| 1. |
- Lahdenperä, Anne, 1974-
(författare)
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Studies of Mucosal Immune Regulation in Celiac Disease and Type 1 Diabetes
- 2014
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background: Celiac disease (CD) and type 1 diabetes (T1D) are two chronic autoimmune diseases with increasing incidence worldwide. A combination of genetic, environmental and immunological factors is considered to be involved in development of the diseases, even though the exact disease mechanisms still are unknown. CD and T1D are both believed to be associated with type 1 like immune responses. However, there is limited knowledge about the complex network of intestinal and peripheral immune responses associated with the diseases.Aims: The aim of this thesis was to explore intestinal and peripheral immune responses in children at different stages of CD and in children with T1D. Further, we studied peripheral immune responses in children at risk for T1D supplemented with probiotics during their first 6 months of life (PRODIA study).Results & Discussion: Children with untreated CD had up-regulated T-helper (Th)1, T-cytotoxic (Tc)1, Th17 and T-regulatory (Treg) responses, but down-regulated Th2 and Th3 responses in the small intestine. The type 1 response (Th1 and Tc1) seemed to remain elevated in CD children under gluten free diet (GFD)-treatment and thus seemed to be related to the disease itself rather than the gluten intake. The Th2, Th3, Th17 and Treg responses seemed to be gluten dependent, since they normalized upon GFD-treatment. The alterations in the intestinal biopsies did not seem to correlate with the alterations seen in the blood Children with potential CD had diminished levels of the Th17 cytokine IL-17, whereas children with untreated CD had elevated levels of IL-17, indicating that IL-17 immunity develops in the late phase of CD when villous atrophy has developed. Furthermore, stimulation of intestinal epithelial cells with IL-17 induced anti-apoptotic mechanisms. The low intestinal expression of Th1, Th17 and Treg markers was normal in children with T1D, whereas children with T1D and CD had the same pattern as children with untreated CD: high intestinal secretion of pro-inflammatory and Th17 cytokines. The immune responses in children with T1D were generally influenced by the degree of villous atrophy.As expected, the number of children in the PRODIA study developing T1D related autoantibodies during their first two years of life was low. No difference in the autoantibody emergence was seen between infants given probiotics compared to placebo. In the probiotic group, the number of circulating CD58+ monocytes was lower at 6 months of age. At 12 months of age the number of circulating CCR5+ monocytes was lower in the probiotic group, whereas the spontaneous expression of TLR9 on PBMCs was higher.Conclusion: Most of the intestinal T-cell associated immune alterations were generally gluten dependent, since they normalized on a GFD treatment, but the type 1 response seemed to be related to the disease itself, since it was still seen in GFD treated individuals. IL-17 immunity seemed to be induced in the late stage of CD, when villous atrophy has developed and it seemed to be involved in protection from tissue damage in the inflamed intestinal mucosa. The intestinal immune responses were generally not reflected in peripheral blood.Probiotic supplementation in infancy modulated the activation stage and stimulation response of monocytes. Thus, early exposure to microbes seemed to influence the function of the innate immune system in later life.
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| 2. |
- Nygren, Maria, 1981-
(författare)
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Stress in childhood and the risk of type 1 diabetes
- 2015
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background: It is still unknown why children develop type 1 diabetes (T1D), although both genetic predisposition and environmental factors seems to be involved. Stress has been suggested as one environmental factor contributing to the development of T1D since the stress hormones may increase the need for insulin or increase insulin resistance. The family is important for the child’s emotional security, development, and regulation of emotions, hence stress among the parent’s may influence the child’s experiences of stress and coping with stressors.Aim: The aim of the current thesis was to evaluate self--‐assessment measurements of psychological stress in the family and to investigate if psychological stress in the family is involved in the development of childhood T1D.Methods: The All Babies in Southeast Sweden (ABIS) study is a prospective cohort study following children born in southeast Sweden between 1997 and 1999. All parents of children born in the region, approximately 21600 were asked to participate. In total, questionnaire data has been obtained from n=16142 (response rate approximately 75%) in some of the six data--‐collections and between 15845 (73%) and 4022 (19%) at each data collection. Psychological stress in the family was measured by questionnaires assessing: Serious life events experienced by the child and the parent, parenting stress, parental dissatisfaction, parental worries, the parent’s adult attachment, and the parents’ social support. Identification of cases with T1D was done through the national register SweDiabKids. At Dec the 31st 2012 had in total 104 (0,64%) children been diagnosed with T1D. Diabetes--‐cases included in the study samples was n=42 and n=58.Results: Parenting stress, parental worries, and size of social support were judged as reliable measurements assessing different aspects of psychological stress in the family, as well as they were all associated to children’s mental health in early adolescence. A serious life event experienced in childhood (measured by checklist at age 5--‐6, 8 and 10--‐ 14 years) was associated with an increase in risk for manifest T1D up to 13--‐15 years of age. None of the variables measuring psychological stress among parents were found to associate with risk of T1D.Conclusions: In addition to a checklist assessing serious life events experienced by the child is self--‐assessment measurements of parenting stress, parental worries and the parent’s social support be useful in large--‐scale studies as proxies for psychological stress of the child. The current study is the first unbiased prospective study that can confirm an association between the experience of a serious life event and increased risk of T1D. The result was independent of the child’s BMI and the parents’ educational level. Our results gives us strong reason to believe that psychological stress caused by serious life events can play a part in the immunological process leading to the onset of T1D.
