Biomedical subjects

Jorma Ilonen

Publications and source records attributed to Jorma Ilonen.

At least 19 recordsLinked to original sources

PubMed2007

Signs of beta-cell autoimmunity in nondiabetic schoolchildren: a comparison between Russian Karelia with a low incidence of type 1 diabetes and Finland with a high incidence rate.

OBJECTIVE: We sought to study the prevalence of autoantibodies to various islet cell antigens in the background population of two neighboring countries with a sixfold difference in the incidence of type 1 diabetes. RESEARCH DESIGN AND METHODS: Serum samples were obtained from 3,652 nondiabetic schoolchildren in Finland and from 1,988 schoolchildren in the adjacent Karelian Republic of Russia. The Karelian children were divided into three groups (Finns/Karelians, Russians, and others) based on the ethnic background of their mother. The samples were analyzed for islet cell antibodies (ICAs), insulin autoantibodies (IAAs), GAD antibodies (GADAs), and the tyrosine phosphatase-like insulinoma antigen 2 (IA-2A) protein and HLA class II genotypes. RESULTS: The frequency of ICAs, IAAs, and GADAs did not differ significantly between the Karelian (3.5, 0.6, and 0.9%, respectively) and Finnish children (2.8, 0.9, and 0.5%, respectively). Similarly, the frequency of multiple (> or = 2) autoantibodies was similar in both countries (0.5 vs. 0.6%). The frequency of IA-2A was, however, four times higher in Finland (0.6 vs. 0.15% in Russian Karelia; P = 0.03). There were no significant differences in autoantibody prevalence among the three ethnic groups in Russian Karelia. There was a falling frequency of GADAs and of positivity for multiple autoantibodies along with decreasing HLA-conferred disease susceptibility among the Finnish schoolchildren. CONCLUSIONS: These data indicate that beta-cell autoimmunity among schoolchildren is as frequent in Russian Karelia as in Finland, although the incidence of clinical type 1 diabetes is six times higher in Finland. However, in contrast to this general trend, IA-2As were more common in Finland. Since IA-2As usually appear late in the preclinical process, this suggests that progressive beta-cell autoimmunity is more rare in Russian Karelia.

Adolescent↗

PubMed2006

Linkage disequilibrium screening for multiple sclerosis implicates JAG1 and POU2AF1 as susceptibility genes in Europeans.

By combining all the data available from the Genetic Analysis of Multiple sclerosis in EuropeanS (GAMES) project, we have been able to identify 17 microsatellite markers showing consistent evidence for apparent association. As might be expected five of these markers map within the Major Histocompatibility Complex (MHC) and are in LD with HLA-DRB1. Individual genotyping of the 12 non-MHC markers confirmed association for three of them--D11S1986, D19S552 and D20S894. Association mapping across the candidate genes implicated by these markers in 937 UK trio families revealed modestly associated haplotypes in JAG1 (p=0.019) on chromosome 20p12.2 and POU2AF1 (p=0.003) on chromosome 11q23.1.

Calcium-Binding Proteins↗

PubMed2006

Human leukocyte antigen non-class II determinants for type 1 diabetes in the Finnish population.

We explored the contribution of non-class II HLA loci to type 1 diabetes genetic susceptibility in the Finnish population. We analyzed 11 markers covering a 4-Mb region telomeric to the DQB1 gene in Finnish nuclear families with parents carrying either the DR8-DQB1*04 (n=188) or the DRB1*0404-DQB1*0302 haplotypes (n=135). On the DRB1*0404-DQB1*0302 haplotype we found independent disease association of the D6S273 and C125 markers (p(corr) = 10(-4) and 0.0095, respectively). The C125*200 alleles on this haplotype conferred an increased disease risk (OR = 3.6; p = 0.003). The B*39 allele also showed disease association (OR = 2.6; p = 0.054). The C125*200 allele appeared at an increased frequency also on transmitted B39 positive DRB1*0404-DQB1*0302 haplotypes, suggesting an independent effect. In addition, the C143*417 allele on the DRB1*08-DQB1*04 haplotype was associated with decreased disease risk (OR = 0.48, p = 0.003). Our data confirm that non-class II HLA loci affect genetic susceptibility to type 1 diabetes. In addition to HLA B*39 the C125 locus contributes to disease risk on the Finnish DRB1*0404-DQB1*0302 haplotypes. Another locus close to D6S273 may also have an effect. For the first time we report that a locus near the C143 marker appear to affect disease association of the DRB1*08-DQB1*04 haplotype.

