Typ 1 diabetes (T1D) är en kronisk autoimmun sjukdom där insulinproduktionen försämrats på grund av selektiv destruktion av de insulinproducerande β-cellerna i pankreas. Etiologin är komplicerad, incidensen är högre vintertid vilket tyder på inblandning av miljöfaktorer, men genetisk predisposition har en betydande roll. De gener som främst associerats med ökad risk finns på kromosom 6 i HLA-regionen och är viktiga för det adaptiva immunförsvaret. Ytterligare triggers hos genetiskt mottagliga individer är troligen virus. Autoimmunitet är ett misslyckande av kroppens immunförsvar när det gäller att tolerera egna antigen, möjliga mekanismer för virusinducerad autoimmunitet är bystander-aktivering och molekylär imitation. Coxsackievirus B (CVB), undergrupp till enterovirus (EV), antas vara förknippat med diabetes, då viruset selektivt förstör β-cellerna, ofta medierat av inflammation. Autoantikroppar (AAb) används som markörer för att tidigt upptäcka ökad risk för T1D. Många forskningsprojekt pågår, framför allt i Skandinavien, som driver kunskapsläget framåt. Syftet med detta arbete var att undersöka om EV-infektioner påverkar immunförsvaret till att angripa β-cellerna och om EV har betydelse för utvecklandet av AAb och T1D. Sökningar utfördes på Pubmed med sökord: ”enterovirus”, ”diabetes” och ”infection”. Fem artiklar valdes som visade EV-infektioners variation när det gäller delaktighet i T1D-progressionen. Resultatet visar att kronisk EV-infektion i mukosa kan spridas till pankreas och leda till inflammation med AAb-utveckling som följd och att EV-RNA förekommer i både endokrin och exokrin vävnad. Utöver det visades att CVB påverkar AAb-utveckling negativt och att långvariga låg-gradiga CVB-infektioner triggar förändringar på transkriptionsnivå som leder till autoimmunitet. Ett vaccin mot CVB skulle eventuellt kunna förhindra dessa förändringar och studier på NOD-möss visar möjligheter. T1D är en mycket heterogen sjukdom vilket är en utmaning för hela forskarkåren. Frågorna är fortfarande många, detta arbete har endast skrapat på ytan av det enorma fält som diabetesforskningen berör. Slutsatsen är att EV fungerar som en accelerator vid T1D-utveckling, men om T1D-utvecklingen underlättas i en inflammatorisk miljö, eller om EV orsakar inflammationen som leder till destruktion av β-celler gav detta arbete inte svar på. / Introduction: Type 1 diabetes (T1D) is a chronic autoimmune disease in which insulin production is completely or partially eliminated due to selective destruction of the insulin-producing β-cells in the pancreas. In Sweden, about 50,000 individuals live with T1D, of which 7,000 are children. There is a higher incidence during the winter, which suggests an involvement of environmental factors. The etiology is complicated, genetic predisposition has a decisive role, and genes that are mainly associated with increased risk are located on chromosome 6 in the HLA region which are important for the adaptive immune system. Other putative environmental factors have been studied with different results. Particular focus has been given to viruses, mainly enteroviruses (EVs), which are triggers of T1D in genetically susceptible individuals. The selective β-cell destruction is mostly mediated by inflammation and insulitis occurs close to T1D diagnosis (<1 year). Autoantibodies (AAb) are used as biomarkers for early detection of T1D. Autoimmunity is a failure of the immune system tolerance to self-antigens. Potential mechanisms for virus-induced autoimmunity are bystander activation and molecular mimicry. EV is a single-stranded RNA virus that has a specific tropism for pancreatic β cells: is cytolytic and kills the host cell. Coxsackievirus B (CVB) is a subgroup of EV that is considered to have association with diabetes. Many research projects are ongoing, especially in Scandinavia, possibly because a high T1D prevalence has created an interest that has driven research and the state of knowledge forward. Aim: This work investigates whether EV infections affects the immune system to attack β cells and what role this has for AAb and T1D development. Method: Literature search was performed in Pubmed with keywords: "enterovirus", "diabetes" and "infection". Five articles were selected that were relevant and showed variations of EV infections in terms of participation in T1D progression. Results: In summary, the studies show that chronic EV infection present in the mucosa can spread and lead to inflammation of the pancreas with AAb development as a result. One study showed that EV-RNA is not only found in endocrine tissue but also exocrine tissue. In addition, it was shown that CVB negatively affects AAb development and that persistent low-grade CVB infections trigger changes in the level of transcription that lead to autoimmunity. A vaccine against CVB might be able to prevent these changes as demonstrated by studies on NOD mice. T1D is a heterogeneous disease, which is a challenge for the entire research community. The questions remain and this work has only scratched the surface of the huge field of diabetes research. Conclusion: EV acts as an accelerator in T1D development, but the question whether T1D development is facilitated in an inflammatory environment, or whether EV itself causes the inflammation that leads to the destruction of β-cells, remains to be answered.

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My PhD dissertation reports my research investigations performed on bone loss projects. 2 projects are described in this thesis. One project dealing with the effect of adipogenic DKK1 on bone loss under normal and under a high-fat-diet (HFD). The 2nd projects aimed to investigate on the potential of miRNAs to be used as potential biomarkers to predict bone fragility in T1D.