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| 3. |
- Karlén, Jerker, 1971-
(författare)
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Early stress, cortisol in hair and health among children in different psychosocial environments
- 2014
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Psychosocial circumstances during early life are increasingly recognized as crucial, not only for the growing individual but also for health throughout life. A possible mechanism could be physiologic dysregulation due to stress. Cortisol in hair is a new biomarker that allows assessment of long-term activity of the hypothalamic-pituitary-adrenal axis.The objective of this thesis was to investigate the relationship between early stress, levels of cortisol in hair and health among children in different psycho-social environments.The ABIS-study is a prospective population-based cohort study of every child born in southeast Sweden between Oct 1 1997 and Oct 1 1999 (N=21,700) in which approximately 17,000 families (79%) participated. The studies presented in Papers I, III and IV were based on ABIS data on children aged 1, 3, 5 and 8 years concerning stress related psychosocial variables as well as hair samples and diabetes related autoantibodies. Papers I and IV compared a subsample (n=2,448) from two different social environments. Paper III consisted of a subsample of 100 children as well as their mothers. Paper II covered 99 university students.Paper I showed that the risk for diabetes-related autoantibodies, both against GADA and IAG2A (>95% cut off), was significantly higher (p<0.0001) among children from the blue-collar than from the white-collar city. This difference persisted still after adjustment for other previously documented risk factors. In paper II the method of measuring cortisol concentrations in hair was developed and mean cortisol levels were significantly related to serious life events (p=0.045) among the students. Paper III demonstrated that, in children from one to eight years of age, cortisol levels in hair decreased over time and correlated to each succeeding age, between years 1 and 3 (r=0.30,p=0.002), 3 and 5 (r=0.39, p=0.001), and 5 and 8 (r=0.44, p=0.001). Repeated measures gave a significant linear association over time (p=0.001). Maternal hair cortisol levels during the second and third trimester and child hair cortisol at year 1 and 3 was also significantly associated. Paper IV showed that children with prenatal psychosocial exposures had higher infant cortisol levels in hair (B=0.40, p<0.0001, adjusted for gender and size for gestational age) in a dose-response manner and were more often (p≤0.05) affected by 12 of the 14 most common childhood diagnoses with a general pattern of rising ORs.In conclusion, the findings in this thesis showed that children born into an environment fraught with adverse psychosocial exposures seem to have an increased hypothalamic-pituitary-adrenal axis activity. It appears to be persistent throughout early childhood and affect health negatively, as evidenced through common childhood diseases and levels of autoantibodies. A widespread and dose response-like effect of adverse psychosocial circumstances was seen on the different outcomes studied throughout this thesis. This supports the model of physiologic dysregulation as a plausible pathway in how the duration and number of early detrimental exposures act as a trajectory to health disparities. Knowledge of these relationships could be valuable in selecting preventive measures, not least in primary care. Moreover, given the prolonged nature of exposure to a stressful social environment, the novel biomarker of cortisol in hair appears to be a useful aid in studies on how long-term stress affects health and may be particularly relevant when applied to research on children.
