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Biomarkers of Infla...
Biomarkers of Inflammation and Intestinal Mucosa Pathology in Celiac Disease
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- Gustafsson Bragde, Hanna, 1979- (författare)
- Linköpings universitet,Institutionen för klinisk och experimentell medicin,Medicinska fakulteten,Laboratory Medicine, Region Jönköping County
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- Söderman, Jan, Docent (preses)
- Linköpings universitet,Institutionen för klinisk och experimentell medicin,Medicinska fakulteten,Laboratoriemedicin, Länssjukhuset Ryhov, Region Jönköpings län
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- Jansson, Ulf, MD (preses)
- Barnkliniken, Länssjukhuset Ryhov, Region Jönköpings län
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- Grodzinsky, Ewa, Docent, 1958- (preses)
- Linköpings universitet,Avdelningen för läkemedelsforskning,Medicinska fakulteten,Region Östergötland, Forsknings- och utvecklingsenheten för Närsjukvården i Östergötland
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- Fredrikson, Mats, 1957- (preses)
- Linköpings universitet,Avdelningen för neuro- och inflammationsvetenskap,Medicinska fakulteten
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- McManus, Ross, Professor (opponent)
- Department of Clinical Medicine, University of Dublin, Ireland; Trinity Translational Medicine Institute, University of Dublin, Ireland
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(creator_code:org_t)
- ISBN 9789176851050
- Linköping : Linköping University Electronic Press, 2019
- Engelska 71 s.
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Serie: Linköping University Medical Dissertations, 0345-0082 ; 1672
- Relaterad länk:
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https://doi.org/10.3...
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http://liu.diva-port...
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Abstract
Ämnesord
Stäng
- Celiac disease (CD) is a chronic small intestinal immune-mediated enteropathy triggered by gluten. The only currently available treatment is complying with a lifelong gluten-free diet, which should not be commenced before a CD diagnosis has been established by diagnostic test results (including histopathologic assessment of small intestinal biopsies and CD-specific antibody levels). This makes diagnostic swiftness and accuracy important. In cases with low CD-specific antibody levels and/or low-grade intestinal injuries the diagnosis can be difficult to establish. The main objective of this thesis was to complement and improve CD diagnostics by identifying and implementing new biomarkers, mainly based on gene expression, in small intestinal biopsies and blood. In paper I, genes were selected to reflect villous height, crypt elongation, immune response, and epithelial integrity. The results showed that a subset of those genes could discriminate active CD mucosa from mucosa without CD-related changes and grade the intestinal injury. In paper III, an unbiased investigation of gene expression in CD mucosa was performed using transcriptome analysis. Active CD and non-CD mucosa showed differential expression in a subset of genes, and some were differentially expressed in CD mucosa before histopathologic assessment could confirm intestinal alterations compatible with a CD diagnosis. Gene set analysis revealed that there are many biological processes affected in CD mucosa, including those associated with immune response, microbial infection, phagocytosis, intestinal barrier function, metabolism, and transportation.In parallel, gene expression was investigated in stabilised whole blood. Blood is a more accessible sampling material than intestinal biopsies, and stabilised blood is suitable for routine diagnostics since transcript levels are preserved at sampling. In paper II, expressions from a selection of genes were quantified in stabilised whole blood (RNA) and/or plasma (protein). Three genes with differential expression in CD were identified. Compared to the CD-specific autoantibodies against tissue transglutaminase (anti-TG2) alone, the addition of the information from the new potential markers resulted in a nonsignificant contribution to the diagnostic capacity of anti-TG2. An unbiased investigation using transcriptome analysis (paper IV) showed that gene level expression differences in stabilised whole blood were small between CD and non-CD. However, expression differences on a gene set level could potentially be used in CD diagnostics. CD-associated biological processes suggested by the results included a pro-inflammatory response, negative regulation of viral replication, proliferation, differentiation, cell migration, cell survival, translation, and haemostasis.Expression analysis using real-time polymerase chain reaction (PCR) is easy to perform, with instrumentation available at most clinical laboratories. Although select solitary biomarkers could be very useful in the diagnosis of CD, basing gene expression profiles on pathway information instead of single genes might also disclose disease heterogeneity between patients and add stability to a diagnostic method based on gene expressions. In conclusion, the results of this work demonstrate that analysing the expression of a few small intestinal genes can complement CD diagnostics. The application of gene expression analysis in cases with minor small intestine histopathological changes shows promising results, but needs further investigations. Additionally, gene expressions in other inflammatory diseases of the small intestine need to be investigated and compared with CD to complete the picture. Moreover, the findings from this work give clues about the biological contexts in which CD resides, and the potential of gene expression in blood at a gene set level is of interest for further investigations.
Ämnesord
- MEDICIN OCH HÄLSOVETENSKAP -- Medicinska och farmaceutiska grundvetenskaper -- Medicinsk genetik (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Basic Medicine -- Medical Genetics (hsv//eng)
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