Triggering Thyroid Autoimmunity: Genes, Viruses, and Epigenetics Yaron Tomer, MD Division of Endocrinology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York Nothing to Disclose PRESENTATION FROM THE 83rd ANNUAL MEETING OF THE AMERICAN THYROID ASSOCIATION, OCTOBER 16-20, 2013 (Yaron Tomer)
Genes Viruses Interactions PRESENTATION FROM THE 83rd ANNUAL MEETING OF THE AMERICAN THYROID ASSOCIATION, OCTOBER 16-20, 2013 (Yaron Tomer)
Genes Viruses Interactions PRESENTATION FROM THE 83rd ANNUAL MEETING OF THE AMERICAN THYROID ASSOCIATION, OCTOBER 16-20, 2013 (Yaron Tomer)
TSHR HLA-DRb1-Arg74 12q (BTG1) CD40 CTLA-4 CD25 PTPN22 Tg GD HT ARID5B Reviewed in: Tomer. Thyroid 2010; 20: 715-725 Huber, et al. Endocr Rev 2008; 29: 697-725 Brand, Gough, Curr Genomics 2011; 12: 526-541 PRESENTATION FROM THE 83rd ANNUAL MEETING OF THE AMERICAN THYROID ASSOCIATION, OCTOBER 16-20, 2013 (Yaron Tomer)
+ B-cell Tg, TSHR Translational Implications PRESENTATION FROM THE 83rd ANNUAL MEETING OF THE AMERICAN THYROID ASSOCIATION, OCTOBER 16-20, 2013 (Yaron Tomer)
Genes Viruses Interactions PRESENTATION FROM THE 83rd ANNUAL MEETING OF THE AMERICAN THYROID ASSOCIATION, OCTOBER 16-20, 2013 (Yaron Tomer)
Hepatitis C and Thyroiditis Country Year Patients Controls P-value Study No. %TAb’s No. %TAb’s France 1993 72 12.5 60 1.7 0.02 Tran Japan 1994 109 9.2 -- -- -- Watanabe Spain 1995 96 5.2 96 8.3 NS Boadas Italy 1995 75 10.7 -- -- -- Carella UK 1997 111 4.5 99 11.1 NS Metcalfe Italy 1999 86 9.3 1147 17.1 NS Loviselli France 2000 97 13.4 97 3.1 0.02 Ganne-Carrie Italy 2004 630 21 389 12 0.0001 Antonelli Reviewed in: Mandac, Chaudhry, Sherman, and Tomer. Hepatology; 2006; 43: 661-672 PRESENTATION FROM THE 83rd ANNUAL MEETING OF THE AMERICAN THYROID ASSOCIATION, OCTOBER 16-20, 2013 (Yaron Tomer)
How can HCV infection trigger thyroiditis? Non-specific effects of the virus Can HCV infect human thyroid cells PRESENTATION FROM THE 83rd ANNUAL MEETING OF THE AMERICAN THYROID ASSOCIATION, OCTOBER 16-20, 2013 (Yaron Tomer)
Detection of HCV-RNA in the thyroid by in-situ hybridization Bartolome et al J Med Virol 2008; 80: 1588-1594 PRESENTATION FROM THE 83rd ANNUAL MEETING OF THE AMERICAN THYROID ASSOCIATION, OCTOBER 16-20, 2013 (Yaron Tomer)
ML-1 Huh7.5 295 bp 295 bp Control – PS cells Control – PS supernatant Control – NS cells Control – NS supernatant NS sup: uninfected NS supernatant: infected NS cells: uninfected NS cells: infected PS sup: uninfected PS sup: infected PS cells: uninfected Blackard et al. Thyroid 2013; PS cells: infected 23: 863-870 PRESENTATION FROM THE 83rd ANNUAL MEETING OF THE AMERICAN THYROID ASSOCIATION, OCTOBER 16-20, 2013 (Yaron Tomer)
HCV Infection in the Presence or Absence of anti-CD81 1.00 0.75 0.50 Huh 7.5 0.25 0.00 1.00 0.75 ML-1 0.50 0.25 0.00 Blackard et al. Thyroid 2013; 23: 863-870 PRESENTATION FROM THE 83rd ANNUAL MEETING OF THE AMERICAN THYROID ASSOCIATION, OCTOBER 16-20, 2013 (Yaron Tomer)
Mechanisms of induction of Thyroiditis by HCV: Bystander Activation Exposure of cryptic Ag’s Inflammatory response Alteration of self Ag’s Secretion of cytokines (IL-8) PRESENTATION FROM THE 83rd ANNUAL MEETING OF THE AMERICAN THYROID ASSOCIATION, OCTOBER 16-20, 2013 (Yaron Tomer)
Genes Viruses Interactions PRESENTATION FROM THE 83rd ANNUAL MEETING OF THE AMERICAN THYROID ASSOCIATION, OCTOBER 16-20, 2013 (Yaron Tomer)
Epigenetics: Definition Non-coding effects on gene expression/function that are mitotically stable (i.e. long lasting) • DNA methylation • Histone modifications • microRNA activation PRESENTATION FROM THE 83rd ANNUAL MEETING OF THE AMERICAN THYROID ASSOCIATION, OCTOBER 16-20, 2013 (Yaron Tomer)
