REVIEWS

AUTOIMMUNE THYROID DISEASE:

NEW MODELS OF CELL DEATH IN
AUTOIMMUNITY
Giorgio Stassi* and Ruggero De Maria‡
Autoimmunity to thyroid antigens leads to two distinct pathogenic processes with opposing
clinical outcomes: hypothyroidism in Hashimoto’s thyroiditis and hyperthyroidism in Graves’
disease. The high frequency of these diseases and easy accessibility of the thyroid gland has
allowed the identification of key pathogenic mechanisms in organ-specific autoimmune diseases.
In early investigations, antibody- and T-cell-mediated death mechanisms were proposed as
being responsible for autoimmune thyrocyte depletion. Later, studies on apoptosis have provided
new insights into autoimmune target destruction, indicating the involvement of death receptors
and cytokine-regulated apoptotic pathways in the pathogenesis of thyroid autoimmunity.

CENTRAL TOLERANCE
Autoreactive T cells that react
strongly with self-ligands are
eliminated during development
in the thymus by a process that
is known as negative selection.
CRYPTIC EPITOPES
Antigenic peptides that are
generated at sub-threshold
levels. When cryptic epitopes
become visible to the immune
system, they might elicit an
immune response that is
responsible for the
autoimmune disease.
*Department of Surgical
and Oncological Sciences,
University of Palermo,
Palermo, Italy.
‡
Laboratory of Haematology
and Oncology,
Istituto Superiore di Sanità,
Rome, Italy.
Correspondence to R.DM.
email: rdemaria@tin.it
DOI: 10.1038/nri750
Classically, autoimmune diseases are characterized by
the activity of autoreactive lymphocytes, which cause
tissue or organ damage through the formation of anti-
bodies that react against host tissues, or effector T cells,
which are specific for endogenous self-peptides1.
Environmental and genetic factors cooperate in the
induction of autoimmunity. Although several genes,
including certain major histocompatibility complex
(MHC) genotypes, are clearly associated with increased
susceptibility to autoimmunity, monozygotic twins do
not show complete concordance2,3. So, a disease-prone
genetic background might not be sufficient for the
clinical onset of autoimmunity.
Responses to self-tissue antigens result from ineffec-
tive control mechanisms that allow survival and expan-
sion of autoreactive lymphocyte clones. The activation of
autoreactive T cells that have escaped CENTRAL TOLERANCE
mechanisms in the thymus is prevented through
peripheral tolerance mechanisms that include the elim-
ination of autoreactive lymphocytes4,5 and the
inhibitory activity of CD4+CD25+ regulatory T cells6,7.
In some circumstances, autoimmunity can arise fol-
lowing protective T- and B-cell responses against
foreign antigens that cross-react with self-antigens
expressed by normal tissues. This phenomenon, which
is known as molecular mimicry, has been implicated in
the pathogenesis of myasthenia gravis and rheumatic
fever, but might also have a role in other common
autoimmune conditions, such as type 1 diabetes and
multiple sclerosis8,9. Moreover, a transient viral infec-
tion might initiate an autoimmune response that
could subsequently be amplified through the exposure
of CRYPTIC EPITOPES that are released by dying cells, a
phenomenon known as epitope spreading10.
Autoimmune diseases are broadly classified as organ
specific or systemic1. Organ-specific autoimmunity
involves chronic T-cell or antibody targeting of a partic-
ular organ. By contrast, systemic autoimmunity is often
the result of the breakdown of immunological tolerance
to ubiquitous self-molecules, which generates immune-
complex-mediated damage in several body sites11,12.
Thyroid autoimmune diseases represent more than
30% of all organ-specific autoimmunity. Hashimoto’s
thyroiditis is the first described and most common
organ-specific autoimmune disease, which affects
about 3% of the population and represents the arche-
type for other T-cell-mediated degenerative diseases,
such as type 1 diabetes and multiple sclerosis13–15.
However, the concept of cytotoxic T lymphocyte
(CTL)-mediated target destruction in thyroid autoim-
munity has recently been challenged16–19. Progress in
apoptosis research and studies of Graves’ disease, a

