**3.1. Humoral immunity**

TSHR is a member of GPCR super family and involves cAMP and phosphoinositol pathways for signal transduction. TSHR has large intracellular domain (subgroup B). It is a glycoprotein consisting of 744 amino acids and having molecular weight of 84 kd. Gene for TSHR is located on chromosome 14q31 and is formed by 10 exons. Circulating autoantibody directed against the TSHR is the primary factor responsible for Graves' disease. TSHR antibodies (TSHR-Ab) are of three types- namely stimulating antibody, blocking antibody and neutral antibody. Stimulating antibodies are those who after binding to TSHR activate adenylate cyclase and cause increased thyroid growth and vascularity, and increases the production of thyroid hormones. Blocking antibodies are those who after binding to TSHR act as an antagonist, whereas neutral antibodies does not have any functional activity.

Almost 50 years ago(in 1956) long acting thyroid stimulators (LATS) was discovered by Adams and Purves during a search for thyroid stimulating activity in patients with Graves' disease. 13 Later on it was found that LATS are nothing but immunoglobulin of IgG1 subclass.

Transplacental transfer of TSHR stimulating antibodies (TSAb) from TSAb positive pregnant mother to fetus causes transient neonatal thyrotoxicasis that improves spontaneously after the disappearance of TSAb. 14 This provides the definite role of TSAb in the causation of Graves' disease. TSAb are oligoclonal.

TSAb are produced mainly by the lymphocytes infiltrating the thyroid gland and lymphocytes present in the draining lymph nodes, and partly by the circulating blood lymphocytes.15,16 There is a positive correlation exists between the TSAb level and serum

triiodothyronine level, serum thyroglobulin level and goiter size. TSAb are found in 90- 100% of untreated Graves' disease patients.17, 18 Level of TSAb decreases after treatment with anti- thyroid drugs and radio-iodine.19, 20

Thyroid Hormone Excess: Graves' Disease 165

patients than patients of Hashimoto's thyroiditis. So the functional role of T cells in Graves'

Structural or conformational similarity between different antigens like infectious agent with a self antigen can lead to crossover of specificity or molecular mimicry. Molecular mimicry has been reported between Reoviral antigen and a tissue antigen expressed in multiple endocrine tissues, Yersinia enterocolitica and TSHR, Retroviral sequences and TSHR &

There is evidence that bystander activation of local resident antigen specific and nonspecific T- cells by a local viral infection would induce an inflammatory reaction and stimulates the production of cytokines induce autoimmunity. This bystander activation can also occur in

MHC class II molecules (HLA-DP, DQ, and DR) are not expressed on the normal thyroid epithelial cells but they are expressed on thyroid epithelial cells in patients of autoimmune thyroid disease. This aberrant expression of class II HLA antigens on thyroid epithelia cells can be induced by local thyroid insult which causes production of interferon γ and other cytokines. Interferon γ is able to over express HLA class I molecule and induce the

Autoimmunity results from the loss of tolerance or the ability to differentiate between self and non self. Tolerance induction is a staged process that initiates in the thymus during T-cell maturation. This process depends in part on the presence of peripheral antigens in the thymus. Peripheral antigens are antigens normally expressed in tissues outside of the immune system which are expressed at low levels in thymus. T cells that react strongly to these peripheral molecules in the context of MHC are deleted in thymus. T cells that react with peripheral antigens that are not expressed in the thymus have a greater opportunity to escape tolerance.

Hygiene hypothesis implies that infection may protect form autoimmune diseases rather than precipitating it. Decreased exposure to antigens due to improved living standards can

disease is primarily a helper than a suppressor or cytotoxic role.

**4.1. Molecular mimicry or specificity crossover** 

any infections and antigens unrelated to the thyroid gland.

**4.3. Aberrant expression of class II HLA Antigens** 

expression of class II molecule on thyroid epithelial cells.

**4. Pathogenic mechanisms**

Borrelia and TSHR.

**4.2. Bystander effect** 

**4.4. Cryptic antigens** 

**4.5. Hygiene hypothesis** 

lead to increased risk of autoimmune disorder.