Alleles↗

PubMed2006

Enteral virus infections in early childhood and an enhanced type 1 diabetes-associated antibody response to dietary insulin.

Enteral virus infections may trigger the development of beta-cell-specific autoimmunity by interacting with the gut-associated lymphoid system. We analyzed the effect of three different virus infections on immunization to dietary insulin in children carrying increased genetic risk for type 1 diabetes. Forty-six of 238 children developed multiple diabetes-associated autoantibodies and 31 clinical diabetes (median follow-up time 75 months). Insulin-binding antibodies were measured with EIA method (median follow-up time 24 months). Antibodies to enteroviruses, rotavirus and adenovirus were measured with EIA in samples drawn at birth and the ages of 3 and 6 months. Nineteen enterovirus, 14 rotavirus and 8 adenovirus infections were diagnosed. At the ages of 6, 12, and 18 months, the concentrations of insulin-binding antibodies were higher in children with postnatal entero-, rota- and/or adenovirus infections than in children without these infections. Children who subsequently developed ICA or IA-2 antibodies or clinical type 1 diabetes had higher concentrations of insulin-binding antibodies than children who remained autoantibody negative. Our data suggest that enteral virus infections can enhance immune response to insulin, induced primarily by bovine insulin in cow's milk. An enhanced antibody response to dietary insulin preceded the development of beta-cell specific autoimmunity and type 1 diabetes.

Administration, Oral↗

PubMed2006

Higher prevalence of autoantibodies to insulin and GAD65 in Swedish compared to Lithuanian children with type 1 diabetes.

We compared the prevalence of beta-cell autoantibodies and genetic risk factors in Sweden and Lithuania. Ninety-six patients from Sweden and 96 from Lithuania matched for age and gender (1-15 years old, median age 9.0 years) were included. We analyzed autoantibodies to insulin (IAA), glutamic acid decarboxylase (GADA) and the protein tyrosine phosphatase like IA-2 (IA-2A) as well as risk-associated polymorphisms of HLA, insulin and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) genes. The frequency of patients positive for IAA and GADA was higher in Sweden than in Lithuania (p = 0.043 and 0.032). The differences remained even when the patients were matched for HLA, insulin and CTLA-4 risk genotypes. Patients with low levels of IAA had higher levels of HbA1c and ketones at diagnosis. The frequency of the risk haplotype DR4-DQ8 was higher in Swedish than in Lithuanian patients (p = 0.004), as well as the high-risk combination of DR4-DQ8 and DR3-DQ2 haplotypes (p = 0.009). Our results suggest that autoimmune process against insulin and GAD(65) is more common at diagnosis in children in areas with high incidence of type 1 diabetes (T1D), independent of genetic risk markers. Furthermore, the disease in patients with insulin autoantibodies seems to be clinically milder.

Adolescent↗

PubMed2006

Parental reactions to information about increased genetic risk of type 1 diabetes mellitus in infants.

OBJECTIVE: To assess the anxiety, emotions, thoughts, and coping behaviors of parents 1 week after they receive the results of screening of their infant's genetic risk of type 1 diabetes mellitus. DESIGN: Survey. SETTING: The population-based Type 1 Diabetes Prediction and Prevention project conducted in Turku. PARTICIPANTS: Parents of 443 consecutive high-risk infants and 506 next-born low-risk infants. INTERVENTIONS: An infant's genetic risk of type 1 diabetes mellitus was measured from cord blood. High-risk information was delivered by telephone and low-risk information by mail 4 weeks later. MAIN OUTCOME MEASURES: Anxiety measured using the state anxiety scale of the State-Trait Anxiety Inventory, and feelings, thoughts, and coping behaviors extracted from the questionnaire. RESULTS: One week after obtaining the results, 67% of mothers and 63% of fathers of high-risk children and 58% of mothers and 54% of fathers of low-risk children had returned the questionnaire. Anxiety levels of parents of high-risk infants were similar to those of parents of low-risk infants (P = .86). More than 90% of the parents thought that it was good to know about the risk. Fifty-five percent of mothers and 37% of fathers of high-risk infants expressed modest worry. Increased anxiety was connected with other stressful life events, catastrophizing thoughts of diabetes mellitus risk, and emotion-focused or avoiding coping attitudes. CONCLUSIONS: Learning about their infant's genetic diabetes mellitus risk induces only mild anxiety in most parents. Identifying the few parents with stronger anxiety helps focus intensified counseling.

