**3. Pathogenesis**

GD is a classical autoimmune disorder, characterised by a complex interplay of genetic susceptibility and environmental factors. GD had long been recognized as having a genetic background in view of clustering of cases in families. Family H/O autoimmune thyroid disease (AITD) is apparent in nearly half of the affected patients. AITD also tends to occur in more than a third of siblings and thyroid autoantibodies occur in over half of asymptomatic children of affected patients. This was further confirmed by twin studies where concordance of AITD in monozygotic twins was 30–40%, as compared to less than 5% concordance in dizygotic twins. It has also been proposed that genetic anticipation may occur in successive generations leading to younger ages at onset of disease [12, 13].

The genetic predisposition to GD is polygenic in origin, with each individual gene conferring a modest increase in risk. The most commonly implicated genes are located in the HLA region in the short arm of chromosome 6, the odds ratio (OR) for GD ranging from 2 to 4. HLA DRB1\*03 and DQA1\*05 in Caucasian patients, and HLA DPB1\*05:01 allele in Han Chinese populations have been found to confer 2–3 times increased risk of GD. Similarly HLA class I alleles C\*07 and B\*08 have also been implicated as risk factors, and DRB1\*07, DRB1\*12:02, DQB1\*03:02, B\*44, C\*03, C\*16 have been observed to have a protective effect in various populations.

Some of the other genes which confer a modest increase in risk of GD (OR ranging from 1.1–2) are Protein Tyrosine Phosphatase-22 (PTPN22), Cluster of Differentiation 40 (CD40), Cytotoxic T-lymphocyte-associated factor 4 (CTLA4), TSH-R, Thyroglobulin (Tg), FC-Receptor Like-3 (FCRL3), Secretoglobin 3A2 (SCGB3A2), Interleukin-2 receptor alpha (IL2RA) etc. Possible mechanisms postulated are variation in binding of self-antigens, defective regulation of thymic selection of autoreactive clones, regulation of T cell responses and effect of HLA class I molecules on natural killer cells.

Some studies have also observed genotype phenotype correlation. For example, several genes like interferon γ (IFN , TNF, IL-1A, IL-23R, IL-5, CTLA4, PTPN-12, ICAM-1 have been associated with development of Graves ophthalmopathy (GO). Similarly several candidate genes have been associated with clinical course of GD, including age of onset (HLA, ICAM-1, PTPN22, NFKB1, CD40), severity and remission/relapse rates of GD (CTLA4, CXCL10) [14].

With the concordance rate in monozygotic twins being clearly less than 100%, it highlights the importance of environmental factors for predisposing an individual for developing GD. Analysis of Danish twin studies in GD attributed 79% of liability to develop GD on genetic factors, whereas 21% could be explained by environmental factors not shared by the twins [15].

Stressful life events and post-partum periods can result in a dysregulated immune response, predisposing to autoimmunity. Smoking, radiation, excess iodine intake, dietary selenium deficiency, drugs like amiodarone, interferons, alemtuzumab have been associated with development of AITD. Recent evidence has brought into light the role of Endocrine disrupting chemicals (EDCs), which are environmental toxicants that interfere with thyroid hormone production, metabolism and action. Most widely studied EDCs are polychlorinated biphenyls (PCBs), which have thyroid-disrupting effects and can have intrinsic thyroid hormone agonist action. Others chemicals like bisphenol A, phthalates, perflourinated chemicals and brominated flame retardants have also been shown to have thyroid-disrupting effects, predisposing to AITD [16, 17].

The thyroid gland typically demonstrates a non-homogenous lymphocytic infiltration and absence of follicular destruction. T-lymphocytes can cause local inflammation and cytokine release resulting in dysregulation of B- cells and production of autoantibodies. These TSH-R auto antibodies (TRAb) can bind to the TSH-R on thyroid follicular cells. These are of the IgG1 subclass and can have different functional implications of stimulation, blockade or neutral effects on the TSH-R. Thyroid stimulating antibodies (TSIs) act via G proteins like Gs and Gq to cause increased thyroid hormone production, secretion and modulation of cell proliferation respectively [2, 18].

Graves ophthalmopathy is a distinct pathological process that may precede or follow the hyperthyroid phase. Orbital fibroblasts are the target cells in the pathology. Plausible explanation for this cellular origin include antigen sharing with the TSH-R, enhanced expression of Thy-1 (CD90) and IGF-1 receptor, exaggerated inflammatory response to cytokines and hyaluronan synthesis. Environmental factors like smoking and radioiodine therapy play a major role in development of ophthalmopathy [19].
