The CD40, CTLA-4, thyroglobulin, TSH receptor, and PTPN22 gene quintet and its contribution to thyroid autoimmunity: back to the future

Abstract

Autoimmune thyroid diseases (AITD) are common autoimmune diseases, affecting up to 5% of the general population. Thyroid-directed autoimmunity is manifested in two classical autoimmune conditions, Hashimoto's thyroiditis, resulting in hypothyroidism and Graves' disease resulting in hyperthyroidism. Autoimmune thyroid diseases arise due to an interplay between environmental and genetic factors. In the past decade significant progress has been made in our understanding of the genetic contribution to the etiology of AITD. Indeed, several AITD susceptibility genes have been identified. Some of these susceptibility genes are specific to either Graves' disease or Hashimoto's thyroiditis, while others confer susceptibility to both conditions. Both immunoregulatory genes and thyroid specific genes contribute to the pathogenesis of AITD. The time is now ripe to examine the mechanistic basis for the contribution of genetic factors to the etiology of AITD. In this review, we will focus on the contribution of non-MHC II genes.

Ribbon diagram of the HLA-DR peptide-binding pocket showing a putative immunogenic thyroglobulin (Tg) peptide that binds with high affinity to a pocket containing the amino acid arginine at position 74 of the DR beta chain. Such a (Tg) peptide could be efficiently presented to T cells resulting in a strong immune response to thyroglobulin.