Adaptation, Psychological↗

PubMed2006

Effect of HLA DQ2, dietary exposure and coeliac disease on the development of antibody response to gliadin in children.

OBJECTIVE: To study the effect of HLA DQ2, dietary history and development of coeliac disease (CD) on the induction of antibody response to wheat gliadin and cow's milk, beta-lactoglobulin between 1 and 2.5 years of age in children who developed CD and in healthy children. MATERIAL AND METHODS: Infants participating in a birth cohort study (the ABIS study) in Sweden were studied. Thirty-nine children developed CD (=cases), confirmed through biopsy, during follow-up until 2.5-5 years of age. A total of 181 healthy control children were matched for duration of exclusive breast-feeding, birth-weight, gender, maternal smoking and season of birth. IgG and IgA antigliadin and anti-beta-lactoglobulin antibodies were measured using enzyme immunoassay (EIA). The effects of HLA-risk genotypes, DQ2 and DQ8, on CD were also considered. RESULTS: Children who developed CD had higher IgG and IgA antigliadin and anti-beta-lactoglobulin antibody levels at 1 year of age than controls (all comparisons: p<0.001). Similar differences were seen between cases with as yet undiagnosed CD by 1 year of age and controls, and also when cases were compared with HLA-matched controls. Higher levels of IgG and IgA antibodies to beta-lactoglobulin (p=0.003; p=0.001), but not to gliadin, were found in treated cases versus controls at 2.5 years of age. HLA-DQ2-positive healthy children had lower levels of IgG and IgA antigliadin antibodies than HLA-DQ2 negative controls at 1 year of age (p=0.004; p=0.012). CONCLUSIONS: Enhanced humoral response emerging not only to gliadin, but also to other food antigens seems to be primarily associated with CD. Poor induction of antibody response to wheat gliadin in healthy children with the HLA-DQ2 risk molecule could at least partly explain the genetic predisposition to gluten intolerance and CD.

Age of Onset↗

PubMed2006

Expression of MxA protein in blood lymphocytes of children receiving anticancer chemotherapy.

The aim of the study was to evaluate whether IFN-alpha/beta-inducible MxA protein expression in children receiving anticancer treatment can be used as an indicator for virus infections during the febrile episodes. Twenty-six children with mainly hematological malignancies entered the study. Children with laboratory-confirmed virus infections had clearly elevated MxA protein levels compared to their counterparts with bacterial or unknown etiology. MxA protein expression increased moderately following the administration of cytostatic agents, even though these children had no clinical signs of infection.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed2006

Dietary insulin as an immunogen and tolerogen.

We have shown that exposure to bovine insulin (BI) in cow's milk (CM) formula induces an insulin-specific immune response in infants. Here we studied the role of human insulin (HI) in breast milk as a modulator of the immune response to insulin. In a group of 128 children participating in the TRIGR pilot study, maternal breast milk samples were collected 3-7 days and/or 3 months after delivery. After exclusive breast-feeding, the children received either CM formula or casein hydrolysate during the first 6-8 months of life. Insulin concentration in breast milk and immunoglobulin G (IgG) antibodies to BI in plasma samples were measured by EIA. The levels of insulin in breast milk samples were higher in mothers affected by type 1 diabetes than in non-diabetic mothers (p = 0.007 and p < 0.001). The concentration of insulin in breast milk correlated inversely with the plasma levels of IgG antibodies to BI at 6 months of age in children who received CM formula (r = -0.39, p = 0.013), and at 12 months of age in all children (r = -0.25, p = 0.029). The levels of breast milk insulin were higher in the mothers of nine children who developed beta-cell autoimmunity when compared with autoantibody-negative children (p = 0.030); this holds true also when only children of diabetic mothers were included (p = 0.045). BI in CM induces higher levels of IgG to insulin in infants than does HI in breast-fed children. Instead, HI in breast milk seems to be tolerogenic and may downregulate the IgG response to dietary BI. However, our results in infants who developed beta-cell autoimmunity suggest that in this subgroup of children breast milk insulin does not promote tolerance.