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GERMINAL CENTRES
Secondary lymphoid follicles
that contain reactive B cells
which undergo intense
proliferation, maturation and
death after encountering their
specific antigens.
ENDOCRINE
OPHTHALMOPATHY
A complex eye disease that is
characterized by lymphocyte
and chronic inflammatory-cell
infiltration in orbital tissues,
oedema and proliferation of
connective tissue.
GOITRE
Diffuse enlargement of the
thyroid gland.
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a Hashimoto's thyroiditis
help help
CD4
T cell
B cell CD8
T cell
Autoreactive Autoreactive
Plasma
cell
CTL
Thyroid cell
Necrosis/apoptosis Thyroid Apoptosis
cell death
Hypothyroidism
Figure 1 | Thyroid autoimmunity produces two opposite pathogenetic processes and clinical outcomes. a | During
Hashimoto’s thyroiditis, self-reactive CD4+ T lymphocytes recruit B cells and CD8+ T cells into the thyroid. Disease progression leads
to the death of thyroid cells and hypothyroidism. Both autoantibodies and thyroid-specific cytotoxic T lymphocytes (CTLs) have
been proposed to be responsible for autoimmune thyrocyte depletion. b | In Graves’ disease, activated CD4+ T cells induce B cells
to secrete thyroid-stimulating immunoglobulins (TSI) against the thyroid-stimulating hormone receptor (TSHR), resulting in
unrestrained thyroid hormone production and hyperthyroidism.
non-destructive form of thyroid autoimmunity, have
led to a new model of autoimmune target destruction in
Hashimoto’s thyroiditis.
Hashimoto’s thyroiditis and Graves’ disease
Hashimoto’s thyroiditis and Graves’ disease are the most
common forms — and the two extremes — of a wide
spectrum of mixed thyroid autoimmune conditions
that lead to thyrocyte death or hyperfunction15.
Hashimoto’s thyroiditis is characterized by an
inflammatory infiltrate of immunocytes that replace
the parenchyma and induce thyroid enlargement,
which eventually leads to gland fibrosis. Progressive
thyrocyte depletion results in impaired thyroid hor-
mone production and clinical hypothyroidism, a con-
dition that involves a marked reduction of metabolic
activity in various cells and tissues15. Hashimoto’s thy-
roiditis has been suggested to be a largely genetic disor-
der of cell-mediated immunity that promotes inflam-
mation and leads to autoantibody formation20. After
initiation of the autoreactive immune response by
CD4+ T cells, thyroid cells are induced to express MHC
class II molecules by interferon-γ (IFN-γ)-producing
activated lymphocytes, possibly contributing to the
expansion of autoreactive T-cell populations and pro-
longing the inflammatory response21,22. As a result,
massive lymphocyte accumulation is the main
© 2002 Macmillan Magazines Ltd
b Graves' disease
help
TSH-reactive
CD4 B cell
T cell
B cell
TSI
TSHR
Thyroid cell
survival
Hyperthyroidism
histopathological feature in glands of patients with
Hashimoto’s thyroiditis. Activated CD8+ and CD4+ T
cells, B cells, plasma cells and macrophages (sometimes
with the formation of ectopic GERMINAL CENTRES) consti-
tute the immunocyte infiltrate. Thyroid autoantibodies
have been proposed to participate in clinical hypothy-
roidism by blocking the thyroid-stimulating hormone
(TSH) receptor or by directly contributing to thyrocyte
destruction15 (FIG. 1).
In patients with Graves’ disease, the production of
anti-TSH-receptor antibodies promotes thyrocyte
growth and unrestrained thyroid hormone secretion,
resulting in the opposite clinical outcome to
Hashimoto’s thyroiditis — hyperthyroidism with
increased gland vascularity, mild lymphocytic infiltra-
tion, OPHTHALMOPATHY and GOITRE15. The autoimmune
process that leads to Graves’ disease is believed to begin
with the activation of thyroid-specific CD4+ T cells,
with subsequent recruitment into the thyroid of
autoreactive B cells and production of anti-thyroid
antibodies (FIG. 1). Although the pathogenetic mecha-
nisms that are responsible for hyperthyroidism have
been extensively characterized, the aetiology of Graves’
disease remains unclear.
Animal models of thyroid autoimmunity. Although a
spontaneous animal model of Graves’ disease is not
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a Plasma
cell
CTL
Thyroid
cell
Complement
activation
Necrosis Apoptosis
Figure 2 | Three different mechanisms of thyrocyte depletion in Hashimoto’s thyroiditis have been sequentially
proposed. a | Autoantibodies deposited as immune complexes on the follicular basement membranes might activate complement
and mediate thyrocyte necrosis. b | After a T-cell receptor/peptide–MHC interaction, cytotoxic T lymphocytes (CTLs) might kill target
thyrocytes through the release of granules that contain perforin and granzyme B. c | Autocrine or paracrine interactions between
death receptors and their ligands might result in thyrocyte apoptosis. MHC, major histocompatibility complex.
available, immunization of selected strains of mice
with either MHC-class-II-positive fibroblasts that
express the TSH receptor23,24, or with an expression
vector that contains the TSH receptor complementary
DNA25, results in hyperthyroidism in female mice.
Although the genetic immunization model has a lower
frequency of hyperthyroidism compared with fibrob-
last immunization, it relates more closely to the
human disease owing to the presence of lymphocytic
infiltration and ophthalmopathy. However, this model
has become available only recently and, so far, has
made only a limited contribution to the understanding
of the pathogenesis of Graves’ disease.
Several experimental models of autoimmune thy-
roiditis have been established on the basis of genetic
predisposition26–28, thyroid-antigen immunization29 or
transfer of cells primed with thyroid antigen30,31.
Studies of these animals have confirmed the central
role of CD4+ T cells in the induction32 and suppres-
sion33 of experimental autoimmune thyroiditis (EAT),
whereas B-cell responses and autoantibody production
might not have a primary role in thyrocyte targeting,
but seem to contribute to the amplification of the
inflammatory response34.
Although experimental models of thyroiditis have
provided considerable insights, significant thyrocyte
destruction is not observed during EAT, unless thy-
roglobulin-reactive T cells are treated in vitro with
anti-CD25 and interleukin-12 (IL-12) before injection.
However, this induces a granulomatous form of thy-
roiditis35, which is histologically distinct from
Hashimoto’s thyroiditis. So, high disease frequency
and easy accessibility of the thyroid gland make
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c Death
receptor
Suicide
Death
ligand
Apoptosis
human studies, at present, the primary source of infor-
mation for understanding the pathogenesis of thyroid
autoimmunity.
Mechanism of thyrocyte destruction
Three different mechanisms have been sequentially pro-
posed to be responsible for autoimmune thyrocyte
depletion (FIG. 2).
Antibodies. The cytotoxic activity of antibodies against
thyrocytes, as a result of immune-complex deposition
in follicular basement membranes and complement
activation, was first suggested in 1977 (REF. 36; FIG. 2). In
subsequent experiments, terminal complement com-
plexes that produce the membrane-attack complexes
were found around thyroid follicles15,37. Antibodies
against thyroid peroxidase in thyroiditis have the ability
to fix complement and have been proposed to promote
antibody-dependent cell-mediated cytotoxicity against
thyroid cells in vitro 38–40. These findings gave support to
the hypothesis that antibodies against the main thyroid
antigens, such as thyroglobulin and thyroid peroxidase,
were directly responsible for the autoimmune destruc-
tion of thyrocytes. Moreover, thyrocytes that were
attacked by complement were shown to release proin-
flammatory molecules, such as prostaglandin E2, IL-1
and IL-6, which might cause infiltration and activation
of lymphocytes, and direct injury of thyroid cells during
Hashimoto’s thyroiditis41. However, the presence and
titre of autoantibodies in euthyroid individuals and in
Hashimoto’s thyroiditis patients are variable and
scarcely correlate with the extent of thyrocyte deple-
tion15. Therefore, it is possible that the pathogenetic role
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a b
T cell T cell

