Autoimmunity of the

Thyroid Gland

Medical Microbiology and Immunology

Learning Objectives:
1. Compare and contrast the pathogenesis, morphological and clinical features,
diagnosis and treatment of Hashimoto thyroiditis and Graves’ Disease.
2. Appraise the role of the following genes in the development of autoimmune
thyroid disease: HLA-DR, CTLA-4, CD40, PTPN22, thyroglobulin, TSH receptor.
3. Understand the role of CTLA-4 in the development/prevention of autoimmune
disease.
4. Compare and contrast the effects of thyroid-stimulating antibodies and thyroid-
inhibitory antibodies on the clinical manifestation of Graves’ disease.
5. Describe, in general, the known/proposed pathogenic mechanisms, and
morphological and clinical features of subacute granulomatous and subacute
lymphocytic thyroiditis.
Required Readings:
• Essentials of Clinical Immunology: Chapter 15
• Robbins Pathology: Chapter 24

Suggested Readings:
• Michels, A. W. and Eisenbarth, G.S. Immunologic Endocrine
Disorders. J Allergy and Clinical Immunol. 2010;125:S226-37.
Autoimmune diseases are characterized by
the activity of auto-reactive lymphocytes:
• formation of antibodies
or
• activation of effector T cells
Autoimmune diseases are broadly classified
as organ specific or systemic:
• Organ specific autoimmunity involves
chronic T cell or Ab targeting of a
particular organ.
• Systemic autoimmunity is often the
result of breakdown of immunological
tolerance to self-molecules, which
generates immune complex damage in
several body sites.
The presence of autoantibodies does not
necessarily indicate autoimmune disease

Clinical immunology tests for the detection

of autoantibodies
ELISA
indirect immunofluorescence
serum Ig measurement (non-
specific)

Which of the following laboratory tests

would you use to detect the presence of
endocrine autoantibodies?
Hypothalamus-pituitary-thyroid axis
 Graves Disease
and
Hashimoto Thyroiditis
(a.k.a. chronic lymphocytic thyroiditis)

are the two most common

immunologically mediated
disorders of the thyroid.
Hypothyroidism: Any
structural or functional
derangement that interferes
with the production of
adequate levels of thyroid
hormone.
-congenital
-autoimmune
-iatrogenic
 Hypothyroidism:
Hashimoto Thyroiditis
• Characterized by autoimmune
destruction of the thyroid gland.
• Involves both cellular and humoral
immune mechanisms.
• Disease progression leads to the
death of thyroid cells and
hypothyroidism.
Hashimoto Thyroiditis
Features:
• Most common cause of hypo-
thyroidism in areas of the world
where iodine levels are sufficient.
• Most prevalent between ages of
45 and 65 years of age.
• Occurs in females 10-20x more
often than in men.
Hashimoto Thyroiditis

Nature Reviews: Immunology

 Hashimoto Thyroiditis
Etiology and Pathogenesis:
The over-riding pathogenic feature of HT is
the inflammatory infiltrate of activated CD8
and CD4 T cells, B cells, plasma cells and
macrophages, that delete and replace the
thyroid epithelial cells, resulting in thyroid
enlargement and eventual gland fibrosis.

GC
Note the dense chronic
lymphocytic infiltrate with
well developed germinal
centers (GC).
IFNγ produced by activated CD8 and CD4 T cells
causes thyrocytes to express MHC class II
molecules, contributing to CD4 T cell expansion
and infiltration in the area.
Hashimoto Thyroiditis
Etiology and Pathogenesis:
The activation and expansion of autoreactive T
and B cells allows for multiple mechanisms of
immune-mediated thyrocyte injury.

