THYROTOXICOSIS 0889-8529/98 $8.00 + .

OO

THE PATHOGENESIS OF
GRAVES' DISEASE
Bryan McIver, MBChB, PhD, and John C. Morris, MD

Graves' disease is an autoimmune condition of the thyroid. Ultimately, the

hyperthyroidism manifested by patients affected by the disease is caused by the
production of autoantibodies against the thyrotropin receptor (TSH-R), which
mimic the effects of the hormone on thyroid cells, thereby stimulating autono-
mous production of thyroxine and triiodothyronine. However, the derangement
of immune function ultimately leading to the production of these pathologic
autoantibodies is complex, involving B and T cells and several autoantigens in
addition to TSH-R. Best known among these autoantigens are thyroid peroxidase
( P O ) and thyroglobulin, although increasing evidence suggests the involvement
of other thyroid proteins. This article discusses current theories regarding the
pathogenesis of Graves' disease, autoimmunity, possible predisposing and pre-
cipitating factors, the nature and character of the autoantigens involved, and
prospects for specific immunotherapy for this autoimmune disease.

EPIDEMIOLOGY

Autoimmune thyroid disease is the most common of the organ-specific

autoimmune diseases, with spontaneous hypothyroidism being approximately
fivefold more common than Graves' disea~e."~ The annual incidence of Graves'
disease in the Whickham a population-based survey in England, was
approximately 80 per 100,000 women per year, with most other surveys re-
porting incidence rates ranging from 15 to 50 per 100,000 persons per year.", 23,
*', 37* 38 The annual incidence in English men was less than 10 per 100,000,1'3
approximately eight to ten fold lower than in women, in keeping with gender
differences seen in other thyroid diseases.116The incidence of Graves' disease

From Mayo Graduate School of Medicine (BM); the Division of Endocrinology, Mayo
Clinic and Foundation (JCM); and Ma yo Medical School (JCM), Rochester, Minnesota

~ ~ ~ ~ ~ ~~~~~~~~~~~~~~

ENDOCRINOLOGY AND METABOLISM CLINICS OF NORTH AMERICA

- -
VOLUME 27 NUMBER 1 MARCH 1998 73
74 McIVER & MORRIS

seemed to rise between 1935 and 1967 in a retrospective survey of Olmsted

County, and between two surveys performed in Malmo, Sweden,
in 197011and 1990.12These observed changes in incidence may reflect improved
case detection as the result of improved methods of diagnosis rather than real
changes in the underlying incidence rates; however, an effect of increased iodine
intake has also been postulated.66, The incidence of Graves’ hyperthyroidism
in Japan, an area of particularly high iodine intake, has been reported to be as
high as 200 cases per 100,000 general population?0 Similarly, increases in the
apparent incidence of Graves’ disease have been reported following the intro-
duction of iodine supplementation,12,37, 54 although in Switzerland, an area of
mild-to-moderate iodine deficiency, iodine supplementation was associated with
a 33% reduction in the incidence of Graves’ disease.I0Further long-term, popula-
tion-based studies are needed.
Although Graves’ disease may present at any age, it is most commonly
seen in adults aged 20 to 50 years.”, 47, 116 It is seen less often in children, at

least p r e p ~ b e r t a l l y .Even
~ ~ ~ in children, however, a female preponderance per-
sists, with girls aged less than 15 years tenfold more likely to have Graves’
disease in comparison with boys of the same age.125

AUTOIMMUNE ASPECTS OF GRAVES’ DISEASE

Evidence for the autoimmune basis of Graves’ disease first emerged with
the detection of a long-acting thyroid stimulator in the serum of patients, and
the recognition that it was distinct from TSH.’ The serum-stimulated iodine
release from the thyroid glands of guinea pigs occurred more slowly and for a
longer period than did pituitary release of TSH. Subsequently, identification of
long-acting thyroid stimulator as an IgG62and of TSH-R as the target for the
antibody occurred over several years.3h The antibodies against TSH-R were
initially found in less than 50% of patients with the disease, leading some
investigators to doubt their pathogenetic significance.10zHowever, improved
assay systems resulted in the detection of thyroid-stimulating antibodies (TSAb)
in peripheral blood in more than 95% of affected, untreated patients.z1,83, ‘I4 The
remaining patients most likely express antibodies transiently at levels below
current levels of detection or possibly at high levels only within the thyroid
itself, with very low concentrations detectable in peripheral blood. It is now
widely accepted that all patients with Graves’ disease possess these autoantibod-
ies which bind to TSH-R and cause its activation, resulting in the uncontrolled
production and release of thyroid hormones. The stimulation of thyroid cellular
activity in vitro by IgG from affected patients’ as well as the passive transfer of
transient hyperthyroidism from pregnant women to their fetuses and newbornsi8
are the strongest direct evidence of the importance of the immunoglobulin in
the pathogenesis of Graves’ disease.
Lymphocytic infiltrates within the thyroid glands of patients with Graves’
disease have been recognized for many years, although the degree of infiltration
is highly variable?* The overlap in histologic appearance between Graves’ dis-
ease and Hashimoto’s thyroiditis is prominent, with only the presence of hyper-
trophic, hyperplastic follicles marking the overproduction of thyroid hormones
characteristic of Graves’ disease. The lymphocytic infiltrate is characterized by a
preponderance of T cells and a smaller number of B cells and plasma cells seen
in association with germinal centers, reminiscent of the lymphoid tissue seen in
association with mucous membranes [mucosa-associated lymphoid tissue
(MALT)] and termed thyroid-associafed lymphoid tissue (TALT).”
 THE PATHOGENESIS OF GRAVES DISEASE 75

A proportion of patients with Graves’ disease undergo spontaneous remis-

sion or experience hypothyroidism in the long possibly related to the
follicular cell destruction seen in both Hashimoto’s thyroiditis and Graves’
diSea~e.6~ Patients with Graves’ disease also express antibodies against TPO and
thyroglobulin at similarly high levels as patients with autoimmune hypothyroid-
The presence of TSH-R-blocking antibodies that bind the TSH receptor in
a similar fashion to the antibodies in patients with Graves’ disease but that
block rather than activate the receptor explains some cases of atrophic hypothy-
roidism.I5 The recognition that some patients with Graves’ disease can experi-
ence periods of hypothyroidism, and that this correlates with the appearance of
TSH-R-blocking antibodies in the serum, completes the apparent continuum of
autoimmunity between Hashimoto’s thyroiditis and hypothyroidism on one
extreme and Graves’ hyperthyroidism on the other.s6
The presence of lymphocytic infiltrates in the extraocular muscles of patients
with Graves’ ~ p h t h a l m o p a t h yand
~ ~ in the subcutaneous tissue of patients with
derm~pathy:~ and the close association of these three apparently distinct aspects
of Graves’ disease, emphasize the systemic nature of the autoimmune process.s9
Whether these apparently disparate manifestations of the disease process repre-
sent a common underlying immune system defect, a single common abnormal
antigen, or the presence of antibodies which cross-react with several antigens
remains the subject of considerable discussion.
There is a clear association between Graves’ disease and the other organ-
specific autoimmune syndromes, including type I diabetes mellitus, Addison’s
disease, vitiligo, myasthenia gravis, and premature ovarian failure.lZhThe exis-
tence of syndromes of failure of multiple endocrine organs, including
Hashimoto’s thyroiditis and Graves’ disease, often in association with evidence
of a generalized immune defect (the polyglandular autoimmune syndromes7’)
supports the hypothesis that these conditions have a common etiology, and that
this is likely to be a subtle but generalized immune system abnormality.

