Interferons in antiviral defense and autoimmunity : Focus on type 1 diabetes
Year: 2008
Type: dissertation
Abstract: Type 1 diabetes (T1D) is a disease characterized by the loss of insulin \nproducing beta-cells in the pancreatic islets of Langerhans. Interferons \n(IFNs), produced by immune cells and infected parenchymal cells, may be \nprotective or damaging in the pathogenesis of T1D. An intact beta-cell \nresponse to IFNs is critical for beta-cell survival and protection from \ndiabetes during a Coxsackievirus B (CVB) infection, a virus associated \nwith T1D in humans. It has also been suggested that IFNs may protect from \nnatural killer (NK) cell dependent destruction. Importantly, while being \nprotective during infection with CVB, the pancreatic beta-cell response \nto cytokines is crucial for the development of type 1 diabetes (T1D) in \nthe non-obese diabetic (NOD) mouse. NOD mice overexpressing the \nSuppressor of Cytokine Signaling 1 (SOCS-1) specifically in the \nbeta-cells are protected from spontaneous diabetes. The work in this \nthesis focuses on the mechanisms behind the protective and damaging \neffects of IFNs in the pathogenesis of T1D. Moreover, it identifies a \npossible source of IFNgamma during CVB infection. \n \n \n \nThis thesis shows that IFNs trigger an antiviral state in mouse and human \nislets. Both the RNase L and the dsRNA-dependent protein kinase (PKR) \npathways are induced by IFNs in mouse islets and play important roles in \nproviding unique and complementary antiviral activities that regulate the \noutcome of CVB infection. Moreover, this thesis shows that human islet \ncells also respond to IFNs by expressing signature genes of antiviral \ndefense. It further demonstrates that human islets express three \nintracellular sensors for viral RNA, the toll like receptor 3 (TLR3) \ngene, the retinoic acid-inducible gene I (RIG-I) and the melanoma \ndifferentiation-associated gene-5 (MDA-5), which contribute to the \nproduction of type I IFN in infected cells. These observations suggest \nthat human islet cells have the possibility to detect an invading virus \nand to produce type I IFNs during an infection. The work presented in \nthis thesis identifies the NK cell as a possible contributor of IFNgamma \nduring CVB infection: it shows that CVB interferes with the expression of \nNK cell receptor ligands on infected cells and that IFNgamma production, \nrather than cytotoxicity, marks the early human NK cell response to CVB \ninfection. Finally, this thesis gives new insights into how IFNs, by \nacting directly on beta-cells, contribute to disease development in the \nNOD mouse. It demonstrates that the beta-cell, by responding to \nthepro-inflammatory pancreas milieu, strongly influences the percentage \nof self-reactive CD8 T-cells in the pancreas. \n \n \n \nIn conclusion, this thesis supports the notion that cytokine-exposed \nislet cells affect islet infection and inflammation, highlighting an \nimportant role for the beta-cell in the local regulation of the \ndiabetogenic process. By providing a basic understanding for how \nbeta-cells respond to IFNs, and how this relates to their defense against \nCVB and to the accumulation of pathogenic cells in the pancreas, it may \ncontribute to a future unraveling of the mechanisms underlying beta-cell \nloss in T1D.
Source: Figshare
Author: Monica Hultcrantz
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: green
OpenAlex ID: W2099612659