Interaction of maternal atopy, CTLA-4 gene polymorphism and gender on antenatal immunoglobulin E production

BACKGROUND: Genetic heritability and maternal atopy have been correlated to antenatal IgE production, but very few studies have studied gene-maternal atopy interaction on antenatal IgE production. This study investigated the interaction of CTLA-4 polymorphism with prenatal factors on the elevation of cord blood IgE (CBIgE). METHODS: Pregnant women were antenatally recruited for collection of prenatal environmental factors by a questionnaire. Umbilical cord blood samples were collected for CBIgE detection by fluorescence-linked enzyme assay and CTLA-4 polymorphism measurement by restriction fragment length polymorphism. RESULTS: A total of 1104 pregnant women initially participated in this cohort study, and 898 of them completed cord blood collection. 21.4% of the newborns had elevation of CBIgE (>or=0.5 kU/L). The CTLA-4+49A allele (P=0.021), maternal atopy (P<0.001) and gender (P=0.034), but not the CTLA-4+49G allele, -318C allele, -318T allele, parental smoking or paternal atopy, were significantly correlated with the CBIgE elevation in multivariate analysis. A dichotomous analysis of gene-maternal atopy interactions identified maternal atopy and CTLA-4+49A allele had an additive effect on the CBIgE elevation, especially prominent in male newborns; and in the absence of maternal atopy, CTLA-4+49GG genotype had a protective effect on CBIgE elevation in female newborns. CONCLUSIONS: Maternal but not paternal atopy has significant impacts on CBIgE elevation depending on gender and CTLA-4+49A/G polymorphism of newborns. Control of maternal atopy and modulation of CTLA-4 expression in the prenatal stage may be a target for the early prevention of perinatal allergy sensitization.     

Association of IL13 with total IgE: evidence against an inverse association of atopy and diabetes

BACKGROUND: Atopic illnesses, related to high circulating IgE levels, and the autoimmune disease type 1 diabetes, have been reported to be inversely associated. One possible explanation is that susceptibility alleles for one disease provide protection for the other. OBJECTIVE: Using the largest sample sizes reported so far for the identification of genetic determinants of circulating IgE levels, we investigated associations between total serum IgE (log-transformed) and single nucleotide polymorphisms in 8 genes that are candidate susceptibility loci for IgE levels/atopic illness (IL13, IL4, IL4RA, FCER1B, IL12B, TBET) and/or type 1 diabetes (CTLA4, PTPN22, IL2RA). METHODS: As many as 4570 DNA samples obtained from members of the British 1958 Birth Cohort were genotyped for 51 candidate variants, and the associations of alleles and genotypes with log-transformed serum IgE levels were evaluated by regression modeling. RESULTS: We obtained evidence of association between IL13 variants and total serum IgE levels (P = .00002, explaining 0.59% of phenotypic variance). However, there was no evidence of association of the confirmed type 1 diabetes susceptibility genes CTLA4 and PTPN22 and the candidate gene IL2RA with IgE levels. CONCLUSION: Allelic variation in the IL-13 gene is robustly confirmed as a contributor to the variance of IgE levels but has no detectable effect in type 1 diabetes. CLINICAL IMPLICATIONS: Although the allelic variation at the confirmed IL-13 locus explains too little of the between-individual variation of circulating IgE to be of use for clinical prediction on its own, the discovery of additional susceptibility loci in the future may aid in the stratification of atopic subjects and improve risk assessment.     

Serum IgE levels, atopy, and asthma in young adults: results from a longitudinal cohort study

To explore the natural history of asthma and its relation to allergic responses, we examined the relation between total serum IgE in early adulthood and a history of respiratory symptoms, airway hyperresponsiveness (AHR), and atopy during childhood. We studied 180 subjects aged 18–20 years who had been studied since the age of 8–10 years. We measured wheeze in the previous year by questionnaire, AHR by histamine inhalation test, atopy by skin prick tests, and serum IgE levels by immunoassay. Subjects with AHR in early adulthood had higher IgE levels (mean 257.0 IU/ml) than subjects with past AHR (mean 93.3 IU/ml) or with lifelong normal responsiveness (mean 67.6 lU/ml) ( P< 0.001). Subjects who had symptoms had higher IgE levels (mean 125.9 IU/ml) than those who were lifelong asymptomatic (mean 63.1 IU/ml) ( P< 0.001). Recent wheeze, AHR, and allergic sensitization all had a positive relation to serum IgE, but IgE was not more predictive of AHR than skin prick tests. The finding that young adults who are sensitized to common allergens are highly likely to have AHR even in the absence of symptoms is further evidence of the fundamental role of IgE-mediated responses in the natural history of AHR throughout childhood and into adulthood.     

Relationships between natural T cells, atopy, IgE levels, and IL-4 production

BACKGROUND: Th2 cells govern allergic disorders. Mechanisms leading to the Th2 commitment are dominated by the requirement of IL-4. A potential source of this triggering IL-4 could be the CD4 + subset of a small population of T cells, natural T (NT) cells. Indeed, this subset is involved in IgE responses in mice and produces promptly high amounts of IL-4 in both mice and man. METHODS: NT cells were identified in peripheral blood by flow cytometry with antibodies against Valpha24 and Vbeta11, recognizing the T-cell receptor specific for NT cells. Simultaneous staining with anti-CD3, anti-CD4, or anti-CD8 antibodies was performed. The frequency of NT cells in man was studied according to the presence of atopy defined by the positivity of skin tests, according to total IgE levels in serum, and according to IL-4 concentration of whole-blood culture supernatants determined by a flow cytometer microsphere-based assay. RESULTS: Seventy subjects were included, of whom 30 were atopