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  • 1.
    Ericsson, Maja
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Skog, Oskar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Uppsala Univ, Dept Immunol Genet & Pathol, Uppsala, Sweden..
    Presence of Human Herpesvirus 6B in the Pancreas of Subjects With and Without Type 1 Diabetes2017In: Pancreas, ISSN 0885-3177, E-ISSN 1536-4828, Vol. 46, no 10, p. 1341-1346Article in journal (Refereed)
    Abstract [en]

    Objectives: The aims of this study were to investigate the presence of human herpesvirus 6 (HHV6) A and B in human pancreata and to search for signs of active infection in this organ of subjects with and without type 1 diabetes (T1D). Methods: Pancreata from brain-dead organ donors with and without T1D were examined for the presence of HHV6 genomic sequences by polymerase chain reaction (PCR), transcripts by reverse transcriptase-PCR, and protein by immunohistochemistry. Quantitative PCR of isolated pancreatic islets and exocrine cell clusters was used to determine the intrapancreatic location of HHV6 DNA. Results: Human herpesvirus 6B genomic sequences were present in 1 of 2 donors who died of acute-onset T1D, 4 of 6 donors with long-standing T1D, and 9 of 12 nondiabetic donors. Higher copy numbers of HHV6B DNA were present in isolated islets than in exocrine tissue from the same donors. No signs of active HHV6 transcription were found. Human herpesvirus 6A was not present in any tested pancreas. Conclusions: The herein presented data demonstrate, for the first time, the presence of a latent HHV6B infection in the pancreas and islets of Langerhans. Whether this virus can contribute to disease in the pancreas remains to be determined.

  • 2. Helker, Christian S M
    et al.
    Mullapudi, Sri-Teja
    Mueller, Laura M
    Preussner, Jens
    Tunaru, Sorin
    Skog, Oskar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Kwon, Hyouk-Bum
    Kreuder, Florian
    Lancman, Joseph J
    Bonnavion, Remy
    Dong, P Duc Si
    Looso, Mario
    Offermanns, Stefan
    Korsgren, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Spagnoli, Francesca M
    Stainier, Didier Y R
    A whole organism small molecule screen identifies novel regulators of pancreatic endocrine development.2019In: Development, ISSN 0950-1991, E-ISSN 1477-9129, Vol. 146, no 14, article id dev172569Article in journal (Refereed)
    Abstract [en]

    An early step in pancreas development is marked by the expression of the transcription factor Pdx1 within the pancreatic endoderm, where it is required for the specification of all endocrine cell types. Subsequently, Pdx1 expression becomes restricted to the β-cell lineage, where it plays a central role in β-cell function. This pivotal role of Pdx1 at various stages of pancreas development makes it an attractive target to enhance pancreatic β-cell differentiation and increase β-cell function. In this study, we used a newly generated zebrafish reporter to screen over 8000 small molecules for modulators of pdx1 expression. We found four hit compounds and validated their efficacy at different stages of pancreas development. Notably, valproic acid treatment increased pancreatic endoderm formation, while inhibition of TGFβ signaling led to α-cell to β-cell transdifferentiation. HC toxin, another HDAC inhibitor, enhances β-cell function in primary mouse and human islets. Thus, using a whole organism screening strategy, this study identified new pdx1 expression modulators that can be used to influence different steps in pancreas and β-cell development.

  • 3.
    Hodik, Monika
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Skog, Oskar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Lukinius, Agneta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Isaza-Correa, J. M.
    Univ Groningen, Univ Med Ctr Groningen, Dept Cell Biol, Groningen, Netherlands..
    Kuipers, J.
    Univ Groningen, Univ Med Ctr Groningen, Dept Cell Biol, Groningen, Netherlands..
    Giepmans, B. N. G.
    Univ Groningen, Univ Med Ctr Groningen, Dept Cell Biol, Groningen, Netherlands..
    Frisk, Gun
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Enterovirus infection of human islets of Langerhans affects beta-cell function resulting in disintegrated islets, decreased glucose stimulated insulin secretion and loss of Golgi structure2016In: BMJ OPEN DIABETES RESEARCH & CARE, ISSN 2052-4897, Vol. 4, no 1, article id e000179Article in journal (Refereed)
    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.

  • 4.
    Hopfgarten, Johan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Stenwall, Per-Anton
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Wiberg, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Anagandula, Mahesh
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Ingvast, Sofie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Rosenling, Therese
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Korsgren, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Skog, Oskar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Gene expression analysis of human islets in a subject at onset of type 1 diabetes2014In: Acta Diabetologica, ISSN 0940-5429, E-ISSN 1432-5233, Vol. 51, no 2, p. 199-204Article in journal (Refereed)
    Abstract [en]

    Swollen islet cells have been repeatedly described at onset of type 1 diabetes, but the underlying mechanism of this observation, termed hydropic degeneration, awaits characterization. In this study, laser capture microdissection was applied to extract the islets from an organ donor that died at onset of type 1 diabetes and from an organ donor without pancreatic disease. Morphologic analysis revealed extensive hydropic degeneration in 73 % of the islets from the donor with type 1 diabetes. Expression levels of genes involved in apoptosis, ER stress, beta cell function, and inflammation were analyzed in isolated and laser-captured islets by qPCR. The chemokine MCP-1 was expressed in islets from the donor with type 1 diabetes while undetectable in the control donor. No other signs of inflammation were detected. There were no signs of apoptosis on the gene expression level, which was also confirmed by negative immunostaining for cleaved caspase-8. There was an increased expression of the transcription factor ATF4, involved in transcription of ER stress genes, in the diabetic islets, but no further signs of ER stress were identified. In summary, on the transcription level, islets at onset of type 1 diabetes in which many beta cells display hydropic degeneration show no obvious signs of apoptosis, ER stress, or inflammation, supporting the notion that these cells are responding normally to high glucose and eventually succumbing to beta cell exhaustion. Also, this study validates the feasibility of performing qPCR analysis of RNA extracted from islets from subjects with recent onset of T1D and healthy controls by laser capture microdissection.

