eRapport

Autoimmune Thyroid Diseases: Immuogenetic loci and use of new methods for detection of virus in thyroid tissue with impact on novel therapy methods.

Prosjekt
Prosjektnummer
2014078
Ansvarlig person
Knut Dahl-Jørgensen
Institusjon
Oslo universitetssykehus HF
Prosjektkategori
Postdoktorstipend
Helsekategori
Inflammatory and Immune System
Forskningsaktivitet
2. Aetiology, 3. Prevention
Rapporter
2024 - sluttrapport
Autoimmune thyroid diseases (AITD. ), mainly consisting of Graves’ disease (GD) and Hashimoto’s thyroiditis (HT). It is generally accepted that genetic factors together with environmental trigger factors leading to a break of tolerance. Viral infection is considered as an important factor. Inn this study we analyzed collected thyroid tissue samples from patients with Graves' disease and Hashimoto thyroiditis. We showed that thyrocytes express several virus receptors on their surface, proving that thyroid cells are susceptible to viral infection. Enteroviral capsid 1 (VP1) was more often present in tissue from patients with GD. Furthermore, we reported an upregulation of several tissue markers for viral infection (HLA class I, signal transducer and activation of transcription 1 (STAT1), and protein kinase R (PKR)) in thyroid tissue from patients with GD and HT, compared to controls. STAT1 was co-expressed with HLA class I. Similar results were found for PKR which was co-localized with VP1. We further used new methods for detection of several virus in collected thyroid tissue. We have previously reported an increase in the downstream interferon type 1 response protein, myxovirus resistance protein 1, plasmacytoid dendritic cells and CD8+ T cells in the same cohort. By using a specific permissive cell line, we co cultured thyroid cells and searched for several common virus. Our results showed that virus is often present in thyroid, most common virus were enterovirus and herpes virus. This might explain why thyroid diseases are so common. In collaboration with Professor Tomer (Mount Sinai NY), we performed experimental studies in thyroid cells. Thyroid cell lines and primary thyroid cells extracted from thyroid tissue were treated with HCV protein E2, or infected with HCV, and the response was evaluated in terms of production of cytokines and RNA seq. The results show the production of proinflammatory cytokines such as IL-8, IL-6, and TNF alpha. Infection induced a strong immune response, but also downregulation of several proteins involved in thyroid hormone synthesis and transport. Our results confirm that viral infections are important triggers for autoimmunity. These finding may give the basis for new therapeutic regiments, immune therapy and/or development of vaccines to prevent the development and/or progression of the disease. We are currently collaboration with international and national partners for such program. We are further continuing the analysis of collected samples. We have developed a protocol for an intervention study with antiviral drug and our protocol is approved by REK. As the role of viral infection as a trigger and driver for autoimmune diseases is generally more in focus, we have organized a group to further test our hypothesis in several autoimmune diseases that share common features. Taken together with previously reported, our results support the hypothesis of an association between viral infections and development of autoimmune thyroid diseases. Furthermore, we are collaborating with internation collaborators who are currently working on development of EV vaccines. Maybe in a long run we can develop new treatment strategies to prevent or to stop the progression of the disease.

Einstein college of Medicine in New York, collaboration with Professor Tomer, for 4 weeks. HLA analyses are performed. Further collaboration studies are planned. A review article is submitted (2024) and we are working on a new scientific article which will be submitted in 2025.

2023
There is growing evidence that viral infection may trigger development of autoimmune thyroid disease are pursuing detection of virus and viral tissue markers. We have further developed a protocol for an intervention study with antiviral drugs to test if this treatment reverse or stop the progression of the disease.Autoimmune thyroid diseases (AITD), mainly consisting of Graves’ disease (GD) and Hashimoto’s thyroiditis (HT). The etiopathogenesis of the disease is not fully elucidated. However, it is generally accepted that genetic factors together with environmental trigger factors leading to a break of tolerance. Viral infection is considered as an important factor, shown by our groups and others. We showed that thyrocytes express Coxsackie and adenovirus receptor (CAR) proving that thyroid cells are susceptible to enteroviral infection. Enteroviral capsid 1 (VP1) was more often present in tissue from patients with GD. Furthermore, we reported an upregulation of several tissue markers for viral infection (HLA class I, signal transducer and activation of transcription 1 (STAT1), and protein kinase R (PKR)) in thyroid tissue from patients with GD and HT, compared to controls. STAT1 was co-expressed with HLA class I. Similar results were found for PKR which was co-localized with VP1. We further used new methods for detection of several virus in collected thyroid tissue. We have previously reported an increase in the downstream interferon type 1 response protein, myxovirus resistance protein 1, plasmacytoid dendritic cells and CD8+ T cells in the same cohort. By using a specific permissive cell line, we co cultured thyroid cells and searched for several common virus. This might explain why thyroid diseases are so common. Our results showed that virus is often present in thyroid, most common virus were enterovirus and herpes. In collaboration with Professor Tomer (Mount Sinai NY), Sara Hammerstad has performed experimental studies in thyroid cells. Thyroid cell lines and primary thyroid cells extracted from thyroid tissue were treated with HCV protein E2, or infected with HCV, and the response was evaluated in terms of production of cytokines and RNA seq. The results show the production of proinflammatory cytokines such as IL-8, IL-6, and TNF alpha. Infection induced a strong immune response, but also downregulation of several proteins involved in thyroid hormone synthesis and transport. Taken together with a previously reported our results support the hypothesis of an association between viral infections and AITD. We want to further test the effect of antiviral drugs. We have developed a protocol for an intervention study with antiviral drug and our protocol is approved by REK. We are continuously applying for funding for the intervention study. Furthermore, we are collaborating with Professor Hyöty who is working on development of enterovirus vaccine. Maybe in a long run we can develop new treatment strategies to prevent or to stop the progression of the disease. We are continuing the analysis of collected samples.

