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Ingvast, Sofie
Publications (8 of 8) Show all publications
Jonsson, A., Yngve, E., Karlsson, M., Ingvast, S., Skog, O. & Korsgren, O. (2019). Protein Kinase R Is Constitutively Expressed in the Human Pancreas. Journal of Histochemistry and Cytochemistry, 67(2), 99-105
Open this publication in new window or tab >>Protein Kinase R Is Constitutively Expressed in the Human Pancreas
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2019 (English)In: Journal of Histochemistry and Cytochemistry, ISSN 0022-1554, E-ISSN 1551-5044, Vol. 67, no 2, p. 99-105Article in journal (Refereed) Published
Abstract [en]

Viral infection of the insulin-producing cells in the pancreas has been proposed in the etiology of type 1 diabetes. Protein kinase R (PKR) is a cytoplasmic protein activated through phosphorylation in response to cellular stress and particularly viral infection. As PKR expression in pancreatic beta-cells has been interpreted as a viral footprint, this cross-sectional study aimed at characterizing the PKR expression in non-diabetic human pancreases. PKR expression was evaluated in pancreas tissue from 16 non-diabetic organ donors, using immunohistochemistry, qPCR, and western blot. Immunohistochemistry and western blot showed readily detectable PKR expression in the pancreatic parenchyma. The qPCR detected PKR mRNA in both endocrine and exocrine samples, with a slightly higher expression in the islets. In conclusion, PKR is constitutively expressed in both endocrine and exocrine parts of the pancreas and its expression should not be interpreted as a viral footprint in pancreatic beta cells.

Place, publisher, year, edition, pages
SAGE PUBLICATIONS LTD, 2019
Keywords
immunohistochemistry, innate immunity, pancreas, PCR, type 1 diabetes, viral footprints, viral sensors
National Category
Endocrinology and Diabetes
Identifiers
urn:nbn:se:uu:diva-377210 (URN)10.1369/0022155418802838 (DOI)000457488700002 ()30265185 (PubMedID)
Funder
Swedish Child Diabetes Foundation
Available from: 2019-02-25 Created: 2019-02-25 Last updated: 2019-02-25Bibliographically approved
Lundberg, M., Seiron, P., Ingvast, S., Korsgren, O. & Skog, O. (2017). Insulitis in human diabetes: a histological evaluation of donor pancreases. Diabetologia, 60(2), 346-353
Open this publication in new window or tab >>Insulitis in human diabetes: a histological evaluation of donor pancreases
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2017 (English)In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 60, no 2, p. 346-353Article in journal (Refereed) Published
Abstract [en]

Aims/hypothesis According to the consensus criteria developed for type 1 diabetes, an individual can be diagnosed with insulitis when >= 15 CD45(+) cells are found within the parenchyma or in the islet-exocrine interface in >= 3 islets. The aim of this study was to determine the frequency of individuals with type 2 diabetes fulfilling these criteria with reference to non-diabetic and type 1 diabetic individuals. Methods Insulitis was determined by examining CD45(+) cells in the pancreases of 50, 13 and 44 organ donors with type 2 diabetes, type 1 diabetes and no diabetes, respectively. CD3(+) cells (T cells) infiltrating the islets were evaluated in insulitic donors. In insulitic donors with type 2 diabetes, the pancreases were characterised according to the presence of CD68 (macrophages), myeloperoxidase (MPO; neutrophils), CD3, CD20 (B cells) and HLA class I hyperstained islets. In all type 2 diabetic donors, potential correlations of insulitis with dynamic glucose-stimulated insulin secretion in vitro or age, BMI, HbA(1c) or autoantibody positivity were examined. Results Overall, 28% of the type 2 diabetic donors fulfilled the consensus criteria for insulitis developed for type 1 diabetes. Of the type 1 diabetic donors, 31% fulfilled the criteria. None of the non-diabetic donors met the criteria. Only type 1 diabetic donors had >= 15 CD3(+) cells in >= 3 islets. Type 2 diabetic donors with insulitis also had a substantial number of CD45(+) cells in the exocrine parenchyma. Macrophages constituted the largest fraction of CD45(+) cells, followed by neutrophils and T cells. Of type 2 diabetic pancreases with insulitis, 36% contained islets that hyperstained for HLA class I. Isolated islets from type 2 diabetic donors secreted less insulin than controls, although with preserved dynamics. Insulitis in the type 2 diabetic donors did not correlate with glucose-stimulated insulin secretion, the presence of autoantibodies, BMI or HbA(1c). Conclusions/interpretation The current definition of insulitis cannot be used to distinguish pancreases retrieved from individuals with type 1 diabetes from those with type 2 diabetes. On the basis of our findings, we propose a revised definition of insulitis, with a positive diagnosis when >= 15 CD3(+) cells, not CD45(+) cells, are found in >= 3 islets.

