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Biomedical subjects

Jorma Ilonen

Publications and source records attributed to Jorma Ilonen.

At least 37 records · Page 2Linked to original sources
PubMed2005

Cow milk is not responsible for most gastrointestinal immune-like syndromes--evidence from a population-based study.

BACKGROUND: Gastrointestinal hypersensitivity to cow milk (CM) may be more common among school-aged children and young adults than previously thought. OBJECTIVE: The objective was to study various gastrointestinal complaints and the immunologic mechanisms associated with food-related, especially CM-related, gastrointestinal disorders in young adults. DESIGN: Of 827 subjects aged 16-21 y who completed a questionnaire on food-related gastrointestinal symptoms, 49 symptomatic subjects agreed to a clinical examination, including an interview, blood tests, a lactose-maldigestion test, a blinded CM challenge and, in severely symptomatic subjects (n = 12), an endoscopic examination. Twenty-nine subjects served as controls. RESULTS: Approximately 10% of the subjects reported having major gastrointestinal symptoms, mainly food-related (n = 70 of 86), during the preceding year. Specific organic disease was found in 2 symptomatic subjects: 1 case of celiac disease and 1 of colitis. The result of the lactose-maldigestion test was positive in 16 of the remaining 47 symptomatic subjects, but only 4 carried the C/C(-13910) genotype for adult-type hypolactasia. The symptomatic subjects had restricted their consumption of certain foods, particularly CM. However, in a blinded challenge, CM-induced symptoms were rare. The symptomatic subjects had higher plasma soluble intercellular adhesion molecule 1 (P = 0.007) and lower granzyme A (P = 0.001) concentrations than did the control subjects. Duodenal biopsy samples tended to have higher intraepithelial CD3(+) cell counts (P = 0.065) and a higher expression of transforming growth factor beta (P = 0.073) and interleukin 12p35 messenger RNA (P = 0.075) than did the control subjects. CONCLUSIONS: In an unselected cohort of young adults, 8% reported food-related gastrointestinal symptoms. The finding of immunologic activity implied the existence of a food-related gastrointestinal syndrome but not one induced by CM.

Abdominal Pain↗
PubMed2005

Recombination in circulating Human enterovirus B: independent evolution of structural and non-structural genome regions.

The complete nucleotide sequences of eight Human enterovirus B (HEV-B) strains were determined, representing five serotypes, E6, E7, E11, CVB3 and CVB5, which were isolated in the former Soviet Union between 1998 and 2002. All strains were mosaic recombinants and only the VP2-VP3-VP1 genome region was similar to that of the corresponding prototype HEV-B strains. In seven of the eight strains studied, the 2C-3D genome region was most similar to the prototype E30, EV74 and EV75 strains, whilst the remaining strain was most similar to the prototype E1 and E9 strains in the non-structural protein genome region. Most viruses also bore marks of additional recombination events in this part of the genome. In the 5' non-translated region, all strains were more similar to the prototype E9 than to other enteroviruses. In most cases, recombination mapped to the VP4 and 2ABC genome regions. This, together with the star-like topology of the phylogenetic trees for these genome regions, identified these genome parts as recombination hot spots. These findings further support the concept of independent evolution of enterovirus genome fragments and indicate a requirement for more advanced typing approaches. A range of available phylogenetic methods was also compared for efficient detection of recombination in enteroviruses.

5' Untranslated Regions↗
PubMed2005

Maternal consumption of dairy products during pregnancy and lactation, and the development of cow's milk antibodies in the offspring.

OBJECTIVE: To assess whether the maternal consumption of milk and milk products affects development of cow's milk (CM) antibodies in infants. DESIGN: A randomized pilot trial using food frequency questionnaires (mothers) and food records (infants). SETTING: Families with a newborn infant with increased HLA-DQB1-conferred risk of type 1 diabetes and at least one first-degree relative affected by type 1 diabetes from 16 hospitals in Finland between April 1995 and November 1997. SUBJECTS AND INTERVENTION: Infants randomized to receive a hydrolysed formula when breast milk was not available during their first 6-8 mo (n=112). Of these, 13 dropped out by the age of 3 mo and two were excluded due to incomplete CM antibody data. RESULTS: Maternal milk protein intake from cheese during pregnancy was inversely related to IgA-class antibody titres to beta-lactoglobulin (BLG) and casein (CAS) at 3 mo, and to IgA antibody titres to BLG at 6 mo. Maternal consumption of raw milk products during lactation was positively related to the development of IgA antibody titres to CAS at 6 mo, and inversely correlated to IgG antibody titres to bovine serum albumin (BSA) and IgA antibody titres to CAS at 2 y. Maternal cheese consumption was inversely related to the IgG antibody titres to CM formula and CAS and to the IgA antibody titres to CAS in early infancy. CONCLUSIONS: Few associations were established between maternal CM protein intake and CM protein antibody levels in the infants. The milk and milk products taken by the mother differed in their impact on the emerging CM antibody response in the offspring.

