Jorma Ilonen

University of Eastern Finland, Kuopio, Northern Savo, Finland

Are you Jorma Ilonen?

Claim your profile

Publications (504)2515.99 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Objective: This study assessed the relationship between autoantibodies against zinc transporter 8 (ZnT8A) and disease characteristics at diagnosis of type 1 diabetes and during the first 2 years. Research design and methods: Children, younger than 15 years of age (n = 723) newly diagnosed with diabetes, were analyzed for ZnT8A, other diabetes-associated autoantibodies, HLA DR-DQ alleles, and metabolic status, which was monitored by pH, plasma glucose, and occurrence of ketoacidosis at diagnosis and through follow-up of C-peptide concentrations, exogenous insulin dose, and glycosylated hemoglobin for two years after the diagnosis. Results: ZnT8A-positivity was detected in 530 children (73%). Positivity for ZnT8A was associated with older age (median 8.9 vs. 8.2 years, P = 0.002) and more frequent ketoacidosis (24% vs. 15%, P = 0.013). Children carrying the HLA DR3 allele were less often ZnT8A positive (66% vs. 77%, P = 0.002) than others. ZnT8A-positive children had lower serum C-peptide concentrations (P = 0.008) and higher insulin doses (P = 0.012) over time than their ZnT8A-negative peers. Conclusions: Positivity for ZnT8A at diagnosis seems to reflect a more aggressive disease process before and after diagnosis.
    Diabetes care 10/2015; DOI:10.2337/dc15-1027 · 8.42 Impact Factor

  • PLoS ONE 09/2015; 10(9):e0139096. DOI:10.1371/journal.pone.0139096 · 3.23 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: SETTING: Complications arising from bacille Calmette-Guérin (BCG) vaccination were recorded in a national register in Finland until 1988. In the period 1960–1988, 222 patients suffered from BCG osteitis. OBJECTIVE: To evaluate whether single nucleotide polymorphisms (SNPs) in the promoter region of the gene encoding interleukin 10 (IL-10) are associated with BCG osteitis after vaccination in neonates. DESIGN: Blood samples of 132 former BCG osteitis patients now aged 21–49 years were analysed in a controlled study for IL10 rs1800896 (−1082G/A), rs1800871 (−819C/T), rs1800872 (−592C/A) and rs1800890 (−3575T/A) polymorphisms. RESULTS: The frequencies of genotypes of IL10 rs1800896, rs1800871, rs1800872 and rs1800890, the frequencies of variant genotypes and the frequencies of major or minor alleles did not differ between patients and controls. Furthermore, the frequencies of the eight possible combinations of the three IL10 alleles located close to each other (IL10 rs1800896, IL10 rs1800871 and IL10 rs1800872) were surprisingly similar. CONCLUSION: Our results suggest that polymorphisms of the IL-10 encoding gene do not play a central role in the development of complications due to BCG vaccination, although the IL10 gene, especially IL10 rs1800896 (−1082G/A) polymorphism, is known to be associated with tuberculosis risk in Europeans and North Americans.
    The International Journal of Tuberculosis and Lung Disease 09/2015; 19(10):1158-1162. DOI:10.5588/ijtld.15.0348 · 2.32 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Viral infections have long been considered potential triggers of beta cell autoimmunity and type 1 diabetes. Recent studies have suggested that influenza A virus might increase the risk of type 1 diabetes. The present study evaluates this risk association in prospectively observed children at the time when islet autoimmunity starts and autoantibodies are first detected. IgG class antibodies to influenza A virus were analysed in 95 case children whose antibody screening test turned permanently positive for two or more islet autoantibodies and from 186 autoantibody-negative and non-diabetic control children who were matched for time of birth, sex, date of sampling and HLA-conferred risk of diabetes in the Finnish Type 1 Diabetes Prediction and Prevention (DIPP) study. Virus antibodies were measured from the first autoantibody-positive sample using an enzyme immunoassay. None of the children had been vaccinated against influenza A. The prevalence of influenza A virus antibodies did not differ between the case and control children (42% vs 38%; p = 0.392) and the median antibody levels were also comparable in the two groups (3.0 vs 3.8 enzyme immunoassay units). A similar result was obtained when case and control children were compared separately in subgroups according to different sex, age and HLA-DQ genotype. However, girls had higher antibody levels than boys among both case and control children (median antibody levels 9.0 vs 2.3 enzyme immunoassay units; p = 0.01). Our results suggest that influenza A infections are not associated with the development of islet autoimmunity in young children with increased genetic susceptibility to type 1 diabetes.