AUTOANTIGENS IN GRAVES’ DISEASE

Patients with Graves’ disease commonly have antibodies to several thyroi-

dal antigens. The most important and frequent of these are directed toward
TSH-R. Other antigens that are frequent targets in the disease include TPO and
thyroglobulin, and recent studies suggest that the thyroidal iodide transporter
may also represent an a ~ t o a n t i g e n . ~ ~
96 , Whereas anti-TSH-R antibodies are
clearly important in the pathogenesis of the disease, anti-TPO and anti-thyro-
globulin seem to have little role, serving instead as markers of thyroid autoim-
munity and susceptibility.112The latter two antigens are not discussed further,
and the interested reader is directed to recent reviews for additional informa-
tion.”, 76, Autoantibodies against the iodide transporter have been detected in
sera of patients with Graves’ disease and Hashimoto’s thyroiditis, but their
pathophysiologic significance is not yet

Thyrotropin Receptor

The TSH-R is the most important autoantigen in Graves’ disease. Antibodies

directed against it mimic the effects of TSH, stimulating thyroid cell function
and causing hyperthyroidism, and it is apparent that all patients with the disease
harbor such antibodies. The TSH-R molecule is a membrane-bound glycoprotein
76 MclVER & MORRIS

which, characteristic of G protein-linked receptors, spans the membrane seven

times. The amino terminal portion of the molecule constitutes an approximately
400-amino acid extracellular domain that contains most of the binding regions
for the ligand hormone,s2,**, lol although some evidence suggests that the small
loops lying between the membrane-spanning segments may also contribute to
this activity.18,46
After interaction of TSH-R with TSH or TSAb, G protein-linked
mechanisms activate adenylate cyclase which produces CAMP.Although CAMP
generation seems to be responsible for the majority of intracellular processes
that occur subsequent to ligand binding, other signaling mechanisms, especially
inositol phosphate turnover and intracellular calcium ion fluxes, are also af-
fected.

immune Response to Thyrotropin Receptor

All patients with Graves’ disease and some patients with other forms of
autoimmune thyroid disease express autoantibodies against TSH-R. However,
the magnitude of the response (titer), the bioactivity of the autoantibodies, and
the range of epitopes involved are highly heterogeneous.
Thyroid-stimulating antibodies which bind to TSH-R and which mimic the
effects of TSH leading to autonomous hyperactivity of the gland are the most
frequently recognized types in Graves’ disease. Current in vitro bioassays detect
these antibodies in circulating plasma in more than 80% to 100% of patient^.^^,^^,
86, 114 However, some autoantibodies bind to TSH-R without exerting stimulating
activity and may, by blocking the binding of TSH, inhibit thyroid f~nction.~, **
Although most often recognized in patients with primary hypothyroidism, these
thyroid-blocking antibodies are also present in some patients with hyperthyroid
Graves’ disease in association with the more typical stimulatory ones.6o,72, 84
Cloning and the subsequent ability to express recombinant TSH-R have
allowed detailed examination of the epitopes for autoantibodies. Most of these
epitopes lie within the extracellular 84, *y although evidence also
exists for involvement of the transmembrane domain, especially the small loops
lying between the membrane-spanning 84 Identification of the spe-
cific regions of TSH-R that are responsible for this interaction has been more
elusive, however; and considerable controversy exists in the literature as to the
nature of these sites. Several phenomena most likely explain this confusion,
including a highly heterogeneous antibody response to TSH-R, the finding that
the antibodies recognize both conformational and linear epitope~,”~and the
apparent low titer of the antibodies in sera?? making direct assessment of their
activity and sites of interaction difficult.

ALTERED IMMUNE SYSTEM FUNCTION IN

GRAVES’ DISEASE

Evidence for abnormalities in immune system function is commonly found

in patients with Graves’ disease. This includes the presence of circulating autoan-
tibodies directed against a variety of antigens, discussed previously. Circulating
levels of various cytokines, including the interleukins 1, 4, 8, and 10 and inter-
feron gamma, are also present in the peripheral blood of patients with Graves’
disease at higher than normal concentration^.^^, 52 The source of these circulating
cytokines is probably the thyroid, and many of the interleukins are expressed at
 THE PATHOGENESIS OF GRAVES DISEASE 77

high levels in the thyroid of patients with Graves’ di~ease,~, l l R mainly by intra-

thyroidal lymphocytes.118
Numerous and often contradictory reports describe changes in the pattern
of circulating T lymphocytes in Graves’ disease.33Clearly, however, activated T
cells directed against thyroidal and nonthyroidal antigens are present in periph-
eral blood from patients with Graves’ disease8,85 and in the thyroid it~e1f.l”~
When stimulated by nonspecific activators, such as phytohemagglutinin, these
lymphocytes produce relatively less IL-2, tumor necrosis factor alpha (TNF-
alpha), and interferon gamma and more IL-4, IL-5, and IL-10 than normals,
consistent with a so-called “Th2” pattern, indicating a bias towards B-cell matu-
ration and an antibody-mediated immune response.s5A similar Th2 pattern has
been observed in thyroid tissue in Graves’ disease:9 particularly in patients with
high concentrations of circulating TPO antibodies. However, T cells from retro-
orbital tissues of patients with Graves’ ophthalmopathy exhibit a Thl pattern,
with production of IL-2, interferon gamma, and TNF-alpha but not IL-4 or IL-
10, suggesting that these cells support a predominantly cell-mediated immune
response.24These divergent results in different tissues, affected presumably by
the same disease process, suggest that the type of immune response is a function
of the tissue and most likely the offending autoantigen rather than being caused
by an underlying defect in the immune system.
Thymic hyperplasia has been reported in untreated Graves’ disease. This
tissue involutes rapidly but incompletely with antithyroid drug treatment.87In
the same study, both mRNA encoding TSH-R and the protein itself were de-
tected in normal thymic tissue of patients without evidence of Graves’ disease.
Given the central role of the thymic microenvironment in determining self-
versus nonself-recognition by T lymph0cytes,3~it is tempting to speculate that an
abnormality of thymic function might be involved in the etiology of autoimmune
thyroid disease. However, other than in rare cases of polyglandular autoimmune
syndrome, which may represent an inherited T-cell defect79 and which are
associated with yeast infections and generalized impairment of mucosal de-
fenses, patients with Graves’ disease do not sustain obviously impaired immune
system function other than their predisposition to autoimmunity.

