| 1. |
- Afonso, Georgia, et al.
(författare)
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Critical parameters in blood processing for T-cell assays: Validation on ELISpot and tetramer platforms
- 2010
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Ingår i: Journal of Immunological Methods. - : Elsevier BV. - 1872-7905 .- 0022-1759. ; 359:1-2, s. 28-36
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Tidskriftsartikel (refereegranskat)abstract
- Assays detecting antigen (Ag)-specific T-cell responses in immune-mediated processes are increasingly employed to understand disease pathogenesis and "immune staging". The quantity and quality of starting peripheral blood mononuclear cell (PBMC) preparations are important factors in the performance of such assays. We therefore compared final PBMC yield and function by modifying parameters at the blood drawing, storage and processing steps. While drawing blood in vacuum-driven tubes or syringes and separating PBMCs on density gradients using standard or membrane (Leucosep (R)) tubes made no difference, storing tubes for 18 h without any agitation led to PBMC preparations contaminated with granulocytes and decreased interferon (IFN)-gamma enzyme-linked immunospot (ELISpot) responses. Even agitated blood showed a trend towards reduced ELISpot responses and increased human leukocyte Ag (HLA) multimer readouts when stored for 18 h compared to 3 h. These changes were reduced by diluting blood prior to storage. Washing PBMCs with media containing 10% human serum increased PBMC yields by 40.5%, without affecting ELISpot responses and multimer counts. However, washes with >10% human serum decreased multimer counts, with no additional improvement in PBMC yields. These findings may be relevant for optimizing and harmonizing PBMC processing procedures for T-cell assays. (C) 2010 Elsevier B.V. All rights reserved.
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| 2. |
- Agardh, Carl-David, et al.
(författare)
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Clinical evidence for the safety of GAD65 immunomodulation in adult-onset autoimmune diabetes.
- 2005
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Ingår i: Journal of Diabetes and its Complications. - : Elsevier BV. - 1873-460X .- 1056-8727. ; 19:4, s. 238-246
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Tidskriftsartikel (refereegranskat)abstract
- The purpose of this Phase II study was to evaluate if alum-formulated human recombinant GAD65 is safe and does not compromise beta cell function. The study was conducted as a randomized, double blind, placebo-controlled, dose-escalation clinical trial in a total of 47 Latent Autoimmune Diabetes in Adults (LADA) patients who received either placebo or 4, 20, 100, or 500 μg Diamyd subcutaneously at Weeks 1 and 4. Safety evaluations, including neurology, beta cell function tests, diabetes status assessment, hematology, biochemistry, and cellular and humoral immunological markers, were repeatedly assessed over 24 weeks. None of the patients had significant study-related adverse events (AE). Fasting c-peptide levels at 24 weeks were increased compared with placebo (P=.0015) in the 20 μg but not in the other dose groups. In addition, both fasting (P=.0081) and stimulated (P=.0236) c-peptide levels increased from baseline to 24 weeks in the 20 μg dose group. GADA log levels clearly increased (P=.0002) in response to 500 μg Diamyd. The CD4+CD25+/CD4+CD25− cell ratio increased (P=.0128) at 24 weeks in the 20 μg group. No sudden increase in HbA1c or plasma glucose or decrease in beta cell function was observed in any of the dose groups. These positive findings for clinical safety further support the clinical development of Diamyd as a therapeutic to prevent autoimmune diabetes.
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| 3. |
- Andersson, Cecilia K, et al.
(författare)
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Glucose tolerance and beta-cell function in islet autoantibody-positive children recruited to a secondary prevention study.
- 2013
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Ingår i: Pediatric Diabetes. - : Hindawi Limited. - 1399-543X .- 1399-5448. ; 14:5, s. 341-349
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Tidskriftsartikel (refereegranskat)abstract
- AIMS: Children with type 1 diabetes (T1D) risk and islet autoantibodies are recruited to a secondary prevention study. The aims were to determine metabolic control in relation to human leukocyte antigen (HLA) genetic risk and islet autoantibodies in prepubertal children. METHODS: In 47 healthy children with GADA and at least one additional islet autoantibody, intravenous glucose tolerance test (IvGTT) and oral glucose tolerance test (OGTT) were performed 8-65 d apart. Hemoglobin A1c, plasma glucose as well as serum insulin and C-peptide were determined at fasting and during IvGTT and OGTT. RESULTS: All children aged median 5.1 (4.0-9.2) yr had autoantibodies to two to six of the beta-cell antigens GAD65, insulin, IA-2, and the three amino acid position 325 variants of the ZnT8 transporter. In total, 20/47 children showed impaired glucose metabolism. Decreased (≤30 μU/mL insulin) first-phase insulin response (FPIR) was found in 14/20 children while 11/20 had impaired glucose tolerance in the OGTT. Five children had both impaired glucose tolerance and FPIR ≤30 μU/mL insulin. Number and levels of autoantibodies were not associated with glucose metabolism, except for an increased frequency (p = 0.03) and level (p = 0.01) of ZnT8QA in children with impaired glucose metabolism. Among the children with impaired glucose metabolism, 13/20 had HLA-DQ2/8, compared to 9/27 of the children with normal glucose metabolism (p = 0.03). CONCLUSION: Secondary prevention studies in children with islet autoantibodies are complicated by variability in baseline glucose metabolism. Evaluation of metabolic control with both IvGTT and OGTT is critical and should be taken into account before randomization. All currently available autoantibody tests should be analyzed, including ZnT8QA.
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| 4. |
- Barchetta, Ilaria, et al.
(författare)
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Epigenetic changes induced by maternal factors during fetal life : Implication for type 1 diabetes
- 2021
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Ingår i: Genes. - : MDPI AG. - 2073-4425. ; 12:6
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Forskningsöversikt (refereegranskat)abstract
- Organ-specific autoimmune diseases, such as type 1 diabetes, are believed to result from T-cell-mediated damage of the target tissue. The immune-mediated tissue injury, in turn, is known to depend on complex interactions between genetic and environmental factors. Nevertheless, the mechanisms whereby environmental factors contribute to the pathogenesis of autoimmune diseases remain elusive and represent a major untapped target to develop novel strategies for disease prevention. Given the impact of the early environment on the developing immune system, epigenetic changes induced by maternal factors during fetal life have been linked to a likelihood of developing an autoimmune disease later in life. In humans, DNA methylation is the epigenetic mechanism most extensively investigated. This review provides an overview of the critical role of DNA methylation changes induced by prenatal maternal conditions contributing to the increased risk of immune-mediated diseases on the offspring, with a particular focus on T1D. A deeper understanding of epigenetic alterations induced by environmental stressors during fetal life may be pivotal for developing targeted prevention strategies of type 1 diabetes by modifying the maternal environment.
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| 5. |
- Behnan, Jinan, et al.
(författare)
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Recruited brain tumor-derived mesenchymal stem cells contribute to brain tumor progression.
- 2014
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Ingår i: Stem Cells. - : Oxford University Press (OUP). - 1549-4918 .- 1066-5099. ; 32:5, s. 1110-1123
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Tidskriftsartikel (refereegranskat)abstract
- The identity of the cells that contribute to brain tumor structure and progression remains unclear. Mesenchymal stem cells (MSCs) have recently been isolated from normal mouse brain. Here, we report the infiltration of MSC-like cells into the GL261 murine glioma model. These Brain Tumor derived Mesenchymal Stem Cells (BT-MSCs) are defined with the phenotype (Lin-Sca-1+CD9+CD44+CD166+/-) and have multipotent differentiation capacity. We show that the infiltration of BT-MSCs correlates to tumor progression; furthermore, BT-MSCs increased the proliferation rate of GL261 cells in vitro. For the first time, we report that the majority of GL261 cells expressed mesenchymal phenotype under both adherent and sphere culture conditions in vitro, and that the non-MSC population is non-tumorigenic in vivo. Although the GL261 cell line expressed mesenchymal phenotype markers in vitro, most BT-MSCs are recruited cells from host origin in both wild type GL261 inoculated into GFP-transgenic mice and GL261-GFP cells inoculated into wild type mice. We show the expression of chemokine receptors CXCR4 and CXCR6 on different recruited cell populations. In vivo, the GL261 cells change marker profile, and acquire a phenotype that is more similar to cells growing in sphere culture conditions. Finally, we identify a BT-MSC population in human glioblastoma that is CD44+CD9+CD166+ both in freshly isolated and culture-expanded cells. Our data indicate that cells with MSC-like phenotype infiltrate into the tumor stroma and play an important role in tumor cell growth in vitro and in vivo. Thus we suggest that targeting BT-MSCs could be a possible strategy for treating glioblastoma patients. Stem Cells 2013.