NEI

2022
There is growing evidence that viral infection may trigger development of autoimmune thyroid disease are pursuing detection of virus and viral tissue markers. We have further developed a protocol for an intervention study with antiviral drugs to test if this treatment reverse or stop the progression of the disease. The study is approved by REK.Autoimmune thyroid diseases (AITD), mainly consisting of Graves’ disease (GD) and Hashimoto’s thyroiditis (HT). The etiopathogenesis of the disease is not fully elucidated. However, it is generally accepted that genetic factors together with environmental trigger factors leading to a break of tolerance. Viral infection is considered as an important factor, shown by our groups and others. We showed that thyrocytes express Coxsackie and adenovirus receptor (CAR) proving that thyroid cells are susceptible to enteroviral infection. Enteroviral capsid 1 (VP1) was more often present in tissue from patients with GD. Furthermore, we reported an upregulation of several tissue markers for viral infection (HLA class I, signal transducer and activation of transcription 1 (STAT1), and protein kinase R (PKR)) in thyroid tissue from patients with GD and HT, compared to controls. STAT1 was co-expressed with HLA class I. Similar results were found for PKR which was co-localized with VP1. We further used new methods for detection of several virus in collected thyroid tissue. We have previously reported an increase in the downstream interferon type 1 response protein, myxovirus resistance protein 1, plasmacytoid dendritic cells and CD8+ T cells in the same cohort. By using a specific permissive cell line, we co cultured thyroid cells and searched for several common virus. This might explain why thyroid diseases are so common. Our results showed that virus is often present in thyroid, most common virus were enterovirus and herpes. In collaboration with Professor Tomer (Mount Sinai NY), Sara Hammerstad has performed experimental studies in thyroid cells. Thyroid cell lines and primary thyroid cells extracted from thyroid tissue were treated with HCV protein E2, or infected with HCV, and the response was evaluated in terms of production of cytokines and RNA seq. The results show the production of proinflammatory cytokines such as IL-8, IL-6, and TNF alpha. Infection induced a strong immune response, but also downregulation of several proteins involved in thyroid hormone synthesis and transport. Taken together with a previously reported our results support the hypothesis of an association between viral infections and AITD. We want to further test the effect of antiviral drugs. We have developed a protocol for an intervention study with antiviral drug and our protocol is approved by REK. Furthermore, we are collaborating with Professor Hyöty who is working on development of enterovirus vaccine. Maybe in a long run we can develop new treatment strategies to prevent or to stop the progression of the disease. Due to Covid pandemic, there have been delay is collaboration analysis with our international partners. We are continuing the analysis of collected samples. HLA analysis of DNA will be performed with our collaborator Professor Tomer, USA; In-situ production of cytokines and chemokines mRNA expression determined by rt-qPCR in fresh frozen tissue or in FFPE tissue and assessment of CD8 T cell presence, specificity and activation in tissues, robing for CD8 T cells reactive against viral antigens (Tetramer protocols), Professor Von-Herath USA; and gene expression with highthroughput RNA/DNA seq in collaboration with Riitta Lahesmaa, Finland.

