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Frisk, Gun
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Publications (10 of 38) Show all publications
Kallionpää, H., Somani, J., Tuomela, S., Ullah, U., de Albuquerque, R., Lönnberg, T., . . . Lahesmaa, R. (2019). Early Detection of Peripheral Blood Cell Signature in Children Developing beta-Cell Autoimmunity at a Young Age. Diabetes, 68(10), 2024-2034
Open this publication in new window or tab >>Early Detection of Peripheral Blood Cell Signature in Children Developing beta-Cell Autoimmunity at a Young Age
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2019 (English)In: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 68, no 10, p. 2024-2034Article in journal (Refereed) Published
Abstract [en]

The appearance of type 1 diabetes (T1D)-associated autoantibodies is the first and only measurable parameter to predict progression toward T1D in genetically susceptible individuals. However, autoantibodies indicate an active autoimmune reaction, wherein the immune tolerance is already broken. Therefore, there is a clear and urgent need for new biomarkers that predict the onset of the autoimmune reaction preceding autoantibody positivity or reflect progressive beta-cell destruction. Here we report the mRNA sequencing-based analysis of 306 samples including fractionated samples of CD4(+) and CD8(+) T cells as well as CD4(-)CD8(-) cell fractions and unfractionated peripheral blood mononuclear cell samples longitudinally collected from seven children who developed beta-cell autoimmunity (case subjects) at a young age and matched control subjects. We identified transcripts, including interleukin 32 (IL32), that were upregulated before T1D-associated autoantibodies appeared. Single-cell RNA sequencing studies revealed that high IL32 in case samples was contributed mainly by activated T cells and NK cells. Further, we showed that IL32 expression can be induced by a virus and cytokines in pancreatic islets and beta-cells, respectively. The results provide a basis for early detection of aberrations in the immune system function before T1D and suggest a potential role for IL32 in the pathogenesis of T1D.

National Category
Endocrinology and Diabetes
Identifiers
urn:nbn:se:uu:diva-395419 (URN)10.2337/db19-0287 (DOI)000487068200014 ()31311800 (PubMedID)
Funder
EU, Horizon 2020Novo Nordisk, 115797EU, FP7, Seventh Framework Programme, 202063
Available from: 2019-10-22 Created: 2019-10-22 Last updated: 2019-10-22Bibliographically approved
Busse, N., Paroni, F., Richardson, S. J., Laiho, J. E., Oikarinen, M., Frisk, G., . . . Maedler, K. (2017). Detection and localization of viral infection in the pancreas of patients with type 1 diabetes using short fluorescently-labelled oligonucleotide probes. OncoTarget, 8(8), 12620-12636
Open this publication in new window or tab >>Detection and localization of viral infection in the pancreas of patients with type 1 diabetes using short fluorescently-labelled oligonucleotide probes
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2017 (English)In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 8, no 8, p. 12620-12636Article in journal (Refereed) Published
Abstract [en]

Enteroviruses, specifically of the Coxsackie B virus family, have been implicated in triggering islet autoimmunity and type 1 diabetes, but their presence in pancreata of patients with diabetes has not been fully confirmed. To detect the presence of very low copies of the virus genome in tissue samples from T1D patients, we designed a panel of fluorescently labeled oligonucleotide probes, each of 17-22 nucleotides in length with a unique sequence to specifically bind to the enteroviral genome of the picornaviridae family. With these probes enteroviral RNA was detected with high sensitivity and specificity in infected cells and tissues, including in FFPE pancreas sections from patients with T1D. Detection was not impeded by variations in sample processing and storage thereby overcoming the potential limitations of fragmented RNA. Co-staining of small RNA probes in parallel with classical immunstaining enabled virus detection in a cell-specific manner and more sensitively than by viral protein.

