Yaron Tomer

Boston Children's Hospital, Boston, MA, United States

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Publications (152)733.58 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: We have previously shown that a (TC)n microsatellite in intron 5 of the Forkhead Box Protein 3 (FOXP3) gene was associated with a variant of the autoimmune polyglandular syndrome type 3 (APS3v), that is defined as the co-occurrence of type 1 diabetes (T1D) and autoimmune thyroiditis (AITD). Allele 10, containing 25 repeats of the microsatellite (long repeats), is preferentially transmitted to offspring with APS3v, while allele 2, containing 14 repeats of the microsatellite (short repeats), is protective. We hypothesized that the long repeats of the intron 5 microsatellite decrease FOXP3 splicing and function, thereby reducing regulatory T cell activity and promoting the development of APS3v. We cloned genomic DNA from two hemizygous males for the long and short repeats of the microsatellite on their X-chromosomes and transfected them into human embryonic kidney 293 (HEK 293) cells to perform direct splicing analysis. We identified a novel splice variant of FOXP3 lacking exon 6, and showed that it is expressed in human thymus and lymph node. However, the length of the repeats in the microsatellite did not significantly influence the expression of this FOXP3 splice variant in vitro. Interestingly, this splice variant was expressed in human regulatory T cells, suggesting that it may play a role in their function. In conclusion, we identified a novel splice variant FOXP3Δ6. The role of its expression in regulatory T cells in the development of autoimmunity remains to be determined. Copyright © 2014. Published by Elsevier B.V.
    Gene 12/2014; · 2.20 Impact Factor
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    ABSTRACT: Context: Amiodarone (AMIO) is one of the most effective antiarrhythmic drugs available, however, its use is limited by a serious side-effect profile, including thyroiditis. The precise mechanisms underlying AMIO thyroid toxicity have been elusive, thus, identification of novel approaches to protect thyroid cells is essential in patients with life-threatening arrhythmias. Objective: Our aim was to evaluate if AMIO treatment could induce Endoplasmic Reticulum (ER) stress in human thyroid cells, and the possible implications of this effect in AMIO-induced destructive thyroiditis. Results: Here, we reported that AMIO but not iodine, significantly induced the expression of ER stress markers such as immunoglobulin heavy chain-binding protein (BiP), phospho-eukaryotic translation initiation factor 2α (eIF2α), C/EBP homologous protein (CHOP) and spliced X-box binding protein-1 (XBP-1) in human thyroid ML-1 cells and human primary thyrocytes. In both experimental systems AMIO downregulated thyroglobulin (Tg) protein but had little effect on Tg mRNA levels, suggesting a mechanism involving Tg protein degradation. Indeed, pretreatment with the specific proteasome inhibitor MG132 reversed AMIO-induced downregulation of Tg protein levels, confirming a proteasome-dependent degradation of Tg protein. Corroborating our findings, pretreatment of ML-1 cells and human primary thyrocytes with the chemical chaperone 4-phenylbutyric acid completely prevented the effect of AMIO on both ER stress induction and Tg downregulation. Conclusions: We identified ER stress as a novel mechanism contributing to AMIO-induced destructive thyroiditis. Our data establish that AMIO-induced ER stress impairs Tg expression via proteasome activation providing a valuable therapeutic avenue for the treatment of AMIO-induced destructive thyroiditis.
    The Journal of clinical endocrinology and metabolism. 10/2014;
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    ABSTRACT: Graves disease (GD) is an autoimmune condition caused by interacting genetic and environmental factors. Genetic studies have mapped several single-nucleotide polymorphisms (SNPs) that are strongly associated with GD, but the mechanisms by which they trigger disease are unknown. We hypothesized that epigenetic modifications induced by microenvironmental influences of cytokines can reveal the functionality of GD-associated SNPs. We analyzed genome-wide histone H3 lysine 4 methylation and gene expression in thyroid cells induced by IFNα, a key cytokine secreted during viral infections, and overlapped them with known GD-associated SNPs. We mapped an open chromatin region overlapping two adjacent GD-associated SNPs (rs12101255 and rs12101261) in intron 1 of the thyroid stimulating hormone receptor (TSHR) gene. We then demonstrated that this region functions as a regulatory element through binding of the transcriptional repressor promyelocytic leukemia zinc finger protein (PLZF) at the rs12101261 site. Repression by PLZF depended on the rs12101261 disease susceptibility allele and was increased by IFNα. Intrathymic TSHR expression was decreased in individuals homozygous for the rs12101261 disease-associated genotype compared with carriers of the disease-protective allele. Our studies discovered a genetic-epigenetic interaction involving a noncoding SNP in the TSHR gene that regulates thymic TSHR gene expression and facilitates escape of TSHR-reactive T cells from central tolerance, triggering GD.
