**4.2. Bystander effect**

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 any infections and antigens unrelated to the thyroid gland.

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

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 expression of class II molecule on thyroid epithelial cells.

#### **4.4. Cryptic antigens**

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.

#### **4.5. Hygiene hypothesis**

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