Ligand

Man-6-P/IGF II R Death receptor

Perforin

Granzymes

BCL2 FADD
Caspase-8
Caspase-8 BID BCL-XL BCL2
cFLIP BCL-XL

Active BID
Caspase-3 Caspase-9 caspase-8
Cer GD3

Caspase-3 Caspase-9
Mitochondria
Apoptotic
substrates
Cytochrome c
Apoptotic
APAF-1 substrates
Cytochrome c
Apoptosis
APAF-1
Apoptosis
Figure 3 | Two independent pathways mediate T-cell cytotoxicity. a | After specific recognition of peptide–MHC complexes, cytotoxic T lymphocytes release lytic
granules that contain perforin and granzyme B. Perforin polymerizes and forms pores in the target cell membrane, while mannose 6-phosphate/insulin-like growth
factor II receptor (man-6-P/IGF II R) allows granzyme B — a serine protease able to directly activate effector caspases and apoptosis — to enter the cell. Caspase
activation is amplified by granzyme-mediated cleavage and activation of BID, a pro-apoptotic member of the BCL2 family that leads to cytochrome c release from
mitochondria, allowing the formation of a high-molecular-weight complex that contains cytochrome c, APAF-1 and caspase-9, which activates downstream caspases
(mitochondrial apoptotic pathway). This process is antagonized by BCL2 and BCL-X L. b | Binding of ligands to death receptors, such as CD178 to CD95 and TRAIL
(tumour-necrosis factor (TNF)-related apoptosis-inducing ligand) to TRAIL receptors, induces the recruitment of the adaptor molecule FADD/MORT-1 and procaspase-
8 to form the death-inducing signalling complex, which results in caspase-8 activation. Active caspase-8 migrates to the cytoplasm to cleave caspase-3 and BID and
amplify the apoptotic cascade. Ceramide (Cer) accumulation participates in this process by increasing the GD3 ganglioside levels and targeting mitochondria.
Although BCL2 and BCL-X L can antagonize this signal, a more effective inhibition of the apoptotic process is mediated by cellular FLICE/caspase-8 inhibitory protein
(cFLIP), which is recruited into the death-receptor signalling complex and prevents caspase-8 activation. GD3, disialoganglioside 3.