    Proceedings of the National Academy of Sciences 08/2014; · 9.81 Impact Factor
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    ABSTRACT: Context: Genetic and environmental factors play an essential role in the pathogenesis of Graves' disease (GD). Children with GD have less exposure time to environmental factors and therefore are believed to harbor stronger genetic susceptibility than adults. Objective: The aim of the study was to identify susceptibility loci that predispose to GD in young age of onset (AO) GD patients. Design and Participants: One hundred and six patients with young AO GD (onset <30 years-old) and 855 healthy subjects were studied. Cases and controls were genotyped using the Illumina infinium immunochip, designed to genotype 196,524 polymorphisms. Case control association analyses were performed using the PLINK computer package. Ingenuity Pathway Analysis program was used to carry out pathway analyses. Results: Immunochip genetic association analysis identified 30 single-nucleotide polymorphisms in several genes that were significantly associated with young AO GD, including MHC class I and class II genes, BTNL2, NOTCH4, TNFAIP3, and CXCR4. Candidate gene analysis revealed that most of the genes previously shown to be associated with adult-onset GD were also associated with young AO GD. Pathway analysis demonstrated that antigen presentation, T-helper cell differentiation and B-cell development were the major pathways contributing to the pathogenesis of young AO GD. Conclusions: Genetic analysis identified novel susceptibility loci in young AO GD adding a new dimension to the understanding of GD etiology.
    The Journal of Clinical Endocrinology and Metabolism 03/2014; · 6.31 Impact Factor
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    ABSTRACT: Type 1 diabetes (T1D) shows ∼40% concordance rate in monozygotic twins (MZ) suggesting a role for environmental factors and/or epigenetic modifications in the etiology of the disease. The aim of our study was to dissect the contribution of epigenetic factors, particularly, DNA methylation (DNAm), to the incomplete penetrance of T1D. We performed DNAm profiling in lymphocyte cell lines from 3 monozygotic (MZ) twin pairs discordant for T1D and 6 MZ twin pairs concordant for the disease using HumanMethylation27 BeadChip. This assay assesses the methylation state of 27,578 CpG sites, mostly located within proximal promoter regions. We identified 88 CpG sites displaying significant methylation changes in all T1D-discordant MZ twin pairs. Functional annotation of the genes with distinct CpG methylation profiles in T1D samples showed differential DNAm of immune response and defense response pathways between affected and unaffected twins. Integration of DNAm data with GWAS data mapped several known T1D associated genes, HLA, INS, IL-2RB, CD226, which showed significant differences in DNAm between affected and unaffected of twins. Our findings suggest that abnormalities of DNA methylation patterns, known to regulate gene transcription, may be involved in the pathogenesis of T1D.
    Journal of Autoimmunity 11/2013; · 8.15 Impact Factor
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    ABSTRACT: Autoimmune thyroid diseases (AITD) have become increasingly recognized as a complication of interferon-alpha (IFNα) therapy in patients with chronic Hepatitis C virus (HCV) infection. Interferon-induced thyroiditis (IIT) can manifest as clinical thyroiditis in approximately 15% of HCV patients receiving IFNα and subclinical thyroiditis in up to 40% of patients, possibly resulting in either dose reduction or discontinuation of IFNα treatment. However, the exact mechanisms that lead to the development of IIT are unknown and may include IFNα-mediated immune-recruitment as well as direct toxic effects on thyroid follicular cells. We hypothesized that IIT develops in genetically predisposed individuals whose threshold for developing thyroiditis is lowered by IFNα. Therefore, our aim was to identify the susceptibility genes for IIT. We used a genomic convergence approach combining genetic association data with transcriptome analysis of genes upregulated by IFNα. Integrating results of genetic association, transcriptome data, pathway, and haplotype analyses enabled the identification of 3 putative loci, SP100/110/140 (2q37.1), HLA (6p21.3), and TAP1 (6p21.3) that may be involved in the pathogenesis of IIT. Immune-regulation and apoptosis emerged as the predominant mechanisms underlying the etiology of IIT.
