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Pathogenesis of Graves' disease

Pathogenesis of Graves' disease


Author
Terry F Davies, MD, FRCP, FACE
Section Editor
Douglas S Ross, MD
Deputy Editor
Jean E Mulder, MD
Disclosures
All topics are updated as new evidence becomes available and our peer review process is complete.
Literature review current through: Oct 2013. | This topic last updated: Jun 18, 2012.

INTRODUCTION — Graves' disease is a syndrome that may consist of hyperthyroidism, goiter, eye
disease (orbitopathy), and occasionally a dermopathy referred to as pretibial or localized myxedema.
The terms Graves' disease and hyperthyroidism are not synonymous, because some patients may have
orbitopathy but no hyperthyroidism, and there are many other causes of hyperthyroidism in addition to
Graves' disease.

Hyperthyroidism is the most common feature of Graves' disease, affecting nearly all patients, and is
caused by autoantibodies to the thyrotropin (TSH) receptor (TSHR-Ab) that activate the receptor,
thereby stimulating thyroid hormone synthesis and secretion as well as thyroid growth (causing a
diffuse goiter). The presence of TSHR-Abs in serum and orbitopathy on clinical examination
distinguishes the disorder from other causes of hyperthyroidism. Other causes of an overactive thyroid
gland are discussed separately. (See "Disorders that cause hyperthyroidism" .)

This topic will review the immune pathogenesis of Graves' thyroid disease, with emphasis on the role
of B and T-cells in the production of the TSHR-Ab that are responsible for the thyroid stimulation and
growth. The pathogenesis of Graves' orbitopathy and dermopathy are reviewed separately. (See
"Pathogenesis and clinical features of Graves' ophthalmopathy (orbitopathy)" and "Pretibial myxedema
in autoimmune thyroid disease" .)

The TSH receptor — In Graves's disease, the main autoantigen is the thyroid stimulating hormone
receptor (TSHR) which is expressed primarily in the thyroid but also in adipocytes, fibroblasts, bone
cells, and a variety of additional sites [ 1,2 ]. This antigen has been reviewed extensively elsewhere [
1,2 ]. The TSHR is a G-protein coupled receptor with seven transmembrane-spanning domains. TSH,
acting via the TSHR, regulates thyroid growth and thyroid hormone production and secretion. The
TSHR undergoes complex post-translational processing involving dimerization and intramolecular
cleavage; the latter modification leaves a two-subunit structural form of the receptor. Data suggest that
there is eventual shedding or degradation of the TSHR ectodomain [ 3 ], although this has not been
demonstrated in vivo. Each of these post-translational events may influence the antigenicity of the
receptor. However, factors that contribute to TSHR presentation as a target for the immune system in
humans are not well understood, but are considered to be primarily factors that build on a state of
enhanced genetic susceptibility.

The thyroid gland in Graves' disease — The thyroid is usually, but not always, diffusely enlarged. The
histology of the thyroid gland in patients with Graves' hyperthyroidism is characterized by follicular
hyperplasia, intracellular colloid droplets, cell scalloping, a reduction in follicular colloid, and a patchy
(multifocal) lymphocytic infiltration. Only rarely are lymphoid germinal centers seen. The histological
picture may be greatly influenced by pretreatment with antithyroid drugs ( picture 1 ). The majority of
intrathyroidal lymphocytes are T-cells but plenty of B cells may be present, though nothing like that
seen in chronic autoimmune thyroiditis (Hashimoto's disease). In some areas, thyroid epithelial cell
size correlates with the intensity of the lymphocytic infiltrate, suggesting thyroid-cell stimulation by
local B cells secreting stimulating TSHR-Ab [ 4 ].

THYROID AUTOANTIBODIES

It is well known that lymphocytes from Graves' thyroid tissue spontaneously secrete thyroid
autoantibodies, including TSHR-Abs, in vitro, providing evidence of their activated state [ 5 ].
Additional evidence for their presence and activated state comes from the decline in serum thyroid
autoantibody concentrations after antithyroid drug treatment, after thyroidectomy, and late after
radioactive iodine therapy. (See 'Influence of radioiodine on TSHR-Abs' below.)