Epigenetics: Definition Non-coding effects on gene expression/function that are mitotically stable (i.e. long lasting) • DNA methylation • Histone modifications • microRNA activation Which environmental factor triggers epigenetic changes in thyroid cells? PRESENTATION FROM THE 83rd ANNUAL MEETING OF THE AMERICAN THYROID ASSOCIATION, OCTOBER 16-20, 2013 (Yaron Tomer)
Interferon and AITD • IFN is a key cytokine secreted during infections • IFN therapy has been associated with autoimmunity – AITD, type 1 DM, SLE • Transgenic mice expressing IFN in thyroid develop thyroiditis IFN is a Key Cytokine Triggering AITD Stewart . Science 1993; 260: 1942-1946 Akeno. J Immunol 2011; 186: 4693-4706 Eisenbarth. Clin Immunol 2004; 111: 225-233 Tomer. J Autoimmun 2010; 34: J322-J326 Diana. Nat Med 2013; 19: 65-73 PRESENTATION FROM THE 83rd ANNUAL MEETING OF THE AMERICAN THYROID ASSOCIATION, OCTOBER 16-20, 2013 (Yaron Tomer)
Epigenetic Effects of IFNa IFNa Human Thyroid Cells Global histone modifications H3K4me1 H3K4me3 Genetic Variants Associated with AITD PRESENTATION FROM THE 83rd ANNUAL MEETING OF THE AMERICAN THYROID ASSOCIATION, OCTOBER 16-20, 2013 (Yaron Tomer)
A Tg Promoter SNP That is Associated with AITD Shows Enrichment in H3K4me1 rs180195 IFNa + IFNa - Tg Promoter 1623 40 cAMP-RE Exon 1 CAAT TATA AAA(A/G)GAAA ATG TSS Stefan et al. JBC 2011; 286; 31168-31179 PRESENTATION FROM THE 83rd ANNUAL MEETING OF THE AMERICAN THYROID ASSOCIATION, OCTOBER 16-20, 2013 (Yaron Tomer)
Tg Promoter -1623 G Allele Binds IRF-1 183 TG (-1623 G) 120 HLA-B promoter 173 TSHR promoter Stefan et al. JBC 2011; 286; 31168-31179 PRESENTATION FROM THE 83rd ANNUAL MEETING OF THE AMERICAN THYROID ASSOCIATION, OCTOBER 16-20, 2013 (Yaron Tomer)
Binding of IRF-1 to the -1623 G-Allele Induces Epigenetic Changes Driving TG Transcription TG -1623 G TG proximal promoter H3Ac Active Active Chromatin Chromatin H3K4me3 Active Enhancer Transcriptional Element Element H3K4me1 Stefan et al. JBC 2011; 286: 31168-31179 PRESENTATION FROM THE 83rd ANNUAL MEETING OF THE AMERICAN THYROID ASSOCIATION, OCTOBER 16-20, 2013 (Yaron Tomer)
Tg Promoter -1623 G Allele Increases Promoter Activity Construct pGL4.10- TG ( A ) p=0.007 pGL4.10- TG ( G ) p=0.008 pGL4.10- TG ( del ) 0 5 10 15 20 25 30 Luciferase Activity Stefan et al. JBC 2011; 286: 31168-31179 PRESENTATION FROM THE 83rd ANNUAL MEETING OF THE AMERICAN THYROID ASSOCIATION, OCTOBER 16-20, 2013 (Yaron Tomer)
Interferon Induces Tg Expression in Thyroid Cells IRF-1 TG * 2.5 ** * 3 * 2 2.5 Fold change Fold change * * 2 1.5 1.5 1 1 0.5 0.5 0 0 0 1000 5000 10,000 0 1000 5000 10,000 IFN α conc. (U/ml) IFN α conc. (U/ml) How can upregulation of Tg trigger AITD? PRESENTATION FROM THE 83rd ANNUAL MEETING OF THE AMERICAN THYROID ASSOCIATION, OCTOBER 16-20, 2013 (Yaron Tomer)
MECHANISM Infection ER Stress Tg PRESENTATION FROM THE 83rd ANNUAL MEETING OF THE AMERICAN THYROID ASSOCIATION, OCTOBER 16-20, 2013 (Yaron Tomer)
Mihaela Stefan Erlinda Concepcion Angela Lombardi Francesca Menconi Cheuk Wun Li Nagako Akeno Eric Jacobson Alia Hasham Collaborators Molecular Modeling Roman Osman Taiji Oashi Proteomics Statistical Genetics Next gen Sequencing, Genotyping Rong Wang David Greenberg Mehdi Keddache Bioinformatics Susan Hodge Weijia Zhang Small molecule screening Cristina Monti Lucy Skrabanek Dan Felsenfeld PRESENTATION FROM THE 83rd ANNUAL MEETING OF THE AMERICAN THYROID ASSOCIATION, OCTOBER 16-20, 2013 (Yaron Tomer)
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