Place, publisher, year, edition, pages
IMPACT JOURNALS LLC, 2017
Keywords
enteroviruses, type 1 diabetes, pancreas, islets, oligonucleotide probes, Pathology Section
National Category
Cancer and Oncology Cell Biology
Identifiers
urn:nbn:se:uu:diva-319301 (URN)10.18632/oncotarget.14896 (DOI)000395692000017 ()
Available from: 2017-04-10 Created: 2017-04-10 Last updated: 2017-11-29Bibliographically approved
Sarmiento, L., Frisk, G., Anagandula, M., Hodik, M., Barchetta, I., Netanyah, E., . . . Cilio, C. M. (2017). Echovirus 6 Infects Human Exocrine and Endocrine Pancreatic Cells and Induces Pro-Inflammatory Innate Immune Response. Viruses, 9(2), Article ID 25.
Open this publication in new window or tab >>Echovirus 6 Infects Human Exocrine and Endocrine Pancreatic Cells and Induces Pro-Inflammatory Innate Immune Response
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2017 (English)In: Viruses, ISSN 1999-4915, E-ISSN 1999-4915, Vol. 9, no 2, article id 25Article in journal (Refereed) Published
Abstract [en]

Human enteroviruses (HEV), especially coxsackievirus serotype B (CVB) and echovirus (E), have been associated with diseases of both the exocrine and endocrine pancreas, but so far evidence on HEV infection in human pancreas has been reported only in islets and ductal cells. This study aimed to investigate the capability of echovirus strains to infect human exocrine and endocrine pancreatic cells. Infection of explanted human islets and exocrine cells with seven field strains of E6 caused cytopathic effect, virus titer increase and production of HEV protein VP1 in both cell types. Virus particles were found in islets and acinar cells infected with E6. No cytopathic effect or infectious progeny production was observed in exocrine cells exposed to the beta cell-tropic strains of E16 and E30. Endocrine cells responded to E6, E16 and E30 by upregulating the transcription of interferon-induced with helicase C domain 1 (IF1H1), 2'-5;-oligoadenylate synthetase 1 (OAS1), interferon-beta (IFN-beta), chemokine (C-X-C motif) ligand 10 (CXCL10) and chemokine (C-C motif) ligand 5 (CCL5). Echovirus 6, but not E16 or E30, led to increased transcription of these genes in exocrine cells. These data demonstrate for the first time that human exocrine cells represent a target for E6 infection and suggest that certain HEV serotypes can replicate in human pancreatic exocrine cells, while the pancreatic endocrine cells are permissive to a wider range of HEV.

Keywords
acinar cells, echovirus, enterovirus, inflammation, islet of Langerhans, pancreas, tropism
National Category
Immunology in the medical area Microbiology
Identifiers
urn:nbn:se:uu:diva-361248 (URN)10.3390/v9020025 (DOI)000397251000003 ()28146100 (PubMedID)
Funder
Swedish Research CouncilEU, FP7, Seventh Framework Programme, 261441Swedish Child Diabetes FoundationThe Crafoord Foundation
Available from: 2018-09-25 Created: 2018-09-25 Last updated: 2018-09-25Bibliographically approved
Busse, N., Paroni, F., Richardson, S. J., Frisk, G., Laiho, J. E., Oikarinen, M., . . . Maedler, K. (2016). Detection of beta cell virus infection in type 1 diabetes by short fluorescently labelled oligonucleotide probes. Paper presented at 52nd Annual Meeting of the European-Association-for-the-Study-of-Diabetes (EASD), SEP 12-16, 2016, Munich, GERMANY. Diabetologia, 59, S170-S171
Open this publication in new window or tab >>Detection of beta cell virus infection in type 1 diabetes by short fluorescently labelled oligonucleotide probes
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2016 (English)In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 59, p. S170-S171Article in journal (Refereed) Published
Place, publisher, year, edition, pages
SPRINGER, 2016
National Category
Endocrinology and Diabetes
Identifiers
urn:nbn:se:uu:diva-322039 (URN)000398373701149 ()
Conference
52nd Annual Meeting of the European-Association-for-the-Study-of-Diabetes (EASD), SEP 12-16, 2016, Munich, GERMANY
Available from: 2017-05-16 Created: 2017-05-16 Last updated: 2017-05-16Bibliographically approved
Hodik, M., Skog, O., Lukinius, A., Isaza-Correa, J. M., Kuipers, J., Giepmans, B. N. & Frisk, G. (2016). Enterovirus infection of human islets of Langerhans affects beta-cell function resulting in disintegrated islets, decreased glucose stimulated insulin secretion and loss of Golgi structure. BMJ OPEN DIABETES RESEARCH & CARE, 4(1), Article ID e000179.
Open this publication in new window or tab >>Enterovirus infection of human islets of Langerhans affects beta-cell function resulting in disintegrated islets, decreased glucose stimulated insulin secretion and loss of Golgi structure
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2016 (English)In: BMJ OPEN DIABETES RESEARCH & CARE, ISSN 2052-4897, Vol. 4, no 1, article id e000179Article in journal (Refereed) Published
Abstract [en]