    Journal of Autoimmunity 05/2013; · 8.15 Impact Factor
  • Giuseppe Barbesino, Yaron Tomer
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    ABSTRACT: CONTEXT:TSH receptor antibodies (TRAb) cause Graves' disease (GD) hyperthyroidism. Widely available TRAb measurement methods have been significantly improved recently. However, the role of TRAb measurement in the differential diagnosis of hyperthyroidism, the prediction of remission of GD hyperthyroidism, the prediction of fetal/neonatal thyrotoxicosis and the clinical assessment of Graves' ophthalmopathy (GO) is controversialEVIDENCE ACQUISITION:We reviewed and analyzed the literature reporting primary data on the clinical use of TRAb. We focused our analyses on clinical studies analyzing third generation TRAb assays.EVIDENCE SYNTHESIS:The performance of TRAb in the differential diagnosis of overt hyperthyroidism is excellent, with sensitivity and specificity in the upper 90%. TRAb can accurately predict short-term relapses of hyperthyroidism after a course of antithyroid drugs, but are less effective in predicting long-term relapses or remissions. Pregnancies in GD women with negative TRAb are highly unlikely to result in fetal hyperthyroidism, while high titers of TRAb in pregnancy require careful fetal monitoring. GD patients with GO frequently have high TRAb levels. However there is insufficient data to use the test to predict the clinical course of GO and response to treatment.CONCLUSIONS:Third generation TRAb assays are suitable in the differential diagnosis of hyperthyroidism. In GD, TRAb should be tested before deciding whether methimazole can be stopped. TRAb should be used in pregnant women with GD to assess the risk of fetal thyrotoxicosis. The use of TRAb in GO requires further studies.
    The Journal of Clinical Endocrinology and Metabolism 03/2013; · 6.31 Impact Factor
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    ABSTRACT: Although HLA alleles are associated with type 1 diabetes, association with microvascular complications remains controversial. We tested HLA association with complications in multiplex type 1 diabetes families. Probands from 425 type 1 diabetes families from the Human Biological Data Interchange (HBDI) collection were analyzed. The frequencies of specific HLA alleles in patients with complications were compared with the frequencies in complications-free patients. The complications we examined were: retinopathy, neuropathy, and nephropathy. We used logistic regression models with covariates to estimate odds ratios. We found that the DRB1∗03:01 allele is a protective factor for complications (OR=0.58; p = 0.03), as is the DQA1∗05:01-DQB1∗02:01 haplotype found in linkage disequilibrium with DRB1∗03:01 (OR= 0.59; p = 0.031). The DRB1∗04:01 allele showed no evidence of association (OR=1.13; p = 0.624), although DRB1∗04:01 showed suggestive evidence when the carriers of the protective DRB1∗03:01 were removed from the analysis. The class II DQA1∗03:01-DQB1∗03:02 haplotype was not associated with complications, but the class I allele B∗39:06 (OR=3.27; P = 0.008) suggested a strong positive association with complications. Our results show that in type 1 diabetes patients, specific HLA alleles may be involved in susceptibility to, or protection from, microvascular complications.