  • 5.
    Jonsson, Alexander
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Yngve, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Karlsson, Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Ingvast, Sofie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Skog, Oskar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Korsgren, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Univ Gothenburg, Inst Biomed, Gothenburg, Sweden.
    Protein Kinase R Is Constitutively Expressed in the Human Pancreas2019In: Journal of Histochemistry and Cytochemistry, ISSN 0022-1554, E-ISSN 1551-5044, Vol. 67, no 2, p. 99-105Article in journal (Refereed)
    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.

  • 6.
    Korsgren, Olle
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Skog, Oskar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Ludvigsson, Johnny
    Linköping University, Linköping, Sweden.
    Teplizumab in Relatives at Risk for Type 1 Diabetes2019In: New England Journal of Medicine, ISSN 0028-4793, E-ISSN 1533-4406, Vol. 381, no 19, p. 1879-1880Article in journal (Other academic)
  • 7.
    Korsgren, Olle
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Univ Gothenburg, Inst Biomed, Dept Clin Chem & Transfus Med, Gothenburg, Sweden.
    Skyler, Jay S
    Division of Endocrinology, Diabetes and Metabolism, Department of Medicine, University of Miami, Miami, FL, USA; Diabetes Research Institute, University of Miami, Miami, FL, USA.
    Skog, Oskar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Sundberg, Frida
    Department of Pediatrics, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden; The Queen Silvia Children’s Hospital, Sahlgrenska University Hospital, Gothenburg, Sweden.
    Forsander, Gun
    Department of Pediatrics, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden; The Queen Silvia Children’s Hospital, Sahlgrenska University Hospital, Gothenburg, Sweden.
    Ludvigsson, Johnny
    Division of Pediatrics, Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden; Crown Princess Victoria Children´s Hospital, Region Östergötland, Linköping, Sweden.
    Imagining a better future for all people with type 1 diabetes mellitus2019In: Nature Reviews Endocrinology, ISSN 1759-5029, E-ISSN 1759-5037, Vol. 15, no 11, p. 623-624Article in journal (Other academic)
    Abstract [en]

    For a person with type 1 diabetes mellitus, lifelong insulin treatment is the only therapeutic option. However, increased blood levels of glucose are just a symptom of impaired beta-cell function. Approaching the centenary of the first insulin injection, broadening of international therapeutic guidelines to improve diagnostics, as well as monitor and preserve beta-cell function, is warranted.

  • 8.
    Krogvold, Lars
    et al.
    Paediatric Department, Oslo University Hospital, Oslo, Norway.
    Edwin, Bjørn
    Intervention Centre and Department of Surgery, Oslo University Hospital, Oslo, Norway Faculty of Medicine, University of Oslo, Oslo, Norway.
    Buanes, Trond
    Frisk, Gun
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Skog, Oskar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Anagandula, Mahesh
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Korsgren, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Undlien, Dag
    Faculty of Medicine, University of Oslo, Oslo, Norway,Department of Medical Genetics, Oslo University Hospital, Oslo, Norway.
    Eike, MortenC
    Department of Medical Genetics, Oslo University Hospital, Oslo, Norway.
    Richardson, Sarah J
    Institute of Biomedical & Clinical Science, University of Exeter Medical School, Exeter, U.K..
    Leete, Pia
    Institute of Biomedical & Clinical Science, University of Exeter Medical School, Exeter, U.K..
    Morgan, Noel G
    Institute of Biomedical & Clinical Science, University of Exeter Medical School, Exeter, U.K..
    Oikarinen, Sami
    Department of Virology, School of Medicine, University of Tampere, Tampere, Finland.
    Oikarinen, Maarit
    Department of Virology, School of Medicine, University of Tampere, Tampere, Finland.
    Laiho, Jutta E
    Department of Virology, School of Medicine, University of Tampere, Tampere, Finland.
    Hyöty, Heikki
    Department of Virology, School of Medicine, University of Tampere, Tampere, Finland,9Fimlab Laboratories, Pirkanmaa Hospital District, Tampere, Finland.
    Ludvigsson, Johnny
    Division of Paediatrics, Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
    Hanssen, Kristian F
    Faculty of Medicine, University of Oslo, Oslo, Norway, Department of Endocrinology, Oslo University Hospital, Oslo, Norway.
    Dahl-Jørgensen, Knut
    Paediatric Department, Oslo University Hospital, Oslo, NorwayFaculty of Medicine, University of Oslo, Oslo, Norway.
    Detection of a low-grade enteroviral infection in the islets of Langerhans of living patients newly diagnosed with type 1 diabetes2015In: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 64, no 5, p. 1682-1687Article in journal (Refereed)
    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.

  • 9. Krogvold, Lars
    et al.
    Skog, Oskar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Sundström, Görel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Edwin, Bjorn
    Buanes, Trond
    Hanssen, Kristian F.
    Ludvigsson, Johnny
    Grabherr, Manfred
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Korsgren, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Dahl-Jorgensen, Knut
    Function of Isolated Pancreatic Islets From Patients at Onset of Type 1 Diabetes: Insulin Secretion Can Be Restored After Some Days in a Nondiabetogenic Environment In Vitro: Results From the DiViD Study2015In: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 64, no 7, p. 2506-2512Article in journal (Refereed)
    Abstract [en]

    The understanding of the etiology of type 1 diabetes (T1D) remains limited. One objective of the Diabetes Virus Detection (DiViD) study was to collect pancreatic tissue from living subjects shortly after the diagnosis of T1D. Here we report the insulin secretion ability by in vitro glucose perifusion and explore the expression of insulin pathway genes in isolated islets of Langerhans from these patients. Whole-genome RNA sequencing was performed on islets from six DiViD study patients and two organ donors who died at the onset of T1D, and the findings were compared with those from three nondiabetic organ donors. All human transcripts involved in the insulin pathway were present in the islets at the onset of T1D. Glucose-induced insulin secretion was present in some patients at the onset of T1D, and a perfectly normalized biphasic insulin release was obtained after some days in a nondiabetogenic environment in vitro. This indicates that the potential for endogenous insulin production is good, which could be taken advantage of if the disease process was reversed at diagnosis.