of thyroid-specific antibodies is essentially confined to thyroiditis contain perforin46. During autoimmune

their potential ability to amplify inflammation.
CTL activity. Later, attention was focused on the role of
T lymphocytes as effector cells responsible for thyrocyte
destruction. The engagement of death receptors and the
release of cytotoxic granules mediate effector-T-cell
cytotoxicity against target cells during the immune
response42,43. These two events are independent, but
exploit similar biochemical pathways to induce target-
cell apoptosis, which involves proteolytic cleavage of key
cellular substrates by caspases or granzymes44,45 (FIG. 3).
The exocytosis of perforin-containing granules by
CTLs on cognate recognition of target cells, and the
engagement of death receptors on cognate or neigh-
bouring target cells by effector T cells, mediates CTL
activity 42,43. Similar to normal peripheral lymphocytes,
a discrete portion of intrathyroidal T cells that are iso-
lated from the thyroids of patients with Hashimoto’s
inflammation, thyrocytes express MHC class II mole-
cules, and are therefore potential targets of both CD4+
and CD8+ cytotoxic T cells47,48 (FIG. 2). T-cell lines and
CD8+ T-cell clones obtained from Hashimoto’s thyroidi-
tis glands have shown specific cytotoxic activity against
autologous human thyroid cells49–51. However, freshly
isolated autoreactive T cells that are infiltrating the thy-
roid gland do not show any spontaneous cytotoxic
activity against thyroid cell targets15. Therefore, it is not
clear whether or not these cells contribute directly to
thyrocyte depletion by acting as cytotoxic effector cells.
Death receptors. Death receptors are a subgroup of the
tumour-necrosis-factor receptor (TNFR) superfamily,
which is characterized by a cytoplasmic death domain
that is responsible for the transmission of the apop-
totic signal. The interaction of death receptors with
their ligands activates apoptotic pathways in several

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Table 1 | Expression of apoptosis-related proteins in thyrocytes

Name Type Control GD HT References
CD95 (Fas/APO-1) Death receptors + ++ +++ 16,17,19,54,57–60,94
TRAILR1 (DR4) + ++ ++ 68, our unpublished data
TRAILR2 (DR5) + ND ND 68, our unpublished data
CD178 (FasL/CD95L) Death ligands + ++ +++ 16–19,57,59,60
TRAIL + ND +++ 67,68
FAP-1 Death inhibitors ++ ND ND 70
cFLIP + +++ + 19
Caspase-3 Pro-apoptotic + + +++ 19
molecules
Caspase-8 + + +++ 19
BAX – ND ++ 95, our unpublished data
BAK + ND ++ 95, our unpublished data
BCL2 Anti-apoptotic ++ +++ + 62,95
molecules
BCL-X L ++ +++ + 19
The table summarizes absent (–), low (+), high (++) and very high (+++) expression of pro-apoptotic and anti-apoptotic proteins in control,
Graves’ disease (GD) and Hashimoto’s thyroiditis (HT) thyroid follicular cells. cFLIP, cellular FLICE/caspase-8 inhibitory protein; FAP-1,
Fas-associated phosphatase-1; FasL, Fas ligand; ND, not determined; TRAIL, tumour-necrosis factor (TNF)-related apoptosis-inducing
ligand; TRAILR, TRAIL receptor.

