title: Functional characterization of human resident intestinal lamina propria dendritic cells under inflammatory conditions in health and disease
creator: Kurzhals, Stefan Ralf
subject: ddc-570
subject: 570 Life sciences
description: Inflammatory Bowel Diseases (IBD) are a group of intestinal disorders which are increasing in prevalence in industrialized countries. Dynamics of intestinal inflammatory disorders are manifold and investigation of coherences might help developing new therapeutic strategies harnessing the acquired knowledge. Keeping a homeostatic balance in the intestinal environment is vital for normal gut functions, regulating inflammatory and anti-inflammatory processes. Dendritic cells are known as key players in the regulation of intestinal homeostasis as they scavenge their surroundings for antigens followed by the induction of an adaptive immune response. The aim of this study was to investigate the functional properties of resident lamina propria myeloid dendritic cells (mLPDCs) in the shift from a homeostatic to an inflammatory milieu. Utilization of an organ culture model (LEL) made it possible to collect migratory lamina propria mDCs from an acute inflammatory environment. Gene expression analysis of LEL mDCs compared to peripheral blood DCs (PBDCs) revealed a variety of functions attributed to their environment and activation status. The LEL mDCs showed a gene expression profile which hinted at contribution to tissue remodeling and wound healing processes. Moreover, the majority of emigrated LEL mDCs could be attributed to the cDC2 fraction of DCs which exhibit mostly anti-inflammatory functionalities. Upregulation of the IL-12 family member mRNAs encoding for the protein subunits IL-23p19 and EBI3 was striking, hinting at the formation of the newly discovered heterodimeric cytokine IL-39. Both subunit proteins could be detected in LEL mDCs but not in PBDCs. Experiments using recombinant proteins confirmed IL-39 heterodimer formation in vitro as well as in cell culture experiments. However, technical difficulties prevented confirmation of heterodimer presence in primary human lamina propria mDCs. Scientific publications and initial experiments might hint at a possible contribution to wound healing processes related to IL-39 or its subunits.  A follow up experiment explored the gene expression profiles of mLPDCs from enzymatically digested IBD patients biopsies under inflammatory and non-inflammatory conditions as well as in healthy individuals. The extracted cells displayed a mixture of cDC1 and cDC2 cells with conserved functional properties across all samples including MHCII dependent antigen presentation and T cell regulatory processes amongst others. The gene expression analysis uncovered new aspects of mLPDCs including involvement in epithelial cell proliferation, humoral immunity and neuronal system development and signaling. Epithelial cell proliferation might contribute to wound healing properties of mLPDCs. Furthermore, the data hints at a mutual influence between mLPDCs and neuronal cells. Another striking observation was the detection of immunoglobulin related mRNAs hinting at yet unexplored functional properties of mLPDCs involving the expression of antibodies. Moreover, differential gene expression in mLPDCs varied for different IBD patient groups compared to healthy individuals.
date: 2021
type: Dissertation
type: info:eu-repo/semantics/doctoralThesis
type: NonPeerReviewed
format: application/pdf
identifier: https://archiv.ub.uni-heidelberg.de/volltextserverhttps://archiv.ub.uni-heidelberg.de/volltextserver/30686/1/PhD_Thesis_KURZHALS_UB_A1.pdf
identifier: DOI:10.11588/heidok.00030686
identifier: urn:nbn:de:bsz:16-heidok-306868
identifier:   Kurzhals, Stefan Ralf  (2021) Functional characterization of human resident intestinal lamina propria dendritic cells under inflammatory conditions in health and disease.  [Dissertation]     
relation: https://archiv.ub.uni-heidelberg.de/volltextserver/30686/
rights: info:eu-repo/semantics/openAccess
rights: http://archiv.ub.uni-heidelberg.de/volltextserver/help/license_urhg.html
language: eng