Keywords
HLA, Inflammation, Insulin secretion, Insulitis, Islets, Macrophages, Tcells, Type 1 diabetes, Type 2 diabetes
National Category
Endocrinology and Diabetes
Identifiers
urn:nbn:se:uu:diva-315054 (URN)10.1007/s00125-016-4140-z (DOI)000391359800016 ()27796420 (PubMedID)
Funder
EU, FP7, Seventh Framework Programme, 261441 PEVNETNovo NordiskÅke Wiberg FoundationSwedish Diabetes Association
Available from: 2017-03-08 Created: 2017-03-08 Last updated: 2018-05-02Bibliographically approved
Lundberg, M., Seiron, P., Ingvast, S., Korsgren, O. & Skog, O. (2017). Re-addressing the 2013 consensus guidelines for the diagnosis of insulitis in human type 1 diabetes: is change necessary? Reply to Campbell-Thompson ML, Atkinson MA, Butler AE et al [letter]. [Letter to the editor]. Diabetologia, 60(4), 756-757
Open this publication in new window or tab >>Re-addressing the 2013 consensus guidelines for the diagnosis of insulitis in human type 1 diabetes: is change necessary? Reply to Campbell-Thompson ML, Atkinson MA, Butler AE et al [letter].
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2017 (English)In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 60, no 4, p. 756-757Article in journal, Letter (Other academic) Published
Keywords
CD45, Immunopathology, Inflammation, Insulitis, Islets, Macrophages, Pancreas, T cells, Type 1 diabetes, Type 2 diabetes
National Category
Endocrinology and Diabetes
Identifiers
urn:nbn:se:uu:diva-318317 (URN)10.1007/s00125-017-4212-8 (DOI)000398046400018 ()28111711 (PubMedID)
Note

Funding: Work in the authors' laboratories was supported by the PEVNET Study Group funded by the European Union's Seventh Framework Programme [FP7/2007-2013] under grant agreement number 261441 PEVNET, the Swedish Medical Research Council (K2015-54X-12219-19-4), the Diabetes Wellness Foundation, the Family Ernfors Foundation, the Novo Nordisk Foundation, the Ake Wiberg Foundation, the Tore Nilsson Foundation, the Swedish Diabetes Association, Gillbergska Stiftelsen, and Barndiabetesfonden. Human pancreatic biopsies and isolated islets were obtained from the Nordic Network for Clinical Islet Transplantation, supported by the Swedish national strategic research initiative Excellence of Diabetes Research in Sweden (EXODIAB) and the JDRF.

Available from: 2017-03-24 Created: 2017-03-24 Last updated: 2017-05-11Bibliographically approved
Wiberg, A., Granstam, A., Ingvast, S., Harkonen, T., Knip, M., Korsgren, O. & Skog, O. (2015). Characterization of human organ donors testing positive for type 1 diabetes-associated autoantibodies. Clinical and Experimental Immunology, 182(3), 278-288
Open this publication in new window or tab >>Characterization of human organ donors testing positive for type 1 diabetes-associated autoantibodies
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2015 (English)In: Clinical and Experimental Immunology, ISSN 0009-9104, E-ISSN 1365-2249, Vol. 182, no 3, p. 278-288Article in journal (Refereed) Published
Abstract [en]