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| 6. |
- Bekris, L. M., et al.
(författare)
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GAD65 autoantibody epitopes in adult patients with latent autoimmune diabetes following GAD65 vaccination
- 2007
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Ingår i: Diabetic Medicine. - : Wiley. - 1464-5491 .- 0742-3071. ; 24:5, s. 521-526
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Tidskriftsartikel (refereegranskat)abstract
- Aims Subcutaneous injection of recombinant human GAD65 (rhGAD65) in patients with latent autoimmune diabetes in adults (LADA) correlates with an increase in C-peptide levels. In this study we analysed the effect of rhGAD65 administration on the GAD65-specific autoimmune response. Methods Longitudinal serum samples obtained from LADA patients (n = 47) who received 4, 20, 100 or 500 mu g alum-formulated rhGAD65 or placebo by subcutaneous injection twice (4 weeks apart) were analysed for their epitope recognition using GAD65-specific recombinant Fab and GAD65/67 fusion proteins. Results Overall, minor changes in the epitope pattern were observed using either approach. Only in the 500-mu g dosage group was an increase in GAD65Ab level associated with a significant increase in the binding to a conformational epitope located at the middle part of GAD65. Conclusions Our data suggest that the apparent beneficial effects of 20 mu g alum-formulated recombinant human GAD65 is not explained by changes in the GAD65Ab epitope pattern.
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| 7. |
- Bergman, Marie-Louise, et al.
(författare)
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CTLA-4-/- mice display T cell-apoptosis resistance resembling that ascribed to autoimmune-prone non-obese diabetic (NOD) mice
- 2001
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Ingår i: Journal of Autoimmunity. - : Elsevier. - 0896-8411 .- 1095-9157. ; 16:2, s. 105-113
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Tidskriftsartikel (refereegranskat)abstract
- The genes conferring susceptibility to autoimmune (insulin-dependent) diabetes mellitus (IDDM) are, in most cases, not defined. Among the loci so far identified as associated with murine IDDM (Idd1-19), only the nature of Idd1 has been assessed. Here we show that thymocytes and peripheral lymphocytes of the non-obese diabetic (NOD) mouse are relatively resistant to apoptosis induced by gamma-irradiation. By linkage analysis of F2 progeny mice, we map this trait to a locus on chromosome 1 containing the Idd5 diabetes susceptibility region. By the use of congenic mice, we confirm the linkage data and map this locus to a 6 cM region on proximal chromosome 1. Ctla4, being localized in this chromosomal region and mediating crucial functions in T cell biology, is a logical candidate gene in the Idd5 susceptibility region. In line with this, we demonstrate that T cells from Ctla4(-/-)deficient mice show a similar resistance to gamma-irradiation-induced apoptosis as observed in the NOD mice. This reinforces the notion that CTLA-4 contributes to the pathogenesis of autoimmune diabetes.
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| 8. |
- Beyan, Huriya, et al.
(författare)
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Guthrie card methylomics identifies temporally stable epialleles that are present at birth in humans
- 2012
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Ingår i: Genome Research. - : Cold Spring Harbor Laboratory. - 1549-5469 .- 1088-9051. ; 22:11, s. 2138-2145
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Tidskriftsartikel (refereegranskat)abstract
- A major concern in common disease epigenomics is distinguishing causal from consequential epigenetic variation. One means of addressing this issue is to identify the temporal origins of epigenetic variants via longitudinal analyses. However, prospective birth-cohort studies are expensive and time consuming. Here, we report DNA methylomics of archived Guthrie cards for the retrospective longitudinal analyses of in-utero-derived DNA methylation variation. We first validate two methodologies for generating comprehensive DNA methylomes from Guthrie cards. Then, using an integrated epigenomic/genomic analysis of Guthrie cards and follow-up samplings, we identify interindividual DNA methylation variation that is present both at birth and 3 yr later. These findings suggest that disease-relevant epigenetic variation could be detected at birth, i.e., before overt clinical disease. Guthrie card methylomics offers a potentially powerful and cost-effective strategy for studying the dynamics of interindividual epigenomic variation in a range of common human diseases.
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| 9. |
- Bolmeson, Caroline, et al.
(författare)
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Differences in islet-enriched miRNAs in healthy and glucose intolerant human subjects.
- 2011
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Ingår i: Biochemical and Biophysical Research Communications. - : Elsevier BV. - 1090-2104 .- 0006-291X. ; Dec, s. 16-22
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Tidskriftsartikel (refereegranskat)abstract
- Many microRNAs (miRNAs) are known to be cell-type specific and are implicated in development of diseases. We investigated the global expression pattern of miRNAs in human pancreatic islets compared to liver and skeletal muscle, using bead-based technology and quantitative RT-PCR. In addition to the known islet-specific miR-375, we also found enrichment of miR-127-3p, miR-184, miR-195 and miR-493∗ in the pancreatic islets. The expression of miR-375, miR-127-3p, miR-184 and the liver-enriched miR-122 were positively correlated to insulin biosynthesis, while the expression of miR-127-3p and miR-184 were negatively correlated to glucose-stimulated insulin secretion (GSIS). These correlations were absent in islets of glucose intolerant donors (HbA1c⩾6.1). We suggest the presence of an islet-specific miRNA network, which consists of at least miR-375, miR-127-3p and miR-184, potentially involved in insulin secretion. Our results provide new insight into miRNA-mediated regulation of insulin secretion in healthy and glucose intolerant subjects.
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| 10. |
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| 11. |
- Brooks-Worrell, B., et al.
(författare)
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Comparison of cryopreservation methods on T-cell responses to islet and control antigens from type 1 diabetic patients and controls
- 2011
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Ingår i: Diabetes/Metabolism Research & Reviews. - : Wiley. - 1520-7552. ; 27:8, s. 737-745
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Tidskriftsartikel (refereegranskat)abstract
- Background Type 1 diabetes (T1D) is a cell-mediated autoimmune disease characterized by destruction of the pancreatic islet cells. The use of cryopreserved cells is preferable to the use of freshly isolated cells to monitor clinical trials to decrease assay and laboratory variability. Methods The T-Cell Workshop Committee of the Immunology of Diabetes Society compared two widely accepted T-cell freezing protocols (warm and cold) to freshly isolated peripheral blood mononuclear cells from patients with T1D and controls in terms of recovery, viability, cell subset composition, and performance in functional assays currently in use in T1D-related research. Nine laboratories participated in the study with four different functional assays included. Results The cold freezing method yielded higher recovery and viability compared with the warm freezing method. Irrespective of freezing protocol, B cells and CD8+ T cells were enriched, monocyte fraction decreased, and islet antigen-reactive responses were lower in frozen versus fresh cells. However, these results need to take in to account that the overall response to islet autoantigens was low in some assays. Conclusions In the current study, none of the tested T-cell functional assays performed well using frozen samples. More research is required to identify a freezing method and a T-cell functional assay that will produce responses in patients with T1D comparable to responses using fresh peripheral blood mononuclear cells. Copyright (C) 2011 John Wiley & Sons, Ltd.
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| 12. |
- Carlsén, Maria, et al.
(författare)
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Evidence for De Novo Expression of Thymic Insulin by Peripheral Bone Marrow-derived Cells.
- 2008
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Ingår i: Scandinavian Journal of Immunology. - : Wiley. - 1365-3083 .- 0300-9475. ; 68, s. 67-74
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Tidskriftsartikel (refereegranskat)abstract
- Thymic expression of insulin has been suggested to play a major role in negative selection of autoreactive T cells and tolerance induction against pancreatic beta cells. Furthermore, the expression of insulin in peripheral antigen-presenting cells (APC) has been clearly demonstrated but whether thymic negative selection and tolerance induction also depends on peripheral influx of self-antigens (Ag) remains to be conclusively demonstrated. In this study, we wanted to test whether peripheral influx of insulin expressing cells might contribute to negative selection. In order to address this question, we used mice deficient in the Ins1 and Ins2 genes. Embryonic thymi either deficient in both insulin genes or expressing Ins2 were dissected and transplanted under the kidney capsule of athymic nude mice recipients. After indicated time points, grafted thymi were removed and analysed for insulin re-expression and for the emergence of autoreactive T cells. The analysis revealed a re-expression of Ins2 in grafted insulin deficient thymi suggesting that self-Ag expression in the thymus is not only intrinsically regulated but peripheral influx of APC capable of expressing insulin might contribute to thymic selection and tolerance induction.