    Human immunology 01/2013; · 2.55 Impact Factor
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    ABSTRACT: Background: Autoimmune and non-autoimmune thyroiditis frequently occur in persons with HCV infection. Treatment with interferon alpha (IFNα) is also associated with significant risk for the development of thyroiditis. To explore HCV-thyroid interactions at a cellular level, we evaluated whether a human thyroid cell line (ML1) could be infected productively with HCV in vitro. Methods and Results: ML1 cells showed robust surface expression of the major HCV receptor CD81. Using a highly sensitive, strand-specific RT-PCR assay, positive-sense and negative-sense HCV RNA were detected in ML1 cell lysates at days 3, 7, and 14 post-infection with HCV. HCV core protein was expressed at high levels in ML1 supernatants at days 1, 3, 5, 7, and 14 post-infection. The non-structural protein NS5A was also detected in ML1 cell lysates by Western Blot. HCV entry into ML1 cells was shown to be dependent on the HCV entry factors CD81 and Claudin-1 (CLA1), while IFNα inhibited HCV replication in ML1 cells in a dose-dependent manner. Supernatants from HCV-infected ML1 cells were able to productively infect fresh ML1 cells, suggesting that infectious virions could be transferred from infected to naïve thyroid cells in vivo. Additionally, HCV infection of ML1 cells led to increased expression of the pro-inflammatory cytokine IL-8. Conclusions: For the first time, we have demonstrated that HCV can infect human thyroid cells in vitro. These findings strongly suggest that HCV infection of thyrocytes may play a role in the association between chronic HCV infection and thyroid autoimmunity. Furthermore, the thyroid may serve as an extrahepatic reservoir for HCV viral replication, thus contributing to the persistence of viral infection and to the development of thyroid autoimmunity.
    Thyroid: official journal of the American Thyroid Association 12/2012; · 2.60 Impact Factor
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    ABSTRACT: Context:Genetic factors play a major role in the etiology of autoimmune thyroid disease (AITD) including Graves' disease (GD) and Hashimoto's thyroiditis (HT). We have previously identified three loci on chromosomes 10q, 12q, and 14q that showed strong linkage with AITD, HT, and GD, respectively.Objectives:The objective of the study was to identify the AITD susceptibility genes at the 10q, 12q, and 14q loci.Design and Participants:Three hundred forty North American Caucasian AITD patients and 183 healthy controls were studied. The 10q, 12q, and 14q loci were fine mapped by genotyping densely spaced single-nucleotide polymorphisms (SNPs) using the Illumina GoldenGate genotyping platform. Case control association analyses were performed using the UNPHASED computer package. Associated SNPs were reanalyzed in a replication set consisting of 238 AITD patients and 276 controls.Results:Fine mapping of the AITD locus, 10q, showed replicated association of the AITD phenotype (both GD and HT) with SNP rs6479778. This SNP was located within the ARID5B gene recently reported to be associated with rheumatoid arthritis and GD in Japanese. Fine mapping of the GD locus, 14q, revealed replicated association of the GD phenotype with two markers, rs12147587 and rs2284720, located within the NRXN3 and TSHR genes, respectively.Conclusions:Fine mapping of three linked loci identified novel susceptibility genes for AITD. The discoveries of new AITD susceptibility genes will engender a new understanding of AITD etiology.
    The Journal of Clinical Endocrinology and Metabolism 11/2012; · 6.31 Impact Factor
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    ABSTRACT: The CD40 gene, an important immune regulatory gene, is also expressed and functional on nonmyeloid-derived cells, many of which are targets for tissue-specific autoimmune diseases, including β cells in type 1 diabetes, intestinal epithelial cells in Crohn's disease, and thyroid follicular cells in Graves' disease (GD). Whether target tissue CD40 expression plays a role in autoimmune disease etiology has yet to be determined. In this study, we show that target tissue overexpression of CD40 plays a key role in the etiology of autoimmunity. Using a murine model of GD, we demonstrated that thyroidal CD40 overexpression augmented the production of thyroid-specific Abs, resulting in more severe experimental autoimmune GD (EAGD), whereas deletion of thyroidal CD40 suppressed disease. Using transcriptome and immune-pathway analyses, we showed that in both EAGD mouse thyroids and human primary thyrocytes, CD40 mediates this effect by activating downstream cytokines and chemokines, most notably IL-6. To translate these findings into therapy, we blocked IL-6 during EAGD induction in the setting of thyroidal CD40 overexpression and showed decreased levels of thyroid stimulating hormone receptor-stimulating Abs and frequency of disease. We conclude that target tissue overexpression of CD40 plays a key role in the etiology of organ-specific autoimmune disease.
