thyroid accompanied with autoantibodies raised against thyroglobulin,
thyroid peroxidase enzymes (Kohno et al., 1988;
Protmann et al., 1985; Mclachian
and Rapoport, 1992; Tomer, 1997;
Lindberg et al., 2001; Noma et al., 1982;
Pop et al., 1998; Okamoto
et al., 1989). It seems that T-cell destruction is step forward for
the production of autoantibodies against the thyroglobulin and the thyroid peroxidase
enzymes (Komiya et al., 2001). T-cell autoimmunity
seems to be adversely effect the thyroid cells and it seems this procedure is
the first step toward the creation of goiter in the thyroid gland, with the
infiltration of lymphocyte and production of compensatory thyroid cells, leading
to the hypothyroid and enlargement of thyroid gland the raised autoantibodies
within patients thyroid gland, also accompanied with T-cell mediate cell
destruction in the thyroid gland with reduction of thyroid hormone synthesis,
but as it was mentioned earlier, it is the T-cell mediated autoimmunity against
the thyroid gland which fundamentally destroy the thyroid cells and these reaction
predispose the gland to face eventually the inflammation seen in Hashimatos
disease, with associated syndrome (Komiya et al.,
2001). It is reported also the Hashimato, disease can be accompanied with
some cancer of thyroid gland. Gravers disease a topic which should have
been taken seriously for the management of Hashimato patients (Woolner
et al., 1959; Holmes et al., 1977;
Giani et al., 1996; Smyth
et al., 1998; Kohn et al., 1997; DeGroot
et al., 1997; Dailey et al., 1955;
Giani et al., 1996).
Graves disease: Graves disease is an autoimmune thyroid disorder, resulting in the over activity and the elevated level of thyroid hormones much more than the healthy body metabolism required, eventually lead to weight loss, nervousness and increasing heart rate intolerance to heat, sleeping problem.
Weakness, tremors, alteration in vision, with eventual, ophthalmopathy. The bases for thyroid disorder in this disease related to the over activity and unwanted immunological reactions by the individual immune system.
The antibodies against peroxidease (TPO) enzyme are found, within the serum
of effected persons (Di Cerbo et al., 1995;
Sawai and Degroot, 2000; Davies
et al., 1993; Caso- Pleaez et al., 1995;
Kite and Witebsky, 1968; Tomer and
Davies, 1993; McLachlan and Rapoport, 1992,
2004; Protmann et al., 1985; Kohno
et al., 1988; Dechairo et al., 2005;
Wong and Cheng, 2001; Kondrashova
et al., 2008; Brix et al., 1998b;
Vali et al., 2000). As it was mentioned earlier Graves disease is
a familial disease and the genetic susceptibility lead the synthesis of autoantibodies
against Tg and TPO. The other most autoantibody which is produced and targeted
against thyroid gland is antibody against receptor of Thyroid Stimulating Hormone
(TSH), the antibody against the TSH receptor which is also known as Thyroid
Stimulating Immunoglobulin (TSI).
TSI binds to the receptor of TSH on the thyroid gland stimulate and mimic the
physiological effect of TSH, producing cAMP the second messenger responsible
for the enlargement of thyroid gland and also the elevated production of T4
and T3 through the stimulation of many enzymes responsible for hormone production.
TSI is not under the negative conyr T4 and T3, therefore the syntheses of T4
and T3 are continued. In healthy persons when T4 and T3 are elevated the negative
feed -back control the hormones production by sending the message to the hypothalamus
and pituitary to slower down the release of TSH and consequently the production
of T4 and T3 are reduced. Also it should be mentioned the at same times the
raised autoantibody against the TSH receptor blocks the TSH receptor in such
way that even TSH can not binds to the TSH receptor and consequently the production
of T4 and T3 are halted and hypothyroidism occur (Tonacchera
et al., 1996; Prabhakar et al., 1997;
Libert et al., 1989; Nagayama
et al., 1989).
In our earlier studies we found high incidence of hyperthyroidism, among pregnant
women and also many of them remained at euthyroid state. In the latter study
we argued the elevated thyroid hormone level was the physiological requirement
pregnancy, but it seems further, studies should have been done to clarify whether
the hyperthyroidism or euthyroid condition observed during pregnancy are either
the direct consequence of pregnancy or the raised autoantibodies against the
thyroid gland enzymes and TSH receptor (Shahmohammadi et
al., 2008; Kung and Jones, 1998; Pratt
et al., 1993; Poppe et al., 2003).
The feature related to the Graves disease is the production of autoantibodies
and T-cell mediated on to autoimmune response.
It should be mentioned that many reports indicated the simultaneous incidence
of autoimmunity to the thyroid gland with the gland hyper activities and the
thyroid gland carcinoma, or even some infection within the thyroid gland (Tomer
and Davies, 1993; Bartalena et al., 1996;
Wenzel et al., 1988; DeGroot
and Paloya, 1973; Woolner et al., 1959; Giani
et al., 1996; Bach, 2002; Smyth
et al., 1998).
The reviews main points are as follow:
||The importance of immune system in protecting the individual
from invading foreign pathogen described
||The adverse effect of autoimmunity against self-antigen explored
||Autoimmunity has a genetic background with familial connection
||The determination of autoantibodies measurements are valuable
diagnostic tools in medical practice
||Autoimmunity to the thyroid gland can be assessed by measuring
autoantibodies raised against thyroglobulin, TSH recpector and thyroid peroxidase
enzyme, involved in T4 and T3 production
||Hashimato thyroiditis and Graves disease are the two
end of spectrum of hypo and hyperthyroidism in thyroid autoimmunity, respectively
||Although, the main focus was on the production of antibodies
in thyroid autoimmunity but it should be remembered that autoantibodies
within the thyroid gland are also produced not only by the autoimmunity
to the gland but also some other diseases such as thyroid cancer and
in during some pregnancies, the elevated autoantibodies to the thyroid gland
has been detected therefore the assessment of thyroid autoimmunity status
should have been taken into account when thyroid cancer and pregnancies
are medically examined
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