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| 13. |
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| 14. |
- Cervin, Camilla, et al.
(författare)
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Characterization of a naturally occurring mutation (L107I) in the HNF1 alpha (MODY3) gene.
- 2002
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Ingår i: Diabetologia. - : Springer Science and Business Media LLC. - 1432-0428 .- 0012-186X. ; 45:12, s. 1703-1708
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Tidskriftsartikel (refereegranskat)abstract
- AIMS/HYPOTHESIS: Maturity onset diabetes of the young type 3 (MODY3) is a monogenic form of diabetes mellitus caused by mutations in the gene encoding for hepatocyte nuclear factor 1 alpha, HNF1 alpha. In this study we have examined the in vivo and in vitro effects of a mutation (L107I) outside the DNA binding and dimerization domains in the N terminal part of the HNF1 alpha gene. METHODS: Beta-cell function of the affected family members was assessed by an oral glucose tolerance test. Functional tests were carried out to explain the role of the mutation in vitro by transcriptional activity assay, Western blotting, DNA-binding assays and subcellular localization experiments. RESULTS: Affected family members showed an 86% decreased insulin response to glucose when compared to age-matched healthy control subjects. In vitro the mutation showed a 79% decrease in transcriptional activity as compared to wild type HNF1 alpha in HeLa cells lacking HNF1 alpha. The transcriptional activity was not suppressed when the mutant was co-expressed with wild type HNF1 alpha suggesting that the decreased activity was not mediated by a dominant negative mechanism. The L107I/HNF1alpha protein showed normal nuclear targeting but impaired binding to an HNF1 alpha consensus sequence. CONCLUSION/INTERPRETATION: Our results suggest that the L107I substitution represents a MODY3 mutation which impairs beta-cell function by a loss-of-function mechanism.
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| 15. |
- Cervin, Camilla, et al.
(författare)
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Cosegregation of MIDD and MODY in a Pedigree: Functional and Clinical Consequences.
- 2004
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Ingår i: Diabetes. - : American Diabetes Association. - 1939-327X .- 0012-1797. ; 53:7, s. 1894-1899
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Tidskriftsartikel (refereegranskat)abstract
- The aim of this study was characterization of a family carrying two mutations known to cause monogenic forms of diabetes, the M626K mutation in the HNF1α gene (MODY3) and the A3243G in mtDNA. β-Cell function and insulin sensitivity were assessed with the Botnia clamp. Heteroplasmy of the A3243G mutation and variants in type 2 diabetes susceptibility genes were determined, and transcriptional activity, DNA binding, and subcellular localization of mutated HNF1α were studied. Thirteen family members carried the mutation in mtDNA; 6 of them also had the M626K mutation, whereas none had only the M626K mutation. The protective Ala12 allele in peroxisome proliferator–activated receptor (PPAR)γ was present in two nondiabetic individuals. Carriers of both mtDNA and HNF1α mutations showed an earlier age at onset of diabetes than carriers of only the mtDNA mutation (median 22 vs. 45 years) but no clear difference in β-cell function or insulin sensitivity. In vitro, the M626K mutation caused a 53% decrease in transcriptional activity in HeLa cells. The mutated protein showed normal nuclear targeting but increased DNA binding. These data demonstrate that several genetic factors might contribute to diabetes risk, even in families with mtDNA and HNF1α mutations.
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| 16. |
- Cervin, Camilla, et al.
(författare)
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Genetic similarities between latent autoimmune diabetes in adults, type 1 diabetes, and type 2 diabetes
- 2008
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Ingår i: Diabetes. - : American Diabetes Association. - 1939-327X .- 0012-1797. ; 57:5, s. 1433-1437
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE-Latent autoimmune diabetes in adults (LADA) is often considered a slowly progressing subtype of type 1 diabetes, although the clinical picture more resembles type 2 diabetes. One way to improve classification is to study whether LADA shares genetic features with type 1 and/or type 2 diabetes. RESEARCH DESIGN AND METHODS-To accomplish this we studied whether LADA shares variation in the HLA locus or INS VNTR and PTPN22 genes with type I diabetes or the TCF7L2 gene with type 2 diabetes in 361 LADA, 718 type 1 diabetic, and 1,676 type 2 diabetic patients, as well as 1,704 healthy control subjects from Sweden and Finland. RESULTS-LADA subjects showed, compared with type 2 diabetic patients, increased frequency of risk for the HLA-DQB1 *0201/*0302 genotype (27 vs. 6.9%; P < 1 X 10(-6)), with similar frequency as with type I diabetes (36%). In addition, LADA subjects showed higher frequencies of protective HLA-DQB1 *0602(3)/X than type I diabetic patients (8.1 vs. 3.2%, P = 0.003). The AA genotype of rs689, referring to the class I allele in the INS VNTR, as well as the CT/TT genotypes of rs2476601 in the PTPN22 gene, were increased both in type 1 diabetic (P = 3 X 10(-14) and P = 1 X 10(-10), respectively) and LADA (P = 0.001 and P = 0.002) subjects compared with control subjects. Notably, the frequency of the type 2 diabetes-associated CT/TT genotypes of rs7903146 in the TCF7L2 were increased in LADA subjects (52.8%; P = 0.03), to the same extent as in type 2 diabetic subjects (54.1%, P = 3 X 10(-7)), compared with control subjects (44.8%) and type I diabetic subjects (43.39%). CONCLUSIONS-LADA shares genetic features with both type I (HLA, INS VNTR, and PTPN22) and type 2 (TCF7L2) diabetes, which justifies considering LADA as an admixture of the two major types of diabetes.
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| 17. |
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| 18. |
- Colucci, Francesco, et al.
(författare)
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Apoptosis resistance of nonobese diabetic peripheral lymphocytes linked to the Idd5 diabetes susceptibility region
- 1997
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : National Academy of Sciences. - 0027-8424 .- 1091-6490. ; 94:16, s. 8670-8674
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Tidskriftsartikel (refereegranskat)abstract
- Defects in lymphocyte apoptosis may lead to autoimmune disorders and contribute to the pathogenesis of type 1 diabetes. Lymphocytes of nonobese diabetic (NOD) mice, an animal model of autoimmune diabetes, have been found resistant to various apoptosis signals, including the alkylating drug cyclophosphamide. Using an F2 intercross between the apoptosis-resistant NOD mouse and the apoptosis-susceptible C57BL/6 mouse, we define a major locus controlling the apoptosis-resistance phenotype and demonstrate its linkage (logarithm of odds score = 3.9) to a group of medial markers on chromosome 1. The newly defined gene cannot be dissociated from Ctla4 and Cd28 and in fact marks a 20-centimorgan region encompassing Idd5, a previously postulated diabetes susceptibility locus. Interestingly, we find that the CTLA-4 (cytotoxic T lymphocyte-associated antigen 4) and the CD28 costimulatory molecules are defectively expressed in NOD mice, suggesting that one or both of these molecules may be involved in the control of apoptosis resistance and, in turn, in diabetes susceptibility.
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| 19. |
- Colucci, Francesco, et al.
(författare)
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Induction of diabetes in NOD‹–›C57BL/6 embryo aggregation chimeras by cyclophosphamide through preferential depletion of C57BL/6 lymphocytes
- 1996
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Ingår i: Journal of Autoimmunity. - : Elsevier. - 0896-8411 .- 1095-9157. ; 9:4, s. 493-499
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Tidskriftsartikel (refereegranskat)abstract
- The majority of embryo aggregation (EA) mouse chimeras between non-obese diabetic (NOD) mice and C57BL/6 (B6) mice show clear signs of insulitis frequently accompanied by beta-cell destruction. Less than 5% of these chimeras, however, spontaneously progress to autoimmune diabetes, an incidence far lower than observed in NOD mice. The resistance in chimeras can be accounted for by the target organ chimerism and/or the immune system chimerism. To investigate the mechanism(s) controlling diabetes resistance in these mice, we studied a total of 92 NOD<-->B6 EA chimeras that showed overt lymphoid chimerism and treated 34 chimeras with cyclophosphamide (CY), a compound known to precipitate an acute form of insulin-dependent diabetes mellitus (IDDM) in pre-diabetic NOD mice, by interfering with regulatory mechanisms. We found that CY-treated EA chimeras displayed an increase in the NOD:B6 lymphocyte ratio and 32% of them developed diabetes that could be adoptively transferred to irradiated NOD or NOD-rag-2-/- mice. These findings suggest that lymphocyte chimerism rather than beta-cell chimerism accounts for diabetes resistance in NOD<-->B6 EA chimeras and that the susceptibility to CY-induced diabetes may be related to the proportion of NOD versus B6 lymphoid cells.