Animals↗

PubMed2006

Time-resolved fluorescence imaging of islet cell autoantibodies.

Time-resolved fluorescence of lanthanide chelates has been widely used in bioanalytical assays. Long fluorescence time, large Stokes shift, and minute fading out of the fluorescence over years are major advantages of the lanthanides over the conventional fluorescent dyes. We have now applied time-resolved fluorescence imaging (TRFI) also for measurement of type 1 diabetes mellitus (T1DM)-related islet cell autoantibodies (ICA). Retaining the accuracy of conventional ICA, TRFI has over 10 times better signal-to-noise ratio than the conventional fluorochromes. The technology allows objective determination of fluorescence intensity with the camera and computer software, and serial dilutions for obtaining the antibody titer in autoantibody-positive samples are unnecessary. We now describe the TRFI as a method and its application for measurement of ICA.

Autoantibodies↗

PubMed2006

Probiotics for the prevention of beta cell autoimmunity in children at genetic risk of type 1 diabetes--the PRODIA study.

The final aim of the PRODIA study is to determine whether the use of probiotics during the first 6 months of life decreases the appearance of type 1 diabetes mellitus (T1DM)-associated autoantibodies in children with genetic risk for T1DM. A pilot study including 200 subjects was planned to show whether the use of probiotics during the first 6 months of life is safe and feasible. The prevalence of autoantibodies among the study subjects at 6, 12, and 24 months of age was at levels close to the expected and the clinical follow-up did not either indicate problems in the feasibility of the study.

Autoantibodies↗

PubMed2006

Early epitope- and isotype-specific humoral immune responses to GAD65 in young children with genetic susceptibility to type 1 diabetes.

OBJECTIVE: The pattern of the humoral immunity to disease-associated autoantigens may reflect the severity of the autoimmune disease process. The purpose of this study was to delineate the maturation of the humoral immunity to one of the main autoantigens in type 1 diabetes (T1D), glutamic acid decarboxylase (GAD65). DESIGN AND METHODS: Serum samples were obtained for the detection of epitope- and isotype-specific antibodies sequentially with short intervals from 36 young children with HLA-conferred genetic susceptibility to T1D starting from the first appearance of GAD65Ab. During prospective observation, ten children developed T1D. Antibodies were analyzed using biotinylated anti-human immunoglobulin (Ig) antibodies and chimeric GAD molecules in radio-binding assays. RESULTS: The immune response to GAD65 started as reactivity to the middle region and spread rapidly to the C-terminal region. IgG1 antibodies dominated among the isotypes from the first appearance of GAD65Ab, while other IgG subclasses were observed to a lesser extent. IgG4 antibodies emerged clearly as the last IgG subclass. A broad initial response comprising three to four IgG subclasses and the lack of an emerging IgG4 response during follow-up was associated with increased risk for progression to clinical diabetes (P<0.05). CONCLUSIONS: The humoral response to GAD65 epitope clusters is relatively uniform in young children, whereas there is conspicuous individual variation in IgG subclass responses except for IgG1. A narrow initial IgG subclass response to GAD65 and the emergence of IgG4 antibodies were characteristic of those who remained non-diabetic over the first few years of GAD65 autoimmunity.

Antibody Formation↗

PubMed2006

Decreased in vitro type 1 immune response against coxsackie virus B4 in children with type 1 diabetes.