Animals↗
PubMed2005

Estimation of diabetes risk in Brazilian population by typing for polymorphisms in HLA-DR-DQ, INS and CTLA-4 genes.

The study aimed to further characterise HLA encoded risk factors of type 1 diabetes (T1D) in Brazilian population and test the capability of a low resolution full-house DR-DQ typing method to find subjects at diabetes risk. Insulin and CTLA-4 gene polymorphisms were also analysed. The method is based on an initial DQB1 typing supplemented by DQA1 and DR4 subtyping when informative. Increased frequencies of both (DR3)-DQA1*05-DQB1*02 and DRB1*04-DQA1*03-DQB1*0302 haplotypes were detected among patients. DRB1*0401, *0402, *0404 and *0405 alleles were all common in DQB1*0302 haplotypes and associated with T1D. (DRB1*11/12/1303)-DQA1*05-DQB1*0301, (DRB1*01/10)-DQB1*0501, (DRB1*15)-DQB1*0602 and (DRB1*1301)-*0603 haplotypes were significantly decreased among patients. Genotypes with two risk haplotypes or a combination of a susceptibility associated and a neutral haplotype were found in 78 of 126 (61.9%) T1D patients compared to 8 of 75 (10.7%) control subjects (P < 0.0001). Insulin gene -2221 C/T polymorphism was also associated with diabetes risk: CC genotype was found among 83.1% of patients compared to 69.3% of healthy controls (P=0.0369, OR 1.98) but CTLA-4 gene +49 A/G polymorphism did not significantly differ between patients and controls. Despite the diversity of the Brazilian population the screening sensitivity and specificity of the used method for T1D risk was similar to that obtained in Europe.

Adolescent↗
PubMed2005

Lack of association of PAX4 gene with type 1 diabetes in the Finnish and Hungarian populations.

We aimed to assess the possible contribution of the PAX4 transcription factor gene to the genetic background of type 1 diabetes. We analyzed four coding polymorphisms of the PAX4 gene in 498 cases with type 1 diabetes and 825 control subjects from Finland and Hungary. All patients were diagnosed under the age of 15 years according to the World Health Organization criteria. All four PAX4 variants (three in exon 9 and one in exon 3) were genotyped using DNA sequencing. In addition, all Finnish subjects were typed for HLA DR-DQ, insulin gene (-23) HphI, and CTLA4 CT60 polymorphisms. The +1,168 C/A coding variant of PAX4 was found to be polymorphic in both populations (P321H, rs712701). No difference was observed in the genotype frequencies between cases and control subjects, nor was any disease association detected when patients were stratified according to age at diagnosis, sex, HLA, insulin gene, or CTLA4 genotypes. Our data indicate that the +1,168 C/A variant of PAX4 gene does not play any essential role in genetic type 1 diabetes susceptibility. The strong coherence between the datasets of the two ethnic groups studied with highly contrasting disease incidence, socioeconomic characteristics, and profoundly diverse environment emphasizes the impact of this finding.

Adolescent↗
PubMed2004

Epitopes recognized by CBV4 responding T cells: effect of type 1 diabetes and associated HLA-DR-DQ haplotypes.