Autoantibodies to the TSH receptor — Over 50 years ago, serum from patients with Graves'
hyperthyroidism was found to contain a long-acting thyroid stimulator (LATS) [ 6 ]. LATS proved to
be an immunoglobulin and inhibited the binding of radiolabeled TSH to thyroid membranes suggesting
that such activity was due to the presence of antibodies to the TSH receptor (TSHR-Ab) [ 7 ].

The proof that TSHR-Abs stimulated the thyroid gland in humans came from infusion experiments in
human volunteers and from the transient detection of TSHR-Ab in the serum of hyperthyroid neonates
of mothers with Graves' disease and persisting TSHR-Abs [ 8,9 ].

Stimulatory TSHR-Abs have several other characteristics:

 They are specific for Graves' disease, in contrast to antibodies to thyroglobulin (Tg) and
thyroid peroxidase (TPO). Almost all patients with Graves' hyperthyroidism have detectable
TSHR-Ab when measured by sensitive assays [ 10-12 ]. They are unique to humans; no
animals develop Graves' disease, although it can be induced in rodents by immunization with
native TSHR [ 13-16 ].
 They are usually of the IgG1 subclass, which suggests that they are oligoclonal [ 17 ], in
contrast to antibodies to TPO and Tg which are polyclonal.
 The serum concentrations of TSHR-Ab tend to decline in patients treated with an antithyroid
drug. If high concentrations persist, the patient is likely to become hyperthyroid again when
the drug is discontinued. However, such a reaction assumes the thyroid is capable of secreting
excess thyroid hormones once again and has not been damaged by ongoing thyroiditis or the
patient has iodine deficiency [ 18-20 ]. Measuring serum TSHR-Ab in these patients can be
helpful, but only when the result is positive. A significant number of patients negative for
TSHR-Ab after a course of antithyroid drugs will still have a recurrence, probably secondary
to the insensitivity of the assays for measuring antibody [ 21 ]. In practice, we always measure
serum TSHR-Ab at the time of planned cessation of drug therapy and continue the drugs if
TSHR-Abs remain detectable [ 18,19 ].
 TSHR-Abs, like TSH, stimulate the synthesis and activity of the sodium-iodide symporter,
explaining the increased uptake of iodide by thyroid tissue in Graves' disease in the absence of
TSH [ 22 ].
 TSHR-Abs stimulate different subtypes of G proteins (Gs), PKA, and thyroid adenylate
cyclase activity, which leads to increased thyroid hormone synthesis, secretion, and cell
survival. High levels of TSHR-Ab also stimulate Gq and the PKC pathway leading to cell
proliferation [ 23,24 ].

Influence of radioiodine on TSHR-Abs — In patients treated with radioactive iodine, the serum
TSHR-Ab concentrations initially rise, reaching a peak three to five months after treatment, and then
gradually decline [ 25 ]. The initial increase in serum antibody concentrations after radioiodine therapy
may explain why, in some patients, Graves' orbitopathy may first appear or may transiently worsen
afterwards. (See "Treatment of Graves' orbitopathy (ophthalmopathy)" .) The TSHR-Abs may then
either gradually decline or, more commonly, persist for many years after radioiodine treatment [ 26 ].
Although it is theoretically possible for extrathyroidal TSHRs to act as antigenic stimuli in the absence
of the thyroid, TSHR-Abs gradually fall after thyroidectomy, and disappear in 70 to 80 percent of
patients after 18 months [ 26 ].