Enteroviruses, particularly Coxsackie virus B4 (CVB4), are considered to be involved in the pathogenesis of type 1 diabetes. We wanted to compare the characteristics of T-cell immune response to CVB4 in children with type 1 diabetes and healthy children with and without HLA risk-associated haplotypes (HLA-DR3-DQ2 or HLA-DR4-DQ8) for type 1 diabetes. Peripheral blood mononuclear cells (PBMCs) were isolated and cultured with CVB4 and analyzed for cytokine and chemokine receptors by flow cytometry and for expression of transcription factors Tbet and GATA-3 by RT-PCR and Western blot. Culture supernatants were analyzed for secretion of gamma-interferon (IFN-gamma). In children with type 1 diabetes, a decreased percentage of T-cells expressed CCR2, CXCR6, interleukin (IL)-18R, and IL-12Rbeta2-chain after in vitro stimulation with CVB4 in comparison with healthy children with or without HLA risk genotype. Moreover, we found that children with type 1 diabetes had decreased IFN-gamma secretion and expression of Tbet, both on mRNA and protein level, in CVB4-stimulated PBMCs. Accordingly, children with type 1 diabetes show an impaired type 1 immune response against CVB4 compared with healthy children. This may lead to a delayed clearance of the virus and, at least partly, explain why children with type 1 diabetes may be more prone to CVB4 infections and related complications, such as beta-cell damage.

Autoantibodies↗

PubMed2005

GAD65- and proinsulin-specific CD4+ T-cells detected by MHC class II tetramers in peripheral blood of type 1 diabetes patients and at-risk subjects.

In type 1 diabetes the major loss of insulin producing beta-cells is caused by autoreactive T-cells specific for antigens expressed by the pancreatic islets. In this study we have analyzed the prevalence of glutamate decarboxylase 65 (GAD65)- and proinsulin-specific CD4(+) T-cells in type 1 diabetes patients, at-risk subjects and in HLA-matched control children. Peripheral blood mononuclear cells were cultured in the presence of two different GAD65 peptides (555-567, 557I and 274-286) or with a proinsulin (B24-C36) peptide for 10-11days. The autoreactive T-cells were detected using antigen specific-MHC class II tetramers by flow cytometry. Our results show that 11 of 18 (61%) type 1 diabetes patients and 7 of the 20 (35%) at-risk subjects were positive for one of the three GAD65 or proinsulin-containing tetramers, whereas only 2 of 21 (9.5%) controls had tetramer binding cells (p = 0.0007 type 1 diabetes vs. controls and p = 0.0488 at-risk subjects vs. controls, Chi-square test). Type 1 diabetes patients responded to all three peptides. At-risk subjects recognized also the GAD65 555-567 557I peptide, while none of the controls responded to it. In conclusion, type 1 diabetes patients and at-risk subjects have a significantly higher prevalence of GAD65- and proinsulin-specific CD4(+) T-cells than the control subjects.

Adolescent↗

PubMed2005

Locked nucleic acid (LNA) probes in high-throughput genetic analysis: application to an assay for type 1 diabetes-related HLA-DQB1 alleles.

OBJECTIVES: In large-scale genetic screening, an assay that is reliable, fast and easy to perform, and straightforwardly adapted to new analytes is a necessity. We describe a one-step assay for analyzing HLA-DQB1 alleles which are associated with susceptibility to type 1 diabetes. DESIGN AND METHODS: The assay is based on asymmetric PCR amplification and a homogeneous hybridization method. The specificity of the probes was improved by substituting LNA (locked nucleic acid) for DNA at the critical bases. RESULTS: The functionality of the LNA containing probes was found to be superior compared to probes consisting of DNA only. The homogeneous assay gave a correct genotyping result in 100% of the cases, which included both extracted DNA samples and blood samples dried on sample collection cards. CONCLUSION: This homogeneous approach provides a simple method to define disease risk associated with HLA alleles for large-scale screening projects.

Base Sequence↗

PubMed2005

Absence of avidity maturation of autoantibodies to the protein tyrosine phosphatase-like IA-2 molecule and glutamic acid decarboxylase (GAD65) during progression to type 1 diabetes.