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| 20. |
- Colucci, Francesco, et al.
(författare)
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Programmed cell death in the pathogenesis of murine IDDM : resistance to apoptosis induced in lymphocytes by cyclophosphamide
- 1996
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Ingår i: Journal of Autoimmunity. - : Elsevier. - 0896-8411 .- 1095-9157. ; 9:2, s. 271-276
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Tidskriftsartikel (refereegranskat)abstract
- The non-obese diabetic (NOD) mouse displays several immune related defects, each of which could potentially contribute to the immunopathogenesis of diabetes that spontaneously develops in these mice. The reported resistance of NOD-lymphocytes to several apoptosis-inducing signals constitutes one such factor. Apoptosis plays a key role in the homeostasis of the immune system, as a means of selecting lymphocyte repertoires both in primary lymphoid organs and in the periphery; distortions in the apoptotic machinery may therefore be hypothesized to be implicated in the pathogenesis of autoimmune disorders. We now report that cyclophosphamide constitutes an apoptosis signal to peripheral lymphocytes and we provide evidence that NOD B cells as well as both CD4 and CD8 T cells display resistance to cyclophosphamide-induced apoptosis. These observations support the notion that apoptosis resistance in NOD mice exists at various levels, and suggest that the CY-sensitive lymphoid population, believed to play an important role in inhibiting the disease in diabetes resistant NOD mice (particularly males), may be controlled by mechanisms that are mediated by apoptosis.
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| 21. |
- Colucci, Francesco, et al.
(författare)
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Taming killer cells may halt diabetes progression
- 2010
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Ingår i: Nature Immunology. - : Springer Science and Business Media LLC. - 1529-2908 .- 1529-2916. ; 11:2, s. 111-112
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Preclinical studies in mice suggest that the natural killer cell receptor NKp46 may be a new molecular target for delaying the progression of type 1 diabetes by interfering with unexpected natural killer cell-mediated recognition of pancreatic beta cells.
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| 22. |
- Elsmén, Emma, et al.
(författare)
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Umbilical Cord Levels of Interleukin-1 Receptor Antagonist and Neonatal Outcome.
- 2006
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Ingår i: Biology of the Neonate. - : S. Karger AG. - 1421-9727. ; 89:4, s. 220-226
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Tidskriftsartikel (refereegranskat)abstract
- Background: Previous studies indicate that there may be infant gender differences in cytokine expression associated with differences in neonatal morbidity. Objective: We tested the hypothesis that umbilical cord interleukin-1 receptor antagonist (IL-1ra) correlates with infant gender and neonatal outcome in preterm infants. Study Design: IL-1ra was measured in cord blood taken from 58 preterm infants (33 males, 25 females) with gestational age less than 32 weeks. Receiver operating characteristics (ROC) curve were used for identifying IL-1ra values with high sensitivity and specificity for neonatal morbidity and adverse outcome, i.e., death or survival with severe intraventricular hemorrhage or periventricular leukomalacia. Results: In the female infants, but not the male infants, cord IL-1ra values correlated with postnatal depression, expressed as Apgar scores at 1 min (correlation coefficient, r(s); p value: -0.542; 0.005), 5 min (-0.571; 0.018), and 10 min (-0.442; 0.035); and postnatal age at intubation (-0.799; 0.001). The ROC area under the curve (AUC) was 0.735 for adverse outcome (p = 0.013), and 0.683 for bronchopulmonary dysplasia (p = 0.021) when all infants were included. However, there was a significant gender difference in the ROC curve for adverse outcome (p = 0.026), with AUC 0.640 (p = 0.240) in males and AUC 0.929 (p = 0.008) in females. Above a chosen cutoff at 13,500 ng/I for IL-1ra cord the sensitivity and specificity for predicting adverse outcome was 100 and 81%, respectively in females versus 50 and 84% in males. Conclusion: Increased levels of cord IL-1ra levels are associated with neonatal morbidity and adverse outcome in preterm infants. Comparable levels of IL-1ra have different predictive value depending on infant gender. Copyright (c) 2006 S. Karger AG, Basel.
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| 23. |
- Esguerra, Jonathan, et al.
(författare)
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Differential Glucose-Regulation of MicroRNAs in Pancreatic Islets of Non-Obese Type 2 Diabetes Model Goto-Kakizaki Rat.
- 2011
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Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 6:4
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Tidskriftsartikel (refereegranskat)abstract
- The Goto-Kakizaki (GK) rat is a well-studied non-obese spontaneous type 2 diabetes (T2D) animal model characterized by impaired glucose-stimulated insulin secretion (GSIS) in the pancreatic beta cells. MicroRNAs (miRNAs) are short regulatory RNAs involved in many fundamental biological processes. We aim to identify miRNAs that are differentially-expressed in the pancreatic islets of the GK rats and investigate both their short- and long term glucose-dependence during glucose-stimulatory conditions.
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| 24. |
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| 25. |
- Fadista, Joao, et al.
(författare)
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Global genomic and transcriptomic analysis of human pancreatic islets reveals novel genes influencing glucose metabolism.
- 2014
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Ingår i: Proceedings of the National Academy of Sciences. - : Proceedings of the National Academy of Sciences. - 1091-6490 .- 0027-8424. ; 111:38, s. 13924-13929
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Tidskriftsartikel (refereegranskat)abstract
- Genetic variation can modulate gene expression, and thereby phenotypic variation and susceptibility to complex diseases such as type 2 diabetes (T2D). Here we harnessed the potential of DNA and RNA sequencing in human pancreatic islets from 89 deceased donors to identify genes of potential importance in the pathogenesis of T2D. We present a catalog of genetic variants regulating gene expression (eQTL) and exon use (sQTL), including many long noncoding RNAs, which are enriched in known T2D-associated loci. Of 35 eQTL genes, whose expression differed between normoglycemic and hyperglycemic individuals, siRNA of tetraspanin 33 (TSPAN33), 5'-nucleotidase, ecto (NT5E), transmembrane emp24 protein transport domain containing 6 (TMED6), and p21 protein activated kinase 7 (PAK7) in INS1 cells resulted in reduced glucose-stimulated insulin secretion. In addition, we provide a genome-wide catalog of allelic expression imbalance, which is also enriched in known T2D-associated loci. Notably, allelic imbalance in paternally expressed gene 3 (PEG3) was associated with its promoter methylation and T2D status. Finally, RNA editing events were less common in islets than previously suggested in other tissues. Taken together, this study provides new insights into the complexity of gene regulation in human pancreatic islets and better understanding of how genetic variation can influence glucose metabolism.
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| 26. |
- Galgani, Mario, et al.
(författare)
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Meta-Immunological Profiling of Children With Type 1 Diabetes Identifies New Biomarkers to Monitor Disease Progression
- 2013
-
Ingår i: Diabetes. - : American Diabetes Association. - 1939-327X .- 0012-1797. ; 62:7, s. 2481-2491
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Tidskriftsartikel (refereegranskat)abstract
- Type 1 diabetes is characterized by autoimmurte destruction of pancreatic beta-cells in genetically susceptible individuals. Triggers of islet autoimmunity, time course, and the precise mechanisms responsible for the progressive beta-cell failure are not completely understood. The recent escalation of obesity in affluent countries has been suggested to contribute to the increased incidence of type 1 diabetes. Understanding the link between metabolism and immune tolerance could lead to the identification of new markers for the monitoring of disease onset and progression. We studied several immune cell subsets and factors with high metabolic impact as markers associated with disease progression in high-risk subjects and type 1 diabetic patients at onset and at 12 and 24 months after diagnosis. A multiple correlation matrix among different parameters was evaluated statistically and assessed visually on two-dimensional graphs. Markers to predict residual beta-cell function up to 1 year after diagnosis were identified in multivariate logistic regression models. The meta-immunological profile changed significantly over time in patients, and a specific signature that was associated with worsening disease was identified. A multivariate logistic regression model measuring age, BMI, fasting C-peptide, number of circulating CD3(+)CD16(+)CD56(+) cells, and the percentage of CD1c(+)CD19(-)CD14(-)CD303(-) type 1 myeloid dendritic cells at disease onset had a significant predictive value. The identification of a specific meta-immunological profile associated with disease status may contribute to our understanding of the basis of diabetes progression.
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| 27. |
- Hafsteinsdottir, Solveig, et al.