The present study aimed at characterizing the epitopes recognized by coxsackievirus B4 (CBV4)-specific T-cell lines established from 23 children with type 1 diabetes (T1D) and 29 healthy children with T1D risk-associated HLA genotypes. Responsiveness to VP1 region was dependent on the specific infection history as 55% of the T-cell lines from donors with neutralizing antibodies to CBV serotypes responded to VP1 peptides compared to none of the T-cell lines from other donors (P = 0.01). The pattern of recognized peptides was dependent of the HLA genotype. Forty-two percent of the T-cell lines from donors carrying the HLA-(DR4)-DQB1*0302 haplotype responded to VP1 peptides 71-80 compared to none of the T-cell lines from donors without this haplotype (P = 0.02). No evidence for the existence of diabetes-specific epitopes was found. Only few epitopes were exclusive recognized by T cells from diabetic children, and in each case only one or two T-cell lines were responding.

Adolescent↗
PubMed2004

Geographical variation in risk HLA-DQB1 genotypes for type 1 diabetes and signs of beta-cell autoimmunity in a high-incidence country.

OBJECTIVE: To assess possible differences in the frequency of HLA-DQB1 risk genotypes and the emergence of signs of beta-cell autoimmunity among three geographical regions in Finland. RESEARCH DESIGN AND METHODS: The series comprised 4,642 children with increased HLA-DQB1-defined genetic risk of type 1 diabetes from the Diabetes Prediction and Prevention (DIPP) study: 1,793 (38.6%) born in Turku, 1,646 (35.5%) in Oulu, and 1,203 (25.9%) in Tampere. These children were examined frequently for the emergence of signs of beta-cell autoimmunity, for the primary screening of which islet cell antibodies (ICA) were used. If the child developed ICA, all samples were also analyzed for insulin autoantibodies (IAA), GAD65 antibodies (GADA), and antibodies to the IA-2 molecule (IA-2A). RESULTS: The high- and moderate-risk genotypes were unevenly distributed among the three areas (P<0.001); the high-risk genotype was less frequent in the Oulu region (20.4%) than in the Turku (28.4%; P<0.001) or Tampere regions (27.2%; P<0.001). This genotype was associated with an increased frequency of ICA seroconversion relative to the moderate risk genotypes (hazard ratio 1.89, 95% CI 1.36-2.62). Seroconversions to ICA positivity occurred less commonly in Tampere than in Turku (0.47, 0.28-0.75), whereas the seroconversion rate in Oulu did not differ from that in Turku (0.72, 0.51-1.03). The Tampere-Turku difference persisted after adjustment for risk genotypes, sex, and time of birth (before January 1998 versus later). Seroconversion for at least one additional autoantibody was also less frequent in Tampere than in Turku (0.39, 0.16-0.82). CONCLUSIONS: These data show that in Finland, the country with the highest incidence of type 1 diabetes in the world, both the frequency of the high-risk HLA-DQB1 genotype and the risk of seroconversion to autoantibody positivity show geographical variation. The difference in seroconversion rate could not be explained by the difference in HLA-DQB1-defined disease susceptibility, implying that the impact of environmental triggers of diabetes-associated autoimmunity may differ between the three regions studied.

Autoantibodies↗
PubMed2003

Insulin autoantibody isotypes during the prediabetic process in young children with increased genetic risk of type 1 diabetes.

This work aimed to assess the maturation of the humoral immune response to insulin in preclinical type 1 diabetes by observing the emergence of various isotypes of insulin autoantibodies (IAA) in children with HLA-DQB1-conferred disease susceptibility. The series was derived from the Finnish Type 1 Diabetes Prediction and Prevention Study and comprised 15 IAA-positive children who presented with type 1 diabetes during prospective observation (progressors) and 30 children who remained nondiabetic (nonprogressors). An isotype-specific radiobinding assay was used to determine isotype-specific IAA (IgG1-4 and IgA) from samples obtained with an interval of 3-12 mo. The progressors had IAA of subclass IgG3 in their first IAA-positive sample more often than did the nonprogressors (13 of 15 versus 12 of 30; p = 0.003). Nine progressors had a dominant IgG1-IAA response initially, and six had a dominant IgG3-IAA response. The corresponding distribution among the nonprogressors was that 20 had a dominant IgG1-IAA response, none had an IgG3-IAA response, and three had a dominant response other than IgG1- or IgG3-IAA (chi(2)(df = 2) = 12.02; p = 0.002). The progressors had higher integrated levels (area under the curve) of IgG1-IAA (p = 0.05) and IgG3-IAA (p = 0.002). Nine progressors had a dominant integrated IgG1-IAA response and six had a dominant IgG3-IAA response over the observation period, whereas 22 nonprogressors had a dominant IgG1-IAA response, six had a dominant IgG2-IAA response, and one an IgG3-IAA response (chi(2)(df = 2) = 11.23; p = 0.004). Genetically susceptible young children who progress rapidly to clinical type 1 diabetes are characterized by strong IgG1 and IgG3 responses to insulin, whereas a weak or absent IgG3 response is associated with relative protection from disease.