TSHR agonists and antagonists — Not all TSHR-Abs are stimulatory. Some, usually found in the
serum of patients with Hashimoto's thyroiditis, block the binding and action of TSH and, therefore, can
cause hypothyroidism ( figure 1 ). Blocking TSHR-Abs can be found in 10 to 15 percent of such
patients. However, some patients with Graves' disease have a mixture of TSHR-Abs, both stimulating
and blocking, and the clinical presentation may depend upon a balance between these different
antibodies. A third group of TSHR-Abs is of the neutral variety, binding to the receptor and not
influencing TSH binding. These antibodies, however, may not be entirely neutral and can have cell
signaling capability of uncertain consequence [ 27 ].
Binding sites for TSHR-Abs — TSHR-Abs bind to a complex conformational epitope in the
extracellular domain of the TSH receptor, principally in the region of the receptor to which TSH binds,
which is a binding pocket encompassing the leucine-rich repeat region ( figure 2 ) [ 28 ]. The
differences in functional activity of TSHR-Abs may relate to their variable molecular binding
characteristics, resulting in variable cell signaling. Stimulating TSHR-Abs only have affinity for a
conformational epitope in the ectodomain with approximately a dozen binding sites and will not
interact with an unfolded/reduced receptor molecule [ 1 ]. Shedding of the subunit of the extracellular
domain into the extracellular fluid may be an important stimulus for TSHR-Ab formation. Only a
minority of TSHR-Abs binds to linear epitopes and these are likely to be of the blocking or neutral
variety [ 29,30 ]. Hence, stimulating antibodies bind to conformational epitopes while blocking
antibodies may bind to either conformational or linear epitopes [ 31-33 ].

Relationship with autoimmune thyroiditis — Lymphocytic infiltration of the thyroid and anti-Tg and
anti-TPO antibodies in the serum occur in both Graves' disease and chronic autoimmune (Hashimoto's)
thyroiditis, suggesting that the two disorders are related in fundamental ways and consistent with their
appearance within the same family and their sharing of a number of susceptibility genes including
HLA. (See "Pathogenesis of Hashimoto's thyroiditis (chronic autoimmune thyroiditis)" .) Therefore, it
appears that Graves' disease may develop on a background of thyroiditis. Several other observations are
compatible with this hypothesis:

 Areas of cellular apoptosis may be seen even in Graves' thyroid glands [ 34,35 ].
 The presence of antibodies that bind to the TSH receptor in both disorders, even if their
biological activities differ (stimulatory versus inhibitory).
 Progression from Graves' hyperthyroidism to chronic autoimmune thyroiditis and
hypothyroidism is well-recognized [ 36 ]. The converse also occurs [ 37 ], and there are
patients who have hypothyroidism one year, Graves' hyperthyroidism another, and
hypothyroidism again later [ 38 ].
 In families of patients, some members may have Graves' disease and others may have chronic
autoimmune thyroiditis [ 39 ].

Modifying the B cell repertoire — Use of a monoclonal antibody to the CD 34 antigen on the surface
of B cells has demonstrated that changing the B cell repertoire can have profound influences on Graves'
disease [ 40 ]. This has been exemplified by the early reports of the effective use of rituximab in
patients with Graves' orbitopathy (GO) [ 40,41 ]. Time will tell whether this is a safe approach to the
treatment of GO, but these treatment examples indicate that B cells not only have a role in
hyperthyroidism of Graves’ disease but also GO and suggest that TSHR-Ab interactions with retro-
orbital TSHRs expressed on fibroblasts and adipocytes may be important in disease etiology.

T-CELLS IN GRAVES' DISEASE

T-cells are present in the immune repertoire of patients with Graves' disease that react with
appropriately processed peptides derived from all thyroid autoantigens ( figure 3 ). These activated T-
cells in turn increase the secretion of thyroid-specific autoantibodies from B cells.