NEI

2021
The results of this project, in vitro study and direct examination of thyroid tissue from patients with autoimmune thyroid diseases, indicate that viral infection may be involved in development of thyroid autoimmunity and thyroid dysfunction. The results highlight the potential benefit of interventions to prevent the development of the disease.Autoimmune thyroid diseases are common conditions affecting up to 6% of the population. Other than genetic predisposing actors, environmental factors are important. We investigated the role of viral infection, by detection of virus an d viral footprints in search for triggers for thyroid autoimmunity. Detection of tissue markers for viral infection in collected thyroid samples is performed by immunohistochemistry in thyroid tissue. Examination of several thyroid samples shows that thyroid cells express Coxsackie adenovirus receptor (CAR) making them susceptible to enterovirus infection. In collaboration with Professor Morgan in Exeter we detected increased expression of HLA class I in thyroid tissue from patients with both Graves' disease and Hashimoto thyroiditis. Furthermore, the expression of STAT1 and PKR (other intracellular molecules produced in response to viral infection) were increased. Moreover, the results are recently published in "The journal of Endocrinology and Metabolism". In collaboration with Prof Toniolo in Varese, we have used new methods for detection of several virus using immunohistochemistry, PCR and new enrichissement methods with in permissive cell lines. Surprisingly, several viruses were frequently found in the thyroid tissue and specimens were rarely devoid of virus. Enterovirus was found in 45% of the investigated specimens. The results will be submitted the journal of American Thyroid Association within a few weeks. RNA sequencing showed that EV strains that are present in the thyroid of AITD cases do repress IFN and cytokine pathways. JAK1/STAT1 upregulation supports activation of TLR pathways and aberrant T cell signaling. All taken together, these results demonstrate a strong link between viral infection and autoimmune thyroid diseases. In the early phases of AITD, our results highlight the potential benefit of interventions aimed at blocking the viral infection and easing the inflammatory response. We are further continuously working to obtain funding to pursue our intervention study ThyrVInt "Thyroid Virus Detection and Intervention".

Nei

2020
There is growing evidence that viral infection may trigger development of autoimmune thyroid disease. In this study, we are pursuing detection of virus and viral tissue markers. Furthermore, we plan to start an intervention study with antiviral drugs to test if this treatment reverse or stop the progression of the disease.Autoimmune thyroid diseases are common diseases affecting up to 6% of the population and specially women. AITD is associated with increase morbidity, sick leaveThe hypothesis of this project is that viral infection may be involved in the development of autoimmune thyroid diseases (AITD) in genetically predisposed individuals. In collaboration with Professor Tomer (Mount Sinai NY), postdoc Sara Hammerstad has performed experimental studies in thyroid cells. Thyroid cell lines and primary thyroid cells extracted from thyroid tissue were treated with HCV protein E2, and the response was evaluated in terms of production of cytokines. The results show the production of proinflammatory cytokines such as IL-8, IL-6, and TNF alpha. Using RNA sequencing, an upregulation of several proinflammatory molecules and heat shock proteins that have shown to be involved in development of AITD. These results are published in Journal of clinical Endocrinology and Metabolism (JCEM). Furthermore and in collaboration with prof. Blackard, thyroid cells were infected with hepatitis C virus. RNA sequencing of RNA extracted from cells in culture shows a strong immune response, but also downregulation of several proteins involved in thyroid hormone synthesis and transport. The results gives new insights through the mechanisms how viral infection may induce thyroid autoimmunity and thyroid dysfunction. The Scientific paper is recently published in Journal of clinical Endocrinology and Metabolism (JCEM). We are further working on detection of tissue markers for viral infection. In collaboration with Professor Morgan in Exeter we detected increased expression of HLA class I in thyroid tissue from patients with autoimmune thyroid diseases that we have previously collected. Furthermore, the expression of STAT1 and PKR (other intracellular molecules produced in response to viral infection) were increased. Moreover, examination of several thyroid samples shows that thyroid cells express Coxsackie adenovirus receptor (CAR) making them susceptible to enterovirus infection. The results are recently published in The official journal of American Thyroid Association"Thyroid". All taken together, these results demonstrate a strong link between viral infection and autoimmune thyroid diseases.

Nei

2019
The results of this project, in vitro study and direct examination of thyroid tissue from patients with autoimmune thyroid diseases (AITD), indicate that viral infection may be involved in development of thyroid autoimmunity and thyroid dysfunction.The hypothesis of this project is that viral infection may be involved in the development of autoimmune thyroid diseases (AITD) in genetically predisposed individuals. In collaboration with Professor Tomer (Mount Sinai NY), postdoc Sara Hammerstad has performed experimental studies in thyroid cells. Thyroid cell lines and primary thyroid cells extracted from thyroid tissue were treated with HCV protein E2, and the response was evaluated in terms of production of cytokines. The results show the production of proinflammatory cytokines such as IL-8, IL-6, and TNF alpha. Using RNA sequencing, an upregulation of several proinflammatory molecules and heat shock proteins that have shown to be involved in development of AITD. These results are published in Journal of clinical Endocrinology and Metabolism (JCEM). Furthermore and in collaboration with prof. Blackard, thyroid cells were infected with hepatitis C virus. RNA sequencing of RNA extracted from cells in culture shows a strong immune response, but also downregulation of several proteins involved in thyroid hormone synthesis and transport. The results gives new insights through the mechanisms how viral infection may induce thyroid autoimmunity and thyroid dysfunction. The Scientific paper is recently published in Journal of clinical Endocrinology and Metabolism (JCEM). We are further working on detection of tissue markers for viral infection. In collaboration with Professor Morgan in Exeter we detected increased expression of HLA class I in thyroid tissue from patients with autoimmune thyroid diseases that we have previously collected. Furthermore, the expression of STAT1 and PKR (other intracellular molecules produced in response to viral infection) were increased. Moreover, examination of several thyroid samples shows that thyroid cells express Coxsackie adenovirus receptor (CAR) making them susceptible to enterovirus infection. The results are recently published in The official journal of American Thyroid Association"Thyroid". All taken together, these results demonstrate a strong link between viral infection and autoimmune thyroid diseases.

