Studies on Antigen-Presenting Cells in Type 1 Diabetes and Crohn's Disease - with Special Emphasis on Dendritic Cells
Year: 2013
Type: dissertation
Study design: Observational Study
Abstract: Type 1 diabetes (T1D) is considered an autoimmune disease wherein autoreactive infiltrate of immune cells destroys the insulin-producing pancreatic β cells. Crohn's disease (CD) is a chronic inflammatory bowel disease thought to result from an exaggerated immune response against the gut commensal microbiota. In this thesis, antigen-presenting cells (APCs), in particular dendritic cells (DCs), were investigated in these conditions. DCs play a central role in the induction of immunity by presenting antigens to T cells and licensing them to mount the immune response. Reduced numbers of both circulating myeloid (mDCs) and plasmacytoid DCs (pDCs) were found in children with recent-onset T1D. Decreased expression of C-C chemokine receptor 2 (CCR2) was also observed in children with T1D, which was confirmed in a separate series of children. In addition, DCs from children with signs of β-cell autoimmunity showed a trend towards an enhanced NF-κB reactivity. These alterations may have functional consequences on DC migration and DC-induced T-cell activation in T1D. T cells from T1D patients, on the other hand, showed elevated induction of IL-17, and the IL-17-producing cells corresponded to the typical Th17 phenotype. Furthermore, it was found that IL-17 has direct detrimental effects on pancreatic β cells in vitro. In CD, alterations in the expression and activation of STAT1, and in particular STAT3, have been described. As these molecules regulate DC function, it was hypothesized in this study that disturbed STAT3 and/or STAT1 signaling would also characterize DCs in CD patients. However, no universal alteration of cytokine-induced STAT3 or STAT1 phosphorylation was found in patients DCs. Instead, a pDC-restricted attenuation of IL-6/STAT3 signaling emerged, and the IFN-α-induced STAT1 and STAT3 signaling responses were decreased in both pDCs and mDCs. IL-6 treatment of healthy donor pDCs resulted in an upregulation of IL-10 in the cocultured naive CD4+ T cells and a decreased ratio of Th1 to Th2 cytokine signature. Hence, impaired IL-6/STAT3 signaling in CD patients pDCs may be connected to the well-established phenomena of enhanced IFN-γ responses and insufficient IL-10 activity in the CD-related inflammation. In addition, the attenuated IFN-α-induced responses may play a role in CD-associated immune dysregulation. pDCs and BDCA3+ mDCs were decreased in patients and counts negatively correlated with the endoscopic disease activity. This reduction may be pathophysiologically relevant, given the known homeostasis-promoting functions of these subsets. However, CD1c+ mDCs were more activated in terms of CD40 expression in CD. Last, a hypothesis was tested that the well-established enhanced IL-17 activation in CD would be supported by an exaggerated Th17 induction by DCs. However, an attenuated DC-supernatant-mediated upregulation of T cell IL-17A expression was found by LPS-stimulated monocyte-derived DCs from patients. In patients DCs, LPS-induced transcription of IL-1β and IL-6, together with autophagy-related LC3 mRNA upregulation, was also decreased. These results therefore reinforce the idea of an innate immune defect in CD. In conclusion, the findings from both T1D and CD in this thesis suggest dysregulated DC function as a part of the immunological background from which these diseases develop.
Source: Työväentutkimus Vuosikirja
Author: Janne Nieminen
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W2242247286