The current concept is that thyroid-specific T-cells in Graves' disease primarily act as helper (CD4+
Th1) cells. However, distinct subsets of T-cells have been identified that are distinguished most easily
by the cytokines that they produce ( table 1 ):

 CD4+ Th1 cells — When activated, these cells secrete interleukin-2 (IL-2), interferon gamma
(IFy), and tumor necrosis factor-alpha (TNFα), which in turn activate cytotoxic (CD8+) cells
and may induce thyroid cell apoptosis.
 CD4+ Th2 cells — These cells secrete IL-4 and IL-5 (but not IFy), and activate antibody
production, amongst other actions.
 CD4+ Th17 cells — This newly identified pro-inflammatory subset of cells secretes IL-17
under the influence of IL-23.
 CD4+ Treg cells — These are the anti-inflammatory regulatory T-cells (CD4+CD25+), which
diminish the activity of Th1 and Th2 cells [ 42 ]. One characteristic of Treg cells is the
expression of the transcription factor Foxp3.
 CD8+ Cytotoxic cells — These act primarily as destructive T-cells under the control of Th2
and Treg cells.

While all types of T-cells are found in the thyroid glands of patients with Graves' hyperthyroidism, it is
helpful to consider Graves' disease as primarily a Th2 type of autoimmune disease since the primary
pathophysiology is related to TSHR-Ab secretion [ 43 ]. Moreover, the Th1 and Th2 types of T helper
cells interact with each other so that a predominance of Th1 cells does not necessarily mean that the
predominant result is apoptosis. T-cells may induce target cell death directly, and there is some
evidence for a minor degree of thyroid-cell apoptosis in Graves' disease [ 44,45 ]. In the past, we have
identified a clone of T-cells that specifically lysed autologous thyroid cells from a patient with goitrous
autoimmune thyroiditis (Hashimoto's disease), but we were unable to identify similar cells in patients
with Graves' hyperthyroidism [ 46 ]. This suggests that thyroid antibodies may be involved in any
thyroid cell death that occurs in Graves' thyroid, and we have suggested that the neutral TSHR-Abs
may be responsible [ 47 ]. In contrast, there are extensive data on the importance of apoptosis in the
thyroid destruction of Hashimoto's disease. (See "Pathogenesis of Hashimoto's thyroiditis (chronic
autoimmune thyroiditis)" .)

Mechanisms of T-cell activation — The T-cell receptor sees antigen in the context of HLA. This
means that the T-cell receptor complexes with an HLA molecule on the surface of an antigen
presenting cell ( figure 4 ); CD8+ cells with HLA class I molecules and CD4+ cells with HLA class II
molecules. This complex forms only when the appropriate antigenic peptide (for example from the
TSHR) is present in the binding pocket of the HLA molecule. Data show that residue Arg 74 is
important for the binding of thyroid related peptides, and helps explain the HLA association with
Graves’ disease [ 48 ]. Once this complex is formed, the T-cell requires an additional stimulus to
proliferate and secrete cytokines. This additional stimulus is called "co-stimulation" and is provided by
co-stimulatory molecules on the same T-cell and antigen presenting cells ( figure 4 and table 2 ) [ 49 ].
If no co-stimulation occurs, the T-cell may become anergic or even apoptotic. Thyroid cells express
MHC molecules in autoimmune thyroid disease and may express co-stimulatory molecules (such as
CD40), aiding in intrathyroidal T-cell activation.

Changing the T-cell population — Perturbing the T-cell repertoire, in particular, disrupting the Treg
cells, can result in Graves' hyperthyroidism in susceptible patients by facilitating production of TSHR-
Ab. In a group of 27 patients with multiple sclerosis (a Th1-predominant disease) treated with a
monoclonal antibody to T-cells, peripheral blood CD4+ and CD8+ T-cell counts fell to less than 20
percent of normal for at least 18 months and multiple-sclerosis disease activity decreased in all
patients, but nine developed Graves' hyperthyroidism 6 to 31 months after treatment [ 50 ]. Graves'
hyperthyroidism has also occasionally been a complication of interferon alpha treatment in patients
with hepatitis C, again thought to be on the basis of changes in T-cell repertoire [ 51 ]. A similar
explanation is given for the improvement in Graves’ disease by the onset of pregnancy where the
action of Treg cells is enhanced [ 52 ].