IMMUNE TOLERANCE AND SELF-RECOGNITION IN

GRAVES’ DISEASE

The most widely accepted concept for the development of autoimmune

disease is that it arises as a failure of the immune system to distinguish self
from nonself, triggering a cascade of humoral and cell-mediated responses
against the offending autoantigen. The induction of self-tolerance is a complex
and incompletely understood phenomenon involving both the elimination of
(by apoptosis) and the induction of anergy or unresponsiveness in self-reactive
T cells in the thymus and peripheral tissues. This subject has been reviewed
extensively and elegantly elsewhere.30,12* Briefly, T lymphocytes mature in the
specialized microenvironment of the thymus, where self-antigens (presumably
including TSH-RS7)are complexed with class I1 major histocompatibility complex
(MHC) molecules on the surface of thymic epithelial cells. Recognition of the
antigen-MHC complex by the T-cell receptor (TCR) of T lymphocytes, in the
absence of essential costimulator signals (most likely, B7CD28/CTLA-497)on
the thymic epithelium, results in apoptosis and removal of the self-reactive T-
cell clone (Fig. 1A). This process does not eliminate all self-reacting clones,
however, removing only cells with the highest affinity for autoantigens or
78 McIVER & MORRIS

Thymus cell Naive T-cell

Apoptosis or Anergy

Clonal expansion
Immune cascade
Antigen Presenting Cell T-cell
0
u
I
Self-reactive T-cell Receptor

/ Costimulator

Apoptosis or Anergy

C
Figure 1. A, The mechanism of self-tolerance involves the elimination of immature, self-
reactive T lymphocytes in the thymus. Interaction of the naive T cell (via its T-cell receptor)
with the thymus epithelial cell expressing MHC-class Wantigen complex, in the absence of
co-stimulator receptor activation, induces apoptosis or anergy in the T cell. B, Presentation
of antigen, together with activation of co-stimulator receptors, by specialized antigen-
presenting cells results in clonal expansion of the T cell and initiation of the immune system
cascade. C,Peripheral tolerance is maintained by the ability of nonimmune cells, including
thyrocytes, to express MHC/antigen complexes when stimulated by cytokines. If antigen is
recognized by weakly self-reactive T cells, the cytokine release from these cells induces
thyrocytes to express MHC/antigen complex. In the absence of co-stimulator receptor
activation, anergy again is induced in the T cell.

possibly with the highest number of surface TCRs." The remaining weakly self-
reactive T cells are subject to control by the process of peripheral t~lerance.'~
Expression o f M H C class I1 molecules/antigen complexes can be induced in
nonimmune cells (including thyrocytesloo) by various cytokines. In the presence
of these M H C class II/antigen complexes, and in the absence of the necessary
costimulatory signal(s), once again the T cells are inactivated'*' (Fig. 1C). The
maintenance o f self-tolerance therefore seems t o be a delicate balance between
weakly self-reactive T cells o n the one hand and inactivating factors o n nonim-
mune system cells o n the other. I f a self-reactive T cell becomes activated and
releases cytokines, the thyrocyte will respond by displaying antigen/MHC class
I1 complexes to inactivate the reaction before a n inflammatory cascade can
commence.1o4Because T cells are essential for the maturation and maintenance
of B cells, antibodies will only be produced i f a T-cell clone becomes activated,
 THE PATHOGENESIS OF GRAVES DISEASE 79

and it seems that the maintenance of self-tolerance is a function exclusively of

T cells."6,121
It seems likely that the process of autoimmunity is triggered by the failure
of the system of immune tolerance. This could occur by one or more mecha-
nisms. First, a failure of apoptotic elimination of self-reactive T-cell clones in the
thymus would result in circulating high-affinity self-reactive T cells. This would
most likely result in aggressive early-onset autoimmunity rather than the usual
pattern of onset of symptoms in early and mid adult life. Secondly, an antigen
might be presented in adult life which has not previously been exposed to the
immune system or presented in the thymus. This antigen would then appear as
nonself and would be the focus of vigorous autoimmunity. It has been postu-
lated that such a phenomenon explains the development of sympathetic ophthal-
mia which results in bilateral ophthalmitis following injury to the lens of one
eye, a presumed "immune-privileged" site.""
An alternative hypothesis is that, whereas thymic elimination of high-
affinity self-reactive T cells is normal, there is a failure of local peripheral
tolerance permitting activation of the weakly self-reactive cells which are not
eliminated in the thymus. This could result from a T-cell defect, causing failure
of the inactivation normally signaled by interaction of a TCR with the MHC/
antigen complex on the stimulated nonimmune cell. This might be expected to
be a global failure which would result in the development of autoimmunity
affecting multiple organ systems. Alternatively, the problem could lie at the
level of the thyrocyte. If this cell is recognized by a weakly self-reactive T cell
but fails to produce an adequate MHC/antigen complex, T-cell inactivation will
fail, the T cell will expand clonally, and further immune system cells will be
recruited to perpetuate the tissue injury.*2D
A third possibility is an increased availability of antigen. If antigen is
released from the thyrocyte and processed by antigen-presenting cells (dendritic
cells, macrophages, or B cells) which express both MHC/antigen complexes and
the necessary costimulators, even weakly reactive T cells might become activated
and trigger the immune cascade (Fig. 1B). Such antigen release might result
from direct cell injury ( e g , following radioactive iodine administration), from
stimulation by TSH or other growth stimuli increasing the surface expression of
the antigen, or alternatively from exogenous antigen ( e g , a cross-reacting anti-
gen carried by an infectious agent). Once initiated, the autoimmune process will
be unlikely to remain focused on a single recognized epitope. The phenomenon
of epitope spreading is well-recognized,'~4resulting in a broad-ranged antibody
and cell-mediated response to the affected tissue, and may result from the
processing by antigen-presenting cells of antigens released during the early
destructive phases of the immune response.
Unlike the lens of the eye, the thyroid is not an immune-privileged site,
with free access of lymphocytes to the normal thyroid. Thyroid injury does not
commonly precede the onset of Graves' disease, except in rare cases which arise
in glands previously treated with radioactive iodine for nonimmune disease.20
No antigen has been detected that is expressed uniquely in glands in Graves'
disease; early reports of polymorphisms of TSH-R which were associated with
subtypes of Graves' disease have not been confirmed in larger series. The multi-
organ involvement of Graves' disease and the multiplex autoimmune diseases
suggest a generalized immune system regulation defect, and linkage with HLA
haplotypes2*supports a role for MHC presentation or antigen processing as a
component of the immune system dysfunction.
80 MclVER & MORRIS

