The role of hereditary and environmental factors in autoimmune thyroid diseases

Abstract

Autoimmune thyroid diseases are the most common organ-specific autoimmune disorders affecting 5% to 10% of the population in Western countries. The clinical presentation varies from hyperthyroidism in Graves' disease to hypothyroidism in Hashimoto's thyroiditis. While the exact etiology of thyroid autoimmunity is not known, the interaction between genetic susceptibility and environmental factors appears to be of fundamental importance to initiate the process of thyroid autoimmunity. The identified autoimmune thyroid disease susceptibility genes include immune-modulating genes, such as the major histocompatibility complex, and thyroid-specific genes, including TSH receptor, thyroglobulin and thyroid peroxidase. The majority of the anti-TSH-receptor antibodies have a stimulating capacity and are responsible for hyperthyroidism. The anti-thyroglobulin- and anti-thyroid peroxidase antibodies belonging to the catalytic type of antibodies destroy the thyrocytes resulting in hypothyroidism. The appearance of anti-thyroid peroxidase antibodies precedes the induction of thyroiditis and the manifestation of hypothyroidism. The molecular analysis of thyroglobulin gene polymorphism is important in the mechanism of autoimmune thyroiditis. The autoantigen presentation by major histocompatibility complex molecules is a key point of the autoimmune mechanism. It has been shown that a HLA-DR variant containing arginine at position 74 of the DRβ1 chain confers a strong genetic susceptibility to autoimmune thyroid diseases, Graves' disease and Hashimoto's thyroiditis, while glutamine at position DRβ1-74 is protective. Human thyroglobulin 2098 peptide represents a strong and specific DRβ1-Arg74 binder, while a non-binding control peptide, thyroglobulin 2766 fails to induce this response. Moreover, thyroglobulin 2098 stimulated T-cells from individuals who were positive for thyroglobulin antibodies, demonstrating that thyroglobulin 2098 is an immunogenic peptide capable of being presented in vivo and activating T-cells in autoimmune thyroid diseases. Taken together these findings suggest that thyroglobulin 2098, a strong and specific binder to the disease-associated HLA-DRβ1-Arg74, is a major human T-cell epitope and it participates in the pathomechanism of the autoimmune thyroid disease. The exact nature of the role of environmental factors in the autoimmune thyroid disease is still not well known, but the importance of several factors such as iodine, drugs and infections has been reported. Further knowledge of the precise mechanisms of interaction between environmental factors and genes in inducing thyroid autoimmunity could result in the development of new strategies for diagnosis, prevention and treatment.