Anti-Thyroid Antibodies:
Thyroid microsomal peroxidase
Thyroglobulin
TSH Receptor
Hashimoto Thyroiditis
Etiology and Pathogenesis:
Effector mechanisms:
1. CD8 cytotoxic T cells can cause thyrocyte
destruction via
a) exocytosis of perforin/granzymes
b) FasL-Fas (CD95L-CD95) pathway.
2. IFNg production by CD4 T cells results in the
recruitment and activation of macrophages
that damage the thyrocytes by cytokine
release.
3. Anti-thyroid antibodies bind to thyrocytes
followed by complement fixation, or antibody
dependent cell mediated cytotoxicity (ADCC).
• Thyroid microsomal peroxidase (95%),
• Thyroglobulin (60%),
• TSH receptor [blocking Ab]
Hashimoto Thyroiditis
Clinical Features:
•HT comes to clinical attention as painless
enlargement of the thyroid, associated with some
degree of hypothyroidism
•Most patients note gradual onset of a goiter.
•Diagnosis is based upon:
1) detection of circulating anti-thyroid
antibodies against thyroglobulin and
thyroid microsomal peroxidase
2) increased TSH levels.
•Classical presentation associated with low levels
of T4 and elevated TSH.
•HT patients are at increased risk for developing
other autoimmune diseases (T1D, autoimmune
adrenalitis, SLE, myasthenia gravis and Sjogren
syndrome, and B cell Hodgkin lymphomas.)
Hashimoto Thyroiditis
Clinical Features:
Hashimoto Thyroiditis
Susceptibility Genes:

**Note: CLT is chronic lymphocytic thyroiditis = HT

• The clustering of HT in certain families suggests genetic etiology.

• Concordance of disease among monozygotic twins as high as 40%.
• It has been estimated that as many as 20-60 potential genes may
contribute to thyroid autoimmune diseases.
• No consistent HLA association has been seen with HT.
Curr Opin Pediatr. 21:523-528. 2009
Hashimoto Thyroiditis
Susceptibility Genes:

PTPN22

PTPN22: Potent inhibitor of the T cell

receptor signaling pathway. Amino acid
substitution is associated with disease in
some ethnic populations.
What is CTLA-4?
 Hypothyroidism:
Idiopathic thyroid atrophy
(myxedema)
• Severe form of hypothyroidism in
which deposition of mucinous
substances leads to thickening of the
skin and subcutaneous tissues.
• Appears to be caused by autoreactive
antibodies that block both the growth
and metabolism of thyroid cells.
• These appear to be primary
antibodies which react with TSH
receptors or other membrane sites,
and the reason for their production is
unknown.
 Hyperthyroidism:
Graves Disease
Characteristics:
• Hyperthyroidism owing to
hyperfunctional, diffuse
enlargement of the thyroid.
• Infiltrative ophthalmopathy with
resultant exophthalmos (protrusion
of the eyeball).
• Localized, infiltrative dermopathy
(pretibial myxedema) presents in a
minority of patients as scaly
thickening and hardening of the
skin.
Graves Disease
Features:
• Most common cause of
endogenous hyperthyroidism
in young adults.
• 7x more frequent in women.
Graves Disease
Etiology and Pathogenesis:
Autoantibodies are central to the
pathogenesis of disease.
• Thyroid-stimulating
immunoglobulins (TSI/TS Ab)
• Thyroid growth-stimulating
immunoglobulins (TGI)
• TSH-binding inhibitor
immunoglobulins (TBII/TI Ab)
Graves Disease
Etiology and Pathogenesis:
Thyroid-stimulating immunoglobulins
(TSI/TS Ab):
• Anti-TSH receptor IgG antibody that binds
to the TSH receptor and mimics the action
of TSH, with resultant increased release of
thyroid hormones, and hyperthyroidism.
• Almost all patients with Graves disease
have detectable levels of this autoantibody
to the TSH receptor.
• TSI is relatively specific for Graves disease,
in contrast to thyroglobulin and thyroid
peroxidase antibodies (also seen with HT).
Graves Disease
Etiology and Pathogenesis:
Graves Disease
Etiology and Pathogenesis:
Thyroid growth-stimulating
immunoglobulins (TGI):
• Directed against TSH receptor.
• Implicated in proliferation of the thyroid
follicular epithelium.
Graves Disease
Etiology and Pathogenesis:
TSH-binding inhibitory
immunoglobulins (TBII)
• Prevent TSH from binding normally to its
receptor on thyroid epithelial cells, thus,
blocking TSH activity.
• Some TBII Abs mimic action of TSH, others
may inhibit thyroid cell function.
• The presence of both stimulating and
inhibiting Abs in a patient could explain
why some patients with Graves disease
have episodes of hypothyroidism.
Graves Disease
Etiology and Pathogenesis:
What type hypersensitivity mechanism is mainly
involved in Grave’s pathology?
 Graves Disease

