Thymic stromal lymphopoietin gene promoter polymorphisms and expression levels in Graves’ disease and Graves’ ophthalmopathy

Kun-Hsi Tsai,Hung-Jung Lin,Yu-Huei Liu,Lei Wan,Wen-Ling Liao,Fuu-Jen Tsai,Hui-Ju Lin

doi:10.1186/1471-2350-13-116

Abstract

BackgroundGraves disease (GD) is an organ-specific autoimmune disease characterized by hyperthyroidism, diffuse goiter, autoantibodies against thyroid-specific antigens, and dermopathy. Studies of GD have demonstrated the importance of the Th2 and Th17 immune responses in mediating disease progression. In the present study, we investigated the role of a Th2 cytokine, thymic stromal lymphopoietin (TSLP), in GD and Th17 differentiation.MethodsIn this study, we genotyped 470 patients with GD at 3 single nucleotide polymorphisms (SNPs) in TSLP. In addition, the serum concentrations of TSLP were determined in 432 patients and 272 controls. Ten patients and controls each were further screened using in vitro Th17 differentiation assays. The SNPs were genotyped using ABI TaqMan® SNP genotyping assays. For the Th17 differentiation assays, peripheral blood mononuclear cells (PBMCs) isolated from the patients and controls were placed into Th17 differentiation media, and interleukin 17 expression levels were determined.ResultsHaplotype analysis indicated that patients with the Ht3 (TCC) haplotype have a 3.28-fold higher risk of developing GD (p = 0.007), whereas those with the Ht5 (TCG) haplotype had a 0.03-fold, reduced risk of developing GD (p = 1 × 10−14). SNP rs3806933 (p = 0.007) was associated with female Graves ophthalmopathy (GO). TSLP expression levels were higher in GD patients than in control subjects, and TLSP was also shown to promote the differentiation of Th17 cells in GD patients.ConclusionsThese results suggest that polymorphisms in TSLP may be used as genetic markers for the diagnosis and prognosis of GD. Furthermore, TLSP may be a target for treating GD.

Highlights

Graves disease (GD) is an organ-specific autoimmune disease characterized by hyperthyroidism, diffuse goiter, autoantibodies against thyroid-specific antigens, and dermopathy
GD patients often present with anti-thyrotropin receptor antibodies (TRAb)—an immune response regulated by Th2 cells—which stimulate a variety of biological responses that lead to hyperthyroidism and goiter [1]
We indicated that thymic stromal lymphopoietin (TSLP) polymorphisms are associated with GD and that expression levels of TSLP are higher in patients than in control subjects

Summary

Introduction

Graves disease (GD) is an organ-specific autoimmune disease characterized by hyperthyroidism, diffuse goiter, autoantibodies against thyroid-specific antigens, and dermopathy. Studies of GD have demonstrated the importance of the Th2 and Th17 immune responses in mediating disease progression. We investigated the role of a Th2 cytokine, thymic stromal lymphopoietin (TSLP), in GD and Th17 differentiation. Graves’ disease (GD) is a complex, organ-specific autoimmune disease characterized by a variety of clinical features, such as hyperthyroidism, diffuse goiter, the presence of autoantibodies against thyroid-specific antigens, and dermopathy. Studies of TSLP in humans have indicated its potential role in the Th2 inflammatory response. Th17 cells play an important role in GD and other inflammatory autoimmune disorders, including multiple sclerosis [8,9], rheumatoid arthritis [10,11], and Crohn’s disease [12]. TSLP was shown to promote Th17 differentiation and enhance arthritis in murine rheumatoid arthritis models, indicating the importance of TSLP in the differentiation of Th17 and the involvement of TSLP in the pathogenesis of autoimmune disease [13]

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Discussion

Conclusion