PRECIPITANTS OF THE AUTOIMMUNE PROCESS

Infection

Infectious processes can potentially initiate autoimmune phenomena if the

infecting agent possesses antigens sufficiently similar to host antigens to elicit a
cross-reactive response. The leading candidate as an infective trigger of Graves’
disease is Yersinia enterocolitica. Immunization of animals with coat proteins of
this bacteria can induce antibodies that cross-react with recombinant TSH-R
extracellular domain.70,71, 127 Evidence also exists for subclinical and persistent
infection with Yersinia in some patients with Graves‘ disease.’= However, evi-
dence that such infection in humans leads directly to autoimmunity and, spe-
cifically, thyroid autoimmunity is 1 a ~ k i n g .Furthermore,
l~~ the incidence of anti-
bodies that react with antigens of Yersinia in patients with Graves‘ disease has
been reported to be very low in some series.’” Currently, there is no conclusive
evidence that infection with Yersinia is a frequent causative agent in the etiology
of Graves’ disease.
Although the concept of infection of the thyroid gland leading to altered
antigen expression and autoimmunity has appeal, little firm evidence for this
mechanism in the pathogenesis of Graves’ disease exists.lO*For example, the
syndrome of painful (de Quervain’s) subacute thyroiditis is commonly recog-
nized, yet the development of thyroid autoimmunity and Graves’ disease follow-
ing the virally mediated disease is rare. Early reports of retroviral sequences
found within the thyroid glands of patients with Graves’ disease were not
confirmed by other investigators.*** 51 Thus, the hypothesis of viral infection as

an important etiology of Graves’ disease, however appealing, is supported by

little direct evidence.

Stress

Recent case-controlled studies have demonstrated that patients with Graves’

disease more often admit to major life stressors within the few months preceding
the onset of thyrotoxic sympt0rns.6~,95, Io3, 124 The pathophysiologic mechanism
behind the influence of such events on the autoimmune process is unclear but
could be related to alterations in the hypothalamic-pituitary-adrenal axis that
occur during and following the events, resulting in overall immune sup-
p r e s s i ~ n .6s~ ~
However,
, the onset of thyrotoxic symptoms is a poor marker of
the earliest immune events in the pathogenesis of Graves’ disease, thus recent
life events may have occurred after initiation of the disease process. The data
on and potential role of stress in the etiology of Graves’ disease, although
increasing, remain controversial.

Iodine

Studies performed in animals indicate that iodine intake and exposure are
important features in the development of experimental thyroid disease. Geneti-
cally susceptible rats develop thyroiditis more often when iodine is supple-
mented into their diet than when it is withheld.6 This does not occur in other
nonsusceptible strains, although other susceptible rat5 and chicken9strains have
been described. At least two mechanisms may be involved in the iodide effect.
The first is related to the degree of iodination of intrathyroidal thyroglobulin
 THE PATHOGENESIS OF GRAVES’ DISEASE 81

that occurs in various iodine states. Iodinated thyroglobulin is more highly

antigenic in comparison with poorly iodinated thyroglobulin, thus higher levels
of iodine intake may lead to more immune response to the thyroidal protein.”,
1a5*106Alternatively, iodide may generate oxygen free radicals within the thyroid,
leading to cellular toxicity more directly. Although numerous data support the
role of iodine in experimental thyroid disease, similar data in human thyroiditis
and especially in Graves’ disease are lacking and unconvincing. The most sug-
gestive human data come from the increased incidence of thyroiditis seen in
iodine-deficient populations after iodine supplementation is provided,l4,45 but
studies performed in iodine-replete areas have not found a relationship between
iodine intake and a u t ~ i m m u n i t y .Therefore,
~~ iodine intake does not seem to
have a major etiologic role in the etiology of Graves’ disease in areas of the
world that are not iodine-deficient.

MODULATORS OF THE AUTOIMMUNE PROCESS

Treatment of Graves‘ disease has remained largely unchanged during the

last four decades and consists of thyroid ablation, either with radioactive iodine
or surgery, or treatment with antithyroid drugs. None of these therapies is ideal,
having either a high rate of iatrogenic hypothyroidism or a high rate of treatment
fail~re.3~Modification of the underlying disease process holds promise of curing
Graves’ disease without the adverse effects of current treatment strategies.

Immunosuppressants

Corticosteroids and other immunosuppressive agents suppress the autoim-

mune process of Graves’ disease, but their associated side effects and risks
are generally regarded as excessive, except in rare cases of sight-threatening
opthalmopathy or as short-term adjunctive therapy while ablating the thyr~id.’~

Octreotide

Activated lymphocytes express receptors for somatostatin, which inhibits

their proliferation.2Scanning with radiolabeled octreotide, a long-acting somato-
statin analogue, reveals uptake in the thyroid and other affected tissues in
Graves’ disease.” Octreotide reduces soft-tissue inflammation and abrogates
the symptoms of Graves’ opthalmopathy, although it is less effective than
corticosteroids in reducing extraocular muscle size.64Its impact on the thyroidal
autoimmune process has not been assessed, but it seems likely that side effects
would limit its usefulness at the doses required to alter intrathyroidal autoimmu-
nity.

Antithyroid Drugs

The thiourea drugs propylthiouracil (PTU) and methimazole have been

used to treat thyroid disease for almost 50 years and work principally by
inhibition of the organification of iodine.11iPTU may inhibit peripheral conver-
sion of T4 to T3, although whether this effect is clinically significant remains
uncertain. In addition to these effects, an immunomodulatory role for antithy-
82 McIVER & MORRIS

roid drugs has been p o s t ~ l a t e d . In

’ ~ ~vitro assays of antithyroid drugs show
dose-dependent inhibition of lymphocyte pr01iferation.l~In vivo, the pattern of
circulating T lymphocytes returns toward although there is no appar-
ent impact on the intrathyroidal autoimmune Despite these findings,
the use of antithyroid drugs is associated with rapid and sustained reductions
in titers of TSH-R antibodies.**,7s In addition, prolonged courses of antithyroid
drugs seem to induce long-term remission in a higher proportion of patients
with Graves’ disease than do short courses? However, initial reports that high-
dose methimazole combined with thyroxine to maintain euthyroidism is more
effective at lowering TSH-R antibodies and inducing remission49have not been
confirmed, at least in whites.”, 93

Thyroid Ablation

Radioactive iodine ablation of the thyroid usually causes a fall in the

concentration of circulating TSH-R antibodies over several weeks, although this
may occur after a transient rise.25Surgical removal of the gland results in a
similar decrease, and both of these effects are thought to reflect the removal of
the autoantigen(s) responsible for the inflammatory process. Whether these
treatment modalities offer any advantages to the management of the extrathy-
roidal manifestations of Graves’ disease remains unknown.

