MECHANISMS OF AUTOIMMUNE THYROID DISEASES: FROM GENETICS TO EPIGENETICS

摘要

Recent advances in our understanding of genetic-epigenetic interactions have unraveled new mechanisms underlying the etiology of complex diseases such as autoimmune diseases. Among autoimmune diseases autoimmune thyroid diseases are highly prevalent affecting 1-5% of the population. The term autoimmune thyroid diseases (AITD) refers to the whole spectrum of thyroid autoimmunity ranging from subclinical disease manifesting by the presence of autoantibodies targeting thyroid antigens to clinical disease. The major AITD include Graves’ disease (GD) and Hashimoto’s thyroiditis (HT). While clinically these are contrasting diseases, GD manifesting by thyrotoxicosis and HT manifesting by hypothyroidism, their pathogenesis involves shared immunegenetic mechanisms. Genetic data point to the involvement of shared genes as well as unique genes for GD and HT. Among the shared susceptibility genes HLA-DR containing arginine at position β74 gives the strongest risk. Other shared immune regulatory genes predisposing to AITD include CTLA-4, PTPN22, and CD25. CD40, in contrast, is specific for GD. Two thyroid specific genes also confer susceptibility to AITD - Tg is associated with both GD and HT while the TSH receptor is associated only with GD. It is clear that other genes are involved and several additional putative genes identified by genome wide analyses have been recently reported. Epigenetic modulation is emerging as a major mechanism by which environmental factors interact with AITD susceptibility genes. Indeed, we have recently shown an epigenetic interaction between interferon alpha, a key cytokine secreted during viral infections, and a Tg promoter variant. Dissecting the genetic-epigenetic interactions underlying the pathogenesis of AITD is essential to uncover new therapeutic targets.