Merja Helminen

Polymorphism of the Interleukin-10 Gene Is Associated with Susceptibility to Epstein-Barr Virus Infection

There are indications that the cytokine interleukin (IL)-10 has a regulatory role in Epstein-Barr virus (EBV)-induced infections. Because the human IL-10 gene demonstrates polymorphism resulting in interindividual differences in cytokine production, the frequencies of the alleles defined by the base exchange polymorphism at the position -1082 (allele 1=G, allele 2=A) were analyzed in EBV-seronegative adults, seropositive adults, and in patients hospitalized because of a severe EBV infection. The frequencies of allele 1 were 0.80, 0.46, and 0.29, respectively. Because this allele is associated with a high IL-10-producing capability, these data suggest that high IL-10 levels protect against EBV infection and, conversely, that low IL-10-producing capability makes individuals more susceptible to a severe EBV infection.

Increased Plasma Levels of Pro‐ and Anti‐inflammatory Cytokines in Patients with Febrile Seizures

Summary:  Purpose: Pro‐ and antiinflammatory cytokines regulate the febrile response during infection. Febrile seizures (FSs) conversely are associated with rapid onset of high fever. Activation of the cytokine network has been shown in previous studies of FSs and cytokines. In this study, the association between cytokines and FSs was further investigated.

Increased frequency of interleukin-1β (−511) allele 2 in febrile seizures

Febrile seizures can be the first sign of epilepsy. In a recent study, patients with temporal lobe epilepsy were reported to carry the interleukin-1beta allele 2 at position -511 more often than healthy control subjects. Because pro-inflammatory cytokines, such as interleukin-1, are well-known inducers of fever and therefore could play an important part in the pathogenesis of febrile seizures, we have, in this study, analyzed the cytokine gene polymorphism of interleukin-1beta at position -511 in children with febrile seizures and control subjects. We found a statistically significant increase in the frequency and the carriage of interleukin-1beta (-511) allele 2 in children with febrile seizures (n = 35) compared with healthy blood donors (n = 400) (P = 0.03 and P = 0.05, respectively). In previous studies, this allele has been connected to increased in vitro production of interleukin-1. Children with febrile seizures may therefore have an increased pro-inflammatory reaction during fever. This pro-inflammatory reaction may also predispose some children to the development of epilepsy.

Susceptibility to Primary Epstein-Barr Virus Infection Is Associated with Interleukin-10 Gene Promoter Polymorphism

In total, 116 children were investigated to determine whether the interleukin (IL)-10 polymorphism influences the age at primary Epstein-Barr virus (EBV) infection. The promoter of IL-10 is polymorphic, with 3 known single base substitutions (G/A at -1082, C/T at -819, and C/A at -592), which form 3 haplotypes: GCC, ACC, and ATA. This study found that carriage of the ATA haplotype protects against early EBV infection. The presence of the ATA haplotype was associated with EBV seronegativity (odds ratio, 2.6; 95% confidence interval, 1.04-6.7; P=.04), when controlled by age. To examine the effect of haplotypes on IL-10 production, IL-10 plasma levels were measured in 50 newborns and 400 adults and were correlated with the IL-10 haplotype. The IL-10 levels were significantly higher in the ATA carriers than in the noncarriers. These data suggest that the IL-10 ATA haplotype confers protection against primary EBV infection and that the effect is mediated by high IL-10 levels.

Preschool asthma after bronchiolitis in infancy

Asthma risk is lower after wheezing associated with respiratory syncytial virus (RSV) than with non-RSV infection in infancy. RSV is the main wheezing-associated virus in infants aged <6 months. We evaluated the outcome of children hospitalised for bronchiolitis at <6 months of age, with special focus on viral aetiology and early risk factors. Out of 205 infants hospitalised for bronchiolitis at <6 months of age, 127 (62%) attended a control visit at a mean age of 6.5 yrs and the parents of an additional 39 children were interviewed by telephone. Thus, follow-up data collected by identical structured questionnaires were available from 166 (81%) children. Viral aetiology of bronchiolitis, studied on admission by antigen detection or PCR, was demonstrable in 97% of cases. Current asthma was present in 21 (12.7%) children: 8.2% in the 110 former RSV patients versus 24% in non-RSV patients (p=0.01). 45 (27%) children had ever had asthma. In adjusted analyses, atopic dermatitis, non-RSV bronchiolitis and maternal asthma were independently significant early-life risk factors for asthma. The risk of asthma was lower after RSV bronchiolitis than after bronchiolitis caused by other viruses in children hospitalised at <6 months of age.

Increased Interleukin-1 (IL-1) Production from LPS-Stimulated Peripheral Blood Monocytes in Children with Febrile Convulsions

ABSTRACT. Peripheral blood mononuclear cells (MNC) from 27 children with a febrile convulsion were tested for production of interleukin‐1 (IL‐1) in culture. MNC stimulated with lipopolysaccharide (LPS) showed a significantly increased production of IL‐1 when compared to MNC from children without convulsions but with bacterial infections (p < 0.001), viral infections (p < 0.005) or no infection (p < 0.005). Children who had experienced a febrile convulsion were retested several months later; this time the IL‐1 production from LPS‐stimulated MNC was not different from controls. These results demonstrate that MNC at the time of febrile convulsions have increased sensitivity to LPS and possibly to other IL‐1 inducers; the resulting enhanced IL‐1 response from sensitized MNC may have a role in the pathogenesis of febrile convulsions.

