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 T-

lymphocyte 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.

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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.

• 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 TSH-receptors 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.*

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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.

Autoantibodies present against TSH-receptor: •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: N

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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

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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 anti-thyroid 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 TGI)

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