  • 10. Krogvold, Lars
    et al.
    Wiberg, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Edwin, Bjørn
    Buanes, Trond
    Jahnsen, Frode Lars
    Hanssen, Kristian F
    Larsson, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Korsgren, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Skog, Oskar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Dahl-Jørgensen, Knut
    Insulitis and characterisation of infiltrating T cells in surgical pancreatic tail resections from patients at onset of type 1 diabetes2016In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 59, no 3, p. 492-501Article in journal (Refereed)
    Abstract [en]

    Aims/hypothesis

    It is thought that T cells play a major role in the immune-mediated destruction of beta cells in type 1 diabetes, causing inflammation of the islets of Langerhans (insulitis). The significance of insulitis at the onset of type 1 diabetes is debated, and the role of the T cells poorly understood.

    Methods

    In the Diabetes Virus Detection (DiViD) study, pancreatic tissue from six living patients with recent-onset type 1 diabetes was collected. The insulitis was characterised quantitatively by counting CD3+ T cells, and qualitatively by transcriptome analysis targeting 84 T and B lymphocyte genes of laser-captured microdissected islets. The findings were compared with gene expression in T cells collected from kidney biopsies from allografts with ongoing cellular rejection. Cytokine and chemokine release from isolated islets was characterised and compared with that from islets from non-diabetic organ donors.

    Results

    All six patients fulfilled the criteria for insulitis (5–58% of the insulin-containing islets in the six patients had ≥ 15 T cells/islet). Of all the islets, 36% contained insulin, with several resembling completely normal islets. The majority (61–83%) of T cells were found as peri-insulitis rather than within the islet parenchyma. The expression pattern of T cell genes was found to be markedly different in islets compared with the rejected kidneys. The islet-infiltrating T cells showed only background levels of cytokine/chemokine release in vitro.

    Conclusions/interpretation

    Insulitis and a significant reserve reservoir for insulin production were present in all six cases of recent-onset type 1 diabetes. Furthermore, the expression patterns and levels of cytokines argue for a different role of the T cells in type 1 diabetes when compared with allograft rejection.

  • 11.
    Kuric, Enida
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Krogvold, Lars
    Oslo Univ Hosp, Div Paediat & Adolescent Med, Oslo, Norway.;Univ Oslo, Fac Odontol, Oslo, Norway..
    Hanssen, Kristian F.
    Oslo Univ Hosp, Dept Endocrinol, Oslo, Norway.;Univ Oslo, Fac Med, Oslo, Norway..
    Dahl-Jorgensen, Knut
    Oslo Univ Hosp, Div Paediat & Adolescent Med, Oslo, Norway.;Univ Oslo, Fac Med, Oslo, Norway..
    Skog, Oskar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Korsgren, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Univ Gothenburg, Dept Biomed, Gothenburg, Sweden..
    No Evidence for Presence of Mucosal-Associated Invariant T Cells in the Insulitic Lesions in Patients Recently Diagnosed with Type 1 Diabetes2018In: American Journal of Pathology, ISSN 0002-9440, E-ISSN 1525-2191, Vol. 188, no 8, p. 1744-1748Article in journal (Refereed)
    Abstract [en]

    Mucosal-associated invariant T (MAIT) cells are innate T cells that recognize bacteria-infected cells and are thought to play a role in autoimmune diseases. Translocation of duodenal bacteria and viruses to the pancreas through the pancreatic duct has been hypothesized to initiate an innate inflammatory response that could contribute to the development of type 1 diabetes, a process that could involve MAIT cells. In this study, we used immunohistochemistry and quantitative PCR to search for evidence of MAIT cells in the insulitic lesions in the pancreas of human patients recently diagnosed with type 1 diabetes. Only a few scattered MAIT cells were found within the exocrine parenchyma in all pancreatic samples, but no MAIT cells were found in association to the islets. Also, only low gene expression levels of the MAIT T-cell receptor V alpha 7.2-3 alpha 33 were found in the pancreas of patients with type 1 diabetes, in similar Levels as that in nondiabetic organ donors used as control. The absence of MAIT cells shown in insulitic lesions in humans questions the direct cytotoxic role of these cells in beta-cell destruction.

  • 12.
    Kuric, Enida
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Seiron, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Krogvold, Lars
    Edwin, Bjørn
    Buanes, Trond
    Hanssen, Kristian F.
    Skog, Oskar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Dahl-Jørgensen, Knut
    Korsgren, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Demonstration of Tissue Resident Memory CD8 T Cells in Insulitic Lesions in Adult Patients with Recent-Onset Type 1 Diabetes2017In: American Journal of Pathology, ISSN 0002-9440, E-ISSN 1525-2191, Vol. 187, no 3, p. 581-588Article in journal (Refereed)
    Abstract [en]

    Subtypes of CD8(+) T cells in insulitic lesions in biopsy specimens from six subjects with recent-onset type 1 diabetes (T1D) and six nondiabetic matched controls were analyzed using simultaneous multicolor immunofluorescence. Also, insulitic islets based on accumulation of CD3(+) T cells were microdissected with laser-capture microscopy, and gene transcripts associated with inflammation and autoimmunity were analyzed. We found a substantial proportion, 43%, of the CD8(+) T cells in the insulitic lesions to display a tissue resident memory T cell (TRM) (CD8(+)CD69(+)CD103(+)) phenotype in T1D subjects. Most TRM cells were located in the insulitic lesion in the endocrine-exocrine interface. TRM cells were also sporadically found in islets of control subjects. Moreover, gene expression analysis showed a lack of active transcription of genes associated with acute inflammatory or cytotoxic T-cell responses. We present evidence that a substantial proportion of T cells in insulitic lesions of recent-onset T1D patients are TRM cells and not classic cytotoxic CD8(+) T cells. Our findings highlight the need for further analysis of the T cells involved in insulitis to elucidate their role in the etiology of T1D.