    The Journal of Immunology 08/2012; 189(6):3043-53. · 5.52 Impact Factor
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    ABSTRACT: Objective: To report a case of apathetic thyrotoxicosis with an etiology of subacute thyroiditis.Methods: We describe the patient's clinical findings, laboratory findings, and clinical course.Results: An 85-year-old woman with no history of thyroid disease presented with severe obtundation and altered mental status. Laboratory testing documented elevated free thyroxine and free triiodothyronine concentrations and a suppressed thyrotropin concentration. Thyroid antibodies were absent. A radioactive iodine study revealed severely diminished uptake, suggestive of thyroiditis. After a short course of steroids, the patient's mental status returned to baseline. Follow-up laboratory testing showed normalizing thyroid function.Conclusion: Even in the absence of a history of thyroid disease, we recommend considering thyroid dysfunction in the differential diagnosis of patients who present with altered mental status, particularly in the elderly population.
    Endocrine Practice 05/2012; 18(5):e127-9. · 2.49 Impact Factor
  • Alia Hasham, Yaron Tomer
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    ABSTRACT: Autoimmune thyroid diseases (AITD), including Graves' disease and Hashimoto's thyroiditis, are among the commonest autoimmune disorders, affecting approximately 5 % of the population. Epidemiological data support strong genetic influences on the development of AITD. Since the identification of HLA-DR3 as a major AITD susceptibility gene, there have been significant advances made in our understanding of the genetic mechanisms leading to AITD. We have shown that an amino acid substitution of alanine or glutamine with arginine at position 74 in the HLA-DR peptide binding pocket is a critical factor in the development of AITD, and we are continuing to dissect these mechanisms at the molecular level. In addition to the MHC class II genes, there are now several other confirmed gene loci associated with AITD, including immune-regulatory (CD40, CTLA-4, PTPN22, FOXP3, and CD25) and thyroid-specific genes (thyroglobulin and TSHR). Mechanistically, it is postulated that susceptibility genes interact with certain environmental triggers to induce AITD through epigenetic effects. In this review, we summarize some of the recent advances made in our laboratory dissecting the genetic-epigenetic interactions underlying AITD. As shown in our recent studies, epigenetic modifications offer an attractive mechanistic possibility that can provide further insight into the etiology of AITD.
    Immunologic Research 03/2012; 54(1-3):204-13. · 3.53 Impact Factor
  • Alia Hasham, Yaron Tomer
    Journal of Autoimmunity 08/2011; 37(1):1-2. · 8.15 Impact Factor
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    ABSTRACT: Autoimmune thyroid diseases (AITD) arise from complex interactions between genetic, epigenetic, and environmental factors. Whole genome linkage scans and association studies have established thyroglobulin (TG) as a major AITD susceptibility gene. However, the causative TG variants and the pathogenic mechanisms are unknown. Here, we describe a genetic/epigenetic mechanism by which a newly identified TG promoter single-nucleotide polymorphism (SNP) variant predisposes to AITD. Sequencing analyses followed by case control and family-based association studies identified an SNP (-1623A→G) that was associated with AITD in the Caucasian population (p = 0.006). We show that the nucleotide substitution introduced by SNP (-1623A/G) modified a binding site for interferon regulatory factor-1 (IRF-1), a major interferon-induced transcription factor. Using chromatin immunoprecipitation, we demonstrated that IRF-1 binds to the 5' TG promoter motif, and the transcription factor binding correlates with active chromatin structure and is marked by enrichment of mono-methylated Lys-4 residue of histone H3, a signature of active transcriptional enhancers. Using reporter mutations and siRNA approaches, we demonstrate that the disease-associated allele (G) conferred increased TG promoter activity through IRF-1 binding. Finally, treatment of thyroid cells with interferon α, a known trigger of AITD, increased TG promoter activity only when it interacted with the disease-associated variant through IRF-1 binding. These results reveal a new mechanism of interaction between environmental (IFNα) and genetic (TG) factors to trigger AITD.
