The HLA gene complex in thyroid autoimmunity: from epidemiology to etiology

Abstract

The autoimmune thyroid diseases (AITD) comprise a cadre of complex diseases whose underlying pathoetiology stems from a genetic-environmental interaction, between susceptibility genes (e.g. CTLA-4, HLA-DR, thyroglobulin) and environmental triggers (e.g. dietary iodine), that orchestrates the initiation of an autoimmune response to thyroid antigens, leading to the onset of disease. Abundant epidemiological data, including family and twin studies, point to a strong genetic influence on the development of AITD. Several AITD susceptibility genes have been identified, with HLA genes, in particular, appearing to be of major importance. Early studies showed association of HLA-DR3 with Graves' disease (GD) in Caucasians. More recently, the importance of an amino acid substitution at position 74 of the DR beta 1 chain of HLA-DR3 (DRb1-Arg74), in susceptibility to Graves' disease, has been shown. Furthermore, there is increasing evidence for a genetic interaction between thyroglobulin variants and DRb1-Arg74 in conferring risk for GD. Mechanistically, the presence of an arginine at position 74 elicits a significant structural change in the peptide binding pocket of HLA-DR, potentially affecting the binding of pathogenic thyroidal peptides. Future therapeutic interventions may attempt to exploit this new bolus of knowledge by endeavoring to block or modulate pathogenic peptide presentation by HLA-DR.

Figure 1

The HLA-DR3 molecule, shown in ribbon diagram format. The alpha chain (yellow) and the beta chain (turquoise) assemble to form a functional heterodimeric MHC II molecule. The peptide binding cleft is flanked by alpha helices, while anti-parallel beta pleated sheets make up its floor. It is estimated that any given MHC II binding cleft can bind anywhere from 650 to 2000 different peptides (the peptidic repertoire), ranging in size from 13 residues to 18 residues. Arg74, due to its strategic location, would be expected to exact an influence on the character of the peptidic repertoire.