physiological and pathological cell-death processes.
Triggering of death receptors transduces apoptotic sig-
nals through the activation of caspases, a family of
fourteen (known) proteases that induce proteolytic
cleavage of several cellular targets52. Activation of ini-
tiator caspases, such as caspase-8 and caspase-9, trig-
gers a cascade of biochemical signals that results in the
activation of downstream caspases and apoptotic cell
death52 (FIG. 3). BCL2 family members show pro-apop-
totic and anti-apoptotic activity by acting on mito-
chondria. The pro-apoptotic members, such as BAX,
BAK and BID, induce mitochondrial membrane per-
meabilization and cytochrome c release. This promotes
the formation of the apoptosome, a high-molecular-
weight complex that consists of apoptosis protease-acti-
vating factor 1 (APAF-1) and caspase-9, which activates
executioner caspases. By contrast, BCL2 and BCL-XL
antagonize this process by preventing the generation of
apoptotic signals by mitochondria53 (FIG. 3).
Inappropriate CD95 (Fas/APO-1)-mediated apop-
tosis has been proposed to be a common pathogenetic
mechanism in organ-specific autoimmune dis-
eases17,54–56. In the past few years, several reports have
investigated the expression and function of CD95 and
its ligand (CD178, also known as Fas ligand) in normal
and pathological tissues that are frequent targets of
destructive autoimmune responses, such as the thyroid,
pancreas and brain16,55,56. The results of these studies
indicate a potential involvement of CD95/CD178-
mediated apoptosis in the pathogenesis of Hashimoto’s
thyroiditis, type 1 diabetes and multiple sclerosis.
The pattern of CD95 and CD178 expression in nor-
mal and Graves’ disease thyrocytes is controversial.
Whereas some authors reported the absence of CD95
and presence of CD178 in control thyrocytes, others
showed the opposite (reviewed in REF. 57). Analysis of
CD95 expression in normal thyrocytes is hindered by
the low sensitivity of immunohistochemistry and by the
spontaneous upregulation of CD95 that is observed in
thyrocytes cultured ex vivo. Also, the absence of reliable
anti-CD178 antibodies in the earlier studies generated
controversy between different groups16,58–60. A further
setback derives from the minimal availability of normal
thyroid specimens and the use of samples from non-
toxic goitre or the contralateral lobe of tumour glands57
— which might have abnormal expression of CD95 and
CD178 — as a source of control thyrocytes. Although it
is not possible to draw a conclusive evaluation from
data in the literature, we have analysed normal thyroid
tissues from two laringectomy patients. We found that
both CD95 and, to a lesser extent, CD178 are expressed
at low levels in normal cells (G.S. and R.D.M., unpub-
lished observations). By contrast, there is general agree-
ment that both CD95 (REFS 19,61) and CD178 (REFS 19,62)
are substantially upregulated and simultaneously
expressed by thyrocytes during Hashimoto’s thyroiditis.
Although the expression of CD178 in the thyroid
inhibits the development of experimental autoimmune
thyroiditis by inducing the death of infiltrating T
cells63,64, implying a protective role for CD178 in this
model, Hashimoto’s thyroiditis thyrocytes are sensitive
to CD95 stimulation and probably die by autocrine or
paracrine expression of CD178 (REF 19; FIG. 2; also see
later discussion).
Other death-receptor ligands might participate in
thyrocyte killing, including TNF-α and the TNF-related
apoptosis-inducing ligand (TRAIL) (TABLE 1). TNF-α is
produced by immunocytes and possibly by thyrocytes
during autoimmune thyroiditis65. The ability of TNFR1
to promote CD95-induced thyrocyte apoptosis indicates
that TNF-α and CD178 might act in concert to produce
thyrocyte depletion in Hashimoto’s thyroiditis66.