(författare)
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Suspected infections in children treated for ALL
- 2009
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Ingår i: Acta Pædiatrica. - : Wiley. - 1651-2227 .- 0803-5253. ; 98:7, s. 1149-1155
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Tidskriftsartikel (refereegranskat)abstract
- The aim of our study was to get epidemiological information on bacterial infections in children treated for ALL and to analyse which patients have an enhanced infection risk. Episodes of suspected or confirmed infections were evaluated during the first 12 months of treatment for childhood acute lymphoblastic leukaemia (ALL). The number of patients was 73 (43 boys). The median age was 4.6 years. A total of 179 episodes occurred, varying from none in six patients to eight in one. Bacteria were cultured in 57 episodes (31.8%), the most common being coagulase-negative staphylococci. The number of episodes fell significantly with increasing age for suspected and confirmed infections (p < 0.001 and p = 0.03). The proportion of confirmed infections was significantly higher (p < 0.001) in the first episodes. The average number of suspected infections was higher in girls than in boys (p = 0.03), but confirmed infections were not. Most of the serious infections occur early in the treatment and the number of suspected and confirmed infections falls with age. Suspicion of infection is more likely in girls, but the number of confirmed infections is equal in both sexes. Coagulase-negative staphylococcus was most commonly isolated, highlighting the importance of careful handling of central venous devices.
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| 28. |
- Haghighi, Mona, et al.
(författare)
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A Comparison of Rule-based Analysis with Regression Methods in Understanding the Risk Factors for Study Withdrawal in a Pediatric Study
- 2016
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 6
-
Tidskriftsartikel (refereegranskat)abstract
- Regression models are extensively used in many epidemiological studies to understand the linkage between specific outcomes of interest and their risk factors. However, regression models in general examine the average effects of the risk factors and ignore subgroups with different risk profiles. As a result, interventions are often geared towards the average member of the population, without consideration of the special health needs of different subgroups within the population. This paper demonstrates the value of using rule-based analysis methods that can identify subgroups with heterogeneous risk profiles in a population without imposing assumptions on the subgroups or method. The rules define the risk pattern of subsets of individuals by not only considering the interactions between the risk factors but also their ranges. We compared the rule-based analysis results with the results from a logistic regression model in The Environmental Determinants of Diabetes in the Young (TEDDY) study. Both methods detected a similar suite of risk factors, but the rule-based analysis was superior at detecting multiple interactions between the risk factors that characterize the subgroups. A further investigation of the particular characteristics of each subgroup may detect the special health needs of the subgroup and lead to tailored interventions.
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| 29. |
- Hillörn, Valter, et al.
(författare)
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Aberrant VHGene Utilization in Patients with Established Insulin-Dependent Diabetes Mellitus
- 1997
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Ingår i: Journal of Autoimmunity. - : Elsevier BV. - 0896-8411 .- 1095-9157. ; 10:2, s. 157-163
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Tidskriftsartikel (refereegranskat)abstract
- We have compared the B-lymphocyte repertoire in seven IDDM patients with 12 healthy controls by examining the variable heavy (VH) gene expression. The VHgene representation in the pool of pokeweed mitogen (PWM) stimulated, immunocompetent B cells and in the pool of naturally activated plasma cells (actual repertoire) was analysed by RNA-RNA in situ hybridization. Differences between IDDM patients and normal controls in the relative expression of several VHgene families were observed. In IDDM patients, the VH3 was significantly underrepresented in the PWM stimulated repertoire. In the actual B cell repertoire the VH5 clones were underrepresented among diabetic patients. Moreover, the altered distribution of VHgene usage between the PWM stimulated repertoire and the actual repertoire observed in normal controls was found to be less pronounced in the IDDM patients. This observation suggests a defect in the V-gene directed cellular selection occurring between resting, immunocompetent B cells and naturally activated plasma cells. The possible implication of the observed aberrations in the B cell selection process for the pathogenesis of autoimmunity is discussed.
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| 30. |
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| 31. |
- Holmkvist, Johan, et al.
(författare)
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Common variants in HNF-1 alpha and risk of type 2 diabetes.
- 2006
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Ingår i: Diabetologia. - : Springer Science and Business Media LLC. - 1432-0428 .- 0012-186X. ; 49:Oct 11, s. 2882-2891
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Tidskriftsartikel (refereegranskat)abstract
- Mutations in the hepatocyte nuclear factor 1-alpha gene (HNF-1 alpha, now known as the transcription factor 1 gene [TCF1]) cause the most common monogenic form of diabetes, MODY3, but it is not known if common variants in HNF-1a are associated with decreased transcriptional activity or phenotypes related to type 2 diabetes, or whether they predict future type 2 diabetes. We studied the effect of four common polymorphisms (rs1920792, I27L, A98V and S487N) in and upstream of the HNF-1 alpha gene on transcriptional activity in vitro, and their possible association with type 2 diabetes and insulin secretion in vivo. Certain combinations of the I27L and A98V polymorphisms in the HNF-1 alpha gene showed decreased transcriptional activity on the target promoters glucose transporter 2 (now known as solute carrier family 2 [facilitated glucose transporter], member 2) and albumin in both HeLa and INS-1 cells. In vivo, these polymorphisms were associated with a modest but significant impairment in insulin secretion in response to oral glucose. Insulin secretion deteriorated over time in individuals carrying the V allele of the A98V polymorphism (n=2,293; p=0.003). In a new case-control (=1,511 and n=2,225 respectively) data set, the I27L polymorphism was associated with increased risk of type 2 diabetes, odds ratio (OR)=1.5 (p=0.002; multiple logistic regression), particularly in elderly (age > 60 years) and overweight (BMI > 25 kg/m(2)) patients (OR=2.3, p=0.002). This study provides in vitro and in vivo evidence that common variants in the MODY3 gene, HNF-1 alpha, influence transcriptional activity and insulin secretion in vivo. These variants are associated with a modestly increased risk of late-onset type 2 diabetes in subsets of elderly overweight individuals.
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| 32. |
- Håkansson, Åsa, et al.
(författare)
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Immunological alteration and changes of gut microbiota after dextran sulfate sodium (DSS) administration in mice
- 2015
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Ingår i: Clinical and Experimental Medicine. - : Springer Science and Business Media LLC. - 1591-9528. ; 15:1, s. 107-120
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Tidskriftsartikel (refereegranskat)abstract
- Ulcerative colitis (UC) is characterized bychronic inflammation of the colonic mucosa. Administrationof dextran sulfate sodium (DSS) to animals is a frequentlyused model to mimic human colitis. Deregulationof the immune response to the enteric microflora orpathogens as well as increased intestinal permeability havebeen proposed as disease-driving mechanisms. To enlargethe understanding of the pathogenesis, we have studied theeffect of DSS on the immune system and gut microbiota inmice. Intestinal inflammation was verified through histologicalevaluation and myeloperoxidase activity. Immunologicalchanges were assessed by flow cytometry inspleen, Peyer0s patches and mesenteric lymph nodes andthrough multiplex cytokine profiling. In addition, quantificationof the total amount of bacteria on colonic mucosaas well as the total amount of lactobacilli, Akkermansia,Desulfovibrio and Enterobacteriaceae was performed bythe use of quantitative PCR. Diversity and communitystructure were analysed by terminal restriction fragmentlength polymorphism (T-RFLP) patterns, and principalcomponent analysis was utilized on immunological andT-RFLP patterns. DSS-induced colitis show clinical andhistological similarities to UC. The composition of thecolonic microflora was profoundly changed and correlatedwith several alterations of the immune system. The resultsdemonstrate a relationship between multiple immunologicalchanges and alterations of the gut microbiota after DSSadministration. These data highlight and improve the definitionof the immunological basis of the disease andsuggest a role for dysregulation of the gut microbiota in thepathogenesis of colitis.
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| 33. |
- Johnson, Randi K., et al.