Intrathyroidal T-cell receptor V gene repertoire — As discussed above, T-cells are activated by the
binding of complexes of HLA (major histocompatibility molecules) and antigenic peptides processed
from proteins by antigen-processing cells. These complexes bind to antigen receptors on the surface of
T-cells. These receptors consist of two non-covalently linked chains (alpha and beta), each with
variable (V), diversity (D), and junctional (J) regions and common constant regions. The V, D, and J
genes code for the sites on the receptors that recognize the MHC-antigen complex, affording antigenic
specificity. In addition to the many V (>100) and J (>50) genes present in the genome, random
nucleotide additions and deletions to the D region add immense complexity to the T-cell antigen
receptor repertoire, causing this region to be the major site of antigen recognition [ 53 ].

Evidence for an etiologic role for T-cells in Graves' hyperthyroidism is the finding that the antigen
receptors of T-cells isolated from thyroid tissue are the products of a limited number of V-gene
families [ 54-56 ]. This observation suggests that the thyroid tissue of these patients attracts and
activates T-cells with particular types of antigen receptors, rather than nonspecifically.
In support of this concept is evidence for clonally expanded T-cell populations within the thyroid gland
in Graves' disease. These data have been obtained by direct sequencing of the genes for T-cell antigen
receptors from intrathyroidal T-cells [ 56-58 ]. These results indicate limited T-cell heterogeneity in
Graves' disease and point to the primacy of T-cells in disease etiology. The findings are similar to those
in synovial tissue from patients with rheumatoid arthritis and central nervous system plaques from
patients with multiple sclerosis [ 59 ]. However, as the pathologic process progresses, there is likely to
be a less restricted response [ 60 ].

The role of suppressor effects of T-cells — The role of Treg cells in thyroid disease is less clear. The
finding of reduced numbers of circulating CD8 T-cells in patients with hyperthyroid Graves' disease
was originally consistent with the hypothesis that lack of suppressor/cytotoxic T-cells might be
responsible for a breakdown of tolerance and persistent production of TSHR-Ab in these patients [ 61 ].
We now understand that the immune system exerts some of its overall control via Treg
(CD4+CD25+Foxp3+) cells which exert "suppression" by cytokine secretion and cell-cell contact. This
function may be diminished in Graves’ disease although not all studies have found this [ 62,63 ]. The
role of Th17 cells remains to be clarified. Even if there were only subtle defects in regulatory T-cell
function in patients with Graves' hyperthyroidism, the phenomena of deletion and anergy will also
contribute to antigen-specific tolerance [ 64,65 ]:

 Deletion of immune cells via apoptosis occurs when immature T and B cells bind antigens in
the absence of co-stimulatory molecules.
 Anergy occurs when mature immune cells bind antigen in the absence of costimulatory
molecules, leading to desensitization rather than deletion.

IMMUNE MECHANISMS OF DISEASE — A variety of immune mechanisms may be involved in


the pathogenesis of Graves' hyperthyroidism. The major mechanisms for which there is some evidence
are molecular mimicry (specificity crossover), thyroid-cell expression of HLA (human leukocyte-
associated) molecules (antigens), and bystander activation.

Molecular mimicry — Molecular mimicry implies structural similarity between some infectious or
other exogenous agent and human proteins, such that antibodies and T-cells activated in response to the
exogenous agent react with the human protein, in this instance one or more thyroid proteins. As an
example, in an analysis of 600 monoclonal antibodies raised against a large variety of viruses, 4
percent of the monoclonal antibodies cross-reacted with uninfected tissues [ 66 ]. With respect to
Graves' hyperthyroidism, there is no strong evidence that molecular mimicry plays a role. The
suggestive evidence is:

