| 1. |
- Barcenilla, Hugo, et al.
(författare)
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Mass Cytometry Identifies Distinct Subsets of Regulatory T Cells and Natural Killer Cells Associated With High Risk for Type 1 Diabetes
- 2019
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Ingår i: Frontiers in Immunology. - : FRONTIERS MEDIA SA. - 1664-3224. ; 10
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Tidskriftsartikel (refereegranskat)abstract
- Type 1 diabetes (T1D) is characterized by autoimmune destruction of insulin producing beta-cells. The time from onset of islet autoimmunity to manifest clinical disease can vary widely in length, and it is fairly uncharacterized both clinically and immunologically. In the current study, peripheral blood mononuclear cells from autoantibody-positive children with high risk for T1D, and from age-matched healthy individuals, were analyzed by mass cytometry using a panel of 32 antibodies. Surface markers were chosen to identify multiple cell types including T, B, NK, monocytes, and DC, and antibodies specific for identification of differentiation, activation and functional markers were also included in the panel. By applying dimensional reduction and computational unsupervised clustering approaches, we delineated in an unbiased fashion 132 phenotypically distinct subsets within the major immune cell populations. We were able to identify an effector memory Treg subset expressing HLA-DR, CCR4, CCR6, CXCR3, and GATA3 that was increased in the high-risk group. In addition, two subsets of NK cells defined by CD16(+) CD8(+) CXCR3(+) and CD16(+) CD8(+) CXCR3(+) CD11c(+) were also higher in the same subjects. High-risk individuals did not show impaired glucose tolerance at the time of sampling, suggesting that the changes observed were not the result of metabolic imbalance, and might be potential biomarkers predictive of T1D.
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| 2. |
- Huus, Karina, et al.
(författare)
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Physical Activity, Blood Glucose and C-Peptide in Healthy School-Children, a Longitudinal Study
- 2016
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Ingår i: Plos One. - : Public Library of Science (PLoS). - 1932-6203. ; 11:6
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Tidskriftsartikel (refereegranskat)abstract
- Aim To further elucidate the relationship between physical activity and several risk factors for development of diabetes (glucose, C-peptide and obesity) over time. A prospective longitudinal study where physical activity was measured on 199 children from Kalmar and Linkoping at age 8, and the same 107 children from Linkoping again at age 12. Anthropometric data was collected and blood was analyzed for C-peptide and f-glucose. The children in the study were representative for the general Swedish child population, and on an average lean. High physical activity was related to lower C-peptide at age 8 and 12. This correlation was especially pronounced in boys, who also were more physically active than girls at both time points. The association seen at 8 years of age was similar at age 12 in most children. Children with higher BMI Z-Score had a higher fasting C-peptide (age 12) but linear regression showed that children with more steps per day were less likely to have a higher fasting C-peptide irrespective of BMI. Longitudinal follow-up showed that a decrease in physical activity increased insulin resistance and beta-cell load. Already in young children, physical activity improves insulin sensitivity and decreases the need of C-peptide over time. This seems to become even more pronounced with increasing age when children are followed longitudinally. Low physical activity increases the load on insulin producing beta-cells, might increase the risk for both type 1- and 2 diabetes.
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| 3. |
- Pihl, Mikael, et al.
