triggering thyroid autoimmunity: genes, viruses, and ... · bartolome et al j med virol 2008; 80:...

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)

HLA-DRb1-Arg74

CTLA-4

PTPN22

Tg

ARID5B GD HT

TSHR

CD40

CD25

12q

(BTG1)

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)

Tg, TSHR

B-cell

Translational Implications

+


Genes

Viruses

Interactions


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

Hepatitis C and Thyroiditis

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?

Can HCV infect human thyroid cells

Non-specific effects of the virus


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)

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 cells: uninfected

PS cells: infected

PS sup: infected

295 bp 295 bp

ML-1 Huh7.5

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)

HCV Infection in the Presence or Absence of anti-CD81

0.00

0.25

0.50

0.75

1.00

0.00

0.25

0.50

0.75

1.00

Huh 7.5

ML-1

Blackard et al. Thyroid 2013; 23: 863-870


Exposure of cryptic Ag’s

Alteration of self Ag’s

Inflammatory response

Secretion of cytokines (IL-8)

Mechanisms of induction of Thyroiditis by HCV: Bystander Activation


Genes

Viruses

Interactions


Non-coding effects on gene expression/function that

are mitotically stable (i.e. long lasting)

• DNA methylation

• Histone modifications

• microRNA activation

Epigenetics: Definition


Non-coding effects on gene expression/function that

are mitotically stable (i.e. long lasting)

• DNA methylation

• Histone modifications

• microRNA activation

Epigenetics: Definition

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 Akeno. J Immunol 2011; 186: 4693-4706

Tomer. J Autoimmun 2010; 34: J322-J326

Stewart . Science 1993; 260: 1942-1946

Eisenbarth. Clin Immunol 2004; 111: 225-233

Diana. Nat Med 2013; 19: 65-73 PRESENTATION FROM THE 83rd ANNUAL MEETING OF THE AMERICAN THYROID ASSOCIATION, OCTOBER 16-20, 2013 (Yaron Tomer)

IFNa

Human Thyroid Cells

Epigenetic Effects of IFNa

Global histone modifications

H3K4me1 H3K4me3

Genetic Variants

Associated with AITD


Tg Promoter

rs180195

IFNa +

IFNa -

AAA(A/G)GAAA

Exon 1

TSS

ATG TATA CAAT

40

cAMP-RE

1623

A Tg Promoter SNP That is Associated with AITD

Shows Enrichment in 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)

183

120

173

TG (-1623 G)

HLA-B promoter

TSHR promoter

Tg Promoter -1623 G Allele Binds IRF-1

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 proximal promoter

H3K4me3

H3K4me1

TG -1623 G

H3Ac Active

Chromatin

Active

Transcriptional

Element

Active

Chromatin

Enhancer

Element

Binding of IRF-1 to the -1623 G-Allele Induces

Epigenetic Changes Driving TG Transcription

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)

Luciferase Activity

0 5 10 15 20 25 30

p=0.007

p=0.008

pGL4.10-TG (A)

pGL4.10-TG (G)

pGL4.10-TG (del)

Construct

Tg Promoter -1623 G Allele Increases

Promoter 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)

Fo

ld c

ha

ng

e

IFNα conc. (U/ml)

1000 5000 10,000 0

TG

IFNα conc. (U/ml)

Fo

ld c

ha

ng

e

IRF-1

0

0.5

1

1.5

2

2.5

3

0 1000 5000 10,000

**

*

*

0

0.5

1

1.5

2

2.5

*

* *

Interferon Induces Tg Expression in Thyroid Cells

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

Tg

ER

Stress


Mihaela Stefan

Erlinda Concepcion

Angela Lombardi

Francesca Menconi

Cheuk Wun Li

Nagako Akeno

Eric Jacobson

Alia Hasham

Molecular Modeling

Roman Osman

Taiji Oashi

Collaborators

Proteomics

Rong Wang

Bioinformatics

Weijia Zhang

Lucy Skrabanek

Statistical Genetics

David Greenberg

Susan Hodge

Cristina Monti

Next gen Sequencing, Genotyping

Mehdi Keddache

Small molecule screening

Dan Felsenfeld PRESENTATION FROM THE 83rd ANNUAL MEETING OF THE AMERICAN THYROID ASSOCIATION, OCTOBER 16-20, 2013 (Yaron Tomer)

triggering thyroid autoimmunity: genes, viruses, and ... · bartolome et al j med virol 2008; 80:...

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