1. Thyroid Autoimmune 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(INF γ ) (or Self-antigen) Expression of HLA Presentation of own cellular proteins; reactive T and B cell response.

2. 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.

3. Chronic lymphocytic 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. -The first disease recognized as autoimmune disease. -Described by the Japanese specialist (Hakaru Hashimoto) in Germany in 1912. -Hypothyroidism, large and lobulated thyroid gland. -Enlargement of thyroid due to lymphocytic infiltration and fibrosis.

4. n General considerations: -Family history of thyroid disease and HLA gene polymorphism (DR4, DR5). -CTLA-4 (Cytotoxic T-Lymphocyte gene A-4) Polymorphism; results in reduced negative regulation of T-lymphocytes. -Studies on Monozygotic twins show: Anti-Thyroid Antibodies (Gene homology of 80%). Other Risk factors: -Infectious agents : Human Herpes Virus-6 (A, and B). -Chromosomal disorders: Turner,Klinefelter’s, and Down’s Syndrome. - Pollutants (Tobacco smoke).

5. n -Most common in middle-aged and starts in adulthood. - 5-10 times more common in woman than in men. -Associated with other autoimmune diseases such as: Systemic lupus erythematosus, dermatitis, and scleroderma. 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.

6. n Pathogenesis: -Expression of MHC Class II-self epitope complex on the thyroid cuboidal cell surface. -Thyroid cell-CD4 + Lymphocyte interaction. -Cytokines production, and chemotaxis of CTL and Macrophage. -CTL-Thyroid cell interaction; Loss of T lymphocyte suppressor function due to CTL gene A mutation. -Killing of target cell by CTL; Apoptosis. -Engulfment of cellular peptide by macrophage; Ag presentation.

7. n -Formation of Auto-reactive antibodies; Anti- thyroid peroxidase(90%), and Anti-thyroglobulin Antibodies(70%). -Sensitization of Thyroid tissue ( thyrocyte). -ADCC for cuboidal cells lining the thyroid follicles by CD8 + and N.K cells.

8. n Histologically: -Diffuse parenchymal infiltration of lymphocyte; mainly B- lymphocytes which can be seen as secondary lymphoid follicles (Germinal center). -Hǖrthle cell ( Kari Hurthle) could be seen in tissue or cytology. -Hurthle cell: metaplasia from cuboidal cells lining the thyroid follicles characterized by eosinophilic-granular cytoplasm.

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

10. Clinical Features of Chronic thyroiditis: Primary stage: -Clinical hyperthyroidism due to inflammatory breakdown of thyroid follicles ( Silent, Painless inflammation). Late stage: -Hypothyroidism due to progressive destruction of thyroid tissue and cellular malfunction. -The most common outcome of Hashimoto’s disease is the hypothyroidism.

11. Clinical presentation of Chronic thyroiditis: -A consistent physical sign seen in Hashimoto’s disease is an enlarged thyroid gland (Goiter). (Rubbery-nodular thyroid). - Lymph nodes surrounding the gland become enlarged. - Depression, Fatigue, Constipation, and dry skin. -Rarely, Symptoms of generalized vasculitis with urticaria and nephritis could be seen due to presence of circulating immune complexes.

12. Differential diagnosis of Chronic thyroiditis: -The hallmark of the diagnosis of this disease is the presence of circulating Autoantibodies: 1-Anti-thyroglobulin antibodies. (Antibodies titer) 2-Anti-thyroid peroxidase antibodies.(Antibodies titer). -These antibodies show a sensitivity of 90% and detected by: 1-Immunofluorescence assay (Colloid aspiration). 2-ELISA. 3-Agglutination assay. -In Seronegative patients, autoantibodies are localized in intrathyroidal lymphoid follicles.

13. 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.

14. 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. Exophthalmos: upper eyelid retraction, edema, erythema, and Graves’ Goiter: hyperthyroidism conjunctivitis.

15. N -Specific cross-reactivity between some microbes (Viruses; Coxsackievirus, and bacteria; Yersinia enterocolitica) 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 factors.

16. N Clinical presentation: -Goiter, exophthalmos(30-50%), muscle weakness, weight loss, diarrhea and frequent defecation, hyperactivity,tachycardia, hair loss, and Oligomenorrhea. Major Immunologic features of Graves’ disease: 1-Antibodies against thyroid antigen (TSH-R) are present in 70-100% of Graves’ patients; that stimulate thyroid cell function. 2-Class II HLA expression on the surface of thyroid cells. 3-Associated autoimmune ophthalmopathy.

17. Graves’ disease Pathogenesis : -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.

18. Pathogenesis mechanism of Graves’ disease: N

19. 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).

20. 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.

21. n N