(författare)
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GAD-specific T cells are induced by GAD-alum treatment in Type-1 diabetes patients
- 2017
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Ingår i: Clinical Immunology. - : ACADEMIC PRESS INC ELSEVIER SCIENCE. - 1521-6616 .- 1521-7035. ; 176, s. 114-121
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Tidskriftsartikel (refereegranskat)abstract
- Administration of Glutamic Acid Decarboxylase (GAD)(65) formulated in aluminium hydroxide preserved insulin secretion in a phase II trial in recent onset Type 1 Diabetes. A subsequent European phase III trial was closed at 15 months after failing to reach primary endpoint, but the majority of the Swedish patients completed the 21 months follow-up. We studied the frequencies and phenotype of T cells, suppressive capacity of Tregs, GAD(65)-induced proliferation, and frequencies of T cells with a GAD(65)-specific TCR in Swedes participating in the trial. Stimulation with GAD(65) induced activated T cells and also cells with a suppressive phenotype. Activated GAD(65)-specific effector T cells were detected by tetramer staining while the frequency of GAD(65)-specific Treg was not affected by the treatment. Additional doses of GAD-alum increased frequencies of CD25(+)CD127(+), but had no effect on CD25(hi)CD127(lo). Our findings indicate that GAD-alum treatment primarily induced activated T cells. GAD(65)-specific cells were mainly of activated phenotype. (C) 2017 Elsevier Inc. All rights reserved.
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| 4. |
- Strollo, Rocky, et al.
(författare)
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Antibodies to oxidized insulin improve prediction of type 1 diabetes in children with positive standard islet autoantibodies
- 2019
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Ingår i: Diabetes/Metabolism Research Reviews. - : John Wiley & Sons. - 1520-7552 .- 1520-7560. ; 35:4
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundAntibodies to posttranslationally modified insulin (oxPTM‐INS‐Ab) are a novel biomarker of type 1 diabetes (T1D). Here, we evaluated whether oxPTM‐INS‐Ab can improve T1D prediction in children with positive standard islet autoantibodies (AAB).MethodsWe evaluated sensitivity, specificity, accuracy, and risk for progression to T1D associated with oxPTM‐INS‐Ab and the standard islet AAB that include insulin (IAA), GAD (GADA), and tyrosine phosphatase 2 (IA‐2A) in a cohort of islet AAB‐positive (AAB+) children from the general population (median follow‐up 8.8 years).ResultsoxPTM‐INS‐Ab was the most sensitive and specific autoantibody biomarker (74% sensitivity, 91% specificity), followed by IA‐2A (71% sensitivity, 91% specificity). GADA and IAA showed lower sensitivity (65% and 50%, respectively) and specificity (66% and 68%, respectively). Accuracy (AUC of ROC) of oxPTM‐INS‐Ab was higher than GADA and IAA (P = 0.003 and P = 0.017, respectively), and similar to IA‐2A (P = 0.896). oxPTM‐INS‐Ab and IA‐2A were more effective than IAA for detecting progr‐T1D when used as second‐line biomarker in GADA+ children. Risk for diabetes was higher (P = 0.03) among multiple AAB+ who were also oxPTM‐INS‐Ab+ compared with those who were oxPTM‐INS‐Ab–. Importantly, when replacing IAA with oxPTM‐INS‐Ab, diabetes risk increased to 100% in children with oxPTM‐INS‐Ab+ in combination with GADA+ and IA‐2A+, compared with 84.37% in those with IAA+, GADA+, and IA‐2A+ (P = 0.04).ConclusionsAntibodies to oxidized insulin (oxPTM‐INS‐Ab), compared with IAA which measure autoantibodies to native insulin, improve T1D risk assessment and prediction accuracy in AAB+ children.
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| 5. |
- Tavira Iglesias, Beatriz, et al.
