TY - JOUR
T1 - The HLA gene complex in thyroid autoimmunity
T2 - From epidemiology to etiology
AU - Jacobson, Eric M.
AU - Huber, Amanda
AU - Tomer, Yaron
N1 - Funding Information:
This work was supported in part by grants DK61659, DK067555, and DK073681 from NIDDK, and by a research grant from the American Thyroid Association (EMJ). We thank Taiji Oashi for his expert help in HLA-DR diagram.
PY - 2008/2
Y1 - 2008/2
N2 - 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.
AB - 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.
KW - Association
KW - Gene
KW - Graves' disease
KW - HLA
KW - Hashimoto's thyroiditis
KW - Linkage
KW - Thyroid
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U2 - 10.1016/j.jaut.2007.11.010
DO - 10.1016/j.jaut.2007.11.010
M3 - Review article
C2 - 18178059
AN - SCOPUS:38049068750
SN - 0896-8411
VL - 30
SP - 58
EP - 62
JO - Journal of Autoimmunity
JF - Journal of Autoimmunity
IS - 1-2
ER -