(författare)
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Metabolite-related dietary patterns and the development of islet autoimmunity
- 2019
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 9:1
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Tidskriftsartikel (refereegranskat)abstract
- The role of diet in type 1 diabetes development is poorly understood. Metabolites, which reflect dietary response, may help elucidate this role. We explored metabolomics and lipidomics differences between 352 cases of islet autoimmunity (IA) and controls in the TEDDY (The Environmental Determinants of Diabetes in the Young) study. We created dietary patterns reflecting pre-IA metabolite differences between groups and examined their association with IA. Secondary outcomes included IA cases positive for multiple autoantibodies (mAb+). The association of 853 plasma metabolites with outcomes was tested at seroconversion to IA, just prior to seroconversion, and during infancy. Key compounds in enriched metabolite sets were used to create dietary patterns reflecting metabolite composition, which were then tested for association with outcomes in the nested case-control subset and the full TEDDY cohort. Unsaturated phosphatidylcholines, sphingomyelins, phosphatidylethanolamines, glucosylceramides, and phospholipid ethers in infancy were inversely associated with mAb+ risk, while dicarboxylic acids were associated with an increased risk. An infancy dietary pattern representing higher levels of unsaturated phosphatidylcholines and phospholipid ethers, and lower sphingomyelins was protective for mAb+ in the nested case-control study only. Characterization of this high-risk infant metabolomics profile may help shape the future of early diagnosis or prevention efforts. © 2019, The Author(s).
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| 34. |
- Jonson, Carl-Oscar, et al.
(författare)
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Regulatory T-cell associated activity in Photopheresis-induced Immune tolerance in Recent Onset Type 1 Diabetes Children
- 2008
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Ingår i: Clinical and Experimental Immunology. - : Oxford University Press (OUP). - 0009-9104 .- 1365-2249. ; 153:2, s. 174-181
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Tidskriftsartikel (refereegranskat)abstract
- Extracorporeal photochemotherapy (ECP) has demonstrated immunological effects. The proposed cytotoxic lymphocyte antigen 4 (CTLA-4) involvement, together with forkhead box P3 (FoxP3) and transforming growth factor (TGF)-β are associated with regulatory T cell activity. The aim of the study was to evaluate the regulatory T cell-associated effect of ECP in recent onset type 1 diabetic (T1D) children. Children (n = 20) with T1D received photopheresis 8-methoxypsoralen + ECP or placebo + shampheresis. Peripheral blood mononuclear cells (PBMC) collected pretreatment (day 1) and post-treatment (day 90) were stimulated with phytohaemagglutinin (PHA) and T1D-associated glutamic acid decarboxylase 65 (GAD65) peptide a.a. 247–279. CTLA-4, sCTLA-4, FoxP3 and TGF-β mRNA transcription was quantified. Photopheresis-treated individuals' relative mRNA expression was generally maintained during the course of the study. Placebo individuals increased in spontaneous CTLA-4 mRNA (P < 0·05) but decreased in expression after stimulation with GAD65-peptide (P < 0·05) and PHA (P < 0·05). Spontaneous TGF-β (P < 0·05) increased whereas PHA- (P < 0·01) and GAD65-peptide (P < 0·01)-induced TGF-β expression decreased in the placebo group, whereas it was maintained in the treated group. Without intervention, expression of CTLA-4 and TGF-β, stimulated with PHA and GAD65 peptide, decreased with time, with a parallel reduction of GAD65-peptide and PHA-stimulated TGF-β expression. These parameters were counteracted by ECP. In conclusion, our results indicate that ECP maintains regulatory T cell-associated activity in recent-onset T1D.
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| 35. |
- Kalis, Martins, et al.
(författare)
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Beta-cell specific deletion of dicer1 leads to defective insulin secretion and diabetes mellitus
- 2011
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Ingår i: PLOS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 6:12, s. e29166-
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Tidskriftsartikel (refereegranskat)abstract
- Mature microRNAs (miRNAs), derived through cleavage of pre-miRNAs by the Dicer1 enzyme, regulate protein expression in many cell-types including cells in the pancreatic islets of Langerhans. To investigate the importance of miRNAs in mouse insulin secreting beta-cells, we have generated mice with a beta-cells specific disruption of the Dicer1 gene using the Cre-lox system controlled by the rat insulin promoter (RIP). In contrast to their normoglycaemic control littermates (RIP-Cre(+/-) Dicer1(Delta/wt)), RIP-Cre(+/-) Dicer1(flox/flox) mice (RIP-Cre Dicer1(Delta/Delta)) developed progressive hyperglycaemia and full-blown diabetes mellitus in adulthood that recapitulated the natural history of the spontaneous disease in mice. Reduced insulin gene expression and concomitant reduced insulin secretion preceded the hyperglycaemic state and diabetes development. Immunohistochemical, flow cytometric and ultrastructural analyses revealed altered islet morphology, marked decreased beta-cell mass, reduced numbers of granules within the beta-cells and reduced granule docking in adult RIP-Cre Dicer1(Delta/Delta) mice. beta-cell specific Dicer1 deletion did not appear to disrupt fetal and neonatal beta-cell development as 2-week old RIP-Cre Dicer1(Delta/Delta) mice showed ultrastructurally normal beta-cells and intact insulin secretion. In conclusion, we have demonstrated that a beta-cell specific disruption of the miRNAs network, although allowing for apparently normal beta-cell development, leads to progressive impairment of insulin secretion, glucose homeostasis and diabetes development.
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| 36. |
- Kalis, Martins, et al.
(författare)
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Variants in the FFAR1 Gene Are Associated with Beta Cell Function
- 2007
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Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 2:11
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: The FFAR1 receptor is expressed mainly in pancreatic beta cells and is activated by medium to long chain free fatty acids (FFAs), as well as by thiazolidinediones, resulting in elevated Ca(2+) concentrations and promotion of insulin secretion. These properties suggest that FFAR1 could be a mediator of lipotoxicity and a potential candidate gene for Type 2 diabetes (T2D). We therefore investigated whether variations at the FFAR1 locus are associated with T2D and beta cell function. METHODOLOGY/PRINCIPAL FINDINGS: We re-sequenced the FFAR1 region in 96 subjects (48 healthy and 48 T2D individuals) and found 13 single nucleotide polymorphisms (SNPs) 8 of which were not previously described. Two SNPs located in the upstream region of the FFAR1 gene (rs1978013 and rs1978014) were chosen and genotyped in 1929 patients with T2D and 1405 healthy control subjects. We observed an association of rs1978013 and rs1978014 with insulinogenic index in males (p = 0.024) and females (p = 0.032), respectively. After Bonferroni corrections, no association with T2D was found in the case-control material, however a haplotype consisting of the T-G alleles conferred protection against T2D (p = 0.0010). CONCLUSIONS/SIGNIFICANCE: Variation in the FFAR1 gene may contribute to impaired beta cell function in T2D.
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| 37. |
- Kalis, Martins, et al.
(författare)
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α 1-antitrypsin enhances insulin secretion and prevents cytokine-mediated apoptosis in pancreatic β-cells.
- 2010
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Ingår i: Islets. - : Informa UK Limited. - 1938-2022 .- 1938-2014. ; 2:3, s. 185-189
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Tidskriftsartikel (refereegranskat)abstract
- α1-antitrypsin (AAT) is a serine protease inhibitor, which recently has been shown to prevent type 1 diabetes (T1D) development, to prolong islet allograft survival and to inhibit β-cell apoptosis in vivo. It has also been reported that T1D patients have significantly lower plasma concentrations of AAT suggesting the potential role of AAT in the pathogenesis of T1D. We have investigated whether plasma-purified AAT can affect β-cell function in vitro. INS-1E cells or primary rat pancreatic islets were used to study the effect of AAT on insulin secretion after glucose, glucagon-like peptide-1 (GLP-1) and forskolin stimulation and on cytokine-mediated apoptosis. The secreted insulin and total cyclic AMP (cAMP) were determined using radioimmunoassay and apoptosis was evaluated by propidium iodide staining followed by FACS analysis. We found that AAT increases insulin secretion in a glucose-dependent manner, potentiates the effect of GLP-1 and forskolin and neutralizes the inhibitory effect of clonidine on insulin secretion. The effect of AAT on insulin secretion was accompanied by an increase in cAMP levels. In addition, AAT protected INS-1E cells from cytokine-induced apoptosis. Our findings show that AAT stimulates insulin secretion and protects β-cells against cytokine-induced apoptosis, and these effects of AAT seem to be mediated through the cAMP pathway. In view of these novel findings we suggest that AAT may represent a novel anti-inflammatory compound to protect β-cells under the immunological attack in T1D but also therapeutic strategy to potentiate insulin secretion in type 2 diabetes (T2D).
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| 38. |
- Karlsson, Caroline, et al.
(författare)
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The pioneer gut microbiota in human neonates vaginally born at term - a pilot study.