  • 13.
    Lundberg, Marcus
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Lindqvist, Andreas
    Lund Univ, Diabet Ctr, Malmo, Sweden..
    Wierup, Nils
    Lund Univ, Diabet Ctr, Malmo, Sweden..
    Krogvold, Lars
    Oslo Univ Hosp, Div Paediat & Adolescent Med, Oslo, Norway.;Univ Oslo, Fac Med, Oslo, Norway..
    Dahl-Jorgensen, Knut
    Oslo Univ Hosp, Div Paediat & Adolescent Med, Oslo, Norway.;Univ Oslo, Fac Med, Oslo, Norway..
    Skog, Oskar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    The density of parasympathetic axons is reduced in the exocrine pancreas of individuals recently diagnosed with type 1 diabetes2017In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 12, no 6, article id e0179911Article in journal (Refereed)
    Abstract [en]

    To elucidate the etiology of type 1 diabetes, the affected pancreas needs to be thoroughly characterized. Pancreatic innervation has been suggested to be involved in the pathology of the disease and a reduction of sympathetic innervation of the islets was recently reported. In the present study, we hypothesized that parasympathetic innervation would be altered in the type 1 diabetes pancreas. Human pancreatic specimens were obtained from a unique cohort of individuals with recent onset or long standing type 1 diabetes. Density of parasympathetic axons was assessed by immunofluorescence and morphometry. Our main finding was a reduced density of parasympathetic axons in the exocrine, but not endocrine compartment of the pancreas in individuals with recent onset type 1 diabetes. The reduced density of parasympathetic axons in the exocrine compartment could have functional implications, e.g. be related to the exocrine insufficiency reported in type 1 diabetes patients. Further studies are needed to understand whether reduced parasympathetic innervation is a cause or consequence of type 1 diabetes.

  • 14.
    Lundberg, Marcus
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Seiron, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Ingvast, Sofie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Korsgren, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Skog, Oskar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Insulitis in human diabetes: a histological evaluation of donor pancreases2017In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 60, no 2, p. 346-353Article in journal (Refereed)
    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.

  • 15.
    Lundberg, Marcus
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Seiron, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Ingvast, Sofie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Korsgren, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Skog, Oskar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    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].2017In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 60, no 4, p. 756-757Article in journal (Other academic)
  • 16.
    Lundberg, Marcus
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Stenwall, Per-Anton
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Tegehall, Angelica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Korsgren, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Skog, Oskar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Expression profiles of stress-related genes in islets from donors with progressively impaired glucose metabolism.2018In: Islets, ISSN 1938-2014, E-ISSN 1938-2022, Vol. 10, no 2, p. 69-79Article in journal (Refereed)
    Abstract [en]

    It is currently unknown how the islet transcriptional pattern changes as glucose metabolism deteriorates and progresses to fulminant type 2 diabetes (T2D). In this study, we hypothesized that islets from donors with elevated HbA1c levels, but not yet diagnosed with T2D, would show signs of cell stress on a transcriptional level. Laser capture microdissection and qPCR arrays including 330 genes related to mitochondria, oxidative stress, or the unfolded protein response were used to extract and analyze islets from organ donors with HbA1c <5.5% (37 mmol/mol), elevated HbA1c (6.0-6.5% (42-48 mmol/mol)), high HbA1c (>6.5% (48 mmol/mol)) or established T2D. Principal component analysis and hierarchical clustering based on the expression of all 330 genes displayed no obvious separation of the four different donor groups, indicating that the inter-donor variations were larger than the differences between groups. However, 44 genes were differentially expressed (P < 0.05, false discovery rate <30%) between islets from donors with HbA1c <5.5% (37 mmol/mol) compared with islets from T2D subjects. Twelve genes were differentially expressed compared to control islets in both donors with established T2D and donors with elevated HbA1c (6.0-6.5% (42-48 mmol/mol)). Overexpressed genes were related mainly to the unfolded protein response, whereas underexpressed genes were related to mitochondria. Our data on transcriptional changes in human islets retrieved by LCM from high-quality biopsies, as pre-diabetes progresses to established T2D, increase our understanding on how islet stress contributes to the disease development.

  • 17.
    Moëll, Annika
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
    Skog, Oskar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
    Åhlin, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
    Korsgren, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Oncology, Radiology and Clinical Immunology, Clinical Immunology.
    Frisk, Gun
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatrics.
    Antiviral effect of nicotinamide on enterovirus-infected human islets in vitro: effect on virus replication and chemokine secretion2009In: Journal of Medical Virology, ISSN 0146-6615, E-ISSN 1096-9071, Vol. 81, no 6, p. 1082-1087Article in journal (Refereed)
    Abstract [en]

    Type 1 diabetes is a chronic disease characterized by the selective destruction of insulin-producing cells in the pancreas. Enterovirus (EV) is the prime candidate to initiate this destruction and several inflammatory chemokines are induced by EV infection. Nicotinamide has been shown to protect isolated human islets, and to modulate chemokine expression. The aim of this study was to evaluate the effect of nicotinamide on EV replication and EV-induced chemokine secretion and cytolysis of human islets. Two EV strains were used to infect human islets in vitro, one lytic (Adrian) isolated from a child at onset of type 1 diabetes, and one non-lytic (VD2921). Secretion of the chemokines IP-10 and MCP-1, viral replication, and virus-induced cytopathic effect (CPE), were measured at different time points post-infection. Addition of nicotinamide to the culture medium reduced viral replication and virus-induced islet destruction/CPE, significantly. Both EV strains increased secretion of IP-10 and MCP-1, when measured days 2-3, and days 5-7 post infection, compared to mock-infected control islets. IP-10 was not produced by uninfected isolated islets, whereas a basal secretion of MCP-1 was detected. Interestingly, addition of nicotinamide blocked completely (Adrian), or reduced significantly (VD2921), the virus-induced secretion of IP-10. Secretion of MCP-1 was also reduced in the presence of nicotinamide, from infected and uninfected islets. The reported antiviral effects of nicotinamide could have implications for the treatment/prevention of virus- and immune-mediated disease. Also, this study highlights a possible mechanism of virus-induced type 1 diabetes through the induction of MCP-1 and IP-10 in pancreatic islets.

