J Ilonen

University of Eastern Finland, Kuopio, Northern Savo, Finland

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Publications (494)2457.05 Total impact

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    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; DOI:10.4049/jimmunol.1500016 · 5.36 Impact Factor
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    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; DOI:10.1530/EJE-14-1078 · 3.69 Impact Factor
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    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
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    ABSTRACT: Streptococcus pneumoniae is a common respiratory pathogen and up to 50% of children acquire S. pneumoniae in their nasopharynx during the first 12 months of life. The cytokine interleukin-17A (IL-17A) plays an important role in host defense against extracellular bacterial pathogens. We investigated the effect of IL-17 G-152A polymorphism on pneumococcal colonization in children. Methods: Nasopharyngeal swabs (NP) and blood samples were collected from healthy Finnish children at 2.6 (N=405), 13 (N=198) and 24 (N=176) months of age. Of them, 160 had both NP and blood samples at each time-point. The semi-quantitative culture method was used for bacterial culture, Sequenom iPlex Gold System for IL-17A genotyping and Luminex 200 for serum IL-17A determination. Results: The frequency of IL-17 G-152A genotypes G/G, G/A and A/A was 36%, 45% and 19% in 405 studied subjects, respectively. The colonization rates of S. pneumoniae increased from 10% at 2.6 months to 33% at 24 months of age. Significantly higher pneumococcal colonization was found in subjects with A/A genotype at 13 and 24 months of age compared to those with G/G (RR, 2.30; P=0.02; RR, 1.91, P=0.03). This genotype was associated with lower levels of serum IL-17A and only 6% of subjects with A/A had detectable serum IL-17A compared to 75% and 33% of subjects with G/G and G/A (P<0.001, P<0.01). Conclusions: Our results indicate that IL-17 G-152A is associated with increased colonization rate of S. pneumoniae in young children, suggesting that IL-17A plays an important role in protection against pneumococcal colonization.
    The Pediatric Infectious Disease Journal 03/2015; DOI:10.1097/INF.0000000000000691 · 3.14 Impact Factor
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    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 · 3.59 Impact Factor
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    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 · 5.08 Impact Factor
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    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 · 3.86 Impact Factor
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    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 · 8.57 Impact Factor
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    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; DOI:10.1007/s00125-015-3514-y · 6.88 Impact Factor
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    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 · 12.19 Impact Factor
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    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 · 2.13 Impact Factor
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    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; DOI:10.2337/db14-0983 · 8.47 Impact Factor
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    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; DOI:10.2337/dc14-1186 · 8.57 Impact Factor
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    ABSTRACT: We examined maternal dietary intake of fatty acids and foods which are sources of fatty acids during lactation and whether they are associated with the risk of preclinical and clinical type 1 diabetes in the offspring. The subjects comprised a cohort of 2,939 mother-child pairs from the prospective Type 1 Diabetes Prediction and Prevention Study. Composition of maternal diet during the third month of lactation was assessed by a validated food frequency questionnaire. Among the children with HLA-conferred susceptibility to type 1 diabetes, 172 developed preclinical and 81 clinical diabetes. Average follow-up for preclinical type 1 diabetes was 7.5 years (range 0.2-14.0 years) and for clinical type 1 diabetes 7.7 years (0.2-14.0 years). Maternal intake of fatty acids during lactation was not associated with the risk of type 1 diabetes in the offspring. After adjusting for putative confounders, maternal total consumption of red meat and meat products during lactation was associated both with increased risk for preclinical [hazard ratio (HR) 1.19, 95 % CI 1.02-1.40, p = 0.038] and clinical type 1 diabetes (HR 1.27, 95 % CI 1.06-1.52, p = 0.025). In particular, consumption of processed meat products showed an association with increased risk for type 1 diabetes (HR 1.23, 95 % CI 1.02-1.48, p = 0.045). Maternal use of vegetable oils was associated with increased risk for preclinical type 1 diabetes (HR 1.21, 95 % CI 1.03-1.41, p = 0.023). Maternal consumption of red meat, especially processed meat, during lactation may increase the risk of type 1 diabetes.
