Elsevier

Journal of Autoimmunity

Volume 32, Issues 3–4, May–June 2009, Pages 231-239
Journal of Autoimmunity

The etiology of autoimmune thyroid disease: A story of genes and environment

https://doi.org/10.1016/j.jaut.2009.02.007Get rights and content

Abstract

Autoimmune thyroid diseases (AITDs), including Graves' disease (GD) and Hashimoto's thyroiditis (HT) are prevalent autoimmune diseases, affecting up to 5% of the general population. Autoimmune thyroid diseases arise due to complex interactions between environmental and genetic factors. Significant progress has been made in our understanding of the genetic and environmental triggers contributing to AITD. However, the interactions between genes and environment are yet to be defined. Among the major AITD susceptibility genes that have been identified and characterized is the HLA-DR gene locus, as well as non-MHC genes including the CTLA-4, CD40, PTPN22, thyroglobulin, and TSH receptor genes. The major environmental triggers of AITD include iodine, medications, infection, smoking, and possibly stress. Recent data on the genetic predisposition to AITD lead to novel putative mechanisms by which the genetic–environmental interactions may lead to the development of thyroid autoimmunity.

Introduction

The two major autoimmune thyroid diseases (AITDs) include Graves' disease (GD) and Hashimoto's thyroiditis (HT), both of which are characterized pathologically by infiltration of the thyroid by T and B-cells reactive to thyroid antigens, biochemically by the production of thyroid autoantibodies, and clinically by abnormal thyroid functions (hyperthyroidism in GD and hypothyroidism in HT) (reviewed in [1], [2]). Additional variants of AITD include post-partum thyroiditis (reviewed in [3], [4], [5]), drug induced thyroiditis, such as interferon induced thyroiditis (IIT) [6], and thyroiditis associated with polyglandular autoimmune syndromes (reviewed in [7], [8]). While the exact etiology of thyroid autoimmunity is not known, it is believed to develop when a combination of genetic susceptibility [9], [10] and environmental encounters leads to breakdown of tolerance. While several major genes and environmental factors contributing to the etiology of AITD have been identified, their interactions are still not understood.

Section snippets

Methodological advances

Recent advances in genetic methods enabled significant progress in the identification of complex disease genes. Complex disease genes can be identified by linkage analysis or by association studies. Classically linkage studies were most powerful for screening the entire genome while association studies were mostly utilized for candidate gene analysis. However, genome wide associations (GWAS) have become a reality and proved to be a powerful tool for gene mapping.

Genetic studies

The major histocompatibility complex (MHC) region, encoding the HLA glycoproteins, consists of a complex of genes located on chromosome 6p21 [19]. HLA class II genes were the first genes to be tested in AITD. While initial studies analyzed different HLA-DR and DQ alleles in AITD [10], more recent studies focused on the specific peptide-binding pocket sequences and 3-D structures that predispose to disease [20], [21]. GD is associated with HLA-DR3 in Caucasians (reviewed in [22]). The frequency

Genetic studies

The cytotoxic T lymphocyte-associated factor 4 (CTLA-4) gene is a major negative regulator of T-cell activation [43]. CTLA-4 may play a role in autoimmunity as CTLA-4 activation has been shown to suppress several experimental autoimmune diseases including murine lupus [44], collagen-induced arthritis [45], experimental autoimmune glomerulonephritis [46], and diabetes in NOD mice [47]. Thus, it was postulated that CTLA-4 polymorphisms which reduce its expression and/or function might predispose

Genetic studies

CD40 is expressed primarily on B-cells and other antigen presenting cells (APCs) [75], and plays a fundamental role in B-cell activation inducing, upon ligation, B-cell proliferation, immunoglobulin class switching, antibody secretion, and generation of memory cells [76], [77]. Using a combination of linkage and association studies we and others have identified CD40 as a major susceptibility gene for GD [78], [79], [80], [81], [82], [83], [84]. Sequencing the entire CD40 gene led to the

Genetic studies

The lymphoid tyrosine phosphatase (LYP), encoded by the protein tyrosine phosphatase-22 (PTPN22) gene, like CTLA-4, is a powerful inhibitor of T-cell activation [92]. A tryptophan/arginine substitution at codon 620 (R620W) of PTPN22 was found to be associated with AITD including both GD [93], and HT [94], as well as with other autoimmune diseases [95], [96], [97], [98]. Unlike CTLA-4 which was associated with AITD across ethnic groups, the PTPN22 gene shows significant ethnic differences in

Genetic studies

Thyroglobulin (Tg) is a 660 kDA homodimeric protein that serves as a precursor and storehouse for thyroid hormones [101]. Tg is one of the main targets of the immune response in AITD and all AITD phenotypes are characterized by the development of Tg antibodies. Mouse models have provided additional evidence for the importance of Tg in the development of thyroid autoimmunity. The mouse model for Hashimoto's thyroiditis, murine experimental autoimmune thyroiditis (EAT), can be induced, in

Genetic studies

The hallmark of GD is the presence of stimulating thyrotropin (TSH) receptor antibodies [1], and, therefore, the TSHR was an attractive candidate gene for GD. Prior to the completion of the human genome project and the availability of detailed SNP maps three missense SNPs of the TSHR have been examined for association with GD [112], D36H, P52T, and D727E. However, studies of these SNPs gave inconsistent results with some showing associations [113], [114], and others not [115], [116], [117],

The role of environmental factors

A recent twin study estimated that 79% of the liability to the development of GD is attributable to genetic factors [125]. Therefore, about 20% of the liability to develop GD is due to non-genetic factors. Among the non-genetic factors postulated to precipitated AITD are iodine [126], [127] (Table 1), medications such as amiodarone and interferon alpha [128] (Table 2), infections [129], smoking (Table 3), and stress (Table 4).

One of the most intriguing environmental triggers of autoimmune

Conclusions

The AITDs are complex diseases that are postulated to be caused by the combined effects of multiple susceptibility genes and environmental triggers. Significant progress has been made in the past decade in mapping the AITD susceptibility genes and understanding the mechanisms by which they confer risk for disease. The AITD susceptibility genes identified so far can be divided into two broad groups: (1) immune modulating genes and (2) thyroid specific genes. The first group includes the HLA-DR,

Acknowledgements

This work was supported in part by grants DK061659, DK067555 and DK073681 from NIDDK (to YT).

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