  • 18.
    Nyström, Niklas
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatrics.
    Berg, Tove
    Lundin, Elin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Skog, Oskar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Hansson, Inga
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Frisk, Gun
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Juko-Pecirep, Ivana
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Genomics.
    Nilsson, Mats
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular tools.
    Gyllensten, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Genomics.
    Finkel, Yigael
    Fuxe, Jonas
    Wanders, Alkwin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular and Morphological Pathology.
    Human enterovirus species B in ileocecal Crohn's disease2013In: Clinical and Translational Gastroenterology, ISSN 2155-384X, E-ISSN 2155-384X, Vol. 4, article id e38Article in journal (Refereed)
    Abstract [en]

    OBJECTIVES:

    Advanced ileocecal Crohn's disease (ICD) is characterized by strictures, inflammation in the enteric nervous system (myenteric plexitis), and a high frequency of NOD2 mutations. Recent findings implicate a role of NOD2 and another CD susceptibility gene, ATG16L1, in the host response against single-stranded RNA (ssRNA) viruses. However, the role of viruses in CD is unknown. We hypothesized that human enterovirus species B (HEV-B), which are ssRNA viruses with dual tropism both for the intestinal epithelium and the nervous system, could play a role in ICD.

    METHODS:

    We used immunohistochemistry and in situ hybridization to study the general presence of HEV-B and the presence of the two HEV-B subspecies, Coxsackie B virus (CBV) and Echovirus, in ileocecal resections from 9 children with advanced, stricturing ICD and 6 patients with volvulus, and in intestinal biopsies from 15 CD patients at the time of diagnosis.

    RESULTS:

    All patients with ICD had disease-associated polymorphisms in NOD2 or ATG16L1. Positive staining for HEV-B was detected both in the mucosa and in myenteric nerve ganglia in all ICD patients, but in none of the volvulus patients. Expression of the cellular receptor for CBV, CAR, was detected in nerve cell ganglia.

    CONCLUSIONS:

    The common presence of HEV-B in the mucosa and enteric nervous system of ICD patients in this small cohort is a novel finding that warrants further investigation to analyze whether HEV-B has a role in disease onset or progress. The presence of CAR in myenteric nerve cell ganglia provides a possible route of entry for CBV into the enteric nervous system.

  • 19. Radenkovic, M
    et al.
    Uvebrant, K
    Skog, Oskar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Sarmiento, L
    Avartsson, J
    Storm, P
    Vickman, P
    Bertilsson, P-A
    Fex, M
    Korsgren, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Cilio, C M
    Characterization of resident lymphocytes in human pancreatic islets2017In: Clinical and Experimental Immunology, ISSN 0009-9104, E-ISSN 1365-2249, Vol. 187, no 3, p. 418-427Article in journal (Refereed)
    Abstract [en]

    The current view of type 1 diabetes (T1D) is that it is an immune-mediated disease where lymphocytes infiltrate the pancreatic islets, promote killing of beta cells and cause overt diabetes. Although tissue resident immune cells have been demonstrated in several organs, the composition of lymphocytes in human healthy pancreatic islets have been scarcely studied. Here we aimed to investigate the phenotype of immune cells associated with human islets of non-diabetic organ donors. A flow cytometry analysis of isolated islets from perfused pancreases (n = 38) was employed to identify alpha, beta, T, natural killer (NK) and B cells. Moreover, the expression of insulin and glucagon transcripts was evaluated by RNA sequencing. Up to 80% of the lymphocytes were CD3(+) T cells with a remarkable bias towards CD8(+) cells. Central memory and effector memory phenotypes dominated within the CD8(+) and CD4(+) T cells and most CD8(+) T cells were positive for CD69 and up to 50-70% for CD103, both markers of resident memory cells. The frequency of B and NK cells was low in most islet preparations (12 and 3% of CD45(+) cells, respectively), and the frequency of alpha and beta cells varied between donors and correlated clearly with insulin and glucagon mRNA expression. In conclusion, we demonstrated the predominance of canonical tissue resident memory CD8(+) T cells associated with human islets. We believe that these results are important to understand more clearly the immunobiology of human islets and the disease-related phenotypes observed in diabetes.

  • 20.
    Seiron, Peter
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Wiberg, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Kuric, Enida
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Krogvold, Lars
    Oslo Univ Hosp, Div Paediat & Adolescent Med, Oslo, Norway.
    Jahnsen, Frode L.
    Oslo Univ Hosp, Dept Pathol, Oslo, Norway.
    Dahl-Jorgensen, Knut
    Oslo Univ Hosp, Div Paediat & Adolescent Med, Oslo, Norway.
    Skog, Oskar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Korsgren, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Univ Gothenburg, Inst Biomed, Dept Clin Chem & Transfus Med, Gothenburg, Sweden.
    Characterisation of the endocrine pancreas in type 1 diabetes: islet size is maintained but islet number is markedly reduced2019In: The journal of pathology. Clinical research, ISSN 2056-4538, Vol. 5, no 4, p. 248-255Article in journal (Refereed)
    Abstract [en]