Type 1 diabetes (T1D) is a chronic disease characterized by an autoimmune-mediated destruction of insulin-producing pancreatic beta cells. Environmental factors such as viruses play an important role in the onset of T1D and interact with predisposing genes. Recent data suggest that viral infection of human islets leads to a decrease in insulin production rather than beta cell death, suggesting loss of beta cell identity. We undertook this study to examine whether viral infection could induce human b cell dedifferentiation. Using the functional human b cell line EndoC-bH1, we demonstrate that polyinosinic-polycytidylic acid (PolyI:C), a synthetic double-stranded RNA that mimics a byproduct of viral replication, induces a decrease in beta cell–specific gene expression. In parallel with this loss, the expression of progenitor-like genes such as SOX9 was activated following PolyI:C treatment or enteroviral infection. SOX9 was induced by the NF-kB pathway and also in a paracrine non–cell-autonomous fashion through the secretion of IFN-a. Lastly, we identified SOX9 targets in human b cells as potentially new markers of dedifferentiation in T1D. These findings reveal that inflammatory signaling has clear implications in human beta cell dedifferentiation.

Type 1 diabetes (T1D) results from the destruction of pancreatic β-cells caused by an altered immune balance in the pancreatic microenvironment. In humans as well as in mouse models, T cells are well recognized as key orchestrators of T1D, which is characterized by T helper (Th) 1 and Th17 cell bias and/or low/defective T-regulatory cells (Treg), and culminates in cytotoxic T-cell (CTL)-mediated destruction of β-cells. Refitting of immune cells toward the non-inflammatory phenotype in the pancreas may represent a way to prevent/treat T1D. Recently we developed a unique spontaneous humanized mouse model of type 1 diabetes, wherein mouse MHC-II molecules were replaced by human DQ8, and β-cells were made to express human glutamic acid decarboxylase (GAD) 65 auto-antigen. The mice spontaneously developed T1D resembling the human disease. Humanized T1D mice showed hyperglycemic (250-300 mg/dl) symptoms by the 4th week of life. The diabetogenic T cells (CD4, CD8) present in our model are GAD65 antigen-specific in nature. Intermolecular antigen spreading recorded during 3rd-6th week of age is like that observed in the human preclinical period of T1D. In this paper, we tested our hypothesis in our spontaneous humanized T1D mouse model. We targeted two cell-signaling pathways and their inhibitions: eIF5A pathway inhibition influences T helper cell dynamics toward the non-inflammatory phenotype and Notch signaling inhibition enrich Tregs and targets auto-reactive CTLs, rescues the pancreatic islet structure, and increases the functionality of β-cells in terms of insulin production. We report that inhibition of (eIF5A + Notch) signaling mediates suppression of diabetogenic T cells by inducing plasticity in CD4 + T cells co-expressing IL-17 and IFNγ (IL-17 + IFNγ +) toward the Treg cells phenotype.

Diabetes is a growing chronic disease and a worldwide problem. Without any available cure in sight for the public other methods needs to be applied to increase the life quality of diabetic patients. Artificial Pancreas (AP), a concept of having a closed loop system to control the glucose level on Type 1 Diabetes (T1D) patients has been introduced and is under development. In this thesis, Model Predictive Control (MPC) has been re implemented from scratch in MATLAB/SIMULINK with associated Kalman filter and prediction function. It was implemented in the latest version of the UVA/Padova Simulator which is a tool approved by FDA for simulating diabetes treatment in order to speed up the AP development. Different MPC cost functions where tested together with integral action on a simplified system using a linear approximation of a population model. It was implemented and tuned with a new simulation tuning method using Genetic Algorithm (GA). It showed that the quadratic cost function without integral action was the best with respect to performance and time efficiency. 3 hours was the best prediction horizon and was used for the individualized tuning using the University of Virginia (UVA)/Padova simulator. For the individualized MPC, models identified by the University of Padova were used. These simulations showed that an individualized model could be used for improved T1D treatment compared to an average population model even though the results were mixed. Almost all of the patients got improved treatment with the closed treatment and non hypoglycemic event occurred. The identification of better models is a great challenge for the future development of the AP MPC due to the excitation problems.

Introduction: Recent findings about the pathogenesis of glaucoma have already demonstrated the presence of some specific autoimmune mechanisms. It has also been shown that autoimmune diseases often manifest in co-occurrence, such as celiac disease and type 1 diabetes mellitus or psoriasis. This association can be explained by sharing some of the risk variants of HLA molecules class II. Considering glaucoma an autoimmune disease, the question raises how the glaucoma genetic risk factors affect the phenotype of another autoimmune disease or vice versa, whether genetic risk variants associated for example with celiac disease can affect the glaucoma phenotype. Aims: The aims of this study were to i) identify possible genetic risk markers associated with the development of glaucoma, based on the available literature, and to map their occurrence among members of a three-generation family suffering from glaucoma and multiple autoimmune diseases, ii) find carriers of HLA-DQ2/DQ8 among the members of the same family, iii) verify whether an individual's genotype correlates with his/her phenotype, and iv) determine the potential effect of specific HLA alleles on the glaucoma phenotype. Material and methods: This study used DNA samples derived from 34 members of a three-generation family, in which coeliac...

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