    Diabetologia 08/2015; DOI:10.1007/s00125-015-3723-4 · 6.67 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The development of gliadin-specific antibody and T-cell responses were longitudinally monitored in young children with genetic risk for celiac disease (CD). 291 newborn children positive for HLA-DQB1*02 and -DQA1*05 alleles were followed until 3-4 years of age by screening for tissue transglutaminase autoantibodies (tTGA) by using a commercial ELISA-based kit and antibodies to deamidated gliadin peptide (anti-DGP) by an immunofluorometric assay. Eighty-five of the children were also followed for peripheral blood gliadin-specific CD4(+) T-cell responses by using a carboxyfluorescein diacetate succinimidyl ester-based in vitro proliferation assay. The cumulative incidence of tTGA seropositivity during the follow-up was 6.5%. CD was diagnosed in nine of the tTGA-positive children (3.1%) by duodenal biopsy at a median 3.5 years of age. All of the children with confirmed CD were both IgA and IgG anti-DGP positive at the time of tTGA seroconversion and in over half of the cases IgG anti-DGP positivity even preceded tTGA seroconversion. Peripheral blood T-cell responses to deamidated and native gliadin were detected in 40.5% and 22.2% of the children at the age of 9 months and these frequencies decreased during the follow-up to the levels of 22.2% and 8.9%, respectively. Anti-DGP antibodies may precede tTGA seroconversion and thus frequent monitoring of both tTGA and anti-DGP antibodies may allow earlier detection of CD in genetically susceptible children. Peripheral blood gliadin-specific T-cell responses are relatively common in HLA-DQ2-positive children and are not directly associated with the development of CD.
    Scandinavian Journal of Gastroenterology 07/2015; 51(2):1-10. DOI:10.3109/00365521.2015.1067328 · 2.36 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: In addition to the HLA region numerous other gene loci have shown association with type 1 diabetes. How these polymorphisms exert their function has not been comprehensively described, however. We assessed the effect of 39 single nucleotide polymorphisms (SNP) on the development of autoantibody positivity, on progression from autoantibody positivity to clinical disease and on the specificity of the antibody initiating the autoimmune process in 521 autoantibody-positive and 989 control children from a follow-up study starting from birth. Interestingly, PTPN2 rs45450798 gene polymorphism was observed to strongly affect the progression rate of beta-cell destruction after the appearance of humoral beta-cell autoimmunity. Moreover, primary autoantigen dependent associations were also observed as effect of the IKZF4-ERBB3 region on the progression rate of β-cell destruction was restricted to children with GAD antibodies as their first autoantibody whereas the effect of the INS rs 689 polymorphism was observed among subjects with insulin as the primary autoantigen. In the whole study cohort, INS rs689, PTPN22 rs2476601 and IFIH1 rs1990760 polymorphisms were associated with the appearance of beta-cell autoantibodies. These findings provide new insights into the role of genetic factors implicated in the pathogenesis of type 1 diabetes. The effect of some of the gene variants is restricted to control the initiation of β-cell autoimmunity whereas others modify the destruction rate of the β-cells. Furthermore, signs of primary autoantigen-related pathways were detected. Copyright © 2015 Elsevier Ltd. All rights reserved.