    Insulin deficiency in type 1 diabetes (T1D) is generally considered a consequence of immune-mediated specific beta-cell loss. Since healthy pancreatic islets consist of similar to 65% beta cells, this would lead to reduced islet size, while the number of islets per pancreas volume (islet density) would not be affected. In this study, we compared the islet density, size, and size distribution in biopsies from subjects with recent-onset or long-standing T1D, with that in matched non-diabetic subjects. The results presented show preserved islet size and islet size distribution, but a marked reduction in islet density in subjects with recent onset T1D compared with non-diabetic subjects. No further reduction in islet density occurred with increased disease duration. Insulin-negative islets in T1D subjects were dominated by glucagon-positive cells that often had lost the alpha-cell transcription factor ARX while instead expressing PDX1, normally only expressed in beta cells within the islets. Based on our findings, we propose that failure to establish a sufficient islet number to reach the beta-cell mass needed to cope with episodes of increased insulin demand contributes to T1D susceptibility. Exhaustion induced by relative lack of beta cells could then potentially drive beta-cell dedifferentiation to alpha-cells, explaining the preserved islet size observed in T1D compared to controls.

  • 21.
    Skog, Oskar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Effects of Enterovirus Infection on Innate Immunity and Beta Cell Function in Human Islets of Langerhans2012Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    This thesis focuses on enteroviral effects on human pancreatic islets. Most knowledge of viral effects on host cells relies on studies of immortalized cell lines or animal models. The islets represent a fundamentally different and less well studied cellular host. Also, enterovirus has been implicated in the etiology of type 1 diabetes (T1D). We show that when enterovirus replicates in human islets it activates innate immunity genes and induces secretion of the chemokines MCP-1 and IP-10. An important difference in activation of innate immunity by replicating EV and synthetic dsRNA is suggested, since the chemokine secretion induced by EV infection but not by dsRNA is reduced by female sex hormone. We also demonstrate a direct antiviral effect of nicotinamide, and even though this substance failed to prevent T1D in a large-scale study, this finding could have implications for the treatment/prevention of virus- and/or immune-mediated disease.

    We also had access to human pancreata from two organ donors with recent onset T1D and several donors with T1D-related autoantibodies, which gave us the opportunity to study ongoing pathogenic processes at and before the onset of T1D. Despite this, we could neither confirm nor reject the hypothesis that EV is involved in T1D development. Several observations, such as ultrastructural remodeling of the beta cell, activation of innate immunity, and immunopositivity to EV capsid protein 1, supported an ongoing virus infection, but direct evidence is still lacking.

    An interesting finding in the donors with recent onset T1D was that the islets were positively stained for insulin, but did not secrete insulin in response to glucose-stimulation. A similar effect was observed in EV-infected islets in vitro; EV destroyed islet function and insulin gene expression, but the islets still stained positive for insulin. This may be indicative of that a functional block in addition to beta cell destruction is involved in T1D pathogenesis.

    In conclusion, these studies of EV in isolated human islets in vitro support that this virus can cause T1D in vivo, but future studies will have to show if and how frequently this happens. 

  • 22.
    Skog, Oskar
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Hodik, Monika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Korsgren, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Frisk, Gun
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Enterovirus Infection Reduces Beta-cell Function and Leads to Decreased Glucose Stimulated Insulin Secretion in Dissociated but not In Intact Pancreatic Human IsletsManuscript (preprint) (Other academic)
  • 23.
    Skog, Oskar
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Hodik, Monika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Lukinius, Agneta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Korsgren, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Frisk, Gun
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Ongoing Pathogenic Processes in the Pancreas at Onset of Type 1 Diabetes in HumansManuscript (preprint) (Other academic)
  • 24.
    Skog, Oskar
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Ingvast, Sofie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Korsgren, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Evaluation of RT-PCR and immunohistochemistry as tools for detection of enterovirus in the human pancreas and islets of Langerhans2014In: Journal of Clinical Virology, ISSN 1386-6532, E-ISSN 1873-5967, Vol. 61, no 2, p. 242-247Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Enteroviruses have been implicated in the etiology of type 1 diabetes, supported by immunoreactivity of enteroviral protein in islets, but presence of enteroviral genome has rarely been reported. Failure to detect enterovirus with RT-PCR has been attributed to the possible presence of PCR inhibitors and that only few cells are infected.

    OBJECTIVES: The aim of this study was to evaluate strategies for detection of enterovirus in human islets.

    STUDY DESIGN: A scenario was modeled with defined infected islets among a large number of uninfected pancreatic cells and the sensitivity of immunohistochemistry and PCR for detection of enterovirus was evaluated.

    RESULTS: Enterovirus was detected with PCR when only one single human islet, infected in vitro with a low dose of virus, was mixed with an uninfected pancreatic biopsy. Enterovirus could not be detected by immunohistochemistry under the same conditions, demonstrating the superior sensitivity of PCR also in pancreatic tissue with only a small fraction of infected cells. In addition, we demonstrate that pancreatic cell culture supernatant does not cause degradation of enterovirus at 37°C, indicating that under normal culture conditions released virus is readily detectable. Utilizing PCR, the pancreases of two organ donors that died at onset of type 1 diabetes were found negative for enterovirus genome despite islet cells being positive using immunohistochemistry.

    CONCLUSIONS: These data suggest that PCR should be the preferred screening method for enterovirus in the pancreas and suggest cautious interpretation of immunostaining for enterovirus that cannot be confirmed with PCR.