 The serum of some patients contains antibodies that react with antigens derived from Yersinia
enterocolitica [ 67 ]. Furthermore, serum from some patients recovering from Yersinia
infections blocks the binding of TSH to its receptors. In addition, in a report of twins
discordant for Graves' disease, the twin with Graves' disease had an increased odds ratio of
prior Yersinia infection [ 68 ]. However, patients who have or have had infections with these
organisms do not have thyroid dysfunction.
 Structural similarities between retroviral sequences and the TSH receptor have been detected [
69 ].
 Bacterial heat shock proteins can elicit antibody and T-cell responses, which may cross-react
with host heat shock proteins. Heat shock protein 72 can be detected in thyroid tissue from
patients with Graves' hyperthyroidism but not in thyroid tissue from normal subjects [ 70 ].

Of note, this use of the term molecular mimicry should not be confused with the relationship between
hyperthyroidism and orbitopathy in Graves' disease, where it is likely that the two tissues contain a
closely related antigen(s), such as the TSHR, so that a cross-over immune reaction against a thyroid
antigen affects the retroorbital tissues. (See "Pathogenesis and clinical features of Graves'
ophthalmopathy (orbitopathy)" .)

Thyroid cell expression of HLA molecules — Thyroid epithelial cells from patients with autoimmune
thyroid disease (including Graves' disease) but not normal subjects express MHC (HLA) class II
molecules, notably HLA-DR molecules ( picture 1 ). This expression could be the direct result of viral
or other infections of thyroid epithelial cells, or it may be induced by cytokines such as IFy produced
by T-cells that have been attracted to the gland either by an infection or directly because of the
presence of thyroid antigens [ 71 ].

Class II molecule expression provides a mechanism for presentation of thyroid antigens to and
activation of autoreactive T-cells, with the potential for persistence of thyroid disease. Several
experimental observations provide support for this hypothesis:

 Induction of class II molecules on thyroid epithelial cells by interferon gamma can induce
autoimmune thyroiditis in susceptible mice [ 72 ].
 Viruses can directly induce class II molecule expression on thyroid cells, independent of
cytokine secretion [ 73,74 ].
 Thyroid epithelial cells expressing class II molecules can present viral peptide antigens to
cloned T-cells [ 75 ]. Thyroid antigen-specific T-cell clones in normal rats react specifically
with cloned autologous thyroid cells in the absence of more conventional antigen-presenting
cells [ 76 ].
 An animal model of Graves' disease induced by cells expressing the TSHR is only effective
when the cells also express MHC class II antigens [ 13,14 ].

These findings strongly support the view that an insult, such as infection, may induce class II molecule
expression on human thyroid cells and that these cells then may act as antigen-presenting cells to
initiate an autoimmune response. The expression of a T-cell co-stimulator molecule, CD40, on thyroid
epithelial cells indicates that co-stimulatory molecules are available for this action. In addition,
intrathyroidal dendritic cells and B cells may also serve as potent antigen-presenting cells [ 49 ]. The
description of hyperthyroidism in mice immunized with fibroblasts co-expressing class II molecules
and human TSH receptors provides further evidence that cells need not be "professional" antigen-
presenting cells to present antigen so long as they can acquire the ability to express class II molecules [
13 ].

However, the context in which HLA class II is induced by cytokines is of prime importance. As an
example, transgenic mice with thyroid cells which secrete IFy limited experimental thyroiditis even in
susceptible strains and this may be due to the high local concentration of IFy [ 60 ].

Bystander activation — In order for this model of HLA class II antigen expression and presentation of
antigens to be realized there must be a local insult to initiate the responses. As mentioned above, this
may take the form of a direct insult to the thyroid by a viral infection of the thyroid cells or of immune
cells. Even the arrival of activated T-cells within the thyroid gland may perhaps initiate such a series of
events in a susceptible subject with the appropriate immune repertoire. Evidence has mounted that such
bystander activation of local T-cells, which may not be thyroid specific, may exert via cytokines a
marked activation effect on resident thyroid-specific T-cells. Evidence for such bystander effects has
been obtained in an animal model of viral induced autoimmune insulitis [ 77 ] and in experimental
autoimmune thyroiditis [ 78 ]. The attractiveness of this sequence of events is that many different types
of infections would lead to the same clinical disease phenotype.