    Journal of Biological Chemistry 07/2011; 286(36):31168-79. · 4.65 Impact Factor
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    ABSTRACT: IFN-α is known to play a key role in autoimmunity, but the mechanisms are uncertain. Although the induction of autoimmunity by IFN-α is consistent with primarily immunomodulatory effects, the high frequency of nonautoimmune inflammation suggests other mechanisms. We used thyroiditis as a model to dissect these possibilities. IFN-α treatment of cultured thyrocytes increased expression of thyroid differentiation markers, thyroglobulin, thyroid-stimulating hormone receptor, thyroid peroxidase, and sodium iodide transporter. RNAseq analysis demonstrated that pathways of Ag presentation, pattern recognition receptors, and cytokines/chemokines were also stimulated. These changes were associated with markedly increased nonapoptotic thyroid cell death, suggesting direct toxicity. To corroborate these in vitro findings, we created transgenic mice with thyroid-specific overexpression of IFN-α under control of the thyroglobulin promoter. Transgenic mice developed marked inflammatory thyroid destruction associated with immune cell infiltration of thyroid and surrounding tissues leading to profound hypothyroidism, findings consistent with our in vitro results. In addition, transgenic mice thyroids showed upregulation of pathways similar to those observed in cultured thyrocytes. In particular, expression of granzyme B, CXCL10, a subset of the tripartite motif-containing family, and other genes involved in recruitment of bystander cytotoxic immune responses were increased. Pathways associated with apoptosis and autophagy were not induced. Taken together, our data demonstrate that the induction of tissue inflammation and autoimmunity by IFN-α involves direct tissue toxic effects as well as provocation of destructive bystander immune responses.
    The Journal of Immunology 03/2011; 186(8):4693-706. · 5.52 Impact Factor
  • F Menconi, A Hasham, Y Tomer
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    ABSTRACT: Autoimmune thyroid diseases (AITD) are postulated to develop as a result of a complex interplay between several genetic and environmental influences. The pathogenesis of AITD is still not clearly defined. However, among the implicated triggers (e.g. iodine, infections, medications), more recent data confirmed strong associations of AITD with the hepatitis C virus (HCV) infection and interferon-α (IFNα) therapy. Moreover, it is likely that HCV and IFN act in synergism to trigger AITD in patients. Indeed, approximately 40% of HCV patients develop either clinical or subclinical disease while receiving IFNα. Interferon induced thyroiditis (IIT) can manifest as non-autoimmune thyroiditis (presenting as destructive thyroiditis, or non-autoimmune hypothyroidism), or autoimmune thyroiditis [presenting with clinical features of Graves' disease (GD) or Hashimoto's thyroiditis (HT)]. Although not yet clearly understood, it is thought that IFNα can induce thyroiditis via both immune stimulatory and direct toxic effects on the thyroid. In view of the high frequency of IIT, routine screening and surveillance of HCV patients receiving IFNα is recommended to avoid the complications, such as cardiac arrhythmias, associated with thyrotoxicosis. In summary, IIT is a common clinical problem that can be readily diagnosed with routine thyroid function screening of HCV patients receiving IFN. The treatment of IIT consists of the standard therapy for differing clinical manifestations of IIT such as GD, HT, or destructive thyroiditis. However, anti-thyroid medications are not recommended in this setting since they can potentially be hepatotoxic.
    Journal of endocrinological investigation 02/2011; 34(1):78-84. · 1.65 Impact Factor
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    ABSTRACT: Significant progress has been made in our understanding of the mechanisms leading to autoimmune thyroid diseases (AITD). For the first time, we are beginning to unravel these mechanisms at the molecular level. AITD, including Graves' disease (GD) and Hashimoto's thyroiditis (HT), are common autoimmune diseases affecting the thyroid. They have a complex etiology that involves genetic and environmental influences. Seven genes have been shown to contribute to the etiology of AITD. The first AITD gene discovered, HLA-DR3, is associated with both GD and HT. More recently, this association was dissected at the molecular level when it was shown that substitution of the neutral amino acids Ala or Gln with arginine at position beta 74 in the HLA-DR peptide binding pocket is the specific sequence change causing AITD. Non-MHC genes that confer susceptibility to AITD can be classified into two groups: (1) immune-regulatory genes (e.g., CD40, CTLA-4, and PTPN22); (2) thyroid-specific genes-thyroglobulin and TSH receptor genes. These genes interact with environmental factors, such as infection, likely through epigenetic mechanisms to trigger disease. In this review, we summarize the latest findings on disease susceptibility and modulation by environmental factors.