  • 25.
    Skog, Oskar
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Klingel, Karin
    Univ Hosp Tuebingen, Inst Pathol & Neuropathol, Tubingen, Germany.
    Roivainen, Merja
    Natl Inst Hlth & Welf, Helsinki, Finland.
    Korsgren, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Univ Gothenburg, Inst Biomed, Dept Clin Chem & Transfus Med, Gothenburg, Sweden.
    Large enteroviral vaccination studies to prevent type 1 diabetes should be well founded and rely on scientific evidence2019In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 62, no 6, p. 1097-1099Article in journal (Other academic)
  • 26.
    Skog, Oskar
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Korsgren, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. University of Gothenburg, Institute of Biomedicine, Gothenburg, Sweden.
    Aetiology of type 1 diabetes: Physiological growth in children affects disease progression2018In: Diabetes, obesity and metabolism, ISSN 1462-8902, E-ISSN 1463-1326, Vol. 20, no 4, p. 775-785Article in journal (Refereed)
    Abstract [en]

    The prevailing view is that type 1 diabetes (T1D) develops as a consequence of a severe decline in β-cell mass resulting from T-cell-mediated autoimmunity; however, progression from islet autoantibody seroconversion to overt diabetes and finally to total loss of C-peptide production occurs in most affected individuals only slowly over many years or even decades. This slow disease progression should be viewed in relation to the total β-cell mass of only 0.2 to 1.5 g in adults without diabetes. Focal lesions of acute pancreatitis with accumulation of leukocytes, often located around the ducts, are frequently observed in people with recent-onset T1D, and most patients display extensive periductal fibrosis, the end stage of inflammation. An injurious inflammatory adverse event, occurring within the periductal area, may have negative implications for islet neogenesis, dependent on stem cells residing within or adjacent to the ductal epithelium. This could in part prevent the 30-fold increase in β-cell mass that would normally occur during the first 20 years of life. This increase occurs in order to maintain glucose metabolism during the physiological increases in insulin production that are required to balance the 20-fold increase in body weight during childhood and increased insulin resistance during puberty. Failure to expand β-cell mass during childhood would lead to clinically overt T1D and could help to explain the apparently more aggressive form of T1D occurring in growing children when compared with that observed in affected adults.

  • 27.
    Skog, Oskar
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Korsgren, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Comment on Rodriguez-Calvo et al. Increase in Pancreatic Proinsulin and Preservation of β-Cell Mass in Autoantibody-Positive Donors Prior to Type 1 Diabetes Onset. Diabetes 2017;66:1334-13452017In: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 66, no 9, p. e8-e9Article in journal (Other academic)
  • 28.
    Skog, Oskar
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatrics. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Korsgren, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Frisk, Gun
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health, Pediatrics.
    Modulation of Innate Immunity in Human Pancreatic Islets Infected With Enterovirus In Vitro2011In: Journal of Medical Virology, ISSN 0146-6615, E-ISSN 1096-9071, Vol. 83, no 4, p. 658-664Article in journal (Refereed)
    Abstract [en]

    Present knowledge of innate immunity in infected cells relies on studies of cell lines and animal models. In this study, primary human pancreatic islets of Langerhans were used to study virus-host interactions in a model of the possible induction of type 1 diabetes by enterovirus (EV). Human islets were infected with a strain of EV isolated at onset of type 1 diabetes, or exposed to synthetic dsRNA (poly(I:C)), used commonly to mimic viral infection. Induction of innate immunity and the effect of the female sex hormone 17 beta-estradiol, known to have cell-protective effects, on islet chemokine secretion were investigated. 17 beta-Estradiol reduced EV but not poly(I:C)-induced IP-10/CXCL10 secretion from human islets, suggesting that separate signaling pathways of the innate immune response are triggered by EV and poly(I:C), respectively. Infection with EV increased the gene-expression of toll-like receptor 3, interferon-beta, and the intracellular helicase MDA5, involved in antiviral innate immunity, multi-fold over time, whereas poly(I:C) increased the expression of these genes transiently. The induced expression pattern was similar in all donors, but the expression levels varied greatly. Pre-exposure to poly(I:C) blocked viral replication in islets from 56% of the donors. These data provide insight on the innate immune responses induced by EV in human islets, and show that this can be modulated by 17 beta-estradiol, and suggest an important difference between virus- and poly(I:C)-induced signaling.

  • 29.
    Skog, Oskar
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Korsgren, Stella
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Melhus, Åsa
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Clinical Microbiology and Infectious Medicine, Clinical Bacteriology.
    Korsgren, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Revisiting the notion of type 1 diabetes being a T-cell-mediated autoimmune disease2013In: Current Opinion In Endocrinology Diabetes And Obesity, ISSN 1752-296X, Vol. 20, no 2, p. 118-123Article, review/survey (Refereed)
    Abstract [en]

    Purpose of review Type 1 diabetes (T1D) research is at present in a critical period of development and during the past few years several large phase III studies targeting T-cell autoimmunity in recent-onset patients with T1D failed to reach the primary endpoint. Recent findings Cause and pathogenesis of T1D remain largely unknown. In humans, insulitis is discrete, affects few islets and is present only in about one-third of patients with recent-onset T1D. The rapid increase in incidence of T1D argues against a decisive role for genetic factors and instead for the hypothesis that infectious agents, possibly entering the pancreas via the ductal compartment, are involved in disease pathogenesis. Repeated episodes of bacteria or virus-induced innate inflammations affecting only certain lobes of the pancreas fit well with the reported heterogeneity of the disease within the pancreas as well as with the slow progression over many years. Summary In humans there is limited support for T1D being primarily an autoimmune disease; instead available findings support the view that T1D can be regarded as an innate inflammatory disease affecting the entire pancreas, but with its main clinical manifestations emanating from the loss of the insulin-producing cells.