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| 4. |
- Kindgren, Erik, 1977-
(författare)
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Early Life Environmental Risk Factors and Gut Microbiota in Juvenile Idiopathic Arthritis : - More than a gut feeling
- 2022
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background: The autoimmune disease juvenile idiopathic arthritis (JIA) is the most common rheumatic disease in children, but the cause is not fully established. Only a small percentage (13–18%) of the risk of contracting the disease can be attributed to genetic factors, but environmental factors are believed to be behind most of the risk. An unfavourable composition of gut bacteria has also been suggested as a factor that may increase the risk of developing JIA. Aims: The main aim of this thesis was to study risk factors during fetal life and in the early childhood environment for future onset of JIA. A further aim was to study the composition and importance of the gut microbiota before the onset of JIA. Methods: In the ABIS study, a population-based prospective birth cohort of 17,055 children, data were collected on environmental factors during pregnancy and childhood. We identified 111 individuals with a JIA diagnosis. Environmental factors were mainly analysed using multivariable logistic regression, with adjustment for confounding factors. The microbiome at one year of age was analysed from stool samples by 16S rRNA PCR. Results: Significant associations could be noted between mode of birth, duration of breastfeeding, birth order and exposure to antibiotics or fish early in life with future onset of JIA. These risk factors were found to pose an even higher cumulative risk if several of the factors were present. Carrying a risk allele in combination with being exposed to a specific environmental factor further increased the risk. In addition, several taxa were identified in the gut microbiota at one year that were associated with future onset of JIA. Many of these taxa were associated with one or more of the identified early childhood environmental risk factors. Conclusion: In these studies, it has been demonstrated that children with JIA have, very early in life, already been exposed to negative environmental factors (caesarean section, short-term breastfeeding, being firstborn and being exposed to antibiotics or fish during the first year of life). The effect from these risk factors appears to be to some extent mediated via a changed composition of the gut microbiota. An environmentally induced dysregulation of the microbiome can trigger or accelerate the development of JIA in genetically predisposed children.
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| 5. |
- Åkerman, Linda, 1983-
(författare)
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Aspects of the Pre-Diabetic Period in Type 1 Diabetes
- 2016
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Type 1 diabetes (T1D) is an autoimmune disease characterized by insulin deficiency, due to immune-mediated destruction of beta cells. Current knowledge regarding the period preceding disease onset comes, to a large extent, from studying risk cohorts based on relatives of T1D-patients, as they have an increased disease risk. Among T1D patients in general, however, few have the disease in their immediate family. It is therefore important to study risk cohorts from the general population as well. An ongoing autoimmune reaction can often be seen in the blood long before disease onset, by detection of autoantibodies directed towards beta cell antigens. By autoantibody screening among participants in the ABIS (All Babies in the South-east of Sweden) cohort, we could identify a group of children from the general population with increased risk for T1D, positive for multiple autoantibodies. They were enrolled in a 2-year prospective follow-up aiming to characterize the prediabetic period and to identify factors indicative of progression/non-progression to T1D. We assessed glucose homeostasis and autoantibody titers over time, and searched for risk-biomarkers by analyzing the expression of immune-related genes (Th1-Th2-Th3) in peripheral blood mononuclear cells (PBMC) from these children, in comparison to healthy children and newly diagnosed T1D patients. In the same groups we also compared serum micro RNA (miRNA) profiles, knowing that miRNA molecules have desirable biomarker properties. We found that two specific autoantibodies, IA2A and ZnT8A, were detected at higher concentrations in risk-individuals who progressed to overt T1D during or after the follow-up period, compared to those who still have not. We also observed disturbed glucose homeostasis long before onset in the progressors, but it was seen among those who remain symptom free as well. Further, we found support for the possible role of insulin resistance as an accelerator of the disease process. For gene expression and serum miRNA, few differences were observed between risk-individuals and healthy children overall. However, for PBMC gene expression and serum miRNA both, there were associations to beta cell function and glucose homeostasis, and for miRNA also to islet autoantibodies. Although specific profiles for prediction of disease onset or identification of risk-individuals could not be found, these results are interesting and deserve to be evaluated further. As part of another sub-study within ABIS, the effects of physical activity on glucose homeostasis were assessed in healthy schoolchildren. The level of physical activity, measured by pedometers, was related to insulin resistance and beta cell-stress, and decreased physical activity was associated with increased insulin resistance and load on the insulin-producing beta cells, already at school-age.
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