Ikke i 2019.

2018
The results of this project, in vitro study and direct examination of thyroid tissue from patients with autoimmune thyroid diseases, indicate that viral infection may be involved in development of thyroid autoimmunity and thyroid dysfunction.The hypothesis of this project is that viral infection may be involved in the development of autoimmune thyroid diseases (AITD) in genetically predisposed individuals. In collaboration with Professor Tomer (Mount Sinai NY), postdoc Sara Hammerstad has performed experimental studies in thyroid cells. Thyroid cell lines and primary thyroid cells extracted from thyroid tissue were treated with HCV protein. Using RNA sequencing, an upregulation of several proinflammatory molecules and heat shock proteins that have shown to be involved in development of AITD. These results are published in Journal of clinical Endocrinology and Metabolism (JCEM). Furthermore and in collaboration with prof. Blackard, thyroid cells were infected with hepatitis C virus. RNA sequencing of RNA extracted from cells in culture shows a strong immune response, but also downregulation of several proteins involved in thyroid hormone synthesis and transport. The results gives new insights through the mechanisms how viral infection may induce thyroid autoimmunity and thyroid dysfunction. The Scientific paper is almost finished and will be submitted to JCEM within few weeks. Sara Hammerstad is the supervisor for PhD candidate Therese Weider who continues the examination of previously collected thyroid samples in search for viruses and viral footprints. In collaboration with Prof. Morgan and Dr. Richardson (Exeter University - UK), H&E samples are tested for the presence of HLA class I by immunohistochemistry. The results show a clear upregulation of HLA class I in thyroid tissue from patients with autoimmune thyroid diseases compared to healthy controls. HLA class I is expressed in non-immune cells, however upregulation of HLA I is induced by viral infection. Furthermore, the expression of STAT1 and PKR (other intracellular molecules produced in response to viral infection) were increased. Moreover, examination of several thyroid samples shows that thyroid cells express Coxsackie adenovirus receptor (CAR) making them susceptible to enterovirus infection. Publication of these results is expected in 2019. In collaboration with Prof. Toniolo (Varese, Italy), we have further analyzed fresh thyroid tissue from patients with AITD and healthy controls using new cell culture methods in order to amplify viral RNA. The preliminary results shows the presens of Coxsackie virus, rhinovirus and Herpes Simplex virus. The results shows that viral infection may be a trigger for autoimmune thyroid diseases. Genetic analysis in search for susceptible genes in AITD are performed in collaboration with Prof. Tomer (NY); some results are already published and other replication tests are in progress. Moreover, we are testing the HLA class II by HLA typing and specific SNPs for HLA DR3/DQ in order to define the risk allele in our cohort (in collaboration with Prof. Lie Oslo university Hospital). Showing the presence of viral proteins, and/or viral RNA, and several viral footprints in thyroid tissue from patients with AITD, we further have initiated an investigator intervention study with antiviral medication. This is a double blind intervention study. The protocol for the study is submitted to Regional Ethic Committee. The estimated time for the start of the study is fall 2019.

Kort opphold i Exeter og Varese.

