Publications by authors named "Riitta Veijola"

191 Publications

Determining the timing of pubertal onset via a multicohort analysis of growth.

PLoS One 2021 18;16(11):e0260137. Epub 2021 Nov 18.

Faculty of Social Sciences, Unit of Health Sciences, Tampere University, Tampere, Finland.

Objective: Growth-based determination of pubertal onset timing would be cheap and practical. We aimed to determine this timing based on pubertal growth markers. Secondary aims were to estimate the differences in growth between cohorts and identify the role of overweight in onset timing.

Design: This multicohort study includes data from three Finnish cohorts-the Type 1 Diabetes Prediction and Prevention (DIPP, N = 2,825) Study, the Special Turku Coronary Risk Factor Intervention Project (STRIP, N = 711), and the Boy cohort (N = 66). Children were monitored for growth and Tanner staging (except in DIPP).

Methods: The growth data were analyzed using a Super-Imposition by Translation And Rotation growth curve model, and pubertal onset analyses were run using a time-to-pubertal onset model.

Results: The time-to-pubertal onset model used age at peak height velocity (aPHV), peak height velocity (PHV), and overweight status as covariates, with interaction between aPHV and overweight status for girls, and succeeded in determining the onset timing. Cross-validation showed a good agreement (71.0% for girls, 77.0% for boys) between the observed and predicted onset timings. Children in STRIP were taller overall (girls: 1.7 [95% CI: 0.9, 2.5] cm, boys: 1.0 [0.3, 2.2] cm) and had higher PHV values (girls: 0.13 [0.02, 0.25] cm/year, boys: 0.35 [0.21, 0.49] cm/year) than those in DIPP. Boys in the Boy cohort were taller (2.3 [0.3, 4.2] cm) compared with DIPP. Overweight girls showed pubertal onset at 1.0 [0.7, 1.4] year earlier compared with other girls. In boys, there was no such difference.

Conclusions: The novel modeling approach provides an opportunity to evaluate the Tanner breast/genital stage-based pubertal onset timing in cohort studies including longitudinal data on growth but lacking pubertal follow-up.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0260137PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8601458PMC
November 2021

Maternal energy-adjusted fatty acid intake during pregnancy and the development of cow's milk allergy in the offspring.

Br J Nutr 2021 Nov 12:1-20. Epub 2021 Nov 12.

Faculty of Social Sciences, Unit of Health Sciences, Tampere University, 33014, Tampere, Finland.

Cow's milk allergy (CMA) is one of the earliest manifestations of allergic diseases. Early dietary factors, like maternal diet during pregnancy, may play a role in the development of allergic diseases in the offspring. We aimed to investigate the association between maternal intake of fatty acids during pregnancy and the risk of CMA in the offspring. Our study was conducted in a population-based cohort, the Finnish Type 1 Diabetes Prediction and Prevention study. We collected the maternal dietary data by a validated food frequency questionnaire. We obtained the information on CMA in the study participants (n=448) from registers and from the parents. Dietary data and information on CMA were available for 4921 children. We used logistic regression in the analyses and fatty acid intakes were energy adjusted. The maternal intake of saturated fatty acids, monounsaturated fatty acids, polyunsaturated fatty acids (PUFA), n-3 PUFA, n-6 PUFA, trans fatty acids, ratio of n-3 PUFA to n-6 PUFA or ratio of linoleic acid to alpha-linolenic acid were not associated with the risk of CMA in the offspring when adjusted for perinatal factors, background factors, parental history of asthma or allergic rhinitis and infant animal contacts. The intake of alpha-linolenic acid was associated with a decreased risk (OR 0.72; 95%CI 0.56-0.93) of CMA in the offspring of mothers without a history of allergic rhinitis or asthma. In conclusion the maternal intake of fatty acids during pregnancy is not associated with the risk of CMA in the offspring.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1017/S0007114521004475DOI Listing
November 2021

Islet Autoantibody Type-Specific Titer Thresholds Improve Stratification of Risk of Progression to Type 1 Diabetes in Children.

Diabetes Care 2021 Nov 10. Epub 2021 Nov 10.

Institute of Diabetes Research, Helmholtz Zentrum München, German Research Center for Environmental Health, Munich-Neuherberg, Germany.

Objective: To use islet autoantibody titers to improve the estimation of future type 1 diabetes risk in children.

Research Design And Methods: Prospective cohort studies in Finland, Germany, Sweden, and the U.S. followed 24,662 children at increased genetic or familial risk to develop islet autoimmunity and diabetes. For 1,604 children with confirmed positivity, titers of autoantibodies against insulin (IAA), GAD antibodies (GADA), and insulinoma-associated antigen 2 (IA-2A) were harmonized for diabetes risk analyses.

Results: Survival analysis from time of confirmed positivity revealed markedly different 5-year diabetes risks associated with IAA ( = 909), GADA ( = 1076), and IA-2A ( = 714), when stratified by quartiles of titer, ranging from 19% (GADA 1st quartile) to 60% (IA-2A 4th quartile). The minimum titer associated with a maximum difference in 5-year risk differed for each autoantibody, corresponding to the 58.6th, 52.4th, and 10.2nd percentile of children specifically positive for each of IAA, GADA, and IA-2A, respectively. Using these autoantibody type-specific titer thresholds in the 1,481 children with all autoantibodies tested, the 5-year risk conferred by single ( = 954) and multiple ( = 527) autoantibodies could be stratified from 6 to 75% ( < 0.0001). The thresholds effectively identified children with a ≥50% 5-year risk when considering age-specific autoantibody screening (57-65% positive predictive value and 56-74% sensitivity for ages 1-5 years). Multivariable analysis confirmed the significance of associations between the three autoantibody titers and diabetes risk, informing a childhood risk surveillance strategy.

Conclusions: This study defined islet autoantibody type-specific titer thresholds that significantly improved type 1 diabetes risk stratification in children.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2337/dc21-0878DOI Listing
November 2021

Autoantibodies to N-Terminally Truncated GAD65(96-585): HLA Associations and Predictive Value for Type 1 Diabetes.

J Clin Endocrinol Metab 2021 Nov 8. Epub 2021 Nov 8.

Pediatric Research Center, Children's Hospital, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.

Objective: To evaluate the role of autoantibodies to N-terminally truncated glutamic acid decarboxylase GAD65(96-585) (t-GADA) as a marker for type 1 diabetes (T1D) and to assess the potential HLA-associations with such autoantibodies.

Design: In this cross-sectional study combining data from the Finnish Pediatric Diabetes Register, the Type 1 Diabetes Prediction and Prevention (DIPP) Study, the DIABIMMUNE Study, and the Early Dietary Intervention and Later Signs of Beta-Cell Autoimmunity (EDIA) Study, venous blood samples from 760 individuals (53.7% males) were analyzed for t-GADA, autoantibodies to full-length GAD65 (f-GADA), and islet cell antibodies. Epitope-specific GAD autoantibodies were analyzed from 189 study participants.

Results: T1D had been diagnosed in 174 (23%) participants. Altogether 631 (83%) individuals tested positive for f-GADA and 451 (59%) for t-GADA at a median age of 9.0 years (range 0.2-61.5). t-GADA demonstrated higher specificity (46%) and positive predictive value (30%) for T1D than positivity for f-GADA alone (15% and 21%, respectively). Among participants positive for f-GADA, those who tested positive for t-GADA carried more frequently HLA genotypes conferring increased risk for T1D than those who tested negative for t-GADA (77 vs. 53%; P<0.001).

Conclusions: Autoantibodies to N-terminally truncated GAD improve the screening for T1D compared to f-GADA and may facilitate the selection of participants for clinical trials. HLA class II-mediated antigen presentation of GAD(96-585)-derived or structurally similar peptides might comprise an important pathomechanism in T1D.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1210/clinem/dgab816DOI Listing
November 2021

Metformin versus insulin therapy for gestational diabetes: Effects on offspring anthropometrics and metabolism at the age of 9 years: A follow-up study of two open-label, randomized controlled trials.

Diabetes Obes Metab 2021 Nov 5. Epub 2021 Nov 5.

Department of Paediatrics and Adolescent Medicine, University of Turku and Turku University Hospital, Turku, Finland.

Aims: To compare anthropometrics, and lipid and glucose metabolism in the 9-year-old offspring of mothers treated with metformin or insulin for gestational diabetes mellitus (GDM).

Materials And Methods: This was a Finnish two-centre, 9-year follow-up study of two open-label, randomized controlled trials comparing the effects observed in the offspring of mothers who received metformin and insulin treatment for GDM. Measurements included anthropometrics, blood pressure, lipoproteins, and oral glucose tolerance tests. This study was registered with ClinicalTrials.gov, number NCT02417090.

Results: At the age of 9 years 172 children (55% of the original study cohort, 82 from the metformin and 90 from the insulin group) participated in the study. No differences were found between the 9-year-old offspring groups in anthropometric variables, including body mass index and waist-to-height ratio. The offspring in the metformin group had higher high-density lipoprotein (HDL) cholesterol concentrations (1.72 vs. 1.54 mmol/L; P = 0.039) but lower low-density lipoprotein cholesterol (2.39 vs. 2.58 mmol/L; P = 0.046) and apolipoprotein B concentrations (0.63 vs. 0.67 g/L; P = 0.043) than the offspring in the insulin group. The difference in HDL cholesterol concentration was found to be significant only in boys (P = 0.003). The 2-hour glucose value in the oral glucose tolerance test was 0.6-mmol/L lower in boys from the metformin group than in those from the insulin group (P = 0.015).

Conclusions: Metformin treatment for GDM is associated with similar offspring growth and glucose metabolism but a more favourable lipid profile at the age of 9 years as compared to insulin treatment.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/dom.14589DOI Listing
November 2021

Frailty modeling under a selective sampling protocol: an application to type 1 diabetes related autoantibodies.

Stat Med 2021 Dec 8;40(28):6410-6420. Epub 2021 Sep 8.

Health Sciences, Faculty of Social Sciences, Tampere University, Tampere, Finland.

In studies following selective sampling protocols for secondary outcomes, conventional analyses regarding their appearance could provide misguided information. In the large type 1 diabetes prevention and prediction (DIPP) cohort study monitoring type 1 diabetes-associated autoantibodies, we propose to model their appearance via a multivariate frailty model, which incorporates a correlation component that is important for unbiased estimation of the baseline hazards under the selective sampling mechanism. As further advantages, the frailty model allows for systematic evaluation of the association and the differences in regression parameters among the autoantibodies. We demonstrate the properties of the model by a simulation study and the analysis of the autoantibodies and their association with background factors in the DIPP study, in which we found that high genetic risk is associated with the appearance of all the autoantibodies, whereas the association with sex and urban municipality was evident for IA-2A and IAA autoantibodies.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/sim.9190DOI Listing
December 2021

Consumption of differently processed milk products and the risk of asthma in children.

Pediatr Allergy Immunol 2021 Sep 2. Epub 2021 Sep 2.

Public Health and Welfare Department, Finnish Institute for Health and Welfare, Helsinki, Finland.

Background: Consumption of unprocessed cow's milk has been associated with a lower risk of childhood asthma and/or atopy. Not much is known about differently processed milk products. We aimed to study the association between the consumption of differently processed milk products and asthma risk in a Finnish birth cohort.

Methods: We included 3053 children from the Finnish Type 1 Diabetes Prediction and Prevention (DIPP) Nutrition Study. Asthma and its subtypes were assessed at the age of 5 years, and food consumption by food records, at the age of 3 and 6 months and 1, 2, 3, 4, and 5 years. We used conventional and processing (heat treatment and homogenization)-based classifications for milk products. The data were analyzed using a joint model for longitudinal and time-to-event data.

Results: At the age of 5 years, 184 (6.0%) children had asthma, of whom 101 (54.9%) were atopic, 75 (40.8%) were nonatopic, and eight (4.3%) could not be categorized. Consumption of infant formulas [adjusted hazard ratio (95% confidence intervals) 1.15 (1.07, 1.23), p < .001] and strongly heat-treated milk products [1.06 (1.01, 1.10), p = .01] was associated with the risk of all asthma. Consumption of all cow's milk products [1.09 (1.03, 1.15), p = .003], nonfermented milk products [1.08 (1.02, 1.14), p = .008], infant formulas [1.23 (1.13, 1.34), p < .001], and strongly heat-treated milk products [1.08 (1.02, 1.15), p = .006] was associated with nonatopic asthma risk. All these associations remained statistically significant after multiple testing correction.

Conclusions: High consumption of infant formula and other strongly heat-treated milk products may be associated with the development of asthma.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/pai.13659DOI Listing
September 2021

Tri-SNP polymorphism in the intron of HLA-DRA1 affects type 1 diabetes susceptibility in the Finnish population.

Hum Immunol 2021 Jul 23. Epub 2021 Jul 23.

Immunogenetics Laboratory, Institute of Biomedicine, University of Turku, Turku, Finland. Electronic address:

Genes in the HLA class II region include the most important inherited risk factors for type 1 diabetes (T1D) although also polymorphisms outside the HLA region modulate the predisposition to T1D. This study set out to confirm a recent observation in which a novel expression quantitative trait locus was formed by three single nucleotide polymorphisms (SNP) in the intron of HLA-DRA1 in DR3-DQ2 haplotypes. The SNPs significantly increased the risk for T1D in DR3-DQ2 homozygous individuals and we intended to further explore this association, in the Finnish population, by comparing two DR3-DQ2 positive genotypes. Cohorts with DR3-DQ2/DR3-DQ2 (N = 570) and DR3-DQ2/DR1-DQ5 (N = 1035) genotypes were studied using TaqMan analysis that typed for rs3135394, rs9268645 and rs3129877. The tri-SNP haplotype was significantly more common in cases than controls in the DR3-DQ2/DR3-DQ2 cohort (OR = 1.70 CI 95% = 1.15-2.51P = 0.007). However, no significant associations could be observed in the DR3-DQ2/DR1-DQ5 cohort.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.humimm.2021.07.010DOI Listing
July 2021

Association of different enteroviruses with atopy and allergic diseases in early childhood.

Pediatr Allergy Immunol 2021 Nov 16;32(8):1629-1636. Epub 2021 Jul 16.

Department of Virology, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland.

Background: Enterovirus (EV) infections, being among the most prevalent viruses worldwide, have been associated with reduced risk of allergic diseases. We sought to determine the association between EVs and allergic sensitization and disease in early childhood.

Methods: The study was carried out in a nested case-control setting within a prospective birth cohort in Finland. We included 138 case children who had specific IgE (s-IgE) sensitization at the age of 5 years and 138 control children without s-IgE sensitization. Allergic disease was recorded at study visits and identified with the ISAAC questionnaire. We screened for the presence of serotype-specific antibodies against 41 EVs at 1-5 years of age and assessed their association with allergic sensitization and disease.

Results: The overall number of EV infections did not differ between s-IgE-sensitized children and non-sensitized control children. However, there was a tendency of case children with an allergic disease having less EV infections than their controls. This observation was statistically significant for species A EVs in case children with atopic dermatitis vs. control children: OR 0.6 (95% CI 0.36-0.99), p = .048.

Conclusion: This study supports the evidence that EV exposure and development of allergic disease are inversely associated. Interestingly, the inverse association was not observed for bare atopic IgE sensitization, but for IgE sensitization coupled with clinical atopic disease. This suggests that environmental factors influencing IgE sensitization may differ from those influencing progression to clinical allergic disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/pai.13577DOI Listing
November 2021

Islet Autoimmunity and HLA Markers of Presymptomatic and Clinical Type 1 Diabetes: Joint Analyses of Prospective Cohort Studies in Finland, Germany, Sweden, and the U.S.

Diabetes Care 2021 Jun 23. Epub 2021 Jun 23.

PEDEGO Research Unit, Department of Pediatrics, University of Oulu and Oulu University Hospital, Oulu, Finland.

Objective: To combine prospective cohort studies, by including HLA harmonization, and estimate risk of islet autoimmunity and progression to clinical diabetes.

Research Design And Methods: For prospective cohorts in Finland, Germany, Sweden, and the U.S., 24,662 children at increased genetic risk for development of islet autoantibodies and type 1 diabetes have been followed. Following harmonization, the outcomes were analyzed in 16,709 infants-toddlers enrolled by age 2.5 years.

Results: In the infant-toddler cohort, 1,413 (8.5%) developed at least one autoantibody confirmed at two or more consecutive visits (seroconversion), 865 (5%) developed multiple autoantibodies, and 655 (4%) progressed to diabetes. The 15-year cumulative incidence of diabetes varied in children with one, two, or three autoantibodies at seroconversion: 45% (95% CI 40-52), 85% (78-90), and 92% (85-97), respectively. Among those with a single autoantibody, status 2 years after seroconversion predicted diabetes risk: 12% (10-25) if reverting to autoantibody negative, 30% (20-40) if retaining a single autoantibody, and 82% (80-95) if developing multiple autoantibodies. HLA-DR-DQ affected the risk of confirmed seroconversion and progression to diabetes in children with stable single-autoantibody status. Their 15-year diabetes incidence for higher- versus lower-risk genotypes was 40% (28-50) vs. 12% (5-38). The rate of progression to diabetes was inversely related to age at development of multiple autoantibodies, ranging from 20% per year to 6% per year in children developing multipositivity in ≤2 years or >7.4 years, respectively.

Conclusions: The number of islet autoantibodies at seroconversion reliably predicts 15-year type 1 diabetes risk. In children retaining a single autoantibody, HLA-DR-DQ genotypes can further refine risk of progression.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2337/dc20-1836DOI Listing
June 2021

ClinFlow - An Interactive Application for Clinical Data Mining.

Stud Health Technol Inform 2021 May;281:268-272

Biomimetics and Intelligent Systems Group, Faculty of Information Technology and Electrical Engineering, University of Oulu, Oulu, Finland.

Analyzing clinical data comes with many challenges. Medical expertise combined with statistical and programming knowledge must go hand-in-hand when applying data mining methods on clinical datasets. This work aims at bridging the gap between clinical expertise and computer science knowledge by providing an application for clinical data analysis with no requirement for statistical programming knowledge. Our tool allows clinical researchers to conduct data processing and visualization in an interactive environment, thus providing an assisting tool for clinical studies. The application was experimentally evaluated with an analysis of Type 1 Diabetes clinical data. The results obtained with the tool are in line with the domain literature, demonstrating the value of our application in data exploration and hypothesis testing.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3233/SHTI210162DOI Listing
May 2021

Land Cover of Early-Life Environment Modulates the Risk of Type 1 Diabetes.

Diabetes Care 2021 07 5;44(7):1506-1514. Epub 2021 May 5.

Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland

Objective: Environmental microbial exposures have been implicated to protect against immune-mediated diseases such as type 1 diabetes. Our objective was to study the association of land cover around the early-life dwelling with the development of islet autoimmunity and type 1 diabetes to evaluate the role of environmental microbial biodiversity in the pathogenesis.

Research Design And Methods: Association between land cover types and the future risk of type 1 diabetes was studied by analyzing land cover types classified according to Coordination of Information on the Environment (CORINE) 2012 and 2000 data around the dwelling during the first year of life for 10,681 children genotyped for disease-associated HLA-DQ alleles and monitored from birth in the Type 1 Diabetes Prediction and Prevention (DIPP) study. Land cover was compared between children who developed type 1 diabetes ( = 271) or multiple diabetes-associated islet autoantibodies ( = 384) and children without diabetes who are negative for diabetes autoantibodies.

Results: Agricultural land cover around the home was inversely associated with diabetes risk (odds ratio 0.37, 95% CI 0.16-0.87, = 0.02 within a distance of 1,500 m). The association was observed among children with the high-risk HLA genotype and among those living in the southernmost study region. Snow cover on the ground seemed to block the transfer of the microbial community indoors, leading to reduced bacterial richness and diversity indoors, which might explain the regional difference in the association. In survival models, an agricultural environment was associated with a decreased risk of multiple islet autoantibodies (hazard ratio [HR] 1.60, = 0.008) and a decreased risk of progression from single to multiple autoantibody positivity (HR 2.07, = 0.001) compared with an urban environment known to have lower environmental microbial diversity.

Conclusions: The study suggests that exposure to an agricultural environment (comprising nonirrigated arable land, fruit trees and berry plantations, pastures, natural pastures, land principally occupied by agriculture with significant areas of natural vegetation, and agroforestry areas) early in life is inversely associated with the risk of type 1 diabetes. This association may be mediated by early exposure to environmental microbial diversity.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.2337/dc20-1719DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8323192PMC
July 2021

Predicting Type 1 Diabetes Onset using Novel Survival Analysis with Biomarker Ontology.

AMIA Annu Symp Proc 2020 25;2020:727-736. Epub 2021 Jan 25.

IBM Research, NY, USA.

Type 1 diabetes (T1D) is a chronic autoimmune disease that affects about 1 in 300 children and up to 1 in 100 adults during their life-time. Improvements in early prediction of T1D onset may help prevent diagnosis for diabetic ketoacidosis, a serious complication often associated with a missed or delayed T1D diagnosis. In addition to genetic factors, progression to T1D is strongly associated with immunologic factors that can be measured during clinical visits. We developed a T1D-specific ontology that captures the dynamic patterns of these biomarkers and used it together with a survival model, RankSvx, proposed in our prior work. We applied this approach to a T1D dataset harmonized from three birth cohort studies from the United States, Finland, and Sweden. Results show that the dynamic biomarker patterns captured in the proposed ontology are able to improve prediction performance (in concordance index) by 5.3%, 3.3%, 2.8%, and 1.0% over baseline for 3, 6, 9, and 12 month duration windows, respectively.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8075541PMC
June 2021

Modeling Disease Progression Trajectories from Longitudinal Observational Data.

AMIA Annu Symp Proc 2020 25;2020:668-676. Epub 2021 Jan 25.

IBM Research, Cambridge, Massachusetts, United States.

Analyzing disease progression patterns can provide useful insights into the disease processes of many chronic conditions. These analyses may help inform recruitment for prevention trials or the development and personalization of treatments for those affected. We learn disease progression patterns using Hidden Markov Models (HMM) and distill them into distinct trajectories using visualization methods. We apply it to the domain of Type 1 Diabetes (T1D) using large longitudinal observational data from the T1DI study group. Our method discovers distinct disease progression trajectories that corroborate with recently published findings. In this paper, we describe the iterative process of developing the model. These methods may also be applied to other chronic conditions that evolve over time.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8075441PMC
June 2021

Beta cell function in participants with single or multiple islet autoantibodies at baseline in the TEDDY Family Prevention Study: TEFA.

Endocrinol Diabetes Metab 2021 04 5;4(2):e00198. Epub 2020 Nov 5.

Department of Clinical Sciences Lund University/CRC Skåne University Hospital Malmö Sweden.

Aim: The aim of the present study was to assess beta cell function based on an oral glucose tolerance test (OGTT) in participants with single islet autoantibody or an intravenous glucose tolerance test (IvGTT) in participants with multiple islet autoantibodies.

Materials And Methods: Healthy participants in Sweden and Finland, between 2 and 49.99 years of age previously identified as positive for a single (n = 30) autoantibody to either insulin, glutamic acid decarboxylase, islet antigen-2, zinc transporter 8 or islet cell antibodies or multiple autoantibodies (n = 46), were included. Participants positive for a single autoantibody underwent a 6-point OGTT while participants positive for multiple autoantibodies underwent an IvGTT. Glucose, insulin and C-peptide were measured from OGTT and IvGTT samples.

Results: All participants positive for a single autoantibody had a normal glucose tolerance test with 120 minutes glucose below 7.70 mmol/L and HbA1c values within the normal range (<42 mmol/mol). Insulin responses to the glucose challenge on OGTT ranged between 13.0 and 143 mIU/L after 120 minutes with C-peptide values between 0.74 and 4.60 nmol/L. In Swedish participants, the first-phase insulin response (FPIR) on IvGTT was lower in those positive for three or more autoantibodies (n = 13; median 83.0 mIU/L; range 20.0-343) compared to those with two autoantibodies (n = 15; median 146 mIU/L; range 19.0-545;  = .0330).

Conclusion: Participants positive for a single autoantibody appeared to have a normal beta cell function. Participants positive for three or more autoantibodies had a lower FPIR as compared to participants with two autoantibodies, supporting the view that their beta cell function had deteriorated.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/edm2.198DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8029501PMC
April 2021

Maternal Vitamin C and Iron Intake during Pregnancy and the Risk of Islet Autoimmunity and Type 1 Diabetes in Children: A Birth Cohort Study.

Nutrients 2021 Mar 13;13(3). Epub 2021 Mar 13.

Unit of Health Sciences, Faculty of Social Sciences, Tampere University, FI-33014 Tampere, Finland.

Our aim was to study the associations between maternal vitamin C and iron intake during pregnancy and the offspring's risk of developing islet autoimmunity and type 1 diabetes. The study was a part of the Finnish Type 1 Diabetes Prediction and Prevention (DIPP) prospective birth cohort including children genetically at risk of type 1 diabetes born between 1997-2004. The diets of 4879 mothers in late pregnancy were assessed with a validated food frequency questionnaire. The outcomes were islet autoimmunity and type 1 diabetes. Cox proportional hazards regression analysis adjusted for energy, family history of diabetes, human leukocyte antigen (HLA) genotype and sex was used for statistical analyses. Total intake of vitamin C or iron from food and supplements was not associated with the risk of islet autoimmunity (vitamin C: HR 0.91: 95% CI (0.80, 1.03), iron: 0.98 (0.87, 1.10)) or type 1 diabetes (vitamin C: 1.01 (0.87, 1.17), iron: 0.92 (0.78, 1.08)), neither was the use of vitamin C or iron supplements associated with the outcomes. In conclusion, no association was found between maternal vitamin C or iron intake during pregnancy and the risk of islet autoimmunity or type 1 diabetes in the offspring.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/nu13030928DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8001228PMC
March 2021

Enterovirus Infections Are Associated With the Development of Celiac Disease in a Birth Cohort Study.

Front Immunol 2020 2;11:604529. Epub 2021 Feb 2.

Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland.

Enterovirus and adenovirus infections have been linked to the development of celiac disease. We evaluated this association in children who developed biopsy-proven celiac disease (N = 41) during prospective observation starting from birth, and in control children (N = 53) matched for the calendar time of birth, sex, and HLA-DQ genotype. Enterovirus and adenovirus infections were diagnosed by seroconversions in virus antibodies in longitudinally collected sera using EIA. Enterovirus infections were more frequent in case children before the appearance of celiac disease-associated tissue transglutaminase autoantibodies compared to the corresponding period in control children (OR 6.3, 95% CI 1.8-22.3; p = 0.005). No difference was observed in the frequency of adenovirus infections. The findings suggest that enterovirus infections may contribute to the process leading to celiac disease.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fimmu.2020.604529DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7884453PMC
June 2021

Infections and systemic inflammation are associated with lower plasma concentration of insulin-like growth factor I among Malawian children.

Am J Clin Nutr 2021 02;113(2):380-390

Center for Child Health Research, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland.

Background: Insulin-like growth factor I (IGF-I) is the most important hormonal promoter of linear growth in infants and young children.

Objectives: The objectives of this study were to compare plasma IGF-I concentration in a low- compared with a high-income country and characterize biological pathways leading to reduced IGF-I concentration in children in a low-income setting.

Methods: We analyzed plasma IGF-I concentration from 716 Malawian and 80 Finnish children at 6-36 mo of age. In the Malawian children, we studied the association between IGF-I concentration and their environmental exposures; nutritional status; systemic and intestinal inflammation; malaria parasitemia and viral, bacterial, and parasitic enteric infections; as well as growth at 18 mo of age. We then conducted a pathway analysis to identify direct and indirect associations between these predictors and IGF-I concentration.

Results: The mean IGF-I concentrations were similar in Malawi and Finland among 6-mo-old infants. At age 18 mo, the mean ± SD concentration was almost double among the Finns compared with the Malawians [24.2 ± 11.3 compared with 12.5 ± 7.7 ng/mL, age- and sex-adjusted difference in mean (95% CI): 11.8 (9.9, 13.7) ng/mL; P < 0.01]. Among 18-mo-old Malawians, plasma IGF-I concentration was inversely associated with systemic inflammation, malaria parasitemia, and intestinal Shigella, Campylobacter, and enterovirus infection and positively associated with the children's weight-for-length z score (WLZ), female sex, maternal height, mother's education, and dry season. Seasonally, mean plasma IGF-I concentration was highest in June and July and lowest in December and January, coinciding with changes in children's length gain and preceded by ∼2 mo by the changes in their WLZ.

Conclusions: The mean plasma IGF-I concentrations are similar in Malawi and Finland among 6-mo-old infants. Thereafter, mean concentrations rise markedly in Finland but not in Malawi. Systemic inflammation and clinically nonapparent infections are strongly associated with lower plasma IGF-I concentrations in Malawi through direct and indirect pathways.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/ajcn/nqaa327DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7851819PMC
February 2021

Factors Associated With the Decline of C-Peptide in a Cohort of Young Children Diagnosed With Type 1 Diabetes.

J Clin Endocrinol Metab 2021 03;106(3):e1380-e1388

Department of Clinical Sciences, Lund University CRC, Skåne University Hospital, Malmö, Sweden.

Context: Understanding factors involved in the rate of C-peptide decline is needed to tailor therapies for type 1 diabetes (T1D).

Objective: Evaluate factors associated with rate of C-peptide decline after a T1D diagnosis in young children.

Design: Observational study.

Setting: Academic centers.

Participants: A total of 57 participants from the Environmental Determinants of Diabetes in the Young (TEDDY) study who were enrolled at 3 months of age and followed until T1D, and 56 age-matched children diagnosed with T1D in the community.

Intervention: A mixed meal tolerance test was used to measure the area under the curve (AUC) C-peptide at 1, 3, 6, 12, and 24 months postdiagnosis.

Outcome: Factors associated with rate of C-peptide decline during the first 2 years postdiagnosis were evaluated using mixed effects models, adjusting for age at diagnosis and baseline C-peptide.

Results: Adjusted slopes of AUC C-peptide decline did not differ between TEDDY subjects and community controls (P = 0.21), although the former had higher C-peptide baseline levels. In univariate analyses combining both groups (n = 113), younger age, higher weight and body mass index z-scores, female sex, an increased number increased number of islet autoantibodies, and IA-2A or ZnT8A positivity at baseline were associated with a higher rate of C-peptide loss. Younger age, female sex, and higher weight z-score remained significant in multivariate analysis (all P < 0.02). At 3 months after diagnosis, higher HbA1c became an additional independent factor associated with a higher rate of C-peptide decline (P < 0.01).

Conclusion: Younger age at diagnosis, female sex, higher weight z-score, and HbA1c were associated with a higher rate of C-peptide decline after T1D diagnosis in young children.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1210/clinem/dgaa715DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8244121PMC
March 2021

Correction: Saarinen, N.V.V., et al. Multiplexed High-Throughput Serological Assay for Human Enteroviruses. 2020, , 963.

Microorganisms 2020 Sep 17;8(9). Epub 2020 Sep 17.

Faculty of Medicine and Health Technology, Tampere University, 33520 Tampere, Finland.

The authors wish to make the following corrections to this paper [...].
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/microorganisms8091426DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7563745PMC
September 2020

Maternal antioxidant intake during pregnancy and the development of cows' milk allergy in the offspring.

Br J Nutr 2021 06 18;125(12):1386-1393. Epub 2020 Sep 18.

Department of Public Health Solutions, Finnish Institute for Health and Welfare, 00271Helsinki, Finland.

Cows' milk allergy (CMA) is the most common food allergy in young children, and it is often the first manifestation of atopic diseases. Accordingly, very early environmental factors, such as maternal diet during pregnancy, may play a role in the development of CMA, but the evidence is limited. The aim of this study was to investigate the association between maternal intake of antioxidant nutrients during pregnancy and the subsequent development of CMA in the offspring in a prospective, population-based birth cohort within the Finnish Type 1 Diabetes Prediction and Prevention Study. Maternal dietary information during pregnancy was collected with a detailed, validated FFQ. The maternal dietary information and the information on putative confounding factors were available for 4403 children. Information on diagnosed CMA (n 448) was obtained from a medical registry and queried from the parents up to child's age of 3 years. The Finnish food composition database was used to calculate the average daily intake of nutrients. Logistic regression was applied for statistical analyses, and the nutrient intakes were adjusted for energy intake. OR are presented per 1 sd increment of the particular nutrient intake. Maternal total and dietary intake of β-carotene was associated with an increased risk of CMA in the offspring when adjusted for the putative confounding factors (total OR 1·10, 95 % CI 1·02, 1·20; dietary OR 1·10; 95 % CI 1·01, 1·19). Using dietary supplements containing antioxidants in addition to a balanced diet may not confer any additional benefits.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1017/S0007114520003633DOI Listing
June 2021

Extended family history of type 1 diabetes in HLA-predisposed children with and without islet autoantibodies.

Pediatr Diabetes 2020 12 1;21(8):1447-1456. Epub 2020 Oct 1.

Department of Pediatrics, PEDEGO Research Unit, Medical Research Center, University of Oulu, Oulu, Finland.

Objective: The aim of this study was to explore the extended family history of type 1 diabetes in children at genetic risk and define the impact of a positive family history on the development of islet autoimmunity and type 1 diabetes.

Methods: The subjects were participants in The Finnish Type 1 Diabetes Prediction and Prevention (DIPP) study and carried increased HLA-conferred risk for type 1 diabetes. The case children (N = 343) were positive for at least one islet autoantibody, and the control children (N = 343) matched by age, gender and class II HLA genotype were negative for islet autoantibodies at the time of data collection. Extended family history of type 1 diabetes was obtained by using a structured questionnaire.

Results: Among children who were autoantibody positive and progressed to type 1 diabetes 62.2% (28/45) had at least one relative with type 1 diabetes. Interestingly, 57.8% of these children (26/45) had such a relative outside the nuclear family compared to 30.7% of children with no autoantibodies (P = .001), 35.2% of those with only classical islet cell antibodies (P = .006), and 35.2% of non-progressors with biochemical autoantibodies (P = 0.011). A positive history of type 1 diabetes in the paternal extended family was more common in children with multiple biochemical autoantibodies compared to those with only one biochemical autoantibody (P = .010). No association between the specificity of the first appearing autoantibody and family history of the disease was found.

Conclusions: Type 1 diabetes in relatives outside the nuclear family is a significant risk factor for islet autoimmunity and progression to clinical disease in HLA susceptible children.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/pedi.13122DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7702069PMC
December 2020

Dynamics of Islet Autoantibodies During Prospective Follow-Up From Birth to Age 15 Years.

J Clin Endocrinol Metab 2020 12;105(12)

Pediatric Research Center, Children's Hospital, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.

Context: We set out to characterize the dynamics of islet autoantibodies over the first 15 years of life in children carrying genetic susceptibility to type 1 diabetes (T1D). We also assessed systematically the role of zinc transporter 8 autoantibodies (ZnT8A) in this context.

Design: HLA-predisposed children (N = 1006, 53.0% boys) recruited from the general population during 1994 to 1997 were observed from birth over a median time of 14.9 years (range, 1.9-15.5 years) for ZnT8A, islet cell (ICA), insulin (IAA), glutamate decarboxylase (GADA), and islet antigen-2 (IA-2A) antibodies, and for T1D.

Results: By age 15.5 years, 35 (3.5%) children had progressed to T1D. Islet autoimmunity developed in 275 (27.3%) children at a median age of 7.4 years (range, 0.3-15.1 years). The ICA seroconversion rate increased toward puberty, but the biochemically defined autoantibodies peaked at a young age. Before age 2 years, ZnT8A and IAA appeared commonly as the first autoantibody, but in the preschool years IA-2A- and especially GADA-initiated autoimmunity increased. Thereafter, GADA-positive seroconversions continued to appear steadily until ages 10 to 15 years. Inverse IAA seroconversions occurred frequently (49.3% turned negative) and marked a prolonged delay from seroconversion to diagnosis compared to persistent IAA (8.2 vs 3.4 years; P = .01).

Conclusions: In HLA-predisposed children, the primary autoantibody is characteristic of age and might reflect the events driving the disease process toward clinical T1D. Autoantibody persistence affects the risk of T1D. These findings provide a framework for identifying disease subpopulations and for personalizing the efforts to predict and prevent T1D.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1210/clinem/dgaa624DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7686032PMC
December 2020

Mucosal-associated invariant T cell alterations during the development of human type 1 diabetes.

Diabetologia 2020 11 3;63(11):2396-2409. Epub 2020 Sep 3.

Department of Clinical Microbiology, Institute of Clinical Medicine, University of Eastern Finland, Kuopio, Finland.

Aims/hypothesis: Mucosal-associated invariant T (MAIT) cells are innate-like T cells that recognise derivatives of bacterial riboflavin metabolites presented by MHC-Ib-related protein 1 (MR1) molecules and are important effector cells for mucosal immunity. Their development can be influenced by the intestinal microbiome. Since the development of type 1 diabetes has been associated with changes in the gut microbiome, this can be hypothesised to lead to alterations in circulating MAIT cells. Accordingly, peripheral blood MAIT cell alterations have been reported previously in patients with type 1 diabetes. However, a comprehensive analysis of the frequency and phenotype of circulating MAIT cells at different stages of type 1 diabetes progression is currently lacking.

Methods: We analysed the frequency, phenotype and functionality of peripheral blood MAIT cells, as well as γδ T cells, invariant natural killer T (iNKT) cells and natural killer (NK) cells with flow cytometry in a cross-sectional paediatric cohort (aged 2-15) consisting of 51 children with newly diagnosed type 1 diabetes, 27 autoantibody-positive (AAb) at-risk children, and 113 healthy control children of similar age and HLA class II background. The frequency of MAIT cells was also assessed in a separate cross-sectional adult cohort (aged 19-39) of 33 adults with established type 1 diabetes and 37 healthy individuals of similar age.

Results: Children with newly diagnosed type 1 diabetes displayed a proportional increase of CD8CD27 MAIT cells compared with healthy control children (median 4.6% vs 3.1% of MAIT cells, respectively, p = 0.004), which was associated with reduced expression of C-C chemokine receptor (CCR)5 (median 90.0% vs 94.3% of MAIT cells, p = 0.02) and β7 integrin (median 73.5% vs 81.7% of MAIT cells, p = 0.004), as well as decreased production of IFN-γ (median 57.1% vs 69.3% of MAIT cells, p = 0.04) by the MAIT cells. The frequency of MAIT cells was also decreased in AAb children who later progressed to type 1 diabetes compared with healthy control children (median 0.44% vs 0.96% of CD3 T cells, p = 0.04), as well as in adult patients with a short duration of type 1 diabetes (less than 6 years after diagnosis) compared with control individuals (median 0.87% vs 2.19% of CD3 T cells, p = 0.007). No alterations in γδ T cell, iNKT cell or NK cell frequencies were observed in children with type 1 diabetes or in AAb children, with the exception of an increased frequency of IL-17A γδ T cells in children with newly diagnosed diabetes compared with healthy control children (median 1.58% vs 1.09% of γδ T cells, p = 0.002).

Conclusions/interpretation: Changes in the frequency and phenotype of circulating MAIT cells were detectable before, at the onset and after diagnosis of type 1 diabetes in cross-sectional cohorts. Our results suggest a possible temporal association between peripheral blood MAIT cell alterations and the clinical onset of type 1 diabetes. Graphical abstract.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1007/s00125-020-05257-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7527319PMC
November 2020

Maternal Nitrate and Nitrite Intakes during Pregnancy and Risk of Islet Autoimmunity and Type 1 Diabetes: The DIPP Cohort Study.

J Nutr 2020 11;150(11):2969-2976

Faculty of Social Sciences, Unit of Health Sciences, Tampere University, Tampere, Finland.

Background: High dietary intake of nitrate and nitrite might increase the risk of type 1 diabetes. To our knowledge, no earlier prospective study has explored whether maternal dietary intake of nitrate and nitrite during pregnancy is associated with the risk of type 1 diabetes in the offspring.

Objective: Our aim was to study association between maternal intake of nitrate and nitrite during pregnancy and the risk of islet autoimmunity and type 1 diabetes in the offspring.

Design: Children born between 1997 and 2004 at Oulu and Tampere University Hospitals in Finland and carrying increased human leukocyte antigen (HLA)-conferred risk for type 1 diabetes were followed in the Type 1 Diabetes Prediction and Prevention (DIPP) study from 3 mo of age. Islet autoantibodies were screened at 3- to 12-mo intervals from serum samples. Of 4879 children, 312 developed islet autoimmunity and 178 developed type 1 diabetes during a 15-y follow-up. Maternal intake of nitrate and nitrite during the eighth month of pregnancy was assessed after birth using a validated self-administered FFQ. Cox proportional hazards regression was used for the statistical analyses.

Results: Maternal intake of nitrate and nitrite during pregnancy was not associated with the child's risk of islet autoimmunity [nitrate: HR 0.99 (95% CI: 0.88, 1.11); nitrite: HR 1.03 (95% CI: 0.92, 1.15)] or type 1 diabetes [nitrate: HR 1.02 (95% CI: 0.88, 1.17); nitrite: HR 0.97 (95% CI: 0.83, 1.12)] when adjusted for energy (residual method), sex, HLA risk group, and family history of diabetes. Further adjustment for dietary antioxidants (vitamin C, vitamin E, and selenium) did not change the results.

Conclusion: Maternal dietary intake of nitrate or nitrite during pregnancy is not associated with the risk of islet autoimmunity or type 1 diabetes in the offspring genetically at risk for type 1 diabetes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/jn/nxaa250DOI Listing
November 2020

Early-life exposure to perfluorinated alkyl substances modulates lipid metabolism in progression to celiac disease.

Environ Res 2020 09 30;188:109864. Epub 2020 Jun 30.

School of Science and Technology, Örebro University, Örebro, Sweden. Electronic address:

Celiac disease (CD) is a systemic immune-mediated disorder with increased frequency in the developed countries over the last decades implicating the potential causal role of various environmental triggers in addition to gluten. Herein, we apply determination of perfluorinated alkyl substances (PFAS) and combine the results with the determination of bile acids (BAs) and molecular lipids, with the aim to elucidate the impact of prenatal exposure on risk of progression to CD in a prospective series of children prior the first exposure to gluten (at birth and at 3 months of age). Here we analyzed PFAS, BAs and lipidomic profiles in 66 plasma samples at birth and at 3 months of age in the Type 1 Diabetes Prediction and Prevention (DIPP) study (n = 17 progressors to CD, n = 16 healthy controls, HCs). Plasma PFAS levels showed a significant inverse association with the age of CD diagnosis in infants who later progressed to the disease. Associations between BAs and triacylglycerols (TGs) showed different patterns already at birth in CD progressors, indicative of different absorption of lipids in these infants. In conclusion, PFAS exposure may modulate lipid and BA metabolism, and the impact is different in the infants who develop CD later in life, in comparison to HCs. The results indicate more efficient uptake of PFAS in such infants. Higher PFAS exposure during prenatal and early life may accelerate the progression to CD in the genetically predisposed children.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.envres.2020.109864DOI Listing
September 2020

HLA-DR-DQ haplotypes and specificity of the initial autoantibody in islet specific autoimmunity.

Pediatr Diabetes 2020 11 23;21(7):1218-1226. Epub 2020 Jul 23.

Immunogenetics Laboratory, Institute of Biomedicine, University of Turku, Turku, Finland.

Objective: We aimed to clarify the association of various HLA risk alleles with different types of autoantibodies initiating islet specific autoimmunity.

Methods: Follow-up cohorts from the Finnish Type 1 Diabetes Prediction and Prevention (DIPP) study and children diagnosed with type 1 diabetes (T1D) from the Finnish Pediatric Diabetes Register (FPDR) were analyzed for the presence of autoantibodies to insulin (IAA), glutamic acid decarboxylase (GADA), IA-2 antigen (IA-2A), and zinc transporter 8 (ZnT8A); and genotyped for HLA DR/DQ alleles. In the DIPP study, autoantibodies were regularly analyzed from birth up to 15 years of age.

Results: In the DIPP cohort, 621 children developed one single persistent autoantibody, GADA in 284, IAA in 268, and IA-2A in 40 cases. Highly significant differences in the specificity of the first autoantibody were observed between HLA genotypes. Homozygotes for the DR3-DQ2 haplotype had almost exclusively GADA as the first autoantibody, whereas a more even distribution between GADA and IAA was found in DR3-DQ2/DR4-DQ8 as well as DR3-DQ/x and DR4-DQ8/x genotypes (x referring to neutral haplotypes). In DR4-DQ8 positive genotypes with the DRB1*04:01 allele IAA was more often the first autoantibody than in DRB1*04:04 positive genotypes. Various neutral haplotypes also significantly affected the relative proportions of different initial autoantibodies. These findings were confirmed and expanded in a series of 1591 T1D children under the age of 10 years from FPDR.

Conclusions: These results emphasize the importance of HLA class II polymorphisms in the recognition of autoantigen epitopes in the initiation of various pathways of the autoimmune response.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1111/pedi.13073DOI Listing
November 2020

Multiplexed High-Throughput Serological Assay for Human Enteroviruses.

Microorganisms 2020 Jun 26;8(6). Epub 2020 Jun 26.

Faculty of Medicine and Health Technology, Tampere University, 33520 Tampere, Finland.

Immunological assays detecting antibodies against enteroviruses typically use a single enterovirus serotype as antigen. This limits the ability of such assays to detect antibodies against different enterovirus types and to detect possible type-specific variation in antibody responses. We set out to develop a multiplexed assay for simultaneous detection of antibodies against multiple enterovirus and rhinovirus types encompassing all human infecting species. Seven recombinant VP1 proteins from enteroviruses EV-A to EV-D and rhinoviruses RV-A to RV-C species were produced. Using Meso Scale Diagnostics U-PLEX platform we were able to study antibody reactions against these proteins as well as non-structural enterovirus proteins in a single well with 140 human serum samples. Adults had on average 33-fold stronger antibody responses to these antigens ( < 10) compared to children, but children had less cross-reactivity between different enterovirus types. The results suggest that this new high-throughput assay offers clear benefits in the evaluation of humoral enterovirus immunity in children, giving more exact information than assays that are based on a single enterovirus type as antigen.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/microorganisms8060963DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7355947PMC
June 2020

Characterization of Proinsulin T Cell Epitopes Restricted by Type 1 Diabetes-Associated HLA Class II Molecules.

J Immunol 2020 05 30;204(9):2349-2359. Epub 2020 Mar 30.

Department of Clinical Microbiology, Institute of Clinical Medicine, University of Eastern Finland, FI-70210 Kuopio, Finland;

Type 1 diabetes (T1D) is a T cell-mediated autoimmune disease in which the insulin-producing β cells within the pancreas are destroyed. Identification of target Ags and epitopes of the β cell-reactive T cells is important both for understanding T1D pathogenesis and for the rational development of Ag-specific immunotherapies for the disease. Several studies suggest that proinsulin is an early and integral target autoantigen in T1D. However, proinsulin epitopes recognized by human CD4 T cells have not been comprehensively characterized. Using a dye dilution-based T cell cloning method, we generated and characterized 24 unique proinsulin-specific CD4 T cell clones from the peripheral blood of 17 individuals who carry the high-risk DR3-DQ2 and/or DR4-DQ8 HLA class II haplotypes. Some of the clones recognized previously reported DR4-restricted epitopes within the C-peptide (C25-35) or A-chain (A1-15) of proinsulin. However, we also characterized DR3-restricted epitopes within both the B-chain (B16-27 and B22-C3) and C-peptide (C25-35). Moreover, we identified DQ2-restricted epitopes within the B-chain and several DQ2- or DQ8-restricted epitopes within the C-terminal region of C-peptide that partially overlap with previously reported DQ-restricted epitopes. Two of the DQ2-restricted epitopes, B18-26 and C22-33, were shown to be naturally processed from whole human proinsulin. Finally, we observed a higher frequency of CDR3 sequences matching the TCR sequences of the proinsulin-specific T cell clones in pancreatic lymph node samples compared with spleen samples. In conclusion, we confirmed several previously reported epitopes but also identified novel (to our knowledge) epitopes within proinsulin, which are presented by HLA class II molecules associated with T1D risk.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.4049/jimmunol.1901079DOI Listing
May 2020

Enhancing and neutralizing anti-coxsackievirus activities in serum samples from patients prior to development of type 1 diabetes.

Diabetes Metab Res Rev 2020 09 25;36(6):e3305. Epub 2020 Mar 25.

Univ Lille, CHU Lille, Laboratoire de virologie ULR3610 F-59000 Lille, France.

Background: Studies in prospective cohorts have suggested that enterovirus infections are associated with the appearance of islet autoantibodies that precede later appearance of type 1 diabetes (T1D). It was shown that in addition to an antibody-mediated anti-coxsackievirus (CV)-B neutralizing activity of serum from patients with T1D, there was also enhancing anti-CV-B activity in vitro. In this study, the patterns of enhancing and neutralizing anti-CV activities were analysed from consecutive serum samples collected from children who were followed from birth until they developed T1D in the Finnish Type 1 Diabetes Prediction and Prevention (DIPP) study and compared to those in non-diabetic control children.

Methods: The titres of serum neutralizing activity were analysed against those CVs which were detected in the stools in these children (CV-B3, CV-B5 or CV-A4) using plaque assay. The enhancing activity of these serum samples was analysed by measuring interferon-alpha (INF-α) production in cultures of peripheral blood mononuclear cells (PBMC) inoculated with a mixture of these viruses and diluted serum.

Results: A sustained anti-CV enhancing activity was observed in consecutive serum samples in patients with T1D. The pattern of responses differed between children who developed T1D and control children. In patients, the anti-CV enhancing activity was predominant or even exclusive over the neutralizing activity, whereas in controls the enhancing and neutralising activities were more balanced or the neutralizing activity was largely predominant.

Conclusions: Evaluating the anti-enterovirus neutralizing and enhancing activity of serum samples can be useful to investigate further the relationship between enteroviruses and the development of T1D.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/dmrr.3305DOI Listing
September 2020
-->