  • 30.
    Skog, Oskar
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Korsgren, Stella
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Wiberg, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Danielsson, Angelika
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Edwin, Bjorn
    Buanes, Trond
    Krogvold, Lars
    Korsgren, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Dahl-Jorgensen, Knut
    Expression of Human Leukocyte Antigen Class I in Endocrine and Exocrine Pancreatic Tissue at Onset of Type 1 Diabetes2015In: American Journal of Pathology, ISSN 0002-9440, E-ISSN 1525-2191, Vol. 185, no 1, p. 129-138Article in journal (Refereed)
    Abstract [en]

    The cause of type 1 diabetes remains unknown. To dissect the Link between hyperexpression of human leukocyte antigen (HLA) class Ion the islet cells, we examined its expression in subjects with recent-onset type 1 diabetes. IHC showed seemingly pronounced hyperexpression in subjects with recent-onset type 1 diabetes, as well as in some nondiabetic subjects. In all subjects, HLA class I expression on exocrine tissue was Low. However, no difference in the level of HLA class I expression was found between islet and exocrine tissue using Western blot, flow cytometry, real-time quantitative PCR, or RNA sequencing analyses. Also, the Level of HLA class I expression on the messenger level was not increased in islets from subjects with recent-onset type 1 diabetes compared with that in nondiabetic subjects. Consistently, the HLA class I specific enhanceosome (NLRC5) and related transcription factors, as well as interferons, were not enhanced in islets from recent-onset type 1 diabetic subjects. In conclusion, a discrepancy in HLA class I expression in islets assessed by IHC was observed compared with that using quantitative techniques showing similar expression of HLA class I in islets and exocrine tissue in subjects with recent-onset type 1 diabetes, nor could any differences be found between type 1 diabetic and nondiabetic subjects. Results presented provide important clues for a better understanding on how this complex disease develops.

  • 31.
    Stenwall, Anton
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Ingvast, Sofie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Skog, Oskar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Korsgren, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. University of Gothenburg, Gothenburg, Sweden.
    Characterization of host defense molecules in the human pancreas2019In: Islets, ISSN 1938-2014, E-ISSN 1938-2022, Vol. 11, no 4, p. 89-101Article in journal (Refereed)
    Abstract [en]

    The gut microbiota can play a role in pancreatitis and, likely, in the development of type 1 diabetes (T1D). Anti-microbial peptides and secretory proteins are important mediators of the innate immune response against bacteria but their expression in the human pancreas is not fully known. In this study, immunohistochemistry was used to analyze the expression of seven anti-microbial peptides (Defensin alpha 1, alpha 4, beta 1-4 and Cathelicidin) and two secretory proteins with known antimicrobial properties (REG3A and GP2) in pancreatic and duodenal biopsies from 10 non-diabetic organ donors and one organ donor that died at onset of T1D. Immunohistochemical data was compared with previously published whole-transcriptome data sets. Seven (Defensin alpha 1, beta 2, beta 3, alpha 4, GP2, Cathelicidin, and REG3A) host defense molecules showed positive staining patterns in most non-diabetic organ donors, whereas two (Defensin beta 1 and beta 4) were negative in all non-diabetic donors. Two molecules (Defensin alpha 1 and GP2) were restricted to the exocrine pancreas whereas two (Defensin beta 3, alpha 4) were only expressed in islet tissue. Cathelicidin, beta 2, and REG3A were expressed in both islets and exocrine tissue. The donor that died at onset of T1D had generally less positivity for the host defense molecules, but, notably, this pancreas was the only one where defensin beta 1 was found. Neither donor age, immune-cell infiltration, nor duodenal expression correlated to the pancreatic expression of host defense molecules. In conclusion, these findings could have important implications for the inflammatory processes in diabetes and pancreatitis as we find several host defense molecules expressed by the pancreatic tissue.

  • 32.
    Stenwall, Anton
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Seiron, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Lundberg, Marcus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Esguerra, Jonathan
    Volkov, Petr
    Renström, Eric
    Skog, Oskar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.
    Korsgren, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology.
    Transcriptional analysis of islets of Langerhans from organ donors of different ages2018In: Article in journal (Refereed)
    Abstract [en]

    Background: The incidence of type 2 diabetes increases with age because of impaired glucose homeostasis. In this study, we hypothesized that aging induces specific transcriptional changes in human islets.

    Results: Full transcriptome analysis of laser-captured islets from 26 deceased organ donors aged 1-81 years revealed 20 genes that co-varied significantly with age; SGIP1, HIST1H3E, UST, LAD1, RORB, SSTR5-AS1, LDHB, KCNJ15, TRABD2B, GLUL, MBPL1P, EFCAB4B, PHLDA3, MAFB, DGKB, TNFRSF10C, C1ORF16B, CDKN2A, MAT1A and ITGB4. However, principal component analysis and hierarchical clustering of the full transcriptomes showed no obvious separation of donors based on age, and the expression of genes in key pathways of beta-cell function, replication, and senescence were not significantly affected by aging.

    Conclusions: Our data from laser-captured islets confirm only partly the age-related differences reported from islets isolated by enzymatic digestion. The largely preserved transcriptomes and function of islets in elderly are surprising considering the enormous metabolic activity exerted by endocrine cells, and our data could be in line with a continuous renewal of islet cells.

  • 33.
    Wiberg, Anna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Granstam, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Ingvast, Sofie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Harkonen, T.
    Univ Helsinki, Childrens Hosp, Helsinki, Finland.;Univ Helsinki, Cent Hosp, Helsinki, Finland.;Univ Helsinki, Diabet & Obes Res Program, Helsinki, Finland..
    Knip, M.
    Univ Helsinki, Childrens Hosp, Helsinki, Finland.;Univ Helsinki, Cent Hosp, Helsinki, Finland.;Univ Helsinki, Diabet & Obes Res Program, Helsinki, Finland.;Folkkhalsan Res Ctr, Helsinki, Finland.;Tampere Univ Hosp, Dept Pediat, Tampere, Finland..
    Korsgren, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Skog, Oskar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Characterization of human organ donors testing positive for type 1 diabetes-associated autoantibodies2015In: Clinical and Experimental Immunology, ISSN 0009-9104, E-ISSN 1365-2249, Vol. 182, no 3, p. 278-288Article in journal (Refereed)
    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.

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