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Although there is no experimental evidence as yet,
TRAIL and its receptors (TRAILR1 and TRAILR2)
might contribute to thyrocyte apoptosis in autoimmune
thyroiditis in a similar way to CD95 and CD178 (REFS 67,
68 and G.S. and R.D.M., unpublished results).
Regulation of thyrocyte survival
It is becoming increasingly clear that the rate of thyrocyte
apoptosis dictates the clinical outcome of thyroid
autoimmunity. The balance between the activities of
pro-apoptotic and anti-apoptotic proteins regulates thy-
rocyte survival. The best-characterized apoptosis-related
genes that are expressed in thyrocytes are death receptors
and their ligands, caspases and BCL2 family members
(TABLE 1).
After complete thyroid formation, normal thyro-
cytes have a very slow turnover rate and are supposed
to undergo very few divisions. Accordingly, apoptosis
has been observed only occasionally in normal thyroid
in vivo. By contrast, thyrocyte apoptosis is a common
finding during the active phases of Hashimoto’s thy-
roiditis19,61,69. Analysis of thyrocytes purified from
Hashimoto’s thyroiditis glands has shown that a vari-
able percentage of these cells undergoes spontaneous
apoptosis ex vivo, indicating that a substantial number
of thyrocytes are committed to cell death by some
apoptogenic factors during autoimmune thyroidi-
tis19,61. The duration of the autoimmune process,
which lasts several years, indicates that thyrocyte
depletion is slow and partially counterbalanced by the
capacity of thyroid replacement. In line with the clini-
cal course of the disease, thyrocyte apoptosis is not
detectable in glands from most patients with Graves’
disease, unless they undergo persistent treatment with
antithyroid drugs.
Normal thyrocytes constitutively express low levels of
several death receptors (TABLE 1). Thyrocyte priming by
cytokines or the use of cyclohexamide are required for
obtaining sensitivity to death-receptor ligands19,54,66. So,
low production of death-receptor ligands by normal
thyrocytes is not harmful. However, after pathological
modifications of the thyroid microenvironment, thyro-
cytes might increase their susceptibility to apoptosis and
acquire sensitivity to death-receptor stimulation. The
mechanisms responsible for the refractoriness of nor-
mal thyrocytes to CD95 stimulation might involve high
expression of Fas-associated phosphatase-1 (FAP-1), a
protein that interacts with the negative regulatory
domain of CD95 and blocks thyrocyte apoptosis70.
The activity of apoptotic and anti-apoptotic genes
during thyroid autoimmunity is a key determinant of
thyrocyte fate. A correlation between thyrocyte destruc-
tion and decreased expression of BCL2 has been pro-
posed as a pathogenetic factor that regulates the survival
of autoimmune thyrocytes62. Moreover, increased
expression of other anti-apoptotic genes in Graves’ dis-
ease thyrocytes, such as cellular FLICE/caspase-8
inhibitory protein (cFLIP) and BCL-XL, could help to
prevent thyrocyte apoptosis during autoimmune
aggression19. Expression and activation of caspases
could represent an important event leading to thyrocyte
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destruction in Hashimoto’s thyroiditis, as the extent of
thyrocyte apoptosis in vivo strictly correlates with the
intensity of caspase activation. In line with the apoptosis
pattern that is observed in thyroid autoimmune dis-
eases, caspase-3 and caspase-8 are upregulated and acti-
vated in Hashimoto’s thyroiditis thyrocytes, whereas
they seem to be normal in Graves’ disease19.
T cells and thyrocytes: who kills whom?
It has been proposed that CD178 expression in selected
tissues, such as the anterior chamber of the eye, con-
tributes to the formation of immune-privileged sites
through the CD95-mediated killing of potentially
harmful lymphocytes71,72. Similarly, CD178 expression
in cancer cells might contribute to tumour immune
privilege by inducing the deletion of T lymphocytes that
approach the tumour73–75. These hypotheses have been
challenged by some investigators, who believe that
CD178 expression does not promote immune privilege
or tumour escape76,77. Using CD178-transgenic mice or
exogenous CD178 expression in transplanted cells, sev-
eral studies reported accelerated destruction rather than
protection of tissues that express CD178 (REFS 76,78).
These experiments indicate that CD178-mediated
immune privilege might be restricted to very few cell
types, such as corneal epithelial cells72.
Normal thyrocytes are not sensitive to CD95 stimu-
lation and constitutively express low levels of CD178
(REFS 19,54). During autoimmune thyroiditis, simultane-
ous receptor and ligand upregulation in thyrocytes
could have remarkable effects on the survival of these
cells and neighbouring lymphocytes. In Hashimoto’s
thyroiditis, T cells that are located in proximity to thy-
roid follicles are apoptotic or seem committed to apop-
tosis, as shown by DNA fragmentation and cytoplasmic
accumulation of the pro-apoptotic GD3 (disialogan-
glioside 3) ganglioside18. In agreement with this, the
killing of infiltrating T cells by thyrocytes that are
ectopically or spontaneously expressing CD178 has
been shown in mouse models of EAT63,79. It is likely that
those intrathyroidal T lymphocytes that interact during
Hashimoto’s thyroiditis with thyroid follicular cells that
are producing large amounts of CD178 do not survive
and are gradually replaced by new infiltrating T cells18.
As a consequence of CD178 expression, thyroid epithe-
lium might constitute an immune-privileged site80.
However, increased CD95 expression and sensitivity dur-
ing human autoimmune thyroiditis might result in
thyrocyte death by autocrine or paracrine CD95–CD178
interactions16,19,62. Opposing this hypothesis, ectopic
expression of CD178 in the mouse thyroid was not
accompanied by autocrine or paracrine CD95-mediated
death63,64. In these animal models, thyrocyte survival in
the presence of CD178 might result from the strong inhi-
bition of the inflammatory response64, which is required
for promoting thyrocyte sensitivity to CD95 stimula-
tion19,66. In humans, however, both thyrocytes19 and lym-
phocytes18 that are resident in Hashimoto’s thyroiditis
glands are susceptible to CD95-induced apoptosis ex vivo
and probably die in vivo after intense thyrocyte CD178
production (FIG. 4).
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ANERGY
A condition of complete
unresponsiveness to antigens
that can affect both T and B cells.
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Thyroid cell
Death
ligand
Death
receptor
T-cell
apoptosis
Infiltrating
activated
T cell
T cell
Fratricide
Suicide
Figure 4 | Infiltrating T cells might be killed by thyrocytes during Hashimoto’s thyroiditis. Activated T lymphocytes in
autoimmune thyroiditis are extremely sensitive to CD95 stimulation and probably die after an interaction with CD178-expressing
thyrocytes. However, because Hashimoto’s thyroiditis thyrocytes acquire sensitivity to CD95 stimulation, they might also die through
suicide or fratricide mechanisms.
The rate of apoptosis in Hashimoto’s thyroiditis
glands seems higher for lymphocytes than for thyrocytes
both in vitro and in vivo18. However, dying T cells are
continuously replaced during the inflammatory process
and infiltrating T cells probably have an important role
in the amplification and perpetuation of the autoim-
mune response through the production of cytokines.
Cytokines and thyroid autoimmunity