    Acta Diabetologica 01/2015; DOI:10.1007/s00592-014-0673-0 · 3.68 Impact Factor
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    ABSTRACT: Prediction of type 1 diabetes is based on the detection of multiple islet autoantibodies in subjects at increased genetic risk. Prediction of the timing of diagnosis is challenging, however. We assessed the utility of HbA1c in predicting the clinical disease in genetically predisposed children with multiple autoantibodies. Cord blood samples from 168,055 newborn infants were screened for class II HLA genotypes in Finland, and 14,876 children with increased genetic risk for type 1 diabetes were invited to regular follow-up including screening for diabetes-associated autoantibodies. When two or more autoantibodies were detected HbA1c was analyzed at each visit. During follow-up 466 children developed multiple (≥2) autoantibodies, and 201 (43%) of these were diagnosed with type 1 diabetes (progressors), while 265 remained disease-free (non-progressors) by December 2011. A 10% increase in HbA1c levels in samples taken 3-12 months apart predicted the diagnosis of clinical disease (HR 5.7, 95% CI 4.1-7.9), after a median time of 1.1 years (IQR 0.6-3.1) from the observed rise of HbA1c. If HbA1c was ≥5.9% (41 mmol/mol) in two consecutive samples, the median time to diagnosis was 0.9 years (IQR 0.3-1.5; HR 11.9, 95% CI 8.8-16.0). In conclusion, HbA1c is a useful biochemical marker when predicting time to diagnosis of type 1 diabetes in children with multiple autoantibodies. © 2014 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 12/2014; 64(5). DOI:10.2337/db14-0497 · 8.47 Impact Factor
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    ABSTRACT: Determinationof antibodies to synthetic deamidatedgliadin peptides (anti-DGP) may work as an alternative or complement the commonly used test for tissue transglutaminase antibodies (TGA) in the diagnosis of celiac disease (CD). We analyzed the performance of a time-resolved immunofluorometry (TR-IFMA) based anti-DGP assay in the diagnosis of CD in children and also retrospectively analyzed the appearance of anti-DGP antibodies before TGA seroconversion. The study included 92 children with biopsy-confirmed CD. Serum samples were taken at the time or just before the clinical diagnosis. The control group comprised of 82 TGA-negative children who were positive for HLA-DQ2 or -DQ8. Based on receiver operating characteristics (ROC) curves, the optimal cut-off value for IgA anti-DGP positivity was 153 arbitrary units (AU) with a sensitivity of 92.4% and specificity of 97.6% and that for IgG anti-DGP 119 AU, with a sensitivity of 97.8% and specificity of 97.6%. All of the 92 children with CD were either IgA or IgG anti-DGP positive at the time of diagnosis. Sera from 48 children with CD were also analyzed retrospectively before the diagnosis. Anti-DGP antibodies preceded TGA positivity in 35 of 48 CD children and appeared a median of one year earlier. The TR-IFMA assay for detecting anti-DGP antibodies shows high sensitivity and specificity for the diagnosis of CD in children. In a majority of our study population anti-DGP seropositivity preceded TGA positivity, indicating that earlier detection of CD may be possible by monitoring anti-DGP antibodies frequently in genetically susceptible children.
    Journal of pediatric gastroenterology and nutrition 12/2014; DOI:10.1097/MPG.0000000000000666 · 2.87 Impact Factor
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    ABSTRACT: Upregulation of IL-17 immunity and detrimental effects of IL-17 on human islets have been implicated in human type 1 diabetes. In animal models, the plasticity of Th1/Th17 cells contributes to the development of autoimmune diabetes. In this study, we demonstrate that the upregulation of the IL-17 pathway and Th1/Th17 plasticity in peripheral blood are markers of advanced β cell autoimmunity and impaired β cell function in human type 1 diabetes. Activated Th17 immunity was observed in the late stage of preclinical diabetes in children with β cell autoimmunity and impaired glucose tolerance, but not in children with early β cell autoimmunity. We found an increased ratio of IFN-γ/IL-17 expression in Th17 cells in children with advanced β cell autoimmunity, which correlated with HbA1c and plasma glucose concentrations in an oral glucose tolerance test, and thus impaired β cell function. Low expression of Helios was seen in Th17 cells, suggesting that Th1/Th17 cells are not converted thymus-derived regulatory T cells. Our results suggest that the development of Th1/Th17 plasticity may serve as a biomarker of disease progression from β cell autoantibody positivity to type 1 diabetes. These data in human type 1 diabetes emphasize the role of Th1/Th17 plasticity as a potential contributor to tissue destruction in autoimmune conditions. Copyright © 2014 by The American Association of Immunologists, Inc.