    Clinical Reviews in Allergy & Immunology 01/2011; 41(2):190-7. · 5.59 Impact Factor
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    ABSTRACT: Thyroglobulin (Tg) represents one of the largest known self-antigens involved in autoimmunity. Numerous studies have implicated it in triggering and perpetuating the autoimmune response in autoimmune thyroid diseases (AITD). Indeed, traditional models of autoimmune thyroid disease, experimental autoimmune thyroiditis (EAT), are generated by immunizing mice with thyroglobulin protein in conjunction with an adjuvant, or by high repeated doses of Tg alone, without adjuvant. These extant models are limited in their experimental flexibility, i.e. the ability to make modifications to the Tg used in immunizations. In this study, we have immunized mice with a plasmid cDNA encoding the full-length human Tg (hTG) protein, in order to generate a model of Hashimoto's thyroiditis which is closer to the human disease and does not require adjuvants to breakdown tolerance. Human thyroglobulin cDNA was injected and subsequently electroporated into skeletal muscle using a square wave generator. Following hTg cDNA immunizations, the mice developed both B and T cell responses to Tg, albeit with no evidence of lymphocytic infiltration of the thyroid. This novel model will afford investigators the means to test various hypotheses which were unavailable with the previous EAT models, specifically the effects of hTg sequence variations on the induction of thyroiditis.
    PLoS ONE 01/2011; 6(4):e19200. · 3.53 Impact Factor
  • Yaron Tomer
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    ABSTRACT: Autoimmune thyroid diseases (AITD) including Graves’ disease (GD) and Hashimoto’s thyroiditis (HT) are the commonest autoimmune endocrine diseases, affecting up to 5% of the general population. Genetic factors play a major role in the etiology of AITD as evidenced by the strong familial aggregation of the AITD and the high concordance rates in monozygotic twins. The past decade has witnessed significant progress in our understanding of the genetic contribution to the etiology of AITD, and several major AITD susceptibility genes have been identified and characterized. Some susceptibility genes are specific to either Graves’ disease or Hashimoto’s thyroiditis, while others are common to both conditions. The first AITD susceptibility gene locus identified was the HLA-DR gene locus. Subsequently, five major non-HLA genes, including the CTLA-4, CD40, PTPN22, thyroglobulin, and TSH receptor (TSHR) gene, have been shown to contribute to the susceptibility to AITD; other putative genes are still being tested and confirmed. Excitingly, we are now beginning to unravel the mechanisms by which these AITD susceptibility genes confer risk for disease. Key WordsThyroid-Genes-Association-Linkage-Graves’ disease-Hashimoto’s thyroiditis-Autoimmune thyroiditis-HLA
    12/2010: pages 427-442;

Publication Stats

5k Citations
733.58 Total Impact Points

Institutions

  • 2013
    • Boston Children's Hospital
      • Division of Endocrinology
      Boston, MA, United States
  • 2011–2013
    • Mount Sinai Medical Center
      New York City, New York, United States
  • 2009–2013
    • James J. Peters VA Medical Center
      New York City, New York, United States
  • 1992–2013
    • Mount Sinai School of Medicine
      • Department of Medicine
      Manhattan, New York, United States
  • 2007–2012
    • University of Cincinnati
      • Department of Internal Medicine
      Cincinnati, Ohio, United States
  • 2010
    • Karmanos Cancer Institute
      Detroit, Michigan, United States
  • 2007–2010
    • Cincinnati Children's Hospital Medical Center
      • Division of Endocrinology
      Cincinnati, OH, United States
  • 2008
    • Nationwide Children's Hospital
      • Battelle Center for Mathematical Medicine
      Columbus, Ohio, United States
  • 2007–2008
    • Showa University
      • • Division of Diabetes, Endocrinology and Metabolism
      • • Department of Internal Medicine
      Shinagawa, Tōkyō, Japan
  • 1990–2008
    • Sheba Medical Center
      • Department of Medicine B
      Gan, Tel Aviv, Israel
  • 2006
    • New York State Psychiatric Institute
      New York City, New York, United States
  • 2002
    • Harbor-UCLA Medical Center
      Torrance, California, United States
  • 1994–1998
    • Tel Aviv University
      • Department of Internal Medicine
      Tell Afif, Tel Aviv, Israel
  • 1988
    • Soroka Medical Center
      • Department of Medicine
      Be'er Sheva`, Southern District, Israel
    • Ben-Gurion University of the Negev
      • Faculty of Health Sciences
      Beersheba, Southern District, Israel