Cytokines drive thyroid autoimmune responses by
influencing both immune and target cells at several
levels. T-cell-derived cytokines are the key regulators of
the autoimmune processes. They provide essential
support for the cell-mediated and humoral immune
response and dictate thyrocyte fate.
Cytokine expression in thyroid autoimmunity. Two
functionally distinct subsets of T-helper (TH) cells have
been characterized on the basis of cytokine production.
TH1 cells secrete IFN-γ and other cytokines that are
associated with inflammation and cell-mediated
immune responses, whereas TH2 cells promote the
humoral immune response and inhibit TH1 responses
by the release of IL-4, IL-5 and IL-10 (REF. 81). In fact,
TH2 cytokines have been shown to inhibit target
destruction in organ-specific autoimmunity82,83.
In line with their pathogeneses, analysis of cytokine
expression in autoimmune thyroid diseases has shown,
with a few exceptions84, a prevalence of TH2 cytokines in
Graves’ disease and TH1 cytokines in Hashimoto’s thy-
roiditis19,85, particularly at the level of activated intrathy-
roidal T cells86. During the active phase of Hashimoto’s
thyroiditis, infiltrating T cells produce IL-2 (REF. 86),
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Paracrine thyroid-cell
apoptosis (fratricide) Suicide
T cell
which acts as an autocrine and paracrine T-cell growth
factor and dictates the extent of the T-cell response. IL-2
also stimulates the synthesis of other T-cell-derived
cytokines, such as IFN-γ 87. This cytokine is a potent
macrophage activator and promotes inflammation and
effector CD8+ T-cell cytotoxicity. Moreover, IFN-γ con-
tributes to the amplification of the immune response by
inducing the expression of MHC class II molecules on
thyroid cells, an effect that is probably potentiated by
thyroid-stimulating antibodies in Graves’ disease and by
high TSH levels in hypothyroidal Hashimoto’s thyroiditis
patients21,22. On the other hand, in Graves’ disease, IL-4
and IL-10 might protect thyrocytes from TH1 responses
by inducing T-cell ANERGY, suppression of cytotoxic
responses and TH1 to TH2 switching88,89. Intrathyroidal
IL-4 and IL-10 production in Graves’ disease might
inhibit macrophage activation and block most of the
activating effects of IFN-γ, including increased produc-
tion of IL-1, nitric oxide and prostaglandins90,91. In sup-
port of this model, after promising experimental evi-
dence in transgenic mice, IL-10 has been proposed as a
potential therapeutic factor for preventing autoimmune
thyrocyte destruction92. It remains to be determined
whether CD4+CD25+ regulatory T cells have a role in
thyroid autoimmunity. These professional suppressor
cells produce IL-10 (REF. 93) in vivo and might therefore
influence the behaviour of both immune and target cells.
Cytokines and thyrocyte apoptosis. There is extensive evi-
dence that cytokines modify the expression of several
genes that are involved in the survival or death of
autoimmune target cells. In type 1 diabetes, the produc-
tion of IL-1β by infiltrating macrophages induces CD95
VOLUME 2 | MARCH 2002 | 2 0 1
REVIEWS
a Hashimoto's thyroiditis
IFN-γ
Caspases
Thyroid cell and CD95
upregulated
Death Death
ligand receptor
Cell death
Figure 5 | Model of thyrocyte fate in thyroid autoimmune diseases. a | Infiltrating CD4+ T cells seem to preferentially produce
T-helper type 1 cell (TH1) cytokines in Hashimoto’s thyroiditis and TH2 cytokines in Graves’ disease. Interferon-γ (IFN-γ) primes
thyrocytes for CD95-mediated destruction by inducing massive upregulation of CD95 and pro-apoptotic caspases in Hashimoto’s
thyroiditis. b | By contrast, interleukin-4 (IL-4) and IL-10 production might protect Graves’ disease thyrocytes from CD95-mediated
apoptosis through the upregulation of cellular FLICE/caspase-8 inhibitory protein (cFLIP) and BCL-XL.
expression in pancreatic β-cells through the activation of
inducible nitric-oxide synthase, resulting in a specific
destruction of insulin-producing cells in the presence of
CD178+ T lymphocytes55. Similarly, IFN-γ released by
autoreactive T cells might contribute to autoimmune
oligodendrocyte destruction in multiple sclerosis by
increasing CD95 expression and susceptibility to CD178-
mediated apoptosis17,56. Although accurate analysis is
hampered by early spontaneous CD95 upregulation in
cultured thyrocytes, both IL-1β and IFN-γ have been
shown to increase CD95 expression in thyrocytes
in vitro94. However, IFN-γ is more effective than IL-1β in
promoting CD95 expression and thyrocyte apoptosis,
and is therefore the most likely candidate for priming
CD178-mediated thyrocyte destruction in Hashimoto’s
thyroiditis19,66. Altered expression of apoptosis-related
proteins, as a result of different cytokine expression pro-
files, could explain the opposite fates of thyrocytes in
Graves’ disease and Hashimoto’s thyroiditis. The suscep-
tibility or resistance of thyrocytes to CD95-induced
apoptosis depend on the thyroid microenvironment and
are only temporary in thyrocytes analysed ex vivo 19. So,
the role of cytokines in the determination of thyrocyte
survival or death has been comparatively investigated in
Graves’ disease and Hashimoto’s thyroiditis.
Increased sensitivity of Hashimoto’s thyroiditis thy-
rocytes to apoptosis might depend on the IFN-γ-medi-
ated upregulation of key pro-apoptotic genes. IFN-γ
treatment increases caspase-3 and caspase-8 expression
and primes Hashimoto’s thyroiditis thyrocytes for
CD95-mediated destruction. By contrast, IL-4 and IL-10
upregulate BCL-XL and cFLIP, two key anti-apoptotic
proteins that can prevent CD95-induced apoptosis in
Graves’ disease thyrocytes19 (FIG. 5).
202 | MARCH 2002 | VOLUME 2
© 2002 Macmillan Magazines Ltd
b Graves disease
IL-4
IL-10
cFLIP and
BCL-XL
upregulated
Cell survival
According to this model, the predominance of TH1
or TH2 cytokines in the autoimmune microenviron-
ment of the thyroid dictates the outcome of both
destructive and non-destructive immune-mediated
processes by acting at two levels. First, they orchestrate
the immune response, and second, they directly regulate
the balance between pro- and anti-apoptotic proteins in
Hashimoto’s thyroiditis and Graves’ disease thyrocytes.
Future prospects
The mechanisms that are responsible for initiating thy-
roid autoimmune responses remain to be determined.
However, the high disease frequency and easy accessi-
bility of the thyroid gland have allowed substantial
advances in the definition of the immune mechanisms
that are involved in the survival or death of thyrocytes.
The relative contributions of individual death recep-
tors in thyrocyte destruction are not known at present.
In this context, it would be of great interest to deter-
mine how CD178 and TRAIL production by thyrocytes
is regulated, and whether the death receptor–ligand sys-
tems have a role in normal thyroid homeostasis. Weak
autocrine or paracrine interactions between CD178 or
TRAIL and their receptors might, for example, explain
the absence of thyrocyte growth observed in vivo,
which is rapidly reversed in vitro after thyroid follicle
disaggregation.
In addition, the role of CD4+CD25+ regulatory
T cells in the pathogenesis of thyroid autoimmunity
remains to be determined. These cells could markedly
influence both the extent of the autoimmune response
and the survival of thyrocytes through the release of
anti-inflammatory and anti-apoptotic cytokines such as
IL-10 and transforming growth factor-β (TGF-β).
www.nature.com/reviews/immunol