Aims/hypothesis: In type 1 diabetes (T1D), most insulin-producing beta cells are destroyed, but the trigger is unknown. One of the possible triggers is a virus infection and the aim of this study was to test if enterovirus infection affects glucose stimulated insulin secretion and the effect of virus replication on cellular macromolecules and organelles involved in insulin secretion. Methods: Isolated human islets were infected with different strains of coxsackievirus B (CVB) virus and the glucose-stimulated insulin release (GSIS) was measured in a dynamic perifusion system. Classical morphological electron microscopy, large-scale electron microscopy, so-called nanotomy, and immunohistochemistry were used to study to what extent virus-infected beta cells contained insulin, and real-time PCR was used to analyze virus induced changes of islet specific genes. Results: In islets infected with CVB, GSIS was reduced in correlation with the degree of virus-induced islet disintegration. The expression of the gene encoding insulin was decreased in infected islets, whereas the expression of glucagon was not affected. Also, in islets that were somewhat disintegrated, there were uninfected beta cells. Ultrastructural analysis revealed that virus particles and virus replication complexes were only present in beta cells. There was a significant number of insulin granules remaining in the virus-infected beta cells, despite decreased expression of insulin mRNA. In addition, no typical Golgi apparatus was detected in these cells. Exposure of islets to synthetic dsRNA potentiated glucose-stimulated insulin secretion. Conclusions/interpretation: Glucose-stimulated insulin secretion; organelles involved in insulin secretion and gene expression were all affected by CVB replication in beta cells.

National Category
Endocrinology and Diabetes
Identifiers
urn:nbn:se:uu:diva-308802 (URN)10.1136/bmjdrc-2015-000179 (DOI)000386333100022 ()27547409 (PubMedID)
Available from: 2016-12-01 Created: 2016-11-30 Last updated: 2016-12-01Bibliographically approved
Krogvold, L., Edwin, B., Buanes, T., Frisk, G., Skog, O., Anagandula, M., . . . Dahl-Jørgensen, K. (2015). Detection of a low-grade enteroviral infection in the islets of Langerhans of living patients newly diagnosed with type 1 diabetes. Diabetes, 64(5), 1682-1687
Open this publication in new window or tab >>Detection of a low-grade enteroviral infection in the islets of Langerhans of living patients newly diagnosed with type 1 diabetes
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2015 (English)In: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 64, no 5, p. 1682-1687Article in journal (Refereed) Published
Abstract [en]

The Diabetes Virus Detection study (DiViD) is the first to examine fresh pancreatic tissue at the diagnosis of type 1 diabetes for the presence of viruses. Minimal pancreatic tail resection was performed 3-9 weeks after onset of type 1 diabetes in 6 adult patients (age 24-35 years). The presence of enteroviral capsid protein 1 (VP1) and the expression of class I HLA were investigated by immunohistochemistry. Enterovirus RNA was analyzed from isolated pancreatic islets and from fresh frozen whole pancreatic tissue using PCR and sequencing. Non-diabetic organ donors served as controls. VP1 was detected in the islets of all type 1 diabetes patients (2 of 9 controls). Hyperexpression of class I HLA molecules was found in the islets of all patients (1 of 9 controls). Enterovirus specific RNA sequences were detected in 4 of 6 cases (0 of 6 controls). The results were confirmed in different laboratories. Only 1.7 % of the islets contained VP1 positive cells and the amount of enterovirus RNA was low. The results provides evidence for the presence of enterovirus in pancreatic islets of type 1 diabetic patients, being consistent with the possibility that a low grade enteroviral infection in the pancreatic islets contribute to disease progression in humans.

