Download Thyroid Autoimmune Diseases

Thyroid Autoimmune
Diseases
Mechanisms of development of
Autoimmune endocrine disease:
Two factors could be involved in
development of human autoimmune
disorders:
• Expression of Class II MHC (HLA:
human leukocyte antigens) on the
surface of the target endocrine cells.
• The antigen Cross-reactivity
Expression of Class II HLA on The Target
Cells
Infectious agent (or self-antigen)
Inflammatory cells chemotaxis & production of
INFγ
Expression of HLA genes (MHC class II)
Presentation of own cellular proteins
Reactive T and B cell response.
The antigen cross-reactivity:
Infectious agents or external organic material
epitopes show antigenic cross- reactivity with
self tissues.
formation of auto-reactive antibodies.
Humoral immune response against self tissues
Tissue destruction.
Chronic Lymphocytic
Thyroiditis:
(Hashimoto’s Thyroiditis):
• The first disease recognized as
autoimmune disease by the Japanese
specialist (Hakaru Hashimoto) in
Germany in 1912.
• The thyroid gland is attacked by cell- and
antibody-mediated immune processes.
• Hypothyroidism, large and lobulated
thyroid gland due to lymphocytic
infiltration and fibrosis.
General considerations:
• Family history of thyroid disease.
• HLA gene polymorphism (DR3,DR4, DR5).
• CTLA-4 *gene polymorphism (cytotoxic Tlymphocyte associated protein) result in
reduced negative regulation of T-cells.
• Most common in middle-aged, starts in
adulthood.
• Woman to men ratio is 5-10: 1.
• Associated with other autoimmune diseases
such as: SLE, dermatitis, and scleroderma.
Other risk factors:
• Chromosomal disorders: Turner,
Klinefelter’s and Down’s Syndrome.
• Tobacco smoking.
Immunological features:
• Lymphocytic infiltration of the thyroid
gland
• Presence of antibodies against thyroid
antigens.
• Cellular sensitization to thyroid antigens.
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Pathogenesis of chronic thyroiditis:
•Expression of MHC class II-self epitope
complex on the thyroid cell surface.
• Thyroid cell-CD4+ Lymphocyte
interaction.
• Chemotaxis of CTL and macrophages.
• Loss of T lymphocyte suppressor
function due to CTLA gene A mutation:
CTL-thyroid cell interaction and killing
of target cells by apoptosis.
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• Engulfment of cellular peptides by
macrophages; antigen presentation.
• Activation of B lymphocytes and
production of anti- thyroid peroxidase
and anti-thyroglobulin antibodies
• ADCC of cuboidal cells lining the
thyroid follicles by CD8 and N.K cells.
Stages & Clinical Features of Chronic
Thyroiditis:
• Primary stage: Transient hyperthyroidism
due to inflammatory breakdown of thyroid
follicles (silent painless inflammation).
Release of thyroid hormones.
• Late stage: Hypothyroidism due to
progressive destruction of thyroid tissue and
cellular malfunction.
• The last outcome of Hashimoto’s disease is
hypothyroidism.
• A consistent physical sign in
Hashimoto’s disease is enlarged thyroid
gland (Goiter).
• Enlarged surrounding lymph nodes.
• Weight gain, muscle weakness, cold
intolerance, depression, fatigue,
constipation, periorbital edema , hoarse
voice and dry skin.
• Rarely, symptoms of urticaria and
nephritis can be seen due to presence of
circulating immune complexes.
Diagnosis of Chronic Thyroiditis:
o The disease is diagnosed by the presence of
autoantibodies:
▫ Anti-thyroglobulin* antibodies.
▫ Anti-thyroid peroxidase antibodies.
o These antibodies can be detected by:
▫ Immunofluorescence assay , ELISA or
agglutination assay.
o In seronegative patients, autoantibodies are
localized intrathyroidal.
o Histopathology
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• Germinal center formation
within thyroid tissues: reactive
lymphocyte infiltrate.
• Pink: dying thyroid cell
• Immunohistochemistry
for P63. Positive in
Germinal center (not
found in normal glands).
Before
After
Graves’ Disease:
• It is an autoimmune disease where the
thyroid is activated by anti-TSH receptor
autoantibodies to produce excessive amount
of thyroid hormones.
• The most common cause of
hyperthyroidism (60-90%), affects up to
2% of the female.
• 5-10 more common in females than in
males.
• It has a powerful hereditary component
General Considerations:
• Hyperthyroidism and thyrotoxicosis
with a diffuse goiter.
• About 30-50% of people with Graves'
disease will also suffer from Graves'
ophthalmopathy caused by
inflammation of the eye muscles by
attacking autoantibodies.
• Exophthalmos: upper eyelid retraction,
edema, erythema, and conjunctivitis.
Graves’ Goiter and Exophthalmos
• Specific cross-reactivity between some
microbes (viruses; Coxsackieviruses, and
bacteria; Yersinia enterocolitica) and TSHreceptors on thyroid follicular cells.
• Strong association with DR3, DQα , and
DQβ genotype of MHC II haplotypes
• Family History: increased risk if other
family members are affected.
• Associated with different types of
autoimmune diseases; such as Hashimoto’s
disease and antibodies to gastric intrinsic
factors.*
Clinical presentation:
o Goiter, exophthalmos (30-50%), muscle
weakness, weight loss, diarrhea and frequent
defecation, hyperactivity, tachycardia, hair
loss, and oligomenorrhea.
o Immunologic features of Graves’ disease:
• Antibodies against TSH receptor; that
stimulate thyroid cell function.
• Class II HLA expression on the surface of
thyroid cells.
• Associated autoimmune ophthalmopathy.
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Autoantibodies present against TSHreceptor:
• Thyroid-stimulating immunoglobulins
(TSI):
Activate TSH-receptor; increase thyroid
hormones levels.
• Thyroid growth immunoglobulins (TGI):
Growth of thyroid follicles.
• Thyrotrophin binding-inhibiting
immunoglobulins (TBII):
Inhibits TSH binding.
• Colloid suspension show lymphocytic
infiltration: CD4, CD8, and B
lymphocytes.
• No cellular immune response;
Histology shows no destruction of
thyroid tissues.
Pathogenesis mechanism of Graves’ disease:
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Diagnosis of Graves’ disease:
o Clinically: Signs and symptoms.
o Radiologically: Increased uptake of radioactive
iodine.
o Serology:
▫ Elevated total and free T4, and T3.
▫ Identification of anti-thyroid antibodies in
patient’s sera:
• Thyroid stimulating Immunoglobulin (TSI).
• Thyroid growth stimulating immunoglobulins
• Thyroid binding-inhibiting immunoglobulins
Anti-thyroid antibodies can be detected by:
• ELISA Test:
Microtiter plate wells should be coated by
recombinant human TSH-receptors.
• Tissue culture(Fisher Rat thyroid cell line)
measure the presence and activity of antithyroid antibodies (IgG) in patient's sera.
▫ Serum specimens are incubated with rat
thyroid cell line culture; then the
incorporation of radioactive thymidine
(pyrimidine) are measured. (action of
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