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    ABSTRACT: The Environmental Determinants of Diabetes in the Young (TEDDY) study prospectively follows 8,677 children enrolled from birth, who carry HLA-susceptibility genotypes for development of islet autoantibodies (IA) and type 1 diabetes (T1D). During the median follow-up time of 57 months, 350 children developed at least one persistent IA (GADA, IA-2A or mIAA) and 84 of them progressed to T1D. We genotyped 5,164 Caucasian children for 41 non-HLA SNPs that achieved genome-wide significance for association with T1D in the GWAS meta-analysis conducted by the Type 1 Diabetes Genetics Consortium. In TEDDY-participants carrying high-risk HLA-genotypes, eight SNPs achieved significant association to development of IA using time-to-event analysis (p<0.05), whereof four were significant after adjustment for multiple testing (p<0.0012): rs2476601 in PTPN22 (hazard ratio [HR] 1.54 [95% CI 1.27-1.88]), rs2292239 in ERBB3 (HR 1.33 [95% CI 1.14-1.55]), rs3184504 in SH2B3 (HR 1.38 [95% CI 1.19-1.61]) and rs1004446 in INS (HR 0.77 [0.66-0.90]). These SNPs were also significantly associated with T1D in particular: rs2476601 (HR 2.42 [95% CI 1.70-3.44]). Although genes in the HLA-region remain the most important genetic risk factors for T1D, other non-HLA genetic factors contribute to IA, a first step in the pathogenesis of T1D, and the progression of the disease. © 2014 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 11/2014; 64(5). DOI:10.2337/db14-1497 · 8.47 Impact Factor
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    ABSTRACT: Type I interferon induced MxA response can differentiate viral from bacterial infections, but MxA responses in rhinovirus or asymptomatic virus infections are not known.Objective To study MxA protein levels in healthy state and during respiratory virus infection of young children in an observational prospective cohort.Study designBlood samples and nasal swabs were collected from 153 and 77 children with and without symptoms of respiratory infections, respectively. Blood MxA protein levels were measured by an enzyme immunoassay and PCR methods were used for the detection of respiratory viruses in nasal swabs.ResultsRespiratory viruses were detected in 81% of symptomatic children. They had higher blood MxA protein levels (median [interquartile range]) than asymptomatic virus-negative children (695 [345–1370] μg/L vs. 110 [55–170] μg/L; p < 0.001). Within asymptomatic children, no significant difference was observed in MxA responses between virus-positive and virus-negative groups. A cut-off level of 175 μg/L had 92% sensitivity and 77% specificity for a symptomatic respiratory virus infection. Rhinovirus, respiratory syncytial virus, parainfluenza virus, influenza virus, coronavirus, and human metapneumovirus infections were associated with elevated MxA responses. Asymptomatic virus-negative children vaccinated with a live virus vaccine had elevated MxA protein levels (240 [120–540] μg/L), but significantly lower than children with an acute respiratory infection, who had not received vaccinations (740 [350–1425] μg/L; p < 0.001).Conclusion Blood MxA protein levels are increased in young children with symptomatic respiratory virus infections, including rhinovirus infections. MxA is an informative general marker for the most common acute virus infections.
    Journal of Clinical Virology 11/2014; 62. DOI:10.1016/j.jcv.2014.11.018 · 3.47 Impact Factor
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    ABSTRACT: Coxsackievirus B4 (CV-B4) belongs to the genus Enterovirus within family Picornaviridae. To investigate target proteins recognised by T-cells in human enterovirus B infections, viral-encoded structural (VP0 [VP4 and VP2], VP1, VP3) and non-structural (2A, 2B, 2C, 3C and 3D) proteins were expressed and purified in E. coli. Peripheral blood of 19 healthy adult donors was used to create enterovirus-specific T-cell lines by repeated stimulation with CV-B4 cell lysate antigen. T-cell lines responded in individual patterns, and responses to all purified proteins were observed. The most often recognised enteroviral protein was VP0, which is the fusion between the most conserved structural proteins, VP4 and VP2. T-cell responses to VP0 were detected in 15 of 19 (79%) donor lines. Non-structural 2C protein was recognised in 11 of 19 (58%) lines, and 11 of 19 (58%) lines also had a response to 3D protein. Furthermore, responses to other non-structural proteins (2A, 2B and 3C) were also detected. T-cell responses did not correlate clearly to the individual HLA-DR-DQ phenotype or the history of past coxsackie B virus infections of the donors.
    Journal of General Virology 11/2014; 96(Pt_2). DOI:10.1099/vir.0.069062-0 · 3.53 Impact Factor