National Category
Endocrinology and Diabetes Microbiology
Identifiers
urn:nbn:se:uu:diva-239513 (URN)10.2337/db14-1370 (DOI)000353431200023 ()25422108 (PubMedID)
Available from: 2014-12-29 Created: 2014-12-29 Last updated: 2017-12-05
Hansson, T., Dahlbom, I., Tuvemo, T. & Frisk, G. (2015). Silent coeliac disease is over-represented in children with type 1 diabetes and their siblings. Acta Paediatrica, 104(2), 185-191
Open this publication in new window or tab >>Silent coeliac disease is over-represented in children with type 1 diabetes and their siblings
2015 (English)In: Acta Paediatrica, ISSN 0803-5253, E-ISSN 1651-2227, Vol. 104, no 2, p. 185-191Article in journal (Refereed) Published
Abstract [en]

AimThis study measured autoantibodies against tissue transglutaminase (anti-tTG) to detect untreated coeliac disease in children with type 1 diabetes and their siblings. MethodsAnti-tTG was measured in prospectively collected sera from 169 children at the onset of diabetes, 88 of their siblings and 96 matched control children. Coeliac disease was confirmed with a small intestinal biopsy. ResultsCoeliac disease was diagnosed in five children before diabetes onset. A further 12 children were diagnosed after diabetes onset, without any gastrointestinal symptoms, and 11 of these had anti-tTG at the onset of diabetes, with the remaining child showing seroconversion within 6months. Hence, all the children with both diseases had anti-tTG at or before diabetes diagnosis, and the prevalence of coeliac disease was 10.1%. Moreover, 6.8% of the siblings and 3.1% of the control children had elevated levels of anti-tTG. None of the siblings reported any coeliac-related symptoms, despite being positive for anti-tTG, and coeliac disease has so far been biopsy confirmed in 4.5%. ConclusionSilent coeliac disease is over-represented in children with type 1 diabetes and their siblings. All diabetes children and their siblings should be tested and followed for the presence of anti-tTG and coeliac disease.

Keywords
Autoantibodies, Coeliac disease, tissue transglutaminase, Type 1 diabetes
National Category
Pediatrics Endocrinology and Diabetes
Identifiers
urn:nbn:se:uu:diva-246809 (URN)10.1111/apa.12823 (DOI)000348731000024 ()25283799 (PubMedID)
Available from: 2015-03-16 Created: 2015-03-10 Last updated: 2017-12-04Bibliographically approved
Hamalainen, S., Nurminen, N., Ahlfors, H., Oikarinen, S., Sioofy-Khojine, A.-B., Frisk, G., . . . Hyoty, H. (2014). Coxsackievirus B1 Reveals Strain Specific Differences in Plasmacytoid Dendritic Cell Mediated Immunogenicity. Journal of Medical Virology, 86(8), 1412-1420
Open this publication in new window or tab >>Coxsackievirus B1 Reveals Strain Specific Differences in Plasmacytoid Dendritic Cell Mediated Immunogenicity
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2014 (English)In: Journal of Medical Virology, ISSN 0146-6615, E-ISSN 1096-9071, Vol. 86, no 8, p. 1412-1420Article in journal (Refereed) Published
Abstract [en]

Enterovirus infections are usually mild but can also cause severe illnesses and play a role in chronic diseases, such as cardiomyopathies and type 1 diabetes. Host response to the invading virus can markedly modulate the course of the infection, and this response varies between individuals due to the polymorphism of immune response genes. However, it is currently not known if virus strains also differ in their ability to stimulate the host immune system. Coxsackievirus B1 (CBV1) causes severe epidemics in young infants and it has recently been connected with type 1 diabetes in seroepidemiological studies. This study evaluated the ability of different field isolates of CBV1 to induce innate immune responses in PBMCs. CBV1 strains differed markedly in their capacity to induce innate immune responses. Out of the 18 tested CBV1 strains two induced exceptionally strong alpha interferon (IFN-alpha) response in PBMC cultures. The responding cell type was found to be the plasmacytoid dendritic cell. Such a strong innate immune response was accompanied by an up-regulation of several other immune response genes and secretion of cytokines, which modulate inflammation, and adaptive immune responses. These results suggest that enterovirus-induced immune activation depends on the virus strain. It is possible that the immunotype of the virus modulates the course of the infection and plays a role in the pathogenesis of chronic immune-mediated enterovirus diseases.  