PRECIPITATING AND PREDISPOSING FACTORS — Several factors that predispose to Graves'


hyperthyroidism have been proposed ( table 3 ).

Genetic susceptibility — There is abundant epidemiologic evidence for genetic susceptibility to


Graves' hyperthyroidism and chronic autoimmune thyroiditis ( table 4 ) [ 79-81 ].

 The diseases cluster in families and are more common in women.


 The concordance rate in monozygotic twins is 20 to 40 percent.
 The sibling recurrence rate for Graves' disease exceeds 10.0 [ 82 ].
 There are associations with a number of immune-related genes which have also been found
with many other autoimmune diseases and presumably underpin the inherited susceptibility to
autoimmunity; for example, with certain alleles of CTLA-4 (cytotoxic T lymphocyte-
associated 4) [ 81,83 ]. As an example, in one study of 379 patients with Graves'
hyperthyroidism in the United Kingdom, 42 percent had a particular allele (G allele) of the
CTLA-4 gene, as compared with 32 percent of 363 normal subjects [ 81,83 ].
 In keeping with an immune-related susceptibility seen in almost all autoimmune diseases,
there is a well known association with certain alleles of HLA on chromosome 6 [ 79 ]. As an
example, a study of Caucasian patients in North America found that HLA-DRB1*08 and
DRB3*0202 were associated with the disease and that DRB1*07 was protective [ 84 ].
Detailed studies have shown convincingly that the presence of Arg-74 is the important peptide
in the HLA DR binding pocket rather than just the HLA subtype [ 48,85 ]. As far as thyroid
specific gene associations are concerned, there is now evidence of increased risks associated
with polymorphisms of intron 1 in the TSH receptor gene [ 86-89 ] and the thyroglobulin gene
[ 90 ]. The data suggest that the influence of HLA and thyroglobulin polymorphisms is more
than additive.
 The associated risks with these gene associations are all relatively low so that their assessment
is not clinically useful.

Infection — Autoimmune thyroiditis can be induced in experimental animals by certain viral


infections. If infection were the direct cause of Graves' hyperthyroidism, an identifiable agent should
be present in the majority of patients and it should be possible to induce the disease by transferring the
agent. Possible infections of the thyroid gland itself (eg, subacute thyroiditis, congenital rubella) have
been associated with thyroid autoimmune disease and could initiate class II molecule expression.
Hepatitis C infection is a well recognized precipitator of autoimmune thyroid disease when treated with
interferon therapy, although most commonly a thyroiditis develops rather than Graves’ disease [ 91 ].
There is, however, no evidence that these or any other infections or exposures lead directly to
autoimmune thyroid disease in the majority of patients [ 92 ]. However, a report of retroviral sequences
in the thyroid glands of patients with Graves' disease was not confirmed [ 93,94 ].

Stress — As compared with normal subjects or patients with toxic nodular goiter, patients with
Graves' hyperthyroidism more often give a history of some type of psychologic stress, in particular
negative life events such as loss of a spouse or a road traffic accident, before the onset of their
hyperthyroidism [ 95-97 ]. In general, stress appears to induce a state of immune suppression, possibly
mediated by the actions of cortisol on immune cells. Stress-induced suppression may be followed by
rebound immunologic hyperactivity. Such a response could precipitate autoimmune thyroid disease in
genetically susceptible subjects.

Gender — More women develop Graves' hyperthyroidism than men, with a ratio of approximately 7:1,
an effect that is often said to be mediated in some way by more estrogen or less testosterone. There is a
large body of evidence that moderate amounts of estrogen enhance immunologic reactivity [ 98-100 ].
However, it is just as likely that the X-chromosome is the source of the enhanced susceptibility rather
than sex steroids since the susceptibility continues after the menopause. For example, X-chromosome
inactivation has been associated with autoimmune thyroid disease [ 101 ].