Publication Stats

11k Citations
2,457.05 Total Impact Points

Institutions

  • 2010–2015
    • University of Eastern Finland
      • Institute of Biomedicine
      Kuopio, Northern Savo, Finland
  • 1981–2015
    • University of Turku
      • • Department of Paediatrics
      • • Aerobiology Unit
      • • Department of Virology
      • • Department of Neurology
      Turku, Varsinais-Suomi, Finland
  • 1992–2013
    • University of Helsinki
      • • The Hospital for Children and Adolescents
      • • Department of Pediatrics
      Helsinki, Southern Finland Province, Finland
    • University of Toronto
      • Hospital for Sick Children
      Toronto, Ontario, Canada
  • 2011
    • Pirkanmaa Hospital District
      Tammerfors, Province of Western Finland, Finland
  • 2006–2011
    • University of Kuopio
      • Department of Clinical Microbiology
      Kuopio, Eastern Finland Province, Finland
  • 1979–2011
    • University of Oulu
      • • Department of Paediatrics
      • • Department of Neurology
      • • Department of Medical Microbiology
      • • Department of Dermatology and Venereology
      Oulu, Oulu, Finland
  • 1998–2010
    • Turku University Hospital
      • Department of Pediatrics
      Turku, Varsinais-Suomi, Finland
    • Kuopio University Hospital
      • Department of Paediatrics
      Kuopio, Province of Eastern Finland, Finland
  • 1994–2008
    • University of Tampere
      • • Department of Virology
      • • Medical School
      • • Institute of Biomedical Sciences
      Tampere, Western Finland, Finland
  • 1997–2006
    • Turku centre for biotechnology, finland
      Turku, Province of Western Finland, Finland
  • 1983–2006
    • National Public Health Institute
      Helsinki, Southern Finland Province, Finland
  • 2003
    • Chumakov Institute of Poliomyelitis and Viral Encephalitides
      Moskva, Moscow, Russia
  • 1995
    • SickKids
      Toronto, Ontario, Canada
  • 1988–1989
    • University of Alberta
      Edmonton, Alberta, Canada
  • 1986
    • Oulu University Hospital
      Uleoborg, Oulu, Finland
  • 1984
    • Finnish Red Cross Blood Service
      Helsinki, Uusimaa, Finland