2017
In an in-vitro study we have tested the effect of Hepatitis C virus E2 Protein, and HCV infection in thyrocytes. Our results shows that thyroid cells express HCV receptors; and HCV infection induce upregulation of pathways involved in immune response. We are currently planning for a RTC to test the effect of antiviral treatment in thyroiditis.Our working hypothesis is that viral infection may induce thyroid autoimmunity. In the first part of the study (in cooperation with Prof. Tomer, NY) HCV infection in thyrocytes and islets was used as a model for viral response. A) HCV E2 protein induced increased expression of IL-8, IL-6 and TNFα in in human primary thyrocytes. Using Illumina, RNAseq was performed. Thyrocytes treated with E2 showed increased expression of genes involved in IL-8 pathways both in thyrocytes and hepatocytes. However, in thyrocytes, E2 protein induced genes involved in IFNα pathways and increased expression of several heat shocks that have been reported to be associated with thyroid autoimmunity. The result of this study was published in JCEM, and was reported in American Association Meeting 2017 as the most important discovery in thyroid autoimmunity during last year. B) HCV infection of thyrocytes induced increased expression of pro-inflammatory cytokines, IL-8, TNF α, and IL-6 in thyrocytes. Interestingly, the results in thyrocytes differed with those in hepatocytes. While Infection induced modification in only a minor number of genes, mainly genes involved in apoptotic pathways in hepatocytes, infection induced activation of immune response in thyrocytes. The results of this paper will soon be submitted to JCEM for publication. Our results showed that infection induced upregulation of expression of mir-122 (unpublished data). This may be of the major reason for the high prevalence of thyroid autoimmunity in patients with chronic hepatitis C. Moreover, new therapies such as antimir-122 (already developed and under testing in HCV infection) can be a potential treatment for autoimmunity in this group of patients. C) HCV infection of islets: In HCV-infected islets, TNFα and IL-6 levels increased after infection. Interferon and an HCV polymerase inhibitor reduced viral replication in islet cells. Overall, the expression of miR-122 was low in islets but increased after viral infection. Based on our findings a) detection of a persistent low grade enterovirus infection and/or b) increased expression of viral footprint in newly diagnosed Graves’ disease and Hashimoto thyroiditis and, c) the results in our cell study; we are planning for a randomized clinical trial with antiviral treatment vs. placebo. The protocol for this study is ready. We are currently negotiation the delivery of the study medication/placebo. Patients with newly diagnosed Graves’ disease or Hashimoto thyroiditis will be included. Our primary endpoint will be the number of patients with normal thyroid function at 12 months. Secondary Endpoints: mean thyroid hormone secretion at 3,6,12,24 and 36 months; and the levels of TRAb, TPO-Ab and Tg-Ab at 3, 6, 12, 24 and 36 months. We are continuing the search for virus and viral footprint in already collected thyroid tissue in patients with Graves’ disease and Hashimoto thyroiditis. In collaboration Exeter Medical School (Dr. Sarah Richardson, and Prof. Noel Morgan), we are currently working on detection of EV capsid protein Furthermore, we are analyzing the expression of HLA class I, STATA 1, and PKR. Increased expression of these markers shown to be associated with IFNα expression, possibly in response to viral infection. Furthermore, we will use newest Methods for search for viral RNA (in collaboration with prof. Antonio Toniolo; Varese) in already collected material.

Dette prosjektet er i samarbeid med vårt internasjonal partner professor Yaron Tomer og hans forskings lab i New York, USA. I forbindesle med siste artikkelen som er under arbeid og vil bli snarlig sendt til publikasjon har Sara Hammerstad hatt ett opphold i NY.