    Journal of Autoimmunity 06/2015; 61. DOI:10.1016/j.jaut.2015.05.005 · 8.41 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: We assessed the utility of the OGTT and random plasma glucose concentrations in predicting the time to diagnosis of type 1 diabetes. A population-derived cohort of 14,876 newborns with HLA-conferred risk of type 1 diabetes were invited to regular follow-up for islet autoantibodies. When two or more autoantibodies were detected, an OGTT was performed once a year and random plasma glucose analysed twice a year. During follow-up, 567 children developed multiple autoantibodies, 255 (45%) of whom were diagnosed with type 1 diabetes, while 312 remained non-diabetic by December 2011. Impaired fasting glucose (IFG) and impaired glucose tolerance (IGT) were risk factors for type 1 diabetes (HR 3.2 [95% CI 1.5, 7.0] and 8.3 [95% CI 6.0, 11.5], respectively). When a random plasma glucose value ≥7.8 mmol/l was observed, the HR for diabetes was 6.0 (95% CI 4.3, 8.6). The median time to diagnosis after the detection of IFG was 5.2 years (interquartile range [IQR] 3.4, 6.3); after IGT, 0.7 years (IQR 0.3, 1.9); and, after a random plasma glucose ≥7.8 mmol/l, 1.0 years (IQR 0.3, 1.5). In a retrospective analysis, both OGTT-derived 2 h plasma glucose and random plasma glucose started to increase 1.5 years before diagnosis (p < 0.001 and p = 0.004, respectively). Dysglycaemia detected in an OGTT or based on random plasma glucose is a useful marker in the prediction of time to onset of type 1 diabetes in high-risk children. Random plasma glucose is a simple and low-cost measurement with comparable predictive characteristics to that of OGTT-derived 2 h glucose.
    Diabetologia 05/2015; 58(8). DOI:10.1007/s00125-015-3621-9 · 6.67 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: GTPase of the immunity-associated protein (GIMAP) family members are differentially regulated during human Th cell differentiation and have been previously connected to immune-mediated disorders in animal studies. GIMAP4 is believed to contribute to the Th cell subtype-driven immunological balance via its role in T cell survival. GIMAP5 has a key role in BB-DR rat and NOD mouse lymphopenia. To elucidate GIMAP4 and GIMAP5 function and role in human immunity, we conducted a study combining genetic association in different immunological diseases and complementing functional analyses. Single nucleotide polymorphisms tagging the GIMAP haplotype variation were genotyped in Finnish type 1 diabetes (T1D) families and in a prospective Swedish asthma and allergic sensitization birth cohort. Initially, GIMAP5 rs6965571 was associated with risk for asthma and allergic sensitization (odds ratio [OR] 3.74, p = 0.00072, and OR 2.70, p = 0.0063, respectively) and protection from T1D (OR 0.64, p = 0.0058); GIMAP4 rs13222905 was associated with asthma (OR 1.28, p = 0.035) and allergic sensitization (OR 1.27, p = 0.0068). However, after false discovery rate correction for multiple testing, only the associations of GIMAP4 with allergic sensitization and GIMAP5 with asthma remained significant. In addition, transcription factor binding sites surrounding the associated loci were predicted. A gene-gene interaction in the T1D data were observed between the IL2RA rs2104286 and GIMAP4 rs9640279 (OR 1.52, p = 0.0064) and indicated between INS rs689 and GIMAP5 rs2286899. The follow-up functional analyses revealed lower IL-2RA expression upon GIMAP4 knockdown and an effect of GIMAP5 rs2286899 genotype on protein expression. Thus, the potential role of GIMAP4 and GIMAP5 as modifiers of immune-mediated diseases cannot be discarded. Copyright © 2015 by The American Association of Immunologists, Inc.
    The Journal of Immunology 05/2015; 194(12). DOI:10.4049/jimmunol.1500016 · 4.92 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: OBJECTIVE: This study aimed at investigating the role of IGF-I and IGF binding protein 3 (IGFBP-3) in the development of β-cell autoimmunity. METHODS: Five hundred sixty-three subjects with HLA-conferred susceptibility to type 1 diabetes were monitored for signs of seroconversion to positivity for insulin and/or GAD, IA-2, and ZnT8 autoantibodies by the age of 3 years. In 40 subjects who developed at least one autoantibody, IGF-I and IGFBP-3 plasma concentrations were measured and compared with 80 control subjects who remained negative for autoantibodies, and were matched for age, sex, country of origin, and HLA genotype. The increment of IGF-I, IGFBP-3 and IGF-I/IGFBP-3 molar ratio before and after seroconverison was compared with corresponding time intervals in controls. RESULTS: The IGF-I concentrations at the age of 12 months, and the IGF-I/IGFBP-3 ratio at the age of 24 months were lower in the autoantibody-positive children (P <0.05). The increase in circulating IGFBP-3 was significantly higher in the autoantibody-positive children before seroconversion than in the corresponding time-intervals in controls (0.43 mg/l; 95% CI 0.29-0.56 vs. 0.22 mg/l; 95% CI 0.10-0.34 mg/l; P <0.01). Children carrying the high-risk HLA genotype had lower plasma IGF-I and IGFBP-3 concentrations at the age of 24 months than those with low-risk genotypes (P < 0.05 and < 0.01, respectively). CONCLUSIONS: Circulating IGF-I and IGFBP-3 appear to have a role in early development of β-cell autoimmunity. The decreased IGF-I concentrations in children with the high-risk HLA genotype may contribute to the reduced growth previously described in such children.