IL-10 Gene Polymorphism at -1082 A/G Is Associated With Severe Rhinovirus Bronchiolitis in Infants

We analyzed polymorphisms of IL‐10 −1082 G/A, IL‐18 −137 G/C, TLR4 +896 A/G, and IFNG +874 T/A in 139 infants under 6 months of age hospitalized with bronchiolitis and 400 unselected blood donors. Causative viruses were determined by PCR. Infants with bronchiolitis associated with a virus other than respiratory syncytial virus (N = 18), were more often IL‐10 −1082 allele G non‐carriers, that is, homozygous for allele A (AA) than controls (66.7% vs. 28.0%, P < 0.0001). Infants with RSV bronchiolitis did not differ from controls. This finding suggests a different pathogenic mechanism for RSV bronchiolitis as compared with wheezing associated with other viral infections, for example, rhinovirus in infants under 6 months of age. Pediatr Pulmonol. 2008; 43:391–395.

Cranberry Juice for the Prevention of Recurrences of Urinary Tract Infections in Children: A Randomized Placebo-Controlled Trial

BACKGROUND Cranberry juice prevents recurrences of urinary tract infections (UTIs) in adult women. The objective of this study was to evaluate whether cranberry juice is effective in preventing UTI recurrences in children. METHODS A double-blind randomized placebo-controlled trial was performed in 7 hospitals in Finland. A total of 263 children treated for UTI were randomized to receive either cranberry juice (n = 129) or placebo (n = 134) for 6 months. Eight children were omitted because of protocol violations, leaving 255 children for the final analyses. The children were monitored for 1 year, and their recurrent UTIs were recorded. RESULTS Twenty children (16%) in the cranberry group and 28 (22%) in the placebo group had at least 1 recurrent UTI (difference, -6%; 95% confidence interval [CI], -16 to 4%; P = .21). There were no differences in timing between these first recurrences (P = .32). Episodes of UTI totaled 27 and 47 in the cranberry and placebo groups, respectively, and the UTI incidence density per person-year at risk was 0.16 episodes lower in the cranberry group (95% CI, -.31 to -.01; P = .035). The children in the cranberry group had significantly fewer days on antimicrobials (-6 days per patient-year; 95% CI, -7 to -5; P < .001). CONCLUSIONS The intervention did not significantly reduce the number of children who experienced a recurrence of UTI, but it was effective in reducing the actual number of recurrences and related antimicrobial use.

Resistance to Human Cytomegalovirus Infection may be Influenced by Genetic Polymorphisms of the Tumour Necrosis Factor-alpha and Interleukin-1 Receptor Antagonist Genes

To examine whether there are genetic differences between cytomegalovirus (CMV)-seronegative and CMV-seropositive adults, the polymorphisms of cytokine genes were analysed in a cohort of 400 adult blood donors. The genes and polymorphic sites studied were the tumour necrosis factor-alpha (TNF-alpha) gene (base exchange polymorphism at position -308; alleles TNF1 and TNF2) and the interleukin-1 receptor antagonist (IL-1RA) gene (variable numbers of 86-bp repeats in intron 2). In this material there were 85 (21%) seronegative persons. The frequencies of the TNF2 and the IL-IRA allele 2 (IL1RN*2) carriers were slightly increased in the seronegative compared with the seropositive samples (39% vs. 29%, and 55% vs. 47%, respectively). The presence of both of these alleles together was significantly (p < 0.05, chi2-test) more frequent in the seronegative population. These data suggest that the alleles of these cytokines, which are known to be associated with a strong inflammatory reaction, may have a protective role against CMV infection.

Toll-like receptor 3 L412F polymorphisms in infants with bronchiolitis and postbronchiolitis wheezing.

Background: Innate immunity receptors play a critical role in host defense. In addition, the expression of Toll-like receptors (TLRs) has been connected to allergy and asthma. Aims: To evaluate the association between the TLR3 L412F polymorphism and viral findings, clinical characteristics and subsequent wheezing in young infants with bronchiolitis. Methods: In all, 129 full-term infants hospitalized for bronchiolitis at age <6 months have been followed-up until the mean age of 1.5 years. Genotyping of the TLR3 L412F gene mutation was made by pyrosequencing. Results: TLR3 L412F gene polymorphism including the minor allele T was overrepresented (52%) in infants hospitalized with bronchiolitis. The presence of the major allele C as homozygous was associated with repeated postbronchiolitis wheezing (7.06, 95% confidence interval 2.30–21.66). Conclusion: Preliminary evidence was found that TLR3 L412F gene polymorphism may be associated with bronchiolitis leading to hospitalization and postbronchiolitis wheezing.