Smoking — Smoking is a risk factor for Graves' hyperthyroidism (relative risk approximately 2.0) and
an even stronger risk factor for Graves' orbitopathy [ 102-104 ]. The mechanism is uncertain [ 105 ].

Pregnancy — Severe Graves' disease is uncommon during pregnancy because hyperthyroidism is


associated with reduced fertility and increased pregnancy loss. When it occurs, however, it can
endanger both mother and fetus. Luckily, pregnancy is a time of immune suppression so that the
disease tends to improve as pregnancy progresses. During pregnancy, both T-cell and B-cell functions
are diminished, while Tregs increase dampening the disease [ 52,106 ]. The slow rebound from this
immunosuppression after delivery results in enhanced immune reactivity and this contributes to the
development of postpartum thyroid disease, including the new onset or recurrence of Graves’ disease [
107 ].

It has also been suggested that fetal microchimerism (the presence of fetal cells in maternal tissue)
might play a role in the development of postpartum autoimmune thyroid disease [ 108 ]. Up to 30
percent of young women give a history of pregnancy in the 12 months before the onset of Graves'
disease [ 58 ], indicating that postpartum Graves' disease is a surprisingly common presentation and
that pregnancy is a major risk factor in susceptible women.
Drugs — Iodine and iodine-containing drugs such as amiodarone may precipitate Graves' disease, or a
recurrence of Graves' disease, in a susceptible individual [ 109 ]. Iodine is most likely to precipitate
thyrotoxicosis in an iodine deficient population simply by allowing the TSHR-Abs to be effective in
stimulating more thyroid hormone to be formed. Whether there is any other precipitating event is
unclear. Iodine and amiodarone may also damage thyroid cells directly and release thyroid antigens to
the immune system [ 110 ]. Interferon alpha treatment of patients with hepatitis C infection has been
widely associated with the development of autoimmune thyroiditis but Graves' disease may also be
precipitated presumably by influencing the immune repertoire [ 111 ].

SUMMARY — Hyperthyroidism is the most common feature of Graves' disease, affecting nearly all
patients, and is caused by autoantibodies to the thyrotropin (TSH) receptor (TSHR-Ab) that activate the
receptor, thereby stimulating thyroid hormone synthesis and secretion and thyroid growth (causing a
diffuse goiter). The presence of TSHR-Ab in the serum and orbitopathy on clinical examination
distinguishes the disorder from other causes of hyperthyroidism.

 TSHR-Abs stimulate the thyroid gland and are specific for Graves' disease, in contrast to
thyroglobulin (Tg) and thyroid peroxidase (TPO) antibodies. They bind mainly to the leucine-
rich repeat region of the TSHR ectodomain to which the TSH binds ( figure 2 ). (See
'Autoantibodies to the TSH receptor' above.)
 T-cells are present in patients with Graves' disease that react with appropriately processed
peptides derived from all thyroid autoantigens but in particular the TSHR ( figure 3 ). These
activated T-cells in turn increase the secretion of thyroid-specific autoantibodies from B cells.
Thyroid-specific T-cells in Graves' disease primarily act as helper (CD4) rather than
suppressor or cytotoxic (CD8) cells. (See 'T-cells in Graves' disease' above.)
 A variety of immune mechanisms may be involved in the pathogenesis of Graves'
hyperthyroidism. The major mechanisms for which there is reasonable evidence are thyroid-
cell expression of HLA (human leukocyte-associated) molecules (antigens) associated with
bystander activation. (See 'Immune mechanisms of disease' above.)
 Possible precipitating and predisposing factors include genetic susceptibility, infection, stress,
smoking, pregnancy, and iodine. (See 'Precipitating and predisposing factors' above.)

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