- 2011
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Ingår i: Pediatric Research. - 1530-0447. ; 70:3, s. 282-286
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Tidskriftsartikel (refereegranskat)abstract
- The pioneer microbiota of the neonate may affect future actions of the immune system. This study aimed to map the pioneer microbiota in healthy neonates vaginally born at term. A subgroup of neonates born large for gestational age (LGA) was compared with the neonates appropriate for gestational age (AGA). Fecal samples were collected, within 48 hours after birth, from 79 neonates. Quantitative polymerase chain reaction was used for enumeration of Lactobacillus, a subgroup of Lactobacillus common in the vagina, Bifidobacterium, Enterococcus, Enterobacteriaceae and the Bacteroides fragilis group. Cloning and sequencing were applied for subgroups of neonates born LGA or AGA. Lactobacillus was detected in all neonates while other bacterial groups were detected only in 14-30% of the subjects. The prevalence of Gram-negative Proteobacteria was higher in neonates born LGA while Gram-positive Firmicutes was more prevalent in neonates born AGA (P<.001). This study contributed to increased knowledge of the pioneer microbiota and indicates that neonates born LGA had significantly different microbiota compare to those born AGA. As the early microbiota can be important for maturation of the immune system, the outcome from this study may be relevant in the care of pregnant woman and newborns. LIST OF ABBREVIATIONS::
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| 39. |
- Kiotseridis, Hampus, et al.
(författare)
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Grass pollen allergy in children and adolescents-symptoms, health related quality of life and the value of pollen prognosis
- 2013
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Ingår i: Clinical and Transnational Allergy. - 2045-7022. ; 3:19
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Tidskriftsartikel (refereegranskat)abstract
- Abstract Introduction An association between pollen count (Poaceae) and symptoms is well known, but to a lesser degree the importance of priming and lag effects. Also, threshold levels for changes in symptom severity need to be validated. The present study aims to investigate the relationship between pollen counts, symptoms and health related quality of life (HRQL), and to validate thresholds levels, useful in public pollen warnings. Material and methods Children aged 7–18 with grass pollen allergy filled out a symptom diary during the pollen season for nose, eyes and lung symptoms, as well as a HRQL questionnaire every week. Pollen counts were monitored using a volumetric spore trap. Results 89 (91%) of the included 98 children completed the study. There was a clear association between pollen count, symptom severity and HRQL during the whole pollen season, but no difference in this respect between early and late pollen season. There was a lag effect of 1–3 days after pollen exposure except for lung symptoms. We found only two threshold levels, at 30 and 80 pollen grains/m3 for the total symptom score, not three as is used today. The nose and eyes reacted to low doses, but for the lung symptoms, symptom strength did hardly change until 50 pollen grains/m3. Conclusion Grass pollen has an effect on symptoms and HRQL, lasting up to 5 days after exposure. Symptoms from the lungs appear to have higher threshold levels than the eyes and the nose. Overall symptom severity does not appear to change during the course of season. Threshold levels need to be revised. We suggest a traffic light model for public pollen warnings directed to children, where green signifies “no problem”, yellow signifies “can be problems, especially if you are highly sensitive” and red signifies “alert – take action”.
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| 40. |
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| 41. |
- Kiotseridis, Hampus, et al.
(författare)
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Quality of life in children and adolescents with respiratory allergy, assessed with a generic and disease-specific instrument
- 2013
-
Ingår i: Clinical Respiratory Journal. - 1752-6981. ; 7:2, s. 168-175
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: Respiratory allergic disorders like rhinitis and asthma are common conditions that not only affect target organs, but complicate the daily life of affected children and adolescents. Objectives: The aim of this study was to investigate the QoL (quality of life) in children with grass pollen allergy in and out of grass pollen season. Methods: We used the Pediatric Allergic Disease Quality of Life Questionnaire (PADQLQ), a disease-specific questionnaire including both asthma and rhinitis symptoms. We also used the DISABKIDS (a European project which aims at enhancing the quality of life and the independence of children with chronic health conditions and their families) questionnaire, a generic questionnaire covering non-organ-specific effects of disease. Results: Ninety-eight children 718 years old with grass pollen allergy were included. Eighty-nine children (91%) completed the study. The QoL was significantly decreased during pollen season assessed both with DISABKIDS and PADQLQ. The correlation between the questionnaires was 0.73. Not only the physical domain score (P=0.00093) but also the emotional domain score (P=0.034) was significantly lowered. Children with multiple manifestations (asthma and rhinitis) had lower QoL than children with rhinitis alone (P=0.01). Multiple regression analysis showed a highly significant impact on QoL for symptoms from nose, eyes and lungs. They were equally important (standardized coefficient 047, 0.47 and 0.46, respectively). Conclusion: The QoL in children and adolescents with respiratory allergy deteriorates during pollen season. This was shown both with generic (DISABKIDS) and disease-specific instrument (PADQLQ). Please cite this paper as: Kiotseridis H, Cilio CM, Bjermer L, Aurivillius M, Jacobsson H, Dahl angstrom and Tunsater A. Quality of life in children and adolescents with respiratory allergy, assessed with a generic and disease-specific instrument. Clin Respir J 2013; 7: 168175.
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| 42. |
- Kiotseridis, Hampus, et al.
(författare)
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Swedish Translation and Validation of the Pediatric Allergic Disease Quality of Life Questionnaire (PADQLQ).
- 2011
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Ingår i: Acta paediatrica. - : Wiley. - 1651-2227 .- 0803-5253. ; 100, s. 242-247
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Tidskriftsartikel (refereegranskat)abstract
- Aim: The aim of the study was to translate and validate the PADQLQ (Pediatric allergic disease quality of life questionnaire), a disease specific quality of life questionnaire for the assessment of quality of life in children with pollen allergy. Methods: The PADQLQ was translated into Swedish according to guidelines. Children 7-18 years with grass pollen allergy were included. Quality of life was assessed in parallel with ordinary symptom scales (VAS) before, during and after the pollen season. Results: 98 children were included. 89 (91%) completed the study. The Results for PADQLQ showed good cross-sectional and longitudinal validity. The retrospective estimation after the season showed good consensus with the assessment during pollen season. Conclusion: Quality of life in children assessed with the PADQLQ (Pediatric allergic disease quality of life questionnaire), is a reliable strategy for evaluating the burden of disease in children with pollen allergy and for the evaluation of treatment.
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| 43. |
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| 44. |
- Larsson, K, et al.
(författare)
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Genetic and perinatal factors as risk for childhood type 1 diabetes
- 2004
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Ingår i: Diabetes/Metabolism Research & Reviews. - : Wiley. - 1520-7552. ; 20:6, s. 429-437
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Forskningsöversikt (refereegranskat)abstract
- The mechanisms by which gestational infections, blood incompatibility, birth weight, mother's age and other prenatal or neonatal events increase the risk for type 1 diabetes are not understood. Studies so far have been retrospective, and there is a lack of population-based prospective studies. The possibility identifying children at type 1 diabetes risk among first-degree relatives has resulted in prospective studies aimed at identifying postnatal events associated with the appearance of autoantibody markers for type 1 diabetes and a possible later onset of diabetes. However, the majority (85%) of new onset type 1 diabetes children do not have a first-degree relative with the disease. Population-based studies are therefore designed to prospectively analyse pregnant mothers and their offspring. One such study is DiPiS (Diabetes Prediction in Skane), which is examining a total of about 10 000 pregnancies expected every year in the Skane (Scania) region of Sweden that has 1.1 million inhabitants. Blood samples from all mothers in this region are obtained during pregnancy and at the time of delivery. Cord blood is analysed for HLA high-risk alleles and for autoantibodies against the 65 kD isoform of glutamic acid decarboxylase (GADA), the protein tyrosine phosphatase-related IA-2 antigen (IA-2A) and insulin (IAA) as a measure of prenatal autoimmune exposure. Identifying high-risk children by genetic, autoimmune and gestational risk factors followed by prospective analyses will make it possible to test the hypothesis that gestational events may trigger beta cell autoimmunity as a prerequisite for childhood type 1 diabetes. Copyright (C) 2004 John Wiley Sons, Ltd.
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| 45. |
- Levéen, Per, et al.
(författare)
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Induced disruption of the transforming growth factor beta type II receptor gene in mice causes a lethal inflammatory disorder that is transplantable.
