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. *CTLA-4 is a receptor that transmits an inhibitory signal to T cells.

Chromosomal disorders: Turner, Klinefelter’s and Down’s Syndrome. 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. n

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. n

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: The disease is diagnosed by the presence of autoantibodies: Anti-thyroglobulin* antibodies. Anti-thyroid peroxidase antibodies. These antibodies can be detected by: Immunofluorescence assay , ELISA or agglutination assay. In seronegative patients, autoantibodies are localized intrathyroidal. Histopathology *Thyroglobulin (Tg) a protein produced by the thyroid and is used to produce the thyroid hormones thyroxine (T4) and triiodothyronine (T3). *Thyroid peroxidase oxidizes iodide to iodine for addition onto tyrosine residues on thyroglobulin for the production of thyroxine (T4) or triiodothyronine (T3),

N Immunohistochemistry for P63. Positive in Germinal center (not found in normal glands). Germinal center formation within thyroid tissues: reactive lymphocyte infiltrate. Pink: dying thyroid cell

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. The volume of the extraocular muscles and retroorbital connective and adipose tissue is increased, due to inflammation . Autoantibodies to various components of retroorbital tissues, particularly components of extraocular muscle cells, have been detected in the serum of patients with Graves' ophthalmopathy.

Graves’ Goiter and Exophthalmos

Family History: increased risk if other family members are affected. 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.* * Graves’ disease can lead to Hashimoto’s thyroiditis and vice versa.

Clinical presentation: Goiter, exophthalmos (30-50%), muscle weakness, weight loss, diarrhea and frequent defecation, hyperactivity, tachycardia, hair loss, and oligomenorrhea. 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. N

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. Thyrotrophin = TSH

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 n

Diagnosis of Graves’ disease: Clinically: Signs and symptoms. Radiologically: Increased uptake of radioactive iodine. 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 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) N

THANKS