• Recent evidence suggests that orbital

fibroblasts express the TSH receptor and thus
become targets of an autoimmune attack.
• T cells reactive against these fibroblasts
secrete cytokines, which stimulate fibroblast
proliferation and synthesis of extracellular
matrix proteins.
• The result is progressive infiltration of the
retro-orbital space and ophthalmopathy.
Graves Disease
Morphology:

• Under continued stimulation, the thyroid

becomes hyperplastic and excessively
vascular.
• Lymphoid infiltrates, consisting
predominantly of T cells (CD4 and CD8),
with fewer B cells and mature plasma cells,
are present throughout the interstitium.
• Germinal centers are common.
 Graves Disease
Clinical Features:
• Anxiety, heat intolerance, tremor, weight
loss, cardiac manifestations
• Diffuse enlargement of the thyroid
• Ophthalmopathy and dermopathy
• Patients are at increased risk for other
autoimmune diseases, such as SLE,
pernicious anemia, type I diabetes and
Addison disease.
• Laboratory findings in Graves disease
include elevated free T4 and T3 levels and
depressed TSH levels
• Because of ongoing stimulation of the
thyroid follicles by thyroid-stimulating
immunoglobulins, radioactive iodine
uptake is increased
Graves Disease
Susceptibility Genes:

**Note: CLT is chronic lymphocytic thyroiditis = HT

• CD40: CD40 polymorphisms associated with Graves are thought to be of

functional significance by lowering the threshold for B cell activation.
*Note that there is no association between CD40 and HT, which is
primarily a cell mediated disorder.
• HLA-DR: an association between HLA-DR3 and -DQA1 *0501 with Graves disease
has been demonstrated in caucasians.
HLA DRB1*0701 is thought to protect patients from developing Grave’s
disease.
Curr Opin Pediatr. 21:523-528. 2009
 On the relationship between HT and Graves:
From Robin’s Pathological Basis of Disease, 7th Ed.
“Autoimmune disorders of the thyroid thus span a continuum in which
Graves disease, characterized by hyperfunction of the thyroid, lies at one
extreme and Hashimoto disease, manifesting as hypothyroidism, occupies
the other end. Sometimes hyperthyroidism may supervene on pre-existing
Hashimoto thyroiditis (hashitoxicosis); at other times, patients with Graves
disease may spontaneously develop thyroid hypofunction; occasionally,
there are families with coexistence of Hashimoto and Graves disease within
the affected kindred. Not surprisingly, there is also an element of histologic
overlap between the autoimmune thyroid disorders (most
characteristically, prominent intrathyroidal lymphoid cell infiltrates with
germinal center formation; see below). In both disorders, the frequency of
other autoimmune diseases, such as systemic lupus erythematosus,
pernicious anemia, type I diabetes, and Addison disease, is increased.”
Neonatal Graves Disease:
•Neonatal Graves disease is due to
transplacental transfer of thyroid-stimulating
immunoglobulin
IgG from mother to fetus.

•Affected babies have a goitre,

exophthalmos, feeding problems, pyrexia,
and tachycardia and may develop heart
failure.