    European Journal of Endocrinology 05/2015; 173(2). DOI:10.1530/EJE-14-1078 · 4.07 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Age-related changes in DNA methylation occurring in blood leukocytes during early childhood may reflect epigenetic maturation. We hypothesized that some of these changes involve gene networks of critical relevance in leukocyte biology and conducted a prospective study to elucidate the dynamics of DNA methylation. Serial blood samples were collected at 3, 6, 12, 24, 36, 48 and 60 months after birth in ten healthy girls born in Finland and participating in the Type 1 Diabetes Prediction and Prevention Study. DNA methylation was measured using the HumanMethylation450 BeadChip. After filtering for the presence of polymorphisms and cell-lineage-specific signatures, 794 CpG sites showed significant DNA methylation differences as a function of age in all children (41.6% age-methylated and 58.4% age-demethylated, Bonferroni-corrected P value <0.01). Age-methylated CpGs were more frequently located in gene bodies and within +5 to +50 kilobases (kb) of transcription start sites (TSS) and enriched in developmental, neuronal and plasma membrane genes. Age-demethylated CpGs were associated to promoters and DNAse-I hypersensitivity sites, located within -5 to +5 kb of the nearest TSS and enriched in genes related to immunity, antigen presentation, the polycomb-group protein complex and cytoplasm. This study reveals that susceptibility loci for complex inflammatory diseases (for example, IRF5, NOD2, and PTGER4) and genes encoding histone modifiers and chromatin remodeling factors (for example, HDAC4, KDM2A, KDM2B, JARID2, ARID3A, and SMARCD3) undergo DNA methylation changes in leukocytes during early childhood. These results open new perspectives to understand leukocyte maturation and provide a catalogue of CpG sites that may need to be corrected for age effects when performing DNA methylation studies in children.
    03/2015; 7(1):34. DOI:10.1186/s13148-015-0064-6
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Objective Some studies have compared the occurrence of croup with air pollution. Results have so far remained contradictory. Motor vehicles represent the principal source of air pollution in the city of Vinnytsya, Ukraine. The objective of this study was to determine the relation of traffic load to traffic-dependent pollutants and croup. Methods Among a population of 8.067 children in residence near areas of high traffic density (>1.500 motor vehicles/ hour) and 2.473 children in residence near areas of low traffic density (<300 motor vehicles/ hour) cases of croup were registered by physicians during a 4 years period in 2000–03. Air pollution by sulfur dioxide (SO2), nitrogen dioxide (NO2), particulate matter, carbon monoxide (CO) were locally measured. Results Areas with high traffic load are characterised by higher concentration of traffic-dependent pollutants and higher annual incidence of croup (Table). Table. Traffic load, traffic-dependent pollutants and annual incidence of croup in children (Vinnytsya, Ukraine, 2000–2003) Conclusions Croup in children is related to traffic load and traffic-dependent pollutants (SO2, NO2, particulate matter, CO).
    The Pediatric Infectious Disease Journal 03/2015; 99(Suppl 2). DOI:10.1097/INF.0000000000000691 · 2.72 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Background The study aimed to define the frequencies of type 1 diabetes-associated gene polymorphisms and their associations with various diabetes-associated autoantibodies in Egyptian children.Methods One hundred one children with type 1 diabetes and 160 healthy controls from the same region were studied for HLA-DQB1, -DQA1 and -DRB1 (DR4 subtypes) alleles, INS and PTPN22 gene polymorphisms (rs689 and rs2476601) and for diabetes-associated autoantibodies.ResultsMost diabetic children (77.2%) were positive for the HLA-(DR3)-DQA1*05-DQB1*02 (DR3-DQ2) haplotype compared to 26.2% of the controls (OR = 9.5; p < 0.001). HLA-DRB1*04:02-DQA1*03-DQB1*03:02 (DR4-DQ8) (26.7%, OR = 3.3; p < 0.001), DRB1*04:05-DQA1*03-DQB1*02 (DR4-DQ2) (23.8%, OR 5.2; p < 0.001) and DRB1*04:05-DQA1*03-DQB1*03:02 (DR4-DQ8) (8.9%, OR = 7.7; p = 0.007) were also significantly increased. HLA-(DR15)-DQB1*06:01, (DR13)-DQB1*06:03 and DRB1*04:03-DQA1*03-DQB1*03:02 were the most protective haplotypes with OR values from 0.04 to 0.06. Patients positive for DR3-DQ2 but negative for DR4 haplotypes had a high frequency of GAD antibodies (78%; p <0.001 vs. other genotypes) but only 26.6% of those with DR3-DQ2/DR4-DQ2 tested positive for GAD antibodies (p = 0.006 vs. other genotypes). Subjects with the DR4-DQ8 haplotype without DR3-DQ2 or DR4-DQ2 were more often positive for IA-2 and ZnT8 antibodies (55.5%; p =0.007 and 55.5%, p =0.01, respectively). The AA genotype of INS gene was more common in patients than controls (75.2% vs 59.5%, OR = 2.07; p = 0.018).Conclusions Besides a strong HLA-DR3-DQ2 association a relatively high frequency of the DR4-DQ2 haplotype characterized the diabetic population. The low frequency of autoantibodies in children with HLA-DR4-DQ2 may indicate specific pathogenetic pathways associated with this haplotype. This article is protected by copyright. All rights reserved.
    Diabetes/Metabolism Research and Reviews 03/2015; 31(3). DOI:10.1002/dmrr.2609 · 3.55 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The rate of inflammation increases in elderly individuals, a phenomenon called inflammaging, and is associated with degenerative diseases. However, the causes of inflammaging and the origin of the associated inflammatory mediators have remained enigmatic. We show herein that there is a positive correlation between the number of sons born and C-reactive protein concentrations in 90-year-old women. This association is influenced by HLA genetics known to regulate the immune response against HY antigens.
    Scientific Reports 02/2015; 5:8631. DOI:10.1038/srep08631 · 5.58 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: The consumption of foods rich in n-3 polyunsaturated fatty acids has been proposed to protect against childhood asthma. This study explores the association of food consumption (including cow's milk (CM) free diet) in early life, and the risk of atopic and non-atopic asthma. Food intake of 182 children with asthma and 728 matched controls was measured using three-day food records, within the Finnish Type 1 Diabetes Prediction and Prevention (DIPP) -Nutrition Study cohort. The diagnoses of food allergies came both from the written questionnaire and from the registers of the Social Insurance Institution. Conditional logistic regression with generalized estimating equations framework was used in the analyses. The diagnosis of cow's milk allergy (CMA) led to multiple dietary restrictions still evident at four years of age. Even after adjusting for CMA, higher consumption of CM products was inversely associated with the risk of atopic asthma and higher consumption of breast milk and oats inversely with the risk of non-atopic asthma. Early consumption of fish was associated with a decreased risk of all asthma. Dietary intake in early life combined with atopy history has a clear impact on the risk of developing asthma. Our results indicate that CM restriction due to CMA significantly increases and mediates the association between food consumption and childhood asthma risk. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.
    Pediatric Allergy and Immunology 02/2015; DOI:10.1111/pai.12352 · 3.40 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: This study used next-generation sequencing (NGS) technologies to characterize the gut virome at the onset of islet autoimmunity. We conducted a case-control study nested within the Finnish Diabetes Prediction and Prevention cohort. The stool virome in 19 case children, who turned islet autoantibody positive before the age of 2 years and later developed clinical type 1 diabetes, and 19 tightly matched control subjects was analyzed using NGS performed from stool samples collected 3, 6, and 9 months before the onset of islet autoimmunity. Human virus findings were verified using real-time PCR. One or more human viruses were present in 10.4% and bacteriophages in 54% of the samples. The virome composition showed no association with islet autoimmunity. NGS was less sensitive and specific than real-time PCR. The present data suggest no dramatic changes in the gut virome shortly before the emergence of islet autoimmunity and emphasize the need of verification of mass sequencing results when viral exposure is assessed in association studies. © 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.
    Diabetes Care 02/2015; 38(5). DOI:10.2337/dc14-2490 · 8.42 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Islet autoantibodies, in addition to elevated blood glucose, define type 1 diabetes. These autoantibodies are detectable for a variable period of time before diabetes onset. Thus, the occurrence of islet autoantibodies is associated with the beginning of the disease process. The age at, and order in, which autoantibodies appear may be associated with different genetic backgrounds or environmental exposures, or both. Infants with HLA-DR high-risk genotypes (DR3/4, DR4/4, DR4/8 and DR3/3) were enrolled and prospectively followed with standardised autoantibody assessments quarterly throughout the first 4 years of life and then semi-annually thereafter. Autoantibodies appeared in 549/8,503 (6.5%) children during 34,091 person-years of follow-up. Autoantibodies at 3 (0.1%) and 6 (0.2%) months of age were rare. Of the 549, 43.7% had islet autoantibodies to insulin (IAA) only, 37.7% had glutamic acid decarboxylase autoantibodies (GADA) only, 13.8% had both GADA and IAA only, 1.6% had insulinoma antigen-2 only and 3.1% had other combinations. The incidence of IAA only peaked within the first year of life and declined over the following 5 years, but GADA only increased until the second year and remained relatively constant. GADA only were more common than IAA only in HLA-DR3/3 children but less common in HLA-DR4/8 children. Islet autoantibodies can occur very early in life and the order of appearance was related to HLA-DR-DQ genotype.
    Diabetologia 02/2015; 58(5). DOI:10.1007/s00125-015-3514-y · 6.67 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Colonization of the fetal and infant gut microbiome results in dynamic changes in diversity, which can impact disease susceptibility. To examine the relationship between human gut microbiome dynamics throughout infancy and type 1 diabetes (T1D), we examined a cohort of 33 infants genetically predisposed to T1D. Modeling trajectories of microbial abundances through infancy revealed a subset of microbial relationships shared across most subjects. Although strain composition of a given species was highly variable between individuals, it was stable within individuals throughout infancy. Metabolic composition and metabolic pathway abundance remained constant across time. A marked drop in alpha-diversity was observed in T1D progressors in the time window between seroconversion and T1D diagnosis, accompanied by spikes in inflammation-favoring organisms, gene functions, and serum and stool metabolites. This work identifies trends in the development of the human infant gut microbiome along with specific alterations that precede T1D onset and distinguish T1D progressors from nonprogressors. Copyright © 2015 Elsevier Inc. All rights reserved.
    Cell Host & Microbe 02/2015; 17(2). DOI:10.1016/j.chom.2015.01.001 · 12.33 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: AimsOur aim was to study whether immune responses to wheat-based proteins are related to the development of type 1 diabetes.Methods We analysed proliferative T-cell responses after in vitro gliadin, gluten, whole wheat, and tetanus toxoid stimulation with a carboxyfluorescein succinimidyl ester (CFSE) based T-cell proliferation assay in children at various phases of type 1 diabetes autoimmunity and in healthy autoantibody-negative control children.ResultsAt an early stage of beta cell autoimmunity the strength and frequencies of positive proliferation responses to gliadin, gluten, and whole wheat did not differ between newly seroconverted children positive for one islet autoantibody and the controls. However, in prediabetic children with at least two islet autoantibodies and also in children with newly diagnosed type 1 diabetes positive T-cell responses to gliadin were significantly less frequent and the strength of gliadin responses was reduced when compared to the controls. No differences were seen in T-cell responses to wheat-based antigens when comparing children with long-lasting type 1 diabetes with healthy controls.Conclusions/InterpretationDecreased in vitro T-cell responses to wheat-based antigens were observed in children with multiple islet autoantibodies and in those with newly diagnosed type 1 diabetes, probably reflecting a generally aberrant immune response during the development of type 1 diabetes.