- 2002
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Ingår i: Blood. - 1528-0020. ; 100:2, s. 560-568
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Tidskriftsartikel (refereegranskat)abstract
- Recent studies in mouse models deficient in transforming growth factor beta (TGF-beta) signaling have documented TGF-beta as one of the major regulators of immune function. TGF-beta1-null animals demonstrated massive autoimmune inflammation affecting multiple organs, but attempts to transfer the phenotype to normal animals by bone marrow transplantation only resulted in minor inflammatory lesions. We wanted to ask whether a lethal inflammatory phenotype would develop following transplantation of bone marrow deficient for the TGF-beta type II receptor (TbetaRII) gene to normal recipient animals. The TbetaRII-null mutation would generate a cell autonomous phenotype that cannot be reverted by the influence of endocrine or paracrine TGF-beta derived from the recipient animal. We have generated conditional knockout mice in which the TbetaRII gene is disrupted upon induction with interferon-alphabeta or polyI:polyC. We show that induction of TbetaRII gene disruption in these mice by polyI:polyC results in a lethal inflammatory disease. Importantly, bone marrow from conditional knockout mice transferred to normal recipent mice caused a similar lethal inflammation, regardless of whether induction of TGF-beta receptor deficiency occurred in donor animals before, or in recipient animals after transplantation. These results show that TGF-beta signaling deficiency within cells of hematopoietic origin is sufficient to cause a lethal inflammatory disorder in mice. This animal model provides an important tool to further clarify the pathogenic mechanisms in animals deficient for TGF-beta signaling and the importance of TGF-beta to regulate immune functions. (Blood. 2002;100:560-568)
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| 46. |
- Levéen, Per, et al.
(författare)
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TGF-{beta} type II receptor deficient thymocytes develop normally but demonstrate increased CD8+ proliferation in vivo.
- 2005
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Ingår i: Blood. - : American Society of Hematology. - 1528-0020 .- 0006-4971. ; 106:13, s. 4234-4240
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Tidskriftsartikel (refereegranskat)abstract
- We have taken advantage of the Cre/lox system to generate a mouse model with inducible deficiency of transforming growth factor β receptor II (TβRII). Using this approach, transforming growth factor β (TGF-β) signaling deficiency can be restricted to the hematopoietic system by bone marrow transplantation. Mice that received transplants with TβRII-/- bone marrow develop a lethal inflammatory disorder closely resembling that of TGF-β1-null mice. Previous in vitro studies have suggested multiple roles for TGF-β in T-cell development, including proliferation, apoptosis, and differentiation. We used our transplantation model to ask whether T-cell development is normal in the absence of TGF-β signaling. The findings show for the first time in vivo and in fetal thymus organ culture (FTOC) that TGF-β is not required for thymocytes to differentiate along the entire pathway of thymic T-cell development, as defined by the expression patterns of CD4, CD8, CD25, and CD44. In contrast to previous investigations, no increase of thymocyte apoptosis was observed. However, TβRII-deficient CD8+ thymocytes displayed a 2-fold increase in proliferation rate, as determined by bromodeoxyuridine (BrdU) incorporation in vivo. These results reinforce the importance of TGF-β as an immune regulator critical for T-cell function.
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| 47. |
- Lindehammer, Sabina, et al.
(författare)
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Temporal trends of HLA genotype frequencies of type 1 diabetes patients in Sweden from 1986 to 2005 suggest altered risk
- 2008
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Ingår i: Acta Diabetologica. - : Springer Science and Business Media LLC. - 0940-5429 .- 1432-5233. ; 45:4, s. 231-5
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Tidskriftsartikel (refereegranskat)abstract
- The aim of this study was to compare the frequency of human leukocyte antigen (HLA) genotypes in 1-18-year-old patients with type 1 diabetes newly diagnosed in 1986-1987 (n = 430), 1996-2000 (n = 342) and in 2003-2005 (n = 171). We tested the hypothesis that the HLA DQ genotype distribution changes over time. Swedish type 1 diabetes patients and controls were typed for HLA using polymerase chain reaction amplification and allele specific probes for DQ A1* and B1* alleles. The most common type 1 diabetes HLA DQA1*-B1*genotype 0501-0201/0301-0302 was 36% (153/430) in 1986-1987 and 37% (127/342) in 1996-2000, but decreased to 19% (33/171) in 2003-2005 (P \ 0.0001). The 0501-0201/0501-0201 genotype increased from 1% in 1986-1987 to 7% in 1996-2000 (P = 0.0047) and to 5% in 2003-2005 (P > 0.05). This study in 1-18-year-old Swedish type 1 diabetes patients supports the notion that there is a temporal change in HLA risk.
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| 48. |
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| 49. |
- Lindholm, Eero, et al.
(författare)
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Association between LTA, TNF and AGER polymorphisms and late diabetic complications.
- 2008
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Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 3:6
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Several candidate genes on the short arm of chromosome 6 including the HLA locus, TNF, LTA and AGER could be associated with late diabetic complications. The aim of our study was therefore to explore whether polymorphisms (TNF -308 G-->A, LTA T60N C-->A and AGER -374 T-->A) in these genes alone or together (as haplotypes) increased the risk for diabetic complications. METHODOLOGY/PRINCIPAL FINDINGS: The studied polymorphisms were genotyped in 742 type 1 and 2957 type 2 diabetic patients as well as in 206 non-diabetic control subjects. The Haploview program was used to analyze putative linkage disequilibrium between studied polymorphisms. The TNF, LTA and AGER polymorphisms were associated with the HLA-DQB1 risk genotypes. The AGER -374 A allele was more common in type 1 diabetic patients with than without diabetic nephropathy (31.2 vs. 28.4%, p = 0.007). In a logistic regression analysis, the LTA but not the AGER polymorphism was associated with diabetic nephropathy (OR 2.55[1.11-5.86], p = 0.03). The AGER -374 A allele was associated with increased risk of sight threatening retinopathy in type 2 diabetic patients (1.65[1.11-2.45], p = 0.01) and also with increased risk for macrovascular disease in type 1 diabetic patients (OR 2.05[1.19-3.54], p = 0.01), but with decreased risk for macrovascular disease in type 2 diabetic patients (OR 0.66[0.49-0.90], p = 0.009). The TNF A allele was associated with increased risk for macrovascular complications in type 2 (OR 1.53 [1.04-2.25], p = 0.03, but not in type 1 diabetic patients. CONCLUSIONS/SIGNIFICANCE: The association between diabetic complications and LTA, TNF and AGER polymorphisms is complex, with partly different alleles conferring susceptibility in type 1 and type 2 diabetic patients. We can not exclude the possibility that the genes are part of a large haplotype block that also includes HLA-DQB1 risk genotypes.
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| 50. |
- Lindholm, Eero, et al.
(författare)
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The -374 T/A polymorphism in the gene encoding RAGE is associated with diabetic nephropathy and retinopathy in type 1 diabetic patients.
- 2006
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Ingår i: Diabetologia. - : Springer Science and Business Media LLC. - 1432-0428 .- 0012-186X. ; 49:Sep 13, s. 2745-2755
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Tidskriftsartikel (refereegranskat)abstract
- Aims/hypothesis The receptor for AGE (RAGE) is considered to be mainly an intracellular signal-transducer or pro-inflammatory peptide of possible importance for inflammation and autoimmune diseases. Our aim was to study whether the -374 T/A polymorphism in the gene encoding RAGE (AGER) is associated with diabetes type and presence of diabetic complications. Methods The AGER -374 T/A polymorphism was genotyped in 867 type 1 diabetic patients, 2,467 type 2 diabetic patients and 205 non-diabetic control subjects of Scandinavian origin. Results AGER polymorphism was related to different HLA-DQB1 genotypes and the presence of diabetic complications. Type 1 diabetic patients had a higher frequency of the AGER -374 A/A or T/A genotypes than type 2 diabetic patients (51.1 vs 44.9%, p=0.002) and control subjects (51.1 vs 47.6%, p=0.0006). The RAGE -374 T/A polymorphism was associated with HLA-DQB1 genotypes; patients with HLA risk genotypes had a higher frequency of the A/A or T/A genotypes than patients with other HLA-DQB1 genotypes (60.3 vs 40.3%, p < 0.000001). In type 1 diabetic patients, the frequency of the A/A or T/A genotypes was higher in patients with diabetic nephropathy than without (61.1 vs 46.8%, p=0.006) and with sight-threatening retinopathy than without (56.1 vs 47.6%, p=0.03). In type 2 diabetic patients with HbA(1c) values below the median, the T/T genotype was more frequent in patients with diabetic nephropathy than without (54.3 vs 38.2%, p=0.02). Conclusions/interpretation Our results show an association between the AGER -374 T/A polymorphism and type 1 diabetes. This association was HLA-DQB1-dependent. The polymorphism was associated with diabetic nephropathy in both type 1 and type 2 diabetes, in an HbA(1c)-dependent manner in the latter group, and also with sight-threatening retinopathy in type 1 diabetic patients.
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