Autoantibodies↗
PubMed2003

Prevalence of Celiac disease among children in Finland.

BACKGROUND: Wheat, rye, and barley proteins induce celiac disease, an autoimmune type of gastrointestinal disorder, in genetically susceptible persons. Because the disease may be underdiagnosed, we estimated the prevalence of the disease and tested the hypothesis that assays for serum autoantibodies can be used to detect untreated celiac disease and that positive findings correlate with specific HLA haplotypes. METHODS: Serum samples were collected from 3654 students (age range, 7 to 16 years) in 1994 and screened in 2001 for endomysial and tissue transglutaminase antibodies. HLA typing was also performed on stored blood samples. All antibody-positive subjects were asked to undergo small-bowel biopsy in 2001. RESULTS: Of the 3654 subjects, 56 (1.5 percent) had positive antibody tests, as determined in 2001. Results of the two antibody tests were highly concordant. As of 1994, none of the subjects had received a clinical diagnosis of celiac disease, but 10 who had positive tests for both antibodies in serum obtained in 1994 received the diagnosis between 1994 and 2001. Of the 36 other subjects with positive antibody assays who agreed to undergo biopsy in 2001, 27 had evidence of celiac disease on biopsy. Thus, the estimated biopsy-proved prevalence was 1 case in 99 children. All but two of the antibody-positive subjects had either the HLA-DQ2 or the HLA-DQ8 haplotype. The prevalence of the combination of antibody positivity and an HLA haplotype associated with celiac disease was 1 in 67. CONCLUSIONS: The presence of serum tissue transglutaminase and endomysial autoantibodies is predictive of small-bowel abnormalities indicative of celiac disease. There is a good correlation between autoantibody positivity and specific HLA haplotypes. We estimate that the prevalence of celiac disease among Finnish schoolchildren is at least 1 case in 99 children.

Adolescent↗
PubMed2003

Enterovirus infections are associated with the induction of beta-cell autoimmunity in a prospective birth cohort study.

Enterovirus infections have been associated with the manifestation of clinical type 1 diabetes in a number of reports, and recent prospective studies have suggested that enterovirus infections may initiate the autoimmune process, leading to the disease. In the present study, we analyzed the role of enterovirus infections in a Finnish birth cohort study, Diabetes Prediction and Prevention (DIPP), in which all newborn infants are screened for diabetes-associated HLA-DQB1 alleles, and those with an increased genetic risk are invited for prospective follow-up. Enterovirus infections were diagnosed by serology and reverse transcriptase-polymerase chain reaction (RT-PCR) from serum samples taken from birth every 3-6 months. Case children included 41 infants who became positive for diabetes-associated autoantibodies during the observation. Control children comprised altogether 196 infants who remained autoantibody negative and were matched for the time of birth, sex, and HLA-DQB1 alleles. Enterovirus infections were more frequent in case children than in control children (P = 0.004), and the average enterovirus antibody levels were also higher in the case children (P = 0.003). Enterovirus infections were particularly frequent during the 6-month period preceding the first detection of autoantibodies: 51% of the case children compared with 28% of the control children had an infection in that time interval (P = 0.003). There was no difference in the frequency of adenovirus infections between the groups (P = 0.9). The present results imply that enterovirus infections are associated with the appearance of beta-cell autoantibodies. A possible causal relationship is supported by the clustering of infections to the time when autoantibodies appeared.

Adenoviridae Infections↗
PubMed2003

Variation in enterovirus receptor genes.