PROSPECTS FOR SPECIFIC IMMUNOTHERAPY

Currently, intervening to modify the autoimmune process requires the use

of agents which affect many aspects of immunity. The use of blockers or
activators of specific T-cell receptors may, in the future, provide a means to
affect more specifically the autoimmune process without altering the immune
response to exogenous antigens. By presenting MHC/antigen complexes via
antigen-presenting cells, modified to reduce the expression of costimulatory
molecules, it may be possible to induce apoptosis or anergy in autoreactive T
cells. Such an approach would have the advantage of being highly selective for
lymphocytes directed against a specific antigen (for example, TSH-R), leaving
the remainder of the immune system entirely unaffected. However, epitope
spreading results in a range of antibodies (and therefore T- and B-cell clones)
directed against a number of different epitopes, often in the same patient.
Selective inactivation may prove to be too selective to impact on the course of
active Graves’ disease. Nevertheless, antigen-presenting cells modified to ex-
press cancer cell antigens in addition to costimulators have proven effective in
inducing an immune response against cancer cells in and a complemen-
tary approach inducing apoptosis or anergy in specific T-cell clones by the use
of antigen-presenting cells modified to present MHC/antigen complexes in the
absence of costimulators is conceivable. To date no such experiments have been
reported.
Monoclonal antibodies directed against specific T-cell receptors can modu-
late the immune response by stimulating or blocking T-cell surface receptors.16
The therapeutic use of such antibodies in autoimmune disease, however, must
await a more detailed understanding of the cell biology of the autoimmune pro-
cess.
 THE PATHOGENESIS OF GRAVES' DISEASE 83

Oral Tolerance
The oral administration of antigen can induce tolerance to the subsequent
systemic administration of the same antigen'" through its effect on the mucosa-
associated lymphoid tissue (MALT) of the gastrointestinal tract." This phenome-
non of induced oral tolerance has been investigated in a variety of experimental
and sporadic autoimmune diseases in both animals and humans and has proven
promising enough for a variety of trials to be started for human diseases,
including type I diabetes.Iz2The phenomenon may operate, in part, by changing
the balance of the immune response from a Thl-type towards a ThZtype
phenotype, reducing cytotoxicity and hence tissue However, an increase
in specific autoantibody titer and more acute disease progression have been
reported following the induction of oral tolerance in a marmoset model of
multiple sclerosis,41 and an increase in the incidence of autoimmune diabetes
was seen after high-dose oral feeding of antigen to chimeric mice despite an
apparent successful induction of tolerance to antigen administered intrave-
no~sly.'~ These results suggest that the phenomenon of induced oral tolerance
is complex, and that its application to Graves' disease, already a Th2-type
response, may prove problematic. Nevertheless, oral administration of thyro-
globulin has been shown to induce tolerance and prevent the subsequent devel-
opment of experimental autoimmune thyroiditis in susceptible strains of mice
while simultaneously reducing the IgG antibody titers.44Whether such an ap-
proach might prove beneficial or harmful in humans awaits further study.

CONCLUSIONS

Understanding of Graves' disease, its etiology and pathogenesis, and the

underlying immune system abnormalities associated with it has advanced rap-
idly during the 40 years since Adams and Purves first described the long-acting
thyroid stimulator. Despite this new information, current therapeutic options
differ little from those available in the 1950s. Recent advances in our understand-
ing of immune system regulation and of self-tolerance in particular hold promise
that, in the future, we may be able to intervene in autoimmune disease in a
highly specific, effective, and safe manner to modify and correct the disease
process before irreversible damage occurs to the thyroid gland.

References

1. Adams D, Purves H: Abnormal responses in the assay of thyrotropin. Proc Univ

Otago Med School 34:11, 1956
2. Aguila M, Rodriguez A, Aguila-Mansilla H, et al: Somatostatin antisense oligodeoxy-
nucleotide-mediated stimulation of lymphocyte proliferation in culture. Endocrinol-
ogy 1371585, 1996
3. Ajjan R, Watson P, Weetman A. Detection of IL-12, IL-13, and IL-15 messenger
ribonucleic acid in the thyroid of patients with autoimmune thyroid disease. J Clin
Endocrinol Metab 82:666, 1997
4. Allannic H, Fauchet R, Orgiazzi J, et al: Antithyroid drugs and Graves' disease: A
prospective randomized evaluation of the efficacy of treatment duration. J Clin
Endocrinol Metab 70:675, 1990
5. Allen E, Braverman L: The effect of iodine on lymphocytic thyroiditis in the thymecto-
mized buffalo rat. Endocrinology 127:1613, 1990
6. Allen E, Appel M, Braverman L: The effect of iodide ingestion on the development of
84 McIVER & MORRIS

spontaneous lymphocytic thyroiditis in the diabetes-prone BB/W rat. Endocrinology

118:1977.1986
7. Arikawa’ K, Ichikawa Y, Yoshida T, et al: Blocking type antithyrotropin receptor
antibody in patients with nongoitrous hypothyroidism: Its incidence and characteris-
tics of action. J Clin Endocrinol Metab 60:953, 1985
8. Aust G, Lehmann I, Laue S, et al: Activated and interferon-gamma producing thyroid-
derived T cells are detected in Graves’ disease, thyroid autonomy as well as in non-
toxic multinodular goiter. Eur J Endocrinol 13560, 1996
9. Bagchi N, Brown T, Urdanivia E, et al: Induction of autoimmune thyroiditis in
chickens by dietary iodine. Science 230:325, 1985
10. Baltisberger B, Minder C, Burgi H: Decrease of incidence of toxic nodular goitre in a
region of Switzerland after full correction of mild iodine deficiency. Eur J Endocrinol
132546, 1995
11. Berglund J, Christensen S, Hallengren B: Total and age-specific incidence of Graves’
thyrotoxicosis, toxic nodular goitre and solitary toxic adenoma in Malmo, 1970-74. J
Intern Med 227:137, 1990
12. Berglund J, Ericsson U, Hallengren B: Increased incidence of thyrotoxicosis in Malmo
during the years 1988-1990 as compared to the years 1970-1974. J Intern Med
23957, 1996
13. Blanas E, Carbone F, Allison J, et al: Induction of autoimmune diabetes by oral
administration of autoantigen. Science 274:1707, 1996
14. Boukis M, Koutras D, Souvatzoglou A, et al: Thyroid hormone and immunological
studies in endemic goiter. J Clin Endocrinol Metab 57859, 1983
15. Bryant W, Bergert E, Morris J: Identification of thyroid blocking antibodies and
receptor epitopes in autoimmune hypothyroidism by affinity purification using syn-
thetic TSH receptor peptides. Autoimmunity 2269, 1995
16. Buysmann S, Schellekens P, Tax W, et al: The pathology of autoimmune thyroid
disease: A review. Different CD3/T cell receptor monoclonal antibodies have distinct
capacities to induce adhesion of T lymphocytes to endothelium. J Lab Clin Med
130:91, 1997
17. Chabernaud M, Lagorce J, Ratinaud M, et al: Methimazole inhibits peripheral lym-
phocyte proliferation by inducing S-quiescent phase arrest. Int J Immunopharmaco!
18:499, 1996
18. Chazenbalk G, Nagayama Y, Russo D, et al: Functional analysis of the cytoplasmic
domains of the human thyrotropin receptor by site-directed mutagenesis. J Biol Chem
265:20970, 1990
19. Chen Y, Inobe J, Weiner H: Inductive events in oral tolerance in the TCR transgenic
adoptive transfer model. Cell Immunol 178:62, 1997
20. Chiovato L, Santini F, Vitti P, et al: Appearance of thyroid stimulating antibody and
Graves’ disease after radioiodine therapy for toxic nodular goitre. Clin Endocrinol
40:803, 1994
21. Chiovato L, Vitti P, Bendinelli G, et al: Detection of antibodies blocking thyrotropin
effect using Chinese hamster ovary cells transfected with the cloned human TSH
receptor. J Endocrinol Invest 17809, 1994
22. Ciampolillo A, Marini V, Mirakian R, et al: Retrovirus-like sequences in Graves’
disease: Implications for human autoimmunity. Lancet 1:1096, 1989
23. Cox SP, Phillips DI, Osmond C: Does infection initiate Graves’ disease? A population
based 10 year study. Autoimmunity 4:43, 1989
24. de Carli M, DElios M, Mariotti S, et al: Cytolytic T cells with Thl-like cytokine
profile predominate in retroorbital lymphocytic infiltrates of Graves’ ophthalmopathy.
J Clin Endocrinol Metab 771120, 1993
25. DeGroot L: Radioiodine and the immune system. Thyroid 7259, 1997
26. Delemarre F, Simons P, Drexhage H: Histomorphological aspects of the development
of thyroid autoimmune diseases: Consequences for our understanding of endocrine
ophthalmopathy. Thyroid 6:369, 1996
27. dos Remedios L, Weber P, Feldman R, et al: Detecting unsuspected thyroid dysfunc-
tion by the free thyroxine index. Arch Intern Med 140:1045, 1980
28. Dugoujon J, Cambon-Thomsen A: Immunoglobulin allotypes (GM and KM) and their
 THE PATHOGENESIS OF GRAVES DISEASE 85

