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Characterization of host defense molecules in the human pancreas
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 Immunology, Genetics and Pathology, Clinical Immunology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology.ORCID iD: 0000-0001-9713-722X
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical Immunology. University of Gothenburg, Gothenburg, Sweden.ORCID iD: 0000-0002-8524-9547
2019 (English)In: Islets, ISSN 1938-2014, E-ISSN 1938-2022, Vol. 11, no 4, p. 89-101Article in journal (Refereed) Published
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.

Place, publisher, year, edition, pages
2019. Vol. 11, no 4, p. 89-101
Keywords [en]
Islet of Langerhans, beta cell, defensin, bacteria, diabetes, pancreas
National Category
Endocrinology and Diabetes Immunology in the medical area
Research subject
Biology with specialization in Molecular Immunology
Identifiers
URN: urn:nbn:se:uu:diva-358717DOI: 10.1080/19382014.2019.1585165ISI: 000475247700001PubMedID: 31242128OAI: oai:DiVA.org:uu-358717DiVA, id: diva2:1243312
Available from: 2018-08-30 Created: 2018-08-30 Last updated: 2019-08-19Bibliographically approved
In thesis
1. Transcriptional and morphological analysis of organ donor pancreata
Open this publication in new window or tab >>Transcriptional and morphological analysis of organ donor pancreata
2018 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The diabetes disease panorama affects more than 400 million people world wide – a number projected to rise above 640 million in the next 20 years. Type 1 and type 2 diabetes are associated with adverse complications, resulting in severe morbidity and high healthcare costs exerting substantial strain on society. Type 1 diabetes results from the destruction of the insulin producing beta-cells, while type 2 diabetes is a multifactorial combination of a decreased ability of the beta cells to secrete sufficient insulin and a peripheral resistance to insulin-mediated glucose uptake. The cause of diabetes is unknown, as are the possibly sequential cellular events resulting in overt disease. In this thesis, organ-donor pancreata from donors with or without diabetes are analysed in order to deepen our understanding of the Islets of Langerhans, the beta cells and the pancreas. 

In Paper I, islets from a donor that died at onset of type 1 diabetes, showing morphological signs of hydropic degeneration are analyzed on a gene-expression level, and the results are compared to islets from a donor without diabetes. We find no signs of ongoing inflammation, apoptosis or ER stress. In Paper IIwe compare the expression levels of genes related to cellular stress, in islets from donors with type 2 diabetes and from donors with high pre-mortal HbA1c levels but without a diabetes diagnosis, to the expression levels in islets from donors with normal HbA1c levels. We report that islets from donors with type 2 diabetes show signs of cellular stress on a transcriptional level compared with islets from donors without diabetes. In Paper III we performed a transcriptional analysis of the islets from organ donors aged between 1 and 81 years in order to elucidate whether age induces specific changes in the islet transcriptome. We found 20 genes that co-varied with increasing age. In Paper IV,the pancreatic expression of host-defense molecules is characterized, and we report the expression of several host-defense molecules not previously described in the human pancreas. Together, these results deepen our understanding of the effects of ageing and prolonged exposure to high blood sugar levels on the islets, as well as our knowledge about the innate immunity of the human pancreas. 

 

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2018. p. 50
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 1493
Keywords
Pancreas, Diabetes, Islet of Langerhans, Beta-cell, Immunology, Inflammation, Ageing
National Category
Immunology in the medical area
Research subject
Biology with specialization in Molecular Immunology
Identifiers
urn:nbn:se:uu:diva-358718 (URN)978-91-513-0430-4 (ISBN)
Public defence
2018-10-20, Sal X, Universitetshuset, Biskopsgatan 3, Uppsala, 09:36 (English)
Opponent
Supervisors
Available from: 2018-09-28 Created: 2018-08-30 Last updated: 2018-10-16

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Stenwall, AntonIngvast, SofieSkog, OskarKorsgren, Olle

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