In this study we aim to describe the characteristics of non-diabetic organ donors with circulating diabetes-associated autoantibodies collected within the Nordic Network for Islet Transplantation. One thousand and thirty organ donors have been screened in Uppsala for antibodies against glutamic acid decarboxylase (GADA) and islet antigen-2 (IA-2A). The 32 non-diabetic donors that tested positive for GADA (33% of all non-diabetic donors) were studied in more detail, together with 32 matched controls. Mean age among the autoantibody-positive donors was 526 (range 21-74), family history of type 1 diabetes (T1D) was unknown, and no donor was genetically predisposed for T1D regarding the human leucocyte antigen (HLA) locus. Subjects were analysed for islet cell antibodies (ICA), insulin autoantibodies (IAA) and zinc transporter 8 antibodies (ZnT8A), and pancreas morphology and clinical data were examined. Eight non-diabetic donors tested positive for two antibodies and one donor tested positive for four antibodies. No insulitis or other signs of a diabetic process were found in any of the donors. While inflammatory cells were present in all donors, subjects with high GADA titres had significantly higher CD45 cell numbers in exocrine tissue than controls. The extent of fibrosis was more pronounced in autoantibody-positive donors, even in subjects with lower GADA titres. Notably, it is possible that events not related directly to T1D (e.g. subclinical pancreatitis) may induce autoantibodies in some cases.

Keywords
autoantibodies, exocrine pancreas, fibrosis, inflammation, type 1 diabetes
National Category
Immunology in the medical area Other Basic Medicine
Identifiers
urn:nbn:se:uu:diva-268390 (URN)10.1111/cei.12698 (DOI)000364235000005 ()26313035 (PubMedID)
Funder
Swedish Research Council, 65X-12219-15-6Swedish Research Council, K2015-54X-12219-19-4EU, FP7, Seventh Framework Programme, PEVNET 261441Novo NordiskSwedish Diabetes AssociationSwedish Child Diabetes Foundation
Available from: 2015-12-09 Created: 2015-12-04 Last updated: 2018-01-10Bibliographically approved
Ståhle, M., Honkanen-Scott, M., Ingvast, S., Korsgren, O. & Friberg, A. S. (2013). Human islet isolation processing times shortened by one hour: minimized incubation time between tissue harvest and islet purification [Letter to the editor]. Transplantation, 96(12), e91-e93
Open this publication in new window or tab >>Human islet isolation processing times shortened by one hour: minimized incubation time between tissue harvest and islet purification
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2013 (English)In: Transplantation, ISSN 0041-1337, E-ISSN 1534-6080, Vol. 96, no 12, p. e91-e93Article in journal, Letter (Refereed) Published
National Category
Biomedical Laboratory Science/Technology
Identifiers
urn:nbn:se:uu:diva-274641 (URN)10.1097/01.TP.0000437562.31212.d5 (DOI)24342944 (PubMedID)
Available from: 2016-01-25 Created: 2016-01-25 Last updated: 2017-11-30Bibliographically approved
Skoglund, L., Brundin, R., Olofsson, T., Kalimo, H., Ingvast, S., Blom, E. S., . . . Glaser, A. (2009). Frontotemporal dementia in a large Swedish family is caused by a progranulin null mutation. Neurogenetics, 10(1), 27-34
Open this publication in new window or tab >>Frontotemporal dementia in a large Swedish family is caused by a progranulin null mutation
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2009 (English)In: Neurogenetics, ISSN 1364-6745, E-ISSN 1364-6753, Vol. 10, no 1, p. 27-34Article in journal (Refereed) Published
Abstract [en]

Mutations in the progranulin (PGRN) gene have recently been identified in families with frontotemporal lobar degeneration and ubiquitin-positive brain inclusions linked to chromosome 17q21. We have previously described a Swedish family displaying frontotemporal dementia with rapid progression and linkage to chromosome 17q21. In this study, we performed an extended clinical and neuropathological investigation of affected members of the family and a genetic analysis of the PGRN gene. There was a large variation of the initial presenting symptoms in this family, but common clinical features were non-fluent aphasia and loss of spontaneous speech as well as personality and behavioural changes. Mean age at onset was 54 years with disease duration of close to 4 years. Neuropathological examination revealed frontotemporal neurodegeneration with ubiquitin and TAR DNA binding protein-43 immunoreactive intraneuronal inclusions. Mutation screening of the PGRN gene identified a 1 bp deletion in exon 1 causing a frameshift of the coding sequence and introducing a premature termination codon in exon 2 (Gly35GlufsX19). Analysis of PGRN messenger RNA (mRNA) levels revealed a considerable decrease in lymphoblasts from mutation carriers and fragment size separation, and sequence analysis confirmed that the mutated mRNA allele was almost absent in these samples. In conclusion, the PGRN Gly35fs mutation causes frontotemporal dementia with variable clinical presentation in a large Swedish family, most likely through nonsense-mediated decay of mutant PGRN mRNA and resulting haploinsufficiency.