The increased incidence of a enterovirus infections observed in patients with type 1 diabetes preceding the development of the clinical disease could be partially explained by variation in the genes coding for enterovirus receptors. We carried out sequence analysis of the most common enterovirus receptor molecules in 21 diabetic children and 20 healthy adults. DNA was isolated from the leukocytes, and gene regions known to code for virus-recognizing domains in major enterovirus receptors were amplified and sequenced. Heterozygous single-nucleotide polymorphism (SNP), Ala 67 (GCG) --> Thr (ACG), was detected in the poliovirus receptor gene in four individuals in the diabetes group, but not in the control group. However, serological studies could not confirm that this substitution would convey different susceptibility to poliovirus infection. A heterozygous SNP, Lys 29 (AAG) --> Met (ATG), was found in the intracellular adhesion molecule-1 (ICAM-1) (receptor for rhinoviruses and some coxsackie A viruses) in one individual in both groups. A silent SNP in the alpha2 integrin subunit gene (echovirus 1 receptor) was frequently found in both groups, a silent heterozygotic SNP in coxsackievirus-adenovirus receptor (coxsackie B virus receptor) gene was seen in one individual in the diabetes group, whereas no variation was found in the DAF (echovirus receptor) and beta3 integrin subunit sequences (receptor for coxsackievirus A9) studied. In conclusion, both synonymous and nonsynonymous sequence variability of genes coding for enterovirus and rhinovirus receptors was shown to occur, but no pattern directly specific for type 1 diabetes was found. =

Autoimmune Diseases↗
PubMed2003

A homogeneous high-throughput genotyping method based on competitive hybridization.

OBJECTIVES: A reliable high-throughput assay system is necessary for the analysis of the ever-increasing numbers of single-nucleotide polymorphisms (SNP) relevant to genetic screening studies. We describe an assay suitable also for large-scale screening programs. DESIGN AND METHODS: The one-step assay is based on asymmetric PCR amplification of the target sequence and subsequent time-resolved fluorescence measurement. Asymmetric amplification results in a single-stranded PCR product that is detected in the amplification vessel with a highly sensitive, homogeneous hybridization method. RESULTS: A dual label, homogeneous high-throughput platform for nucleic acid sequence analysis was developed and validated using a C/T single-nucleotide polymorphism in the insulin gene as a model analyte and applied also to two other SNP-assays (poliovirus receptor A/G-polymorphism and CD86-gene exon 2 A/G-polymorphism). CONCLUSIONS: The described high-throughput genotyping technology is very competitive in price, simple in design and easily applied to any analyte sequence.

Genetic Testing↗
PubMed2003

Intercellular adhesion molecule-1 K469E polymorphism: study of association with multiple sclerosis.

Intercellular adhesion molecule-1 (ICAM-1) is involved in the pathogenesis of multiple sclerosis (MS), whereas sequence variations in the ICAM-1 gene could potentially be responsible for the genetic susceptibility to MS. We studied an association of MS with the 13,848A>G (K469E) polymorphism of the ICAM-1 gene in Finnish and Spanish cases and controls and affected families. An increased risk for the AA (Lys(469)/Lys(469)) genotype was found in both populations. The effect observed was found to be strongest among the HLA-DQB1*0602-positive subjects, which implies genetic heterogeneity of MS. Meta-analysis of all published datasets supports increased risk of MS for the ICAM-1 Lys(469) homozygotes (relative risk = 1.3, p = 0.002).

Cohort Studies↗
PubMed2003

A prospective study of Chlamydia pneumoniae antibodies in children between 7 months and 8 years of age.

To provide insight into the appearance and longitudinal course of Chlamydia pneumoniae antibodies in childhood, C. pneumoniae immunoglobulin G (IgG), IgA and, in selected children, IgM antibodies were measured annually in 199 healthy children, followed prospectively from age 7 months to age 8 y (number of samples 1225) using a commercial enzyme immunoassay kit. IgG antibodies to C. pneumoniae were common throughout the follow-up, and the values declined rapidly after apparent infections during early childhood. Of the 128 identified seroconversions, 94 were probably primary infections and 34 reinfections. IgM antibodies were detected in 28% of the samples that showed a clear increase in IgG. IgA antibodies were scarce before 2 y of age, but their proportion then increased gradually. At the ages of 7 and 8 y, 10% of the children had clearly positive IgG and IgA antibody values. Increases in IgG were not associated with clinical respiratory symptoms. This study shows that C. pneumoniae infections probably occur commonly already at an early age, and that the infections are often asymptomatic. Consecutive high IgG and IgA antibody concentrations at the ages of 7 and 8 y indicate that persistent seropositivity for both antibodies may already develop in young children.