2016
Stimulation of human thyroid cells with virus protein or infection of cells with virus induces activation of pathways that may induce autoimmunity by bystander mechanisms. Antiviral treatment will be used in RTC to test the hypothesis that viral infection may be an important trigger and driver for thyroid autoimmunity.In cooperation with Professor Tomer at Mount Sinai Hospital NY-USA, we have conducted cell studies to look for the cellular response to virus protein and virus infection in human thyroid cells. Studies have shown that different viral proteins may individually induce host responses to infection. Hepatitis C virus (HCV) infection was used as a model as thyroiditis is one of the most common extra hepatic manifestations of HCV. We demonstrated that thyroid cells express HCV receptors. Stimulation of human thyroid cells in culture with HCV envelop protein activates a cascade of inflammatory responses. HCV envelope protein induced production of several major cytokines and chemokines involved in autoimmunity. Furthermore, HCV envelop protein induced production of several heat shock proteins. We complemented our study with direct HCV infection of humane thyrocytes and to compare the molecular mechanisms of HCV infection in thyroid with hepatic cells. While HCV infection induces activation of mainly apoptotic pathways, infection of thyrocytes induces activation of by far more genes and cellular pathways. Our data support a key role for viral infection in triggering thyroid autoimmunity by bystander mechanisms. We have further developed a protocol for an intervention study (RTC). We want to test if antiviral treatment may reverse the development of thyroiditis in preclinical conditions, and or shorten then duration of the disease at the onset of disease. We will continue our investigation on viruses and molecular pathways in search for development of new therapy strategies.
2015
Virusinfeksjon kan være en utløsende faktor for utvikling av thyreoidea autoimmunitet. Stimulering av normale humane thyreoidea celler med virus protein eller infisering av cellene induserer produksjon av sentrale cytokiner som er involvert i utvikling av autoimmunitet.Hovedformål med denne studien er å undersøke hvordan virus infeksjon kan bidra til utvikling av thyreoidea autoimmunitet. Årsak til autoimmune thyreoidea sykdommer er ikke helt kartlagt men det er økende evidens at virus infeksjon kan være utløsende faktor i genetisk disponerte personer. Vår tidligere studie viste at virus eller virus markører som interferon, var hyppigere til stede i vevsprøven tatt fra thyreoidea hos pasienter med autoimmune thyreoidea sykdommer (Graves’ hyperthyreose og Hashimoto thyreoiditt) enn i friske personer. I denne studien og i samarbeid med professor Yaron Tomer ved Mount Sina Hospital i NY og Professor Jason Blackard ved Univesity of Cincinnati, har vi undersøkt humane thyreoidea celler og om disse kan bli infisert med virus, og hvilke immunologisk respons som oppstår etter infeksjonen. I dette prosjektet har vi brukt hepatitt C virus (HCV) som en modell for virus infeksjon. Grunnen er at hepatitt C infeksjon ofte har vært assosiert med autoimmune tilstander. Autoimmune thyreoidea sykdommer har vært en av de hyppigste former for ekstrahepatiske manifestasjoner ved Hepatitt C. Hepatitt C virus er et RNA virus som koder for 10 forskjellige proteiner. Studier har vist at de forskjellige virus proteiner alene kan indusere immunologiske reaksjoner. I den første delen av studien har vi påvist at thyreoideaceller på lik linje med hepatocytter uttrykker den hoved reseptor for HCV, CD-81. Stimulering med HCV E2 protein (envelope protein 2) induserer overekspresjon av de fleste HCV reseptorene i thyreoideaceller inkludert CD81. Videre E2 protein induserer en sterk økning i viktige cytokiner og potente kjemokiner i normale humane thyreoidea celler . Disse markørene er kjent for å være involvert i utvikling av autoimmunitet. RNA sekvensering med de nyeste metodene med transkriptom analyse viser oppregulering av flere tusen gener. Mange av disse genene er dokumentert medvirkende i utvikling av autoimmunitet. Ved hjelp av Ingenuity Pathway program identifiserer man mange oppregulert mange pathways. Av særlig interesse er at det ble konstatert en overekspresjon av flere «heat shock proteiner» (HSP). HSP har vist å være involvert i utvikling av autoimmune thyreoidea sykdommer. I den andre delen av studien har vi vurdert effekten av HCV infeksjon på thyreoidea celler sammenlignet med hepatocytter. HCV induserer apoptose i hepatocytter mens thyreoideaceller lettere overlever infeksjonen. Derimot setter infeksjon i thyreoideaceller i gang en rekke immunologiske responser. Resultatene fra RNA sekvensering er under arbeid.
2014
The cause of AITD is not clear but both susceptibility genes and environment factors play an important role. In this study we look for genetic factors and the effect of viral infection in development of thyroid autoimmunity.Autoimmune thyroid diseases (AITD) are prevalent and complex diseases affecting up to 6% of the population. AITD mainly include Graves' disease (autoimmune hyperthyroidism), and Hashimoto thyroiditis (autoimmune hypothyroidism). Studies have shown that GD and HT share some common. AITDs are multifactorial diseases and despite decades of basic research the cause of the disease is still unclear. However, it is of general acceptance that the disease is caused by interplay between genetic factors and environmental triggers. Epidemiological studies, twin studies and family studies and other genetic studies support the importance of environmental factors. In this study we focus on both genetic factors and an important environmental factor, viral infection. In this international project, we are working with highly qualified group with many years of research within genetics, immunology and virology. We have been a part of a study looking for the susceptibility genes in patients with young-age of onset Graves' disease. HLA haplotype has so far shown the strongest association with AITD in all previous studies. The results of our study revealed new susceptibility genes such as BTNL2, NOTCH4, TNFAIP3, and CXCR4, in addition to the well known HLA class II loci. Not surprising, pathway analysis shows the importance of the involvement of immunological cells T helper cells, B cells and antigen presenting cells. The results of this study are published in highly ranked journal JCEM. Lately, it has become clear that the biology and the mechanisms behind diseases are important factors for development of new therapeutic regiments. In collaboration with Dr. Tomer's research lab at Mount Sinai Hospital in NY (Postdoc candidate Sara Hammerstad), we are currently working on the effect of viral infection on thyroid tissue. It is known that 40% of patients with hepatitis C infection present thyroid antibodies, also up to 40% of these patients develop thyroid diseases after treatment with IFNa. In the current study we are studying the mechanisms that viral infection induces autoimmunity. Specifically, we are looking for the effect of hepatitis C virus infection in thyroid cell lines in terms of expression and secretion of cytokines, involved immunological pathways, and epigenetic changes. The results of this study will be presented and published during 2015. Furthermore, we aim to start an intervention study to evaluate the effect of anti viral treatment. We are currently working on development of protocols. If viruses are important for the development of autoimmune thyroid disease, new therapeutic regiments might be developed.
Vitenskapelige artikler
Dahll LK, Westbye AB, Vinorum K, Sejersted Y, Barøy T, Thorsby PM, Hammerstad SS

Clinical and Biochemical Characteristics of Untreated Adult Patients With Resistance to Thyroid Hormone Alpha.

J Endocr Soc 2023 Jul 03;7(8):bvad089. Epub 2023 jul 4

PMID: 37469961

Weider T, Genoni A, Broccolo F, Paulsen TH, Dahl-Jørgensen K, Toniolo A, Hammerstad SS

High Prevalence of Common Human Viruses in Thyroid Tissue.