Although it is not clear whether the anti-apoptotic
activity of TH2 cytokines is a general phenomenon or
restricted to limited cell types, the model of cell death
versus cell survival presented in this article is not neces-
sarily confined to organ-specific autoimmune diseases.
Information on molecules and pathways that are
involved in destructive and non-destructive thyroid
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Acknowledgements
G.S. and R.D.M. are supported by the Associazione Italiana per la
Ricerca sul Cancro.
Online links
DATABASES
The following terms in this article are linked online to:
LocusLink: http://www.ncbi.nlm.nih.gov/LocusLink/
APAF-1 | BAK | BAX | BCL2 | BCL-XL | BID | caspase-3 |
caspase-8 | caspase-9 | CD95 | CD178 | cFLIP | cytochrome c |
FAP-1 | IFN-γ | IL-1 | IL-1β | IL-2 | IL-4 | IL-5 | IL-6 | IL-10 | IL-12 |
inducible nitric-oxide syntase | perforin | TGF-β | thyroglobulin |
thyroid peroxidase | TNF-α | TNFR superfamily | TRAIL |
TRAILR1 | TRAILR2 | TSH receptor
OMIM: http://www.ncbi.nlm.nih.gov/Omim/
Graves’ disease | Hashimoto’s thyroiditis | multiple sclerosis |
myasthenia gravis | type 1 diabetes
FURTHER INFORMATION
Encyclopedia of Life Sciences: http://www.els.net/
autoimmune disease
Access to this interactive links box is free online.
www.nature.com/reviews/immunol