Immunoglobulin G avidity assays are used to distinguish between the acute and chronic phase of several infectious diseases, and there is evidence of autoantibody affinity maturation also in autoimmune diseases. To assess whether the analysis of the avidity of autoantibodies against the protein tyrosine phosphatase-like IA-2 molecule and glutamic acid decarboxylase (GAD65) could improve the accuracy of risk assessment of progression to clinical type 1 diabetes, we established methods for the determination of the autoantibody avidity based on our previously developed time-resolved fluorometric IA-2 and GAD65 autoantibody (IA-2A and GADA) assays. The avidity indices of sequential plasma samples from six IA-2A-positive and seven GADA-positive prediabetic children were analysed applying elution with urea and diethylamine (DEA). For comparison, corresponding avidity indices of control children, who have remained non-diabetic for at least 3 years after seroconversion to IA-2A and GADA positivity, were analysed. For most of the children, only a slight fluctuation in the avidity index values was observed over time, although the titres for IA-2A and GADA varied substantially in some cases. The avidity indices of the prediabetic children remained within the same range as those of the control group throughout the follow-up. Our results indicate that the analysis of the avidity index levels of IA-2A and GADA does not improve the accuracy of the prediction of type 1 diabetes based on autoantibody detection.

Aged↗

PubMed2005

Natural history of transglutaminase autoantibodies and mucosal changes in children carrying HLA-conferred celiac disease susceptibility.

OBJECTIVE: The natural history of the appearance and fate of transglutaminase autoantibodies (TGAs) and mucosal changes in children carrying HLA-conferred celiac disease (CD) risk remains obscure. The aim of this study was to investigate the sequence of events leading to overt CD by retrospective analysis of TGA values in serum samples collected frequently from genetically susceptible children since birth or early childhood. MATERIAL AND METHODS: A total of 1101 at-risk children were recruited in the study. A duodenal biopsy was recommended to all TGA-positive children and performed if parental consent was obtained. RESULTS: During up to 8 years of follow-up, 35 of the cohort children developed TGAs, the youngest at age 1.3 years. After age 1.3 years the annual TGA seroconversion rate was constantly around 1% at least until age 6 years. However, 18 of the 35 TGA-positive children (51%) lost TGAs, without any dietary manipulation. A further 7 children were IgA deficient; of these children, 2 developed IgG antigliadin antibodies (IgG-AGA). Only 13 of the 21 children (62%) who had duodenal biopsies had villous atrophy. The time that passed since emergence of TGAs failed to predict the biopsy findings. Only one of the children with TGAs and both of the IgA-deficient children with IgG-AGA had noticeable abdominal symptoms. CONCLUSIONS: TGAs appear in children at a constant rate after 1 year of age until at least the age of 6 years. Over half of the children loose TGA without gluten exclusion, challenging TGA positivity-based CD prevalence estimates. In symptom-free children, a requirement of two consecutive TGA-positive samples taken >or=3 months apart before performing a duodenal biopsy might diminish the number of unnecessary intestinal biopsies.

Autoantibodies↗

PubMed2005

A six-fold gradient in the incidence of type 1 diabetes at the eastern border of Finland.

OBJECTIVE: Type 1 diabetes results from gene-environment interactions in subjects with genetic susceptibility to the disease. We assessed the contribution of environmental and genetic factors to type 1 diabetes by comparing the incidence in two neighboring populations living in conspicuously different socioeconomic circumstances. RESEARCH DESIGN AND METHODS: We compared the incidence over a 10-year period (1990-99) in children younger than 15 years of age living in the Karelian Republic of Russia and in Finland. The frequency of susceptible and protective human leukocyte antigen (HLA)-DQ alleles was analyzed in 400 non-diabetic schoolchildren from Russian Karelia and 1000 Finnish subjects. RESULTS: The average annual age-adjusted incidence of type 1 diabetes was lower in Russian Karelia than in Finland: 7.4 per 100000 (95% confidence interval 3.5-11.3) versus 41.4 per 100000 (37.3-45.5), while there were no differences in the frequency of the HLA DQ genotypes predisposing to type 1 diabetes in the background populations. The incidence rate did not differ significantly between different ethnic groups in Russian Karelia (Finns/Karelians, Russians, others). CONCLUSIONS: There is a close to six-fold gradient in the incidence of type 1 diabetes between Russian Karelia and Finland, although the predisposing HLA DQ genotypes are equally frequent in the two populations. This suggests that environmental factors contribute to this steep difference in the incidence rate between these adjacent regions.

Adolescent↗