(författare)
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Effect of simultaneous vaccination with H1N1 and GAD-alum on GAD(65)-induced immune response
- 2017
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Ingår i: Diabetologia. - : SPRINGER. - 0012-186X .- 1432-0428. ; 60:7, s. 1276-1283
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Tidskriftsartikel (refereegranskat)abstract
- Aims/hypothesis A European Phase III trial of GAD formulated with aluminiumhydroxide (GAD-alum) failed to reach its primary endpoint (preservation of stimulated C-peptide secretion from baseline to 15 months in type 1 diabetes patients), but subgroup analysis showed a clinical effect when participants from Nordic countries were excluded, raising concern as to whether the mass vaccination of the Swedish and Finnish populations with the Pandemrix influenza vaccine could have influenced the study outcomes. In the current study, we aimed to assess whether Pandemrix vaccination affects the specific immune responses induced by GAD-alum and the C-peptide response. Methods In this secondary analysis, we analysed data acquired from the Swedish participants in the Phase III GAD-alum trial who received subcutaneous GAD-alum vaccination (two doses, n = 43; four doses, n = 46) or placebo (n = 48). GAD autoantibodies (GADA) and H1N1 autoantibodies, GAD(65)-induced cytokine secretion and change in fasting and stimulated C-peptide levels from baseline to 15 months were analysed with respect to the relative time between H1N1 vaccination and the first injection of GAD-alum. Results GADA levels at 15 months were associated with the relative time between GAD-alum and Pandemrix administration in participants who received two doses of the GAD-alum vaccine (p = 0.015, r = 0.4). Both in participants treated with two doses and four doses of GAD-alum, GADA levels were higher when the relative time between vaccines was amp;gt;= 210 days (p amp;lt; 0.05). In the group that received two doses of GAD-alum, levels of several GAD(65)-induced cytokines were higher in participants who received the H1N1 vaccination and the first GADalum injection at least 150 days apart, and the change in fasting and stimulated C-peptide at 15 months was associated with the relative time between vaccines. Neither of these effects were observed in individuals who received four doses of GAD-alum. Conclusions/interpretation In individuals who received two doses of GAD-alum, receiving the Pandemrix vaccine closer to the first GAD-alum injection, i.e. amp;lt; 150 days, seemed to affect both GAD(65)-induced immune response and C-peptide preservation.
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| 6. |
- Åkerman, Ingrid, et al.
(författare)
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Kunskapsbehov inom socialtjänsten om våld mot barn
- 2017
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Rapport (övrigt vetenskapligt/konstnärligt)abstract
- Syftet med den aktuella studien var att skapa ett underlag för hur ett socialtjänstnätverk i Barnafrids regi skulle kunna utvecklas. Därför undersöktes socialsekreterares uppfattning av hur de ser på den kompetens de redan har samt vad de är i behov av för vidare kunskap gällande våld och andra övergrepp mot barn. Ytterligare frågeställningar rörde vilken typ av kunskapsstöd som behövs, vilka kommunikativa lösningar kunskapen ska paketeras i samt hur de önskar att ett nätverk för socialtjänsten ska utformas. Nedan sammanfattas några huvuddrag från rapporten:Det finns ett stort behov av kunskap bland svenska socialsekreterare om våld och andra övergrepp mot barn. Behovet beskrevs som något större bland socialsekreterare från mindre kommuner (< 50 000 invånare) och från socialsekreterare anställda kortare tid inom socialtjänsten (0-2 år).Det behövs både generell kunskap om våld mot barn men också fördjupad kunskap inom mer specifika områden såsom nyanlända familjer, ensamkommande barn, hedersrelaterad våldsproblematik samt arbetsverktyg för risk och skyddsbedömningar.Deltagarna önskade lättillgängliga manualer och guidelines som stöd i akuta eller särskilda situationer. Att kunna ta del av information via regionala konferenser/utbildningsdagar samt via en uppdaterad hemsida var prioriterat. Även kunskapspåfyllning via nationella föreläsningar var efterfrågat.Mer än hälften av de svarande upplevde behov av en konsultationstelefon dit man kan ringa och få råd och stöd i svåra och komplicerade ärenden.Mindre prioriterat var kunskap genom webbutbildningar, appar, frågelåda med svar via mejl och chattforum med andra verksamma.Sammanfattningsvis visar studien att det viktigaste är att socialsekreterare kan känna sig trygga och säkra när de utför sitt arbete. Det innebär ett arbete där barnets bästa alltid sätts i främsta rummet! Utifrån resultaten från denna studie kvarstår en hel del arbete för att uppnå det.Denna studie liksom tidigare undersökningar (se t.ex. Barnskyddsutredningen, 2009; Socialstyrelsen, 2016) pekar på brister och behov, såväl i grundutbildning, introduktionsutbildning som på specialistutbildning för de som ansvarar för myndighetsutövning inom den svenska sociala barn- och ungdomsvården. Personal inom socialtjänsten måste få kontinuerlig tillgång till en flora av olika former av kunskap som innebär både teoretisk och praktisk kunskap om hur man arbetar med barn som utsatts för våld. Utifrån resultaten bedömer vi också att det bland annat finns ett behov av såväl ett kunskapsbaserat socialtjänstnätverk som en konsultationstelefon. Detta är något Barnafrid – Nationellt kunskapscentrum mot våld och andra övergrepp mot barn vore en naturlig värd för i en framtid.