interactions with HLA antigens in autoimmune diseases: A review. Autoimmunity

22245, 1995
29 Ebner S, Lueprasitsakul W, Alex S, et al: Iodine content of rat thyroglobulin affects
its antigenici<yin inducing lymphocytic thyroiditis in the BB/W or ;at.-Autoimmunity
13209, 1992
30 Eguchi K, Matsuoka N, Nagataki S: Cellular immunity in autoimmune thyroid dis-
ease. Baillieres Clin Endocrinol Metab 9:71, 1995
31. Endo T, Kogai T, Nakazato M, et al: Autoantibody against Na + /I-symporter in the
sera of patients with autoimmune thyroid disease. Biochem Biophys Res Commun
224:92, 1996
32. Endo T, Ohmori M, Ikeda M, et al: Rabbit antibodies toward extracellular loops
of the membrane spanning region of human thyrotropin receptor possess thyroid
stimulating activities. Biochem Biophys Res Commun 181:1035, 1991
33. Flynn S, Nishiyama R, Bigos S Autoimmune thyroid disease: Immunological, patho-
logical and clinical aspects. Crit Rev Clin Lab Sci 26:43, 1988
34. Franklyn J: The management of hyperthyroidism. N Engl J Med 330:1731, 1994
35. Fricchione G, Stefan0 G: The stress response and autoimmunoregulation. Adv Neu-
roimmunol413,1994
36. Furmaniak J, Smith B: The structure of thyroid autoantigens. Autoimmunity 763,1990
37. Furszyfer J, Kurland L, McConahey W, et al: Graves’ disease in Olmsted County,
Minnesota, 1935 through 1967. Mayo Clin Proc 45:636, 1970
38. Galofre J, Garcia-Mayor R, Fluiters E, et al: Incidence of different forms of thyroid
dysfunction and its degrees in an iodine sufficient area. Thyroidology 6:49, 1994
39. Gardner D, Centor R, Utiger R Effects of low dose oral iodide supplementation on
thyroid function in normal men. Clin Endocrinol 28283, 1988
40. Garside P, Mowat A: Mechanisms of oral tolerance. Crit Rev Immunol 17:119, 1997
41. Genain C, Abel K, Belmar N, et al: Late complications of immune deviation therapy
in a nonhuman primate. Science 174:2054,1996
42. Gessl A, Wilfing A, Agis H, et a1 Activated naive CD4 + peripheral blood T cells in
autoimmune thyroid disease. Thyroid 5:117, 1995
43. Gong J, Chen D, Kashiwaba M, et a1 Induction of antitumor activity by immunization
with fusions of dendritic and carcinoma cells. Nat Med 3:558, 1997
44. Guimaraes V, Quintans J, Fisfalen M, et al: Suppression of development of experimen-
tal autoimmune thyroiditis by oral administration of thyroglobulin. Endocrinology
1363353, 1995
45. Harach H, Escalante D, Onativia A, et al: Thyroid carcinoma and thyroiditis in an
endemic goitre region before and after iodine prophylaxis. Acta Endocrinol 108:55,
1985
46. Haraguchi K, Saito T, Endo T, et al: Disruption of the first extracellular loop of
thyrotropin receptor prevents ligand binding. Life Sci 55:961, 1994
47. Haraldsson A, Gudmundsson S, Larusson G, et al: Thyrotoxicosis in Iceland 1980-
1982 An epidemiological survey. Acta Med Scand 217253, 1985
48. Hashizume K, Ichikawa K, Sakurai A, et al: Administration of thvroxine in treated
Graves’ disease: Effects on the level of antibodies to thyroid-stimulating hormone
receptors and on the risk of recurrence of hyperthyroidism. N Engl J Med 324:947,
1991
49. Heuer M, Aust G, Ode-Hakim S, et al: Different cytokine mRNA profiles in Graves‘
disease, Hashimoto’s thyroiditis, and nonautoimmune thyroid disorders determined
by quantitative reverse transcriptase polymerase chain reaction (RT-PCR). Thyroid
697, 1996
50. Heufelder A: Involvement of the orbital fibroblast and TSH receptor in the pathogene-
sis of Graves’ ophthalmopathy. Thyroid 5:331, 1995
51. Humphrey M, Mosca J, Baker J, et a1 Absence of retroviral sequences in Graves’
disease. Lancet 337:17, 1991
52. Hussain M, Peakman M, Gallati H, et al: Elevated serum levels of macrophage-
derived cytokines precede and accompany the onset of IDDM. Diabetologia 39:60,
1996
53. Jaume J, Kakinuma A, Chazenbalk G, et al: Thyrotropin receptor autoantibodies in
86 McIVER & MORRIS