Keywords
coxsackievirus B1 (CBV1), innate immunity, interferon-alpha (IFN-alpha), pDC
National Category
Infectious Medicine
Identifiers
urn:nbn:se:uu:diva-231114 (URN)10.1002/jmv.23903 (DOI)000339486200016 ()24616040 (PubMedID)
Available from: 2014-09-05 Created: 2014-09-04 Last updated: 2017-12-05Bibliographically approved
Richardson, S. J., Leete, P., Dhayal, S., Russell, M. A., Oikarinen, M., Laiho, J. E., . . . Morgan, N. G. (2014). Detection of enterovirus in the islet cells of patients with type 1 diabetes: what do we learn from immunohistochemistry? Reply to Hansson SF, Korsgren S, Ponten F et al [letter] [Letter to the editor]. Diabetologia, 57(3), 647-649
Open this publication in new window or tab >>Detection of enterovirus in the islet cells of patients with type 1 diabetes: what do we learn from immunohistochemistry? Reply to Hansson SF, Korsgren S, Ponten F et al [letter]
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2014 (English)In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 57, no 3, p. 647-649Article in journal, Letter (Refereed) Published
Keywords
ATP5B, Beta cell, Clone 5D8/1, Coxsackievirus, Creatine kinase B, Islet, VP1
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-222326 (URN)10.1007/s00125-014-3167-2 (DOI)000331558400026 ()
Available from: 2014-04-10 Created: 2014-04-10 Last updated: 2017-12-05Bibliographically approved
Richardson, S. J., Leete, P., Dhayal, S., Russell, M. A., Oikarinen, M., Laiho, J. E., . . . Morgan, N. G. (2014). Evaluation of the fidelity of immunolabelling obtained with clone 5D8/1, a monoclonal antibody directed against the enteroviral capsid protein, VP1, in human pancreas. Diabetologia, 57(2), 392-401
Open this publication in new window or tab >>Evaluation of the fidelity of immunolabelling obtained with clone 5D8/1, a monoclonal antibody directed against the enteroviral capsid protein, VP1, in human pancreas
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2014 (English)In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 57, no 2, p. 392-401Article in journal (Refereed) Published
Abstract [en]

Aims/hypothesis

Enteroviral infection has been implicated in the development of islet autoimmunity in type 1 diabetes and enteroviral antigen expression has been detected by immunohistochemistry in the pancreatic beta cells of patients with recent-onset type 1 diabetes. However, the immunohistochemical evidence relies heavily on the use of a monoclonal antibody, clone 5D8/1, raised against an enteroviral capsid protein, VP1. Recent data suggest that the clone 5D8/1 may also recognise non-viral antigens; in particular, a component of the mitochondrial ATP synthase (ATP5B) and an isoform of creatine kinase (CKB). Therefore, we evaluated the fidelity of immunolabelling by clone 5D8/1 in the islets of patients with type 1 diabetes.

Methods

Enteroviral VP1, CKB and ATP5B expression were analysed by western blotting, RT-PCR and immunocytochemistry in a range of cultured cell lines, isolated human islets and human tissue.

Results

Clone 5D8/1 labelled CKB, but not ATP5B, on western blots performed under denaturing conditions. In cultured human cell lines, isolated human islets and pancreas sections from patients with type 1 diabetes, the immunolabelling of ATP5B, CKB and VP1 by 5D8/1 was readily distinguishable. Moreover, in a human tissue microarray displaying more than 80 different cells and tissues, only two (stomach and colon; both of which are potential sites of enterovirus infection) were immunopositive when stained with clone 5D8/1.

Conclusions/interpretation

When used under carefully optimised conditions, the immunolabelling pattern detected in sections of human pancreas with clone 5D8/1 did not reflect cross-reactivity with either ATP5B or CKB. Rather, 5D8/1 is likely to be representative of enteroviral antigen expression.

Keywords
ATP5B, Coxsackievirus, Creatine kinase, Dako 5D8/1, Immunohistochemistry, Islets of Langerhans, Pancreatic beta cell
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-218545 (URN)10.1007/s00125-013-3094-7 (DOI)000329615100017 ()
Available from: 2014-02-12 Created: 2014-02-12 Last updated: 2017-12-06Bibliographically approved
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