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| 7. |
- 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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| 8. |
- Åkerman, Linda, et al.
(författare)
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Characteristics of the pre-diabetic period in children with high risk of type 1 diabetes recruited from the general Swedish population-The ABIS study
- 2017
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Ingår i: Diabetes/Metabolism Research and Reviews. - : Wiley. - 1520-7552 .- 1520-7560. ; 33:6
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Tidskriftsartikel (refereegranskat)abstract
- Background: There is a need for increased understanding of the pre-diabetic period in individuals with high risk of type 1 diabetes from the general population. Methods: High-risk children (n = 21) positive for multiple islet autoantibodies were identified by autoantibody screening within the All Babies in Southeast Sweden study. The children and their parents were enrolled in a 2-year prospective follow-up study aiming to characterize the pre-diabetic period. Blood samples were collected every 6 months for measurement of C-peptide, HbA1c, fasting glucose, and autoantibodies. Human leukocyte antigen-genotype was determined, and oral glucose tolerance test was performed every 12 months. Results: Despite positivity for multiple autoantibodies, 9 out of 21 individuals had low-risk human leukocyte antigen-genotypes. Children who progressed to manifest diabetes (progressors, n = 12) had higher levels of IA2A and ZnT8A than children who did not (non-progressors, n = 9). Impaired glucose tolerance and impaired fasting glucose was observed to the same extent in progressors and non-progressors, but HbA1c increased over time in progressors in spite of increased C-peptide. Conclusions: Autoantibodies to IA2 and ZnT8 may be useful discriminators for disease progression in at-risk children from the general population. Dysglycemia was observed long before diagnosis, and difficulties in maintaining glucose homeostasis despite increased C-peptide indicate that insulin resistance might be an important accelerator of disease in risk individuals.
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| 9. |
- Åkerman, Linda, et al.
(författare)
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Serum miRNA levels are related to glucose homeostasis and islet autoantibodies in children with high risk for type 1 diabetes
- 2018
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Ingår i: PLOS ONE. - : PUBLIC LIBRARY SCIENCE. - 1932-6203. ; 13:1
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Tidskriftsartikel (refereegranskat)abstract
- Micro RNAs (miRNAs) are promising disease biomarkers due to their high stability. Their expression in serum is altered in type 1 diabetes, but whether deviations exist in individuals with high risk for type 1 diabetes remains unexplored. We therefore assessed serum miRNAs in high-risk individuals (n = 21) positive for multiple islet autoantibodies, age-matched healthy children (n = 17) and recent-onset type 1 diabetes patients (n = 8), using Serum/Plasma Focus microRNA PCR Panels from Exiqon. The miRNA levels in the high-risk group were similar to healthy controls, and no specific miRNA profile was identified for the high-risk group. However, serum miRNAs appeared to reflect glycemic status and ongoing islet auto-immunity in high-risk individuals, since several miRNAs were associated to glucose homeostasis and autoantibody titers. High-risk individuals progressing to clinical disease after the sampling could not be clearly distinguished from non-progressors, while miRNA expression in the type 1 diabetes group deviated significantly from high-risk individuals and healthy controls, perhaps explained by major metabolic disturbances around the time of diagnosis.
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