Age Distribution↗
PubMed2003

Development of antibodies against cytomegalovirus, varicella-zoster virus and herpes simplex virus in Finland during the first eight years of life: a prospective study.

To clarify when antibodies against cytomegalovirus (CMV), varicella-zoster virus (VZV) and herpes simplex virus (HSV) develop among young children, 1206 serum samples collected prospectively from 199 children born in 1989 and 1990 were studied. The samples were drawn at the ages of 7 and 13 months, then yearly until the age of 5 y and then at 7 and 8 y. In each age group at least 106 samples were collected. Immunoglobulin G class antibodies to the 3 viruses were measured using an enzyme immunoassay. At the age of 7 months 27% of the children had CMV antibodies, whereas only 3% had antibodies against VZV and 2% against HSV. The prevalence of seropositivity for CMV increased slowly to 41% by the age of 8 y. Seroconversions to VZV antibody positivity occurred frequently after 2 y of age, so that by 8 y 83% of children had VZV antibodies. The proportion of children with HSV antibodies remained low throughout the study, as only 17% of children had HSV antibodies at the age of 8 y. The data show that HSV infection is becoming acquired later in life and the proportion of uninfected children is increasing. The proportion of CMV infections during the perinatal period and early infancy remains high, in one-third of the children, and most children also have VZV infection during the early years of life.

Age Factors↗
PubMed2003

Diagnostic potential of parechovirus capsid proteins.

To study humoral and cellular immunity against human parechovirus type 1 (HPEV1), the viral capsid proteins VP0, VP1, and VP3 were expressed and purified as glutathione S-transferase (GST)-tagged recombinant proteins. The fusion proteins were used to raise antisera in rabbits. VP0 and VP1 antisera specifically detected HPEV1-infected cells in culture by immunoperoxidase staining and immunofluorescence. Furthermore, antisera against the VP0 and VP1 proteins had neutralizing effects against HPEV1 infection. When the HPEV1 antibody titers of 20 adults and 55 children were determined by a microneutralization test, the prevalence of HPEV1 antibodies in the adult population was 96%, while 50% of children were seropositive. Selected sera were used to evaluate HPEV1 fusion proteins as antigens in an enzyme immunoassay. The VP3 capsid protein appeared to be suitable for the purpose, with specificity of 100% and sensitivity of 96% compared to the neutralization test. Furthermore, T-cell responses to the purified HPEV1 and HPEV1 capsid fusion proteins were studied in 20 adults. Sixty percent of the subjects had T-cell proliferation responses to purified HPEV1, and 90% of the subjects also had positive T-cell responses to at least one of the GST capsid proteins.

Adult↗
PubMed2003

Recombination in circulating enteroviruses.

Recombination is a well-known phenomenon for enteroviruses. However, the actual extent of recombination in circulating nonpoliovirus enteroviruses is not known. We have analyzed the phylogenetic relationships in four genome regions, VP1, 2A, 3D, and the 5' nontranslated region (NTR), of 40 enterovirus B strains (coxsackie B viruses and echoviruses) representing 11 serotypes and isolated in 1981 to 2002 in the former Soviet Union states. In the VP1 region, strains of the same serotype expectedly grouped with their prototype strain. However, as early as the 2A region, phylogenetic grouping differed significantly from that in the VP1 region and indicated recombination within the 2A region. Moreover, in the 5' NTR and 3D region, only 1 strain of 40 grouped with its prototype strain. Instead, we observed a major group in both the 5' NTR and the 3D region that united most (in the 5' NTR) or all (in the 3D region) of the strains studied, regardless of the serotype. Subdivision within that major group in the 3D region correlated with the time of virus isolation but not with the serotype. Therefore, we conclude that a majority, if not all, circulating enterovirus B strains are recombinants relative to the prototype strains, isolated mostly in the 1950s. Moreover, the ubiquitous recombination has allowed different regions of the enterovirus genome to evolve independently. Thus, a novel model of enterovirus genetics is proposed: the enterovirus genome is a stable symbiosis of genes, and enterovirus species consist of a finite set of capsid genes responsible for different serotypes and a continuum of nonstructural protein genes that seem to evolve in a relatively independent manner.

5' Untranslated Regions↗