Front Endocrinol (Lausanne) 2022;13():938633. Epub 2022 jul 14

PMID: 35909527

Bjerkreim BA, Hammerstad SS, Gulseth HL, Berg TJ, Omdal LJ, Lee-Ødegård S, Eriksen EF

Effect of Liothyronine Treatment on Quality of Life in Female Hypothyroid Patients With Residual Symptoms on Levothyroxine Therapy: A Randomized Crossover Study.

Front Endocrinol (Lausanne) 2022;13():816566. Epub 2022 feb 22

PMID: 35273566

Bjerkreim BA, Hammerstad SS, Eriksen EF

Bone Turnover in Relation to Thyroid-Stimulating Hormone in Hypothyroid Patients on Thyroid Hormone Substitution Therapy.

J Thyroid Res 2022;2022():8950546. Epub 2022 sep 22

PMID: 36248357

Bjerkreim BA, Hammerstad SS, Gulseth HL, Berg TJ, Lee-Ødegård S, Eriksen EF

Thyroid Signaling Biomarkers in Female Symptomatic Hypothyroid Patients on Liothyronine versus Levothyroxine Monotherapy: A Randomized Crossover Trial.

J Thyroid Res 2022;2022():6423023. Epub 2022 mai 4

PMID: 35572853

Hammerstad SS, Celius EG, Husby H, Sørensen IM, Norheim IE

Management of Severe Graves' Hyperthyroidism in Pregnancy Following Immune Reconstitution Therapy in Multiple Sclerosis.

J Endocr Soc 2021 Jun 01;5(6):bvab044. Epub 2021 mar 17

PMID: 34017934

Sletner L, Jenum AK, Qvigstad E, Hammerstad SS

Thyroid Function During Pregnancy in A Multiethnic Population in Norway.

J Endocr Soc 2021 Jul 01;5(7):bvab078. Epub 2021 mai 4

PMID: 34159284

Bjerkreim BA, Hammerstad SS, Gulseth HL, Berg TJ, Lee-Ødegård S, Rangberg A, Jonassen CM, Budge H, Morris D, Law J, Symonds M, Eriksen EF

Effect of Liothyronine Treatment on Dermal Temperature and Activation of Brown Adipose Tissue in Female Hypothyroid Patients: A Randomized Crossover Study.

Front Endocrinol (Lausanne) 2021;12():785175. Epub 2021 nov 19

PMID: 34867829

Poma AM, Hammerstad SS, Genoni A, Basolo A, Dahl-Jorgensen K, Toniolo A

Immune Transcriptome of Cells Infected with Enterovirus Strains Obtained from Cases of Autoimmune Thyroid Disease.

Microorganisms 2021 Apr 19;9(4). Epub 2021 apr 19

PMID: 33921891

Weider T, Richardson SJ, Morgan NG, Paulsen TH, Dahl-Jørgensen K, Hammerstad SS

HLA Class I Upregulation and Antiviral Immune Responses in Graves Disease.

J Clin Endocrinol Metab 2021 03 25;106(4):e1763-e1774.

PMID: 33367784

Weider T, Richardson SJ, Morgan NG, Paulsen TH, Dahl-Jørgensen K, Hammerstad SS

Upregulation of HLA Class I and Antiviral Tissue Responses in Hashimoto's Thyroiditis.

Thyroid 2020 03;30(3):432-442. Epub 2020 jan 30

PMID: 31910110

Bøhmer T, Bachtyari Z, Sommer C, Hammerstad SS

Auto regulatory capacity of the thyroid gland after numerous iodinated contrast media investigations.

Scand J Clin Lab Invest 2020 May;80(3):191-195. Epub 2020 jan 28

PMID: 31990217

Hammerstad SS, Blackard JT, Lombardi A, Owen RP, Concepcion E, Yi Z, Zhang W, Tomer Y

Hepatitis C Virus Infection of Human Thyrocytes: Metabolic, Hormonal, and Immunological Implications.

J Clin Endocrinol Metab 2020 04 01;105(4).

PMID: 31784757

Lombardi A, Tsomos E, Hammerstad SS, Tomer Y

Interferon alpha: The key trigger of type 1 diabetes.

J Autoimmun 2018 Nov;94():7-15. Epub 2018 aug 14

PMID: 30115527

Blackard JT, Kong L, Lombardi A, Homann D, Hammerstad SS, Tomer Y

A preliminary analysis of hepatitis C virus in pancreatic islet cells.

Virol J 2017 Dec 20;14(1):237. Epub 2017 des 20

PMID: 29258547

Lambertini L, Saul SR, Copperman AB, Hammerstad SS, Yi Z, Zhang W, Tomer Y, Kase N

Intrauterine Reprogramming of the Polycystic Ovary Syndrome: Evidence from a Pilot Study of Cord Blood Global Methylation Analysis.

