Unravelling the genetic complexity of autoimmune thyroid disease: HLA, CTLA‐4 and beyond

Division of Medical Sciences, University of Birmingham, Institute of Biomedical Research, Birmingham, UK.
Clinical & Experimental Immunology (Impact Factor: 3.04). 05/2004; 136(1):1-10. DOI: 10.1111/j.1365-2249.2004.02424.x
Source: PubMed


The autoimmune thyroid diseases (AITDs) including Graves' disease (GD) and autoimmune hypothyroidism (AIH) are the commonest of the autoimmune conditions affecting 2-5% of the western population. Twin studies have clearly demonstrated that AITDs are caused by a combination of both environmental and genetic factors. Association of the HLA class II region with AITD has been documented for over 20 years now, but the primary aetiological variant in this region remains unknown. More recently the CTLA-4 gene region has been identified as the second locus conferring susceptibility to AITD. In contrast to HLA, a polymorphism of the CTLA-4 gene, which encodes an important negative regulator of the immune system, has been identified as a candidate for a primary determinant for AITD. A large number of candidate gene and genome wide linkage studies have been involved in the search for the elusive 'third' locus. The thyroglobulin (Tg) gene in humans maps to chromosome 8q, which has been linked in family studies to AITD. A number of association studies in humans and the mouse model for AITD are beginning to implicate the Tg gene although convincing evidence for a primary causative role is still needed. The establishment of large DNA disease resources along with more detailed genetic maps and the development of faster, more effective, high throughput genotyping and sequencing methods, provides some sense of optimism that novel loci will be identified in the near future and the complex aetiology of AITD will be further unraveled.

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Available from: Stephen Gough, Nov 21, 2014
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    • "GD is characterized by the production of thyroid-stimulating hormone receptor-stimulating antibodies, leading to hyperthyroidism, whereas HT is characterized by the apoptosis of the thyrocytes, resulting in hypothyroidism [3] [4]. Twin studies and familial aggregation have clearly indicated that AITD is caused by a combination of both environmental and genetic factors [5] [6]. Through linkage and association analyses on a cohort of Japanese AITD patients [7] [8], we have previously identified ZFAT (zinc-finger gene in Available online at "
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    ABSTRACT: The human ZFAT gene encodes a 1243-amino-acid protein containing one AT hook and 18 C2H2 zinc finger domains, which are highly conserved among ZFAT orthologues from fish to mammalian species. Consistent with the presence of multiple predicted nuclear localization signals, endogenous ZFAT protein was found to be localized to the nucleus. In the mouse tissues examined by Western blotting, ZFAT was found to be expressed in thymus, spleen, and lymph nodes, but not in other tissues, including bone marrow. Furthermore, ZFAT protein was found to be up-regulated during the transition from CD4(-)CD8(-) to CD4(+)CD8(+) thymocytes and to be expressed only in B and T lymphocytes in peripheral lymphoid tissues. Expression array analyses demonstrated that genes that are down-regulated upon ZFAT overexpression in mouse Ba/F3 cells are significantly enriched for those functionally related to immune responses. These results suggest that ZFAT functions as a critical transcriptional regulator in B and T lymphocytes.
    Full-text · Article · Jun 2008 · Genomics
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    • "The importance of the HLA-DR3 allele has further been shown recently, when GravesÕ diseaselike symptoms were induced in DR3-transgenic mice by immunization with thyrotropin receptor plasmid DNA [8]. These studies support the HLA-DR3 association with autoimmune thyroid disease in humans, as reviewed recently [9]. While mTg and hTg induce EAT in DR3-transgenic mice, the T cell epitope(s) responsible for stimulating pathogenic T cells remains to be determined. "
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    ABSTRACT: To identify pathogenic epitopes on human thyroglobulin (hTg), a homodimer of 660kDa, we have applied a computer-based algorithm to predict potential HLA-DR3-binding peptides and have tested them in DR3-transgenic mice. Of the 39 peptides selected, four stimulated a proliferative response from hTg-primed cells of DR3+ mice, but not DQ8+ mice. Of the four peptides, one, hTg2079, was consistently pathogenic. Thyroiditis was not only produced by adoptive transfer of hTg-primed, hTg2079-activated cells but also by direct immunization with the peptide. These results demonstrate the utility of using this computer-based algorithm with synthetic peptides to help identify pathogenic T cell epitopes on hTg.
    Full-text · Article · Jul 2004 · Cellular Immunology
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