Endocrine Diseases:

Mechanism of development of Autoimmune endocrine disease:Two factors could be involved in development of human autoimmune disorders: 1-Expression of Class II HLA (human leukocyte antigen) on the surface of target endocrine cells. Infectious agent Inflammatory cells chemotaxis(INFγ)

Expression of HLA Presentation of own cellular proteins; reactive T and B cell response.

N

2-The antigen Cross-reactivity: external organic material or infectious agents epitopes Show antigenic cross- reactivity with target tissues.

formation of Auto-reactive Humoral immune response antibodies. Tissue destruction.

Thyroid Autoimmune Diseases:Chronic Thyroiditis: (Hashimoto’s thyroiditis):

Definition: It is an autoimmune disease in which the thyroid gland is attacked by a variety of cell- and antibody-mediated immune processes.

General considerations: -Family history of thyroid disease and HLA gene polymorphism (DR4, DR5).-Most common in middle-aged and elderly patients. -Females make up the vast majority of patients (85%).

N

Major Immunologic features of Hashimoto’s thyroiditis: 1-The lymphocytic infiltration of the thyroid gland.2-The Antibodies against thyroid antigens are present. 3-The cellular sensitization to thyroid antigens.

Germinal center: lymphocyte infiltrate.Pink reactive dying thyroid cell : Immunohistochemistry for P63. with cytoplasmic-acidophilic granules. :Positive in Germinal center (H.T).

N

Pathogenesis mechanism in Hashimoto’s thyroiditis: -Various Autoantibodies are present against thyroid peroxidase, and thyroglobulin. -Sensitization of Thyroid tissue ( thyrocyte).-CD8 and NK cell hyperactivity by ADCC (Antibody-Dependent Cell-Mediated Cytotoxicity ) mechanism.

-Apoptosis of thyrocyte. -CD4 response, and chemotaxis of macrophage.

Clinical Features of chronic thyroiditis:

Primary stage: -Clinical hyperthyroidism due to inflammatory breakdown of thyroid follicles.

Late stage:-Hypothyroidism due to progressive destruction of thyroid tissue and cellular malfunction.

-The most common outcome of Hashimoto’s disease is the hypothyroidism.

Signs and Symptoms of Chronic thyroiditis:

-A consistent physical sign seen in Hashimoto’s disease is

an enlarged thyroid gland (Goiter).

-Often, lymph nodes surrounding

the gland become enlarged.

-Rarely, Symptoms of generalized vasculitis with urticaria

and nephritis could be seen due to presence of circulating

immune complexes.

Differential diagnosis of Chronic thyroiditis:

-The hallmark of the diagnosis of this disease is the presence of circulating Autoantibodies:1-Anti-thyroglobulin antibodies.2-Anti-thyroid peroxidase antibodies.

-These antibodies show a sensitivity of 90% and detected by: 1-Immunofluorescence assay. 2-ELISA. 3-Agglutination assay.

-In patients without serum antibodies, autoantibodies are localized in intrathyroidal lymphoid follicles.

Graves’ Disease: Definition:

-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% of

all cases).

-It has a powerful hereditary component, affects up to 2%

of the female population, and is between five and ten

times as common in females as in males.

n

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.

The orbit around the eye: upper eyelid retraction, edema, erythema, and Graves’ Goiter: hyperthyroidism conjunctivitis.

N

-Specific cross-reactivity between some microbes (Viruses;

Coxsackievirus, and bacteria; Yersinia) and TSH-Receptor

of thyroid follicular cells.

-Strong association with DR3, DQα , and DQβ genotype of

MHC II haplotypes.

-Family History:

The disease is associated with different types of generalized

autoimmune susceptibility; such as Hashimoto’s disease and

antibodies to gastric intrinsic factor.

N

Major Immunologic features of Graves’ disease:

1-Antibodies against thyroid antigen are present; that

stimulate thyroid cell function.

2-Class II HLA expression on the surface of thyroid cells.

3-Associated autoimmune ophthalmopathy.

Pathogenesis mechanism of Graves’ disease:

-Autoantibodies present against TSH-receptor: 1- Thyroid-stimulating immunoglobulins (TSI): Activate TSH-receptor; elevated thyroid hormones.2- Thyroid growth immunoglobulins( TGI) : Growth of thyroid follicles. 3-Thyroid binding-inhibiting immunoglobulins (TBII) : Inhibits TSH binding.-No Cellular immune response; Histology show no destruction of thyroid tissues.-Colloid suspension show lymphocytic infiltration: CD4, CD8, and B lymphocytes.

Pathogenesis mechanism of Graves’ disease: N

Diagnosis of Graves’ disease: -Clinically: Signs and symptoms of hyperthyroidism. -Radiology: Increased uptake of radioactive iodine.

-Serology: A-Elevated Total and free T4, and T3. B-Identification of Anti-thyroid antibodies in patient’s sera: 1-Antibodies that activate cellular cAMP ; Thyroid stimulating Immunoglobulin (TSI). 2-Thyroid growth stimulating immunoglobulins (TGI). 3-Antibodies that displace the binding of TSH from its receptor (TBII).

N

Anti-thyroid antibodies could be detected by:1-ELISA Test: Microtiter plate wells should be coated by recombinant Human TSH-receptors.2-Tissue culture (Fisher Rat thyroid cell line 5): -It can be used to measure the presence and activity of Anti-thyroid antibodies ( IgG) in patient's sera. -Serum specimens should be incubated with cell line culture; then : The cAMP activity and the incorporation of radioactive thymidine are measured.