    Pediatric Diabetes 01/2015; 16(3). DOI:10.1111/pedi.12256 · 2.57 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: We determined longitudinal serum proteomics profiles from children with HLA-conferred diabetes susceptibility to identify changes that could be detected before seroconversion and positivity for disease-associated autoantibodies. Comparisons were made between children who seroconverted and progressed to type 1 diabetes (progressors) and those who remained autoantibody negative, matched by age, gender, sample periodicity and risk group. The samples represented the pre-diabetic period and ranged from the age of 3 months to 12 years.Following immunoaffinity-depletion of the most abundant serum proteins, isobaric Tags for Relative and Absolute Quantification (iTRAQ) were used for sample labelling. Quantitative proteomic profiles were thus measured for 13 case-control pairs by HPLC-tandem mass spectrometry (LC-MS/MS). Additionally, a label free LC-MS/MS approach was used to analyze depleted sera from six case-control pairs.Importantly, differences in abundance of a set of proteins were consistently detected already before the appearance of autoantibodies in the progressors. On the basis of top scoring pair analysis, classification of such progressors was observed with a high success rate. Overall the data provides a reference of temporal changes in the serum proteome in healthy children and children who develop type 1 diabetes, including new protein candidates, the levels of which change prior to clinical diagnosis. © 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.
    Diabetes 01/2015; 64(6). DOI:10.2337/db14-0983 · 8.10 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Dietary advanced glycation end products (AGEs) and their interactions with the receptor for AGEs (RAGE) may play a role in the pathogenesis of type 1 diabetes. This study set out to assess whether there is any association between circulating concentrations of soluble RAGE (sRAGE), AGEs, and their ratio with the appearance of diabetes-associated autoantibodies in children progressing to clinical diabetes. Serum concentrations of sRAGE, N-ε(carboxymethyl)lysine (CML) adducts and the sRAGE/CML ratio were analyzed in children who progressed to type 1 diabetes. The samples were taken at four time points: before seroconversion, at the time of the first autoantibody-positive sample, at the time of the first sample positive for multiple (>2) autoantibodies, and close to the disease diagnosis. Samples of autoantibody-negative controls matched for age, sex, and HLA-conferred diabetes risk were analyzed at corresponding time points. The prediabetic children had higher sRAGE concentrations before seroconversion (Pc = 0.03), at the appearance of multiple autoantibodies (Pc = 0.008), and close to diagnosis (Pc = 0.04). Close to diagnosis, the cases had lower CML concentrations than the controls (Pc = 0.004). Prediabetic children had a higher sRAGE/CML ratio than the controls before seroconversion (Pc = 0.008) and at diagnosis (Pc < 0.001). Prediabetic children have higher concentrations of sRAGE and a higher sRAGE/CML ratio than healthy controls. Circulating sRAGE concentrations seem to decline with the appearance of diabetes-predictive autoantibodies in children progressing to type 1 diabetes. The higher sRAGE/CML ratio in prediabetic children may reflect a higher AGE scavenger capacity. © 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.
    Diabetes Care 01/2015; 38(4). DOI:10.2337/dc14-1186 · 8.42 Impact Factor

Publication Stats

13k Citations
2,515.99 Total Impact Points


  • 2010-2015
    • University of Eastern Finland
      • Institute of Biomedicine
      Kuopio, Northern Savo, Finland
  • 1981-2015
    • University of Turku
      • • Department of Paediatrics
      • • Department of Virology
      Turku, Varsinais-Suomi, Finland
  • 2006-2011
    • University of Kuopio
      • Department of Clinical Microbiology
      Kuopio, Eastern Finland Province, Finland
  • 1992-2011
    • University of Helsinki
      • • The Hospital for Children and Adolescents
      • • Department of Pediatrics
      Helsinki, Uusimaa, Finland
  • 1978-2009
    • University of Oulu
      • • Department of Neurology
      • • Department of Medical Microbiology
      • • Department of Paediatrics
      • • Department of Dermatology and Venereology
      Uleoborg, Oulu, Finland
  • 2000-2006
    • Turku centre for biotechnology, finland
      Turku, Province of Western Finland, Finland
  • 1983-2006
    • National Public Health Institute
      Helsinki, Southern Finland Province, Finland
  • 1999
    • Turku University Hospital
      • Department of Pediatrics
      Turku, Varsinais-Suomi, Finland
  • 1994-1997
    • University of Tampere
      • • Medical School
      • • Institute of Biomedical Sciences
      Tampere, Western Finland, Finland
  • 1995
    • SickKids
      Toronto, Ontario, Canada
  • 1986
    • Oulu University Hospital
      Uleoborg, Oulu, Finland
  • 1984
    • Finnish Red Cross Blood Service
      Helsinki, Uusimaa, Finland