Keywords
Frontotemporal lobar degeneration, Frontotemporal dementia, Progranulinn, Ubiquitin, TDP-43
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-98042 (URN)10.1007/s10048-008-0155-z (DOI)000262652300005 ()18855025 (PubMedID)
Available from: 2009-02-13 Created: 2009-02-13 Last updated: 2017-12-14Bibliographically approved
Skoglund, L., Ingvast, S., Matsui, T., Freeman, S., Frosch, M., Brundin, R., . . . Glaser, A. (2009). No evidence of PGRN or MAPT gene dosage alterations in a collection of patients with frontotemporal lobar degeneration. Dementia and Geriatric Cognitive Disorders, 28(5), 471-475
Open this publication in new window or tab >>No evidence of PGRN or MAPT gene dosage alterations in a collection of patients with frontotemporal lobar degeneration
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2009 (English)In: Dementia and Geriatric Cognitive Disorders, ISSN 1420-8008, E-ISSN 1421-9824, Vol. 28, no 5, p. 471-475Article in journal (Refereed) Published
Abstract [en]

Background/Aims

Alterations in gene dosage have recently been associated with neurodegenerative disorders, such as Alzheimer's disease and Parkinson's disease, and deletions of the progranulin (PGRN) locus were recently described in patients with frontotemporal lobar degeneration (FTLD). FTLD is a genetically complex neurodegenerative disorder with mutations in the PGRN and the microtubule-associated protein tau (MAPT) genes being the most common known causes of familial FTLD. In this study, we investigated 39 patients with FTLD, previously found negative for mutations in PGRN and MAPT, for copy number alterations of these 2 genes.

Methods

Gene dosage analysis of PGRN and MAPT was performed using multiplex ligation-dependent probe amplification.

Results

We did not identify any PGRN or MAPT gene dosage variations in the 39 FTLD patients investigated.

Conclusion

We therefore conclude that alterations in gene copy number of PGRN and MAPT are not a cause of disease in this ollection of FTLD patients.

Keywords
Frontotemporal lobar degeneration, Frontotemporal dementia, Progranulin, Tau, Gene dosage alterations
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-98044 (URN)10.1159/000260046 (DOI)000272607200012 ()19940479 (PubMedID)
Available from: 2009-02-13 Created: 2009-02-13 Last updated: 2017-12-13Bibliographically approved
Giedraitis, V., Hedlund, M., Skoglund, L., Blom, E., Ingvast, S., Brundin, R., . . . Glaser, A. (2006). New Alzheimer's disease locus on chromosome 8. Journal of Medical Genetics, 43(12), 931-935
Open this publication in new window or tab >>New Alzheimer's disease locus on chromosome 8
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2006 (English)In: Journal of Medical Genetics, ISSN 0022-2593, E-ISSN 1468-6244, Vol. 43, no 12, p. 931-935Article in journal (Refereed) Published
Abstract [en]

Background: Family history is one of the most consistent risk factors for dementia. Therefore, analysis of families with a distinct inheritance pattern of disease can be a powerful approach for the identification of previously unknown disease genes.

Objective: To map susceptibility regions for Alzheimer's disease.

Methods: A complete genome scan with 369 microsatellite markers was carried out in 12 extended families collected in Sweden. Age at disease onset ranged from 53 to 78 years, but in 10 of the families there was at least one member with age at onset of <= 65 years. Mutations in known early-onset Alzheimer's disease susceptibility genes have been excluded. All people were genotyped for APOE, but no clear linkage with the epsilon 4 allele was observed.

Results: Although no common disease locus could be found in all families, in two families an extended haplotype was identified on chromosome 8q shared by all affected members. In one of the families, a non-parametric multi-marker logarithm of the odds (LOD) score of 4.2 (p = 0.004) was obtained and analysis based on a dominant model showed a parametric LOD score of 2.4 for this region. All six affected members of this family shared a haplotype of 10 markers spanning about 40 cM. Three affected members in another family also shared a haplotype in the same region.

Conclusion: On the basis of our data, we propose the existence of a dominantly acting Alzheimer's disease susceptibility locus on chromosome 8.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-81349 (URN)10.1136/jmg.2006.043000 (DOI)000242483900006 ()16825432 (PubMedID)
Available from: 2006-08-18 Created: 2006-08-18 Last updated: 2017-12-14Bibliographically approved
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