•Spontaneous recovery gradually occurs over

2-3 months, as the maternal IgG is
metabolized.
 Subacute Lymphocytic
(painless) Thyroiditis
•This is an uncommon form of thyroidism. It usually
comes to clinical attention because of mild hyper-
thyroidism, goitrous enlargement of the gland, or
both.
•A similar disease is observed during the postpartum
period in up to 5% of women (postpartum
thyroiditis).
•SLT and postpartum thyroiditis are thought to be
variants of Hashimoto thyroiditis, since the majority
of patients have elevated levels of antibodies against
thyroglobulin and thyroid peroxidase or a family
history of thyroid autoimmune disease. Occasionally
the disease evolves into overt HT several years later.
•The most specific histologic features consist of
lymphocytic infiltration with hyperplastic germinal
centers.
 Subacute (granulomatous)
thyroiditis (SGT)
•SGT is believed to be caused by a viral infection or a
post-viral inflammatory process.
• Reported in assoc. with coxsackie virus, mumps,
measles, adenovirus, and other viral illnesses.
• The majority of patients have a history of an
upper respiratory infection just before the onset.
•Host tissue damage caused by a viral infection results
in the release of either viral or thyroid antigen, which
stimulates cytotoxic T cells, that damage thyroid
follicular cells. Antibodies to thyroid antigens are
transient and low titer.
•Manifests as transient hyperthyroidism.
•Nearly all patients have high serum T4 and T3 and
low serum TSH. However, unlike Graves disease,
radioactive iodine uptake is diminished.
 Subacute (granulomatous)
thyroiditis (SGT)
•The gland may be enlarged, firm and painful.
•Early in the inflammatory process, scattered
follicles may be entirely disrupted and replaced
by neutrophils forming microabscesses.
•Later, the more characteristic features appear
in the form of aggregations of lymphocytes,
histiocytes, and plasma cells about collapsed
and damaged thyroid follicles. Mutinucleate
giant cells are also seen, hence the designation
granulomatous thyroiditis.
•Also called De Quervain thyroiditis.
•70% of diagnosed patients express HLA-B35.
A 29-year-old woman presented with a 3-month history of increased
sweating and palpitations with weight loss of 7kg. On examination, she was
a nervous, agitated woman with an obvious, diffuse, non-tender, smooth
enlargement of her thyroid, over which a bruit could be heard. She had a
fine tremor of her fingers and a resting pulse rate of 150/minute. She had
no evidence of exophthalmos. A maternal aunt had suffered from 'thyroid
disease'. On investigation, she had a raised serum T3 of 4.8 nmol/l (NR 0.8-
2.4) and a T4 of 48 nmol/l (NR 9-23). Measurement of her thyroid
stimulating hormone showed that this was low normal, 0.4 mU/l (NR 0.4-5).
Circulating antibodies to thyroid peroxidase (titer 1/3000; 200iu/ml) were
detected by agglutination.

What is the most likely diagnosis? Explain.

Describe the roll of CD4 T cells in this disease.

A 39-year-old woman presented with a large, painless swelling in her neck.
The enlargement had been a gradual process over 2 years. She had no other
symptoms and felt generally well. On examination, her thyroid was
diffusively enlarged and had a rubbery consistency. Thyroid function tests
showed that she was euthyroid; T3 was 1.2nmol/l (NR 0.8-2.4), T4 was
12nmol/l (NR 9-23) and TSH was 6.3mU/l (NR 0.4-5mU/l). However, her
serum contained high titer antibodies to thyroid peroxidase (1/64000;
4000iu/ml).

What is the most likely diagnosis? Explain.

Learning Objectives:
1. Compare and contrast the pathogenesis, morphological and clinical features,
diagnosis and treatment of Hashimoto thyroiditis and Graves’ Disease.
2. Appraise the role of the following genes in the development of autoimmune
thyroid disease: HLA-DR, CTLA-4, CD40, PTPN22, thyroglobulin, TSH receptor.
3. Understand the role of CTLA-4 in the development/prevention of autoimmune
disease.
4. Compare and contrast the effects of thyroid-stimulating antibodies and thyroid-
inhibitory antibodies on the clinical manifestation of Graves’ disease.
5. Describe, in general, the known/proposed pathogenic mechanisms, and
morphological and clinical features of subacute granulomatous and subacute
lymphocytic thyroiditis.