serum are present at much lower levels than thyroid peroxidase autoantibodies:
Analysis by flow cytometry. J Clin Endocrinol Metab 82:500, 1997
54. Kalk W, Kalk J: Incidence and causes of hyperthyroidism in blacks. South Afr Med J
75114, 1989
55. Kallmann B, Huther M, Tubes M, et al: Systemic bias of cytokine production toward
cell-mediated immune regulation in IDDM and toward humoral immunity in Graves’
disease. Diabetes 46:237, 1997
56. Kasagi K, Hidaka A, Nakamura H, et al: Thyrotropin receptor antibodies in hypothy-
roid Graves’ disease. J Clin Endocrinol Metab 76:504, 1993
57. Kasagi K, Konishi J, Iida Y, et al: A sensitive and practical assay for thyroid stimulat-
ing antibodies using FRTLS thyroid cells. Acta Endocrinol (Copenh) 11530, 1987
58. Kasuga Y, Sugenoya A, Kasuga Y, et al: Development of hypothyroidism with thyroid
stimulation blocking antibody long after treatment with antithyroid drugs in a patient
with hyperthyroid Graves’ disease: A case report. Endocr J 40:227, 1993
59. Kiljanski J, Nebes V, Wall J: Significance of tissue specific and tissue nonspecific
autoimmune reactions of Graves’ disease. Clin Exp Rheumatol 14(suppl 15):S69, 1996
60. Kosuai S, Ban T, Akamizu T, et al: Identification of seuarate determinants on the
thyrotiropin receptor reactive with Graves’ thyroid-stimhating antibodies and with
thyroid-stimulating blocking antibodies in idiopathic myxedema: These determinants
have no homologous sequence on gonadotropin receptors. Mol Endocrinol6:168,1992
61 Kosugi S, Ban T, Kohn L D Identification of thyroid-stimulating antibody-specific
interaction sites in the N-terminal region of the thyrotropin receptor. Mol Endocrinol
7114, 1993
62 Kriss J, Pleshakov V, Chien J: Isolation and identification of the long acting thyroid
stimulator and its relation to hyperthyroidism and circumscribed pretibial myxedema.
J Clin Endocrinol Metab 24:1005, 1964
63 Kung A: Life events, daily stresses and coping in patients with Graves’ disease. Clin
Endocrinol42:303, 1995
64 Kung A, Michon J, Tai K, et al: The effect of somatostatin versus corticosteroid in the
treatment of Graves’ ophthalmopathy. Thyroid 6:381, 1996
65 Kusnecov A, Rabin B: Stressor-induced alterations of immune function: Mechanisms
and issues. Int Arch Allergy Immunol 105:107, 1994
66. Laurberg P, Pedersen K, Vestergaard H, et al: High incidence of multinodular toxic
goitre in the elderly population in a low iodine intake area vs high incidence of
Graves’ disease in the young in a high iodine intake area: Comparative surveys of
thyrotoxicosis epidemiology in East-Jutland, Denmark and Iceland. J Intern Med
229:415, 1991
67. LiVolsi V: The pathology of autoimmune thyroid disease: A review. Thyroid 4333,
1994
68. LiVolsi V Thyroid pathology. In Braverman L, Utiger R (eds): The Thyroid: A
Fundamental and Clinical Text, ed 7. Philadelphia, Lippincott-Raven, 1996, p 497
69. Ludgate M, Vassart G: The molecular genetics of three thyroid autoantigens: Thyro-
globulin, thyroid peroxidase and the thyrotropin receptor. Autoimmunity 7201,1990
70. Luo G, Fan J, Seetharamaiah G, et al: Immunization of mice with Yersiniu enterocoliticu
leads to the induction of antithyrotropin receptor antibodies. J Immunol 151:922,1993
71. Luo G, Seetharamaiah G, Niesel D, et al: Purification and characterization of Yersiniu
enterocoliticu envelope proteins which induce antibodies that react with human thyro-
tropin receptor. J Immunol 152:2555, 1994
72. Macchia E, Concetti R, Carone G, et al: Demonstration of blocking immunoglobulins
G, having a heterogeneous behaviour in sera of patients with Graves’ disease: Possible
coexistence of different autoantibodies directed to the TSH receptor. Clin Endocrinol
(Oxf) 28:147, 1988
73. Mansi L, Rambaldi P, Bizzarro A, et al: “‘In-octreotide in the evaluation of autoim-
mune thyroid diseases. Q J Nucl Med 39(suppl 1):127, 1995
74. McFarland H: Complexities in the treatment of autoimmune disease. Science
274:2037, 1996
75. McIver 8, Rae P, Beckett G, et al: Lack of effect of thyroxine in patients with
 THE PATHOGENESIS OF GRAVES’ DISEASE 87

Graves’ hyperthyroidism who are treated with an antithyroid drug. N Engl J Med
334220,1996
76. McKenzie J, Zakarija M: Antibodies in autoimmune thyroid disease. In Braverman L,
Utiger R (eds): The Thyroid: A Fundamental and Clinical Text, ed 7. Philadelphia,
Lippincott, 1996, p 416
77. McLachlan S, Rapoport B: The molecular biology of thyroid peroxidase: Cloning,
expression and role as autoantigen in autoimmune thyroid disease. Endocr Rev
13192, 1992
78. Mestman J: Hyperthyroidism in pregnancy. Clin Obstet Gynecol 40:45, 1997
79. Leor J, Levartowsky D, Sharon C: Polyglandular autoimmune syndrome, type 2.
South Med J 82374, 1989
80. Morgenthaler N, Tremble J, Huang G, et al: Binding of antithyrotropin receptor
autoantibodies in Graves’ disease serum to nascent, in vitro translated thyrotropin
receptor: Ability to map epitopes recognized by antibodies. J Clin Endocrinol Metab
81:700, 1996
81. Morris J, Bergert E, Bryant W Binding of IgG from patients with autoimmune thyroid
disease to rat sodium-iodide symporter peptides: Evidence for the iodide transporter
as an autoantigen. Thyroid 7527, 1997
82. Morris J, Bergert E, McCormick D Structure-function studies of the human thyrotro-
pin receptor: Inhibition of binding of labeled thyrotropin (TSH) by synthetic human
TSH receptor peptides. J Biol Chem 268:10900, 1993
83. Morris J, Hay I, Nelson R, et al: Clinical utility of thyrotropin-receptor antibody
assays: Comparison of radioreceptor and bioassay methods. Mayo Clin Proc 63:707,
1988
84. Morris J, Gibson J, Haas E, et al: Identification of epitopes and affinity purificatic,. of
thyroid stimulating auto-antibodies using synthetic human TSH receptor peptides.
Autoimmunity 17287, 1994
85. Mullins R, Cohen S, Webb L, et al: Identification of thyroid stimulating hormone
receptor-specific T cells in Graves’ disease thyroid using autoantigen-transfected
Epstein-Barr virus-transformed B cell lines. J Clin Invest 96:30, 1995
86. Murakami M, Miyashita K, Kakizaki S, et al: Clinical usefulness of thyroid-stimulating
antibody measurement using Chinese hamster ovary cells expressing human thyrotro-
pin receptors. Eur J Endocrinol 1995:80, 1995
87. Murakami M, Hosoi Y, Negishi T, et al: Thymic hyperplasia in patients with Graves’
disease: Identification of thyrotropin receptors in human thymus. J Clin Invest
982228, 1996
88. Nagayama Y, Wadsworth HL, Russo D, et al: Binding domains of stimulatory and
inhibitory thyrotropin (TSH) receptor autoantibodies determined with chimeric TSH-
lutropin/chorionic gonadotropin receptors. J Clin Invest 88:336, 1991
89. Nagy EV, Burch HB, Mahoney K, et al: Graves’ IgG recognizes linear epitopes in the
human thyrotropin receptor. Biochem Biophys Res Commun 188:28, 1992
90. Okamura K, Nakashima T, Ueda K, et a1 Thyroid disorders in the general population
of Hisayama, Japan, with special reference to prevalence and sex differences. Int J
Epidemiol 16:545, 1987
91. Paschke R, Schuppert F, Taton M, et al: Intrathyroidal cytokine gene expression
profiles in autoimmune thyroiditis. J Endocrinol 141:309, 1994
92. Paschke R, Vogg M, Kristoferitsch R, et al: Methimazole has no dose-related effect on
the intensity of the intrathyroidal autoimmune process in relapsing Graves‘ disease. J
Clin Endocrinol Metab 802470, 1995
93. Pfeilschifter J, Ziegler R Suppression of serum thyrotropin with thyroxine in patients
with Graves’ disease: Effects on recurrence of hyperthyroidism and thyroid volume.
Eur J Endocrinol 136:81, 1997
94. Prummel M, Wiersinga W: Medical management of Graves’ ophthalmopathy. Thyroid
5231, 1995
95. Radosavljevic V, Jankovic S, Marinkovic J: Stressful life events in the pathogenesis of
Graves’ disease. Eur J Endocrinol 134:699, 1996
96. Raspe E, Costagliola S, Ruf J, et al: Identification of the thyroid Na + /I-cotransporter
88 McIVER & MORRIS