Front Endocrinol (Lausanne) 2017;8():352. Epub 2017 des 18

PMID: 29326659

Hammerstad SS, Stefan M, Blackard J, Owen RP, Lee HJ, Concepcion E, Yi Z, Zhang W, Tomer Y

HEPATITIS C VIRUS E2 PROTEIN INDUCES UPREGULATION OF IL-8 PATHWAYS AND PRODUCTION OF HEAT SHOCK PROTEINS IN HUMAN THYROID CELLS.

J Clin Endocrinol Metab 2016 Nov 18. Epub 2016 nov 18

PMID: 27860532

Tomer Y, Dolan LM, Kahaly G, Divers J, D'Agostino RB, Imperatore G, Dabelea D, Marcovina S, Black MH, Pihoker C, Hasham A, Hammerstad SS, Greenberg DA, Lotay V, Zhang W, Monti MC, Matheis N,

Genome wide identification of new genes and pathways in patients with both autoimmune thyroiditis and type 1 diabetes.

J Autoimmun 2015 Jun;60():32-9. Epub 2015 apr 27

PMID: 25936594

Lee HJ, Li CW, Hammerstad SS, Stefan M, Tomer Y

Immunogenetics of autoimmune thyroid diseases: A comprehensive review.

J Autoimmun 2015 Nov;64():82-90. Epub 2015 jul 30

PMID: 26235382

Hammerstad SS, Grock SF, Lee HJ, Hasham A, Sundaram N, Tomer Y

Diabetes and Hepatitis C: A Two-Way Association.

Front Endocrinol (Lausanne) 2015;6():134. Epub 2015 sep 14

PMID: 26441826

Brown Rosalind S, Lombardi Angela, Hasham Alia, Greenberg David A, Gordon Joshua, Concepcion Erlinda, Hammerstad Sara S, Lotay Vaneet, Zhang Weijia, Tomer Yaron

Genetic analysis in young-age-of-onset Graves' disease reveals new susceptibility loci.

J Clin Endocrinol Metab 2014 Jul;99(7):E1387-91. Epub 2014 mar 31

PMID: 24684463

Hammerstad Sara Salehi, Jahnsen Frode Lars, Tauriainen Sisko, Hyöty Heikki, Paulsen Trond, Norheim Ingrid, Dahl-Jørgensen Knut

Immunological changes and increased expression of myxovirus resistance protein a in thyroid tissue of patients with recent onset and untreated Graves' disease.

Thyroid 2014 Mar;24(3):537-44. Epub 2014 jan 15

PMID: 24032645

Therese Weider, Sarah Richardson, Noel Morgan, Trond Paulsen, Knut Dahl-Jorgensen and Sara Hammerstad

Upregulation of HLA class I and Antiviral Tissue Responses in Hashimoto's Thyroiditis

THYROID, 2020 Jan 7 doi: 10.1089/thy.2019.0607. [Epub ahead of print]

Hammerstad Sara Salehi

Hepatitt C og Diabetes: Et Tosidig Forhold

BestPractice Infeksjonsmedisin 2016

Hammerstad SS and Tomer Y

Epidemiology and Genetic factors in Graves' Disease. In book: Graves' Disease A comprehensive Guide for Clinicians

Chapter: 3, Publisher: Springer, Editors: Rebecca S. Bahn, pp.21-37ease and Graves' Ophthalmopathy, April 2015

Hammerstad SS, Ronald Villanueva, Tomer Y

Infection and Autoimmune thyroid Diseases

Book Infection and Autoimmunity Second Edition, Publisher Elsevier Editors Shoenfeld, Agmon-Levin and Rose. February 2015

Doktorgrader
Therese Weider

Autoimmune Thyroid Diseases and Virus - Immunological Traces of Viral Infections

Disputert:
desember 2022
Hovedveileder:
Sara Salehi Hammerstad
Betty Ann Bjerkreim

The effect of liothyronine monotherapy in hypothyroidism

Disputert:
desember 2022
Hovedveileder:
Erik Fink Eriksen
Deltagere
  • Riitta Lahesmaa Internasjonal samarbeidspartner
  • Matthias Von-Herath Internasjonal samarbeidspartner
  • Therese Weider Doktorgradsstipendiat (annen finansiering)
  • Antonio Toniolo Prosjektdeltaker
  • Noel Morgan Prosjektdeltaker
  • Sarah Richardson Prosjektdeltaker
  • Yaron Tomer Prosjektdeltaker
  • Knut Dahl-Jørgensen Hovedveileder
  • Sara Salehi Hammerstad Postdoktorstipendiat (finansiert av denne bevilgning)
  • Frode Lars Jahnsen Forsker (annen finansiering)
  • Heikki Hyöty Forsker (annen finansiering)

eRapport er utarbeidet av Sølvi Lerfald og Reidar Thorstensen, Regionalt kompetansesenter for klinisk forskning, Helse Vest RHF, og videreutvikles av de fire RHF-ene i fellesskap, med støtte fra Helse Vest IKT

Alle henvendelser rettes til eRapport

Personvern  -  Informasjonskapsler