as a potential autoantigen in thyroid autoimmune disease. Eur J Endocrinol 132:399,

1995
97. Reiser H, Stadecker M: Costimulatory B7 molecules in the pathogenesis of infectious
and autoimmune diseases. N Engl J Med 335:1369, 1996
98. Resetkova E, Notenboom R, Arreaza G, et al: Seroreactivity to bacterial antigens is
not a unique phenomenon in patients with autoimmune thyroid diseases in Canada.
Thyroid 4:269, 1994
99. Rothenberg E: How T cells count. Science 273:78, 1996
100. Schuppert F, Reiser M, Scheumann G, et al: Expression levels of the thyrotropin
receptor gene in autoimmune thyroid disease: Coregulation with parameters of thy-
roid function and inverse relation to major histocompatibility complex classes I and
11. J Clin Endocrinol Metab 76:1349, 1993
101. Seetharamaiah G, Kesai R, Dallas J, et al: Induction of TSH binding inhibitory
immunoglobulins with the extracellular domain of human thyrotropin receptor pro-
duced using baculovirus expression system. Autoimmunity 14:315, 1993
102. Solomon D, Chopra I: Graves’ Disease-1972. Mayo Clin Proc 47:803, 1972
103. Sonino N, Girelli M, Boscaro M, et al: Life events in the pathogenesis of Graves’
disease: A controlled study. Acta Endocrinol 128:293, 1993
104. Sospedra M, Obiols G, Babi L, et al: Hyperinducibility of HLA class I1 expression of
thyroid follicular cells from Graves’ disease: A primary defect? J Immunol 1544213,
1995
105. Sundick R, Bagchi N, Brown T: The role of iodine in thyroid autoimmunity: From
chickens to humans. A review. Autoimmunity 13:61, 1992
106. Sundick R, Herdegen D, Brown T, et al: The incorporation of dietary iodine into
thyroglobulin increases its immunogenicity. Endocrinology 120:2078, 1987
107. Toivanen P, Toivanen A: Does Yersinia induce autoimmunity? Int Arch Allergy
Immunol 104:107, 1994
108. Tomer Y, Davies T: Infection, thyroid disease, and autoimmunity. Endocr Rev
14:107, 1993
109. Totterman T, Andersson L, Hayry P: Evidence for thyroid antigen-reactive T lympho-
cytes infiltrating the thyroid gland in Graves’ disease. Clin Endocrinol 11:59, 1979
110. Towler H, Lightman S: Sympathetic ophthalmia. Int Ophthalmol Clin 35:31, 1995
111. Tunbridge W, Caldwell G: The epidemiology of thyroid diseases. In Braverman L,
Utiger R (eds): The Thyroid, ed 6. Philadelphia, Lippencott, 1991, p 578
112. Vanderpump M, Tunbridge W The epidemiology of thyroid diseases. In Braverman
L, Utiger R (eds): The Thyroid, ed 7. Philadelphia, Lippincott, 1996, p 474
113. Vanderpump M, Tunbridge W, French J, et a1 The incidence of thyroid disorders in
the community: A twenty-year follow-up of the Whickham Survey. Clin Endocrinol
4355,1995
114. Vitti P, Elisei R, Tonacchera M, et al: Detection of thyroid-stimulating antibody using
Chinese hamster ovary cells transfected with cloned human thyrotropin receptor. J
Clin Endocrinol Metab 76:499, 1993
115. Vlase H, Graves P, Magnussion R, et a1 Human autoantibodies to the thyrotropin
receptor: Recognition of linear, folded, and glycosylated recombinant extracellular
domain. J Clin Endocrinol Metab 80:46, 1995
116. Volpe R: Graves’ disease. In Braverman L, Utiger R (eds): The Thyroid, ed 6. Philadel-
phia, Lippincott, 1991, p 648
117. Wartofsky L: Has the use of antithyroid drugs for Graves’ disease become obsolete?
Thyroid 3:335, 1993
118. Watson P, Pickerill A, Davies R, et al: Analysis of cytokine gene expression in Graves’
disease and multinodular goiter. J Clin Endocrinol Metab 79:355, 1994
119. Weetman A: The immunomodulatory effects of antithyroid drugs. Thyroid 4:145,1994
120. Weetman A: The potential immunological role of the thyroid cell in autoimmune
thyroid disease. Thyroid 4493, 1994
121. Weetman A, McGregor A: Autoimmune thyroid disease: Further developments in
our understanding. Endocr Rev 15:788, 1994
122. Weiner H: Oral tolerance for the treatment of autoimmune diseases. Annu Rev Med
48:341, 1997
 THE PATHOGENESIS OF GRAVES’ DISEASE 89

123. Wenzel B, Peters A, Zubaschev I Bacterial virulence antigens and the pathogenesis
of autoimmune thyroid diseases (AITD). Exp Clin Endocrinol Diabetes 104:75, 1996
124. Winsa B, Adami H, Bergstrom R, et al: Stressful life events and Graves’ disease.
Lancet 338:1475, 1991
125. Wong G, Kwok M, Ou Y: High incidence of juvenile Graves’ disease in Hong Kong.
Clin Endocrinol 43:697, 1995
126. Zelissen P, Bast E, Croughs R: Associated autoimmunity in Addison’s disease. J
Autoimmun 8:121, 1995
127. Zhang H, Kaur I, Niesel D, et al: Yersiniu enterocoliticu envelope proteins that are
crossreactive with the thyrotropin receptor (TSHR) also have B-cell mitogenic activity.
J Immunol 158:1976,1997

Address reprint requests to

Bryan McIver, MBChB PhD
Division of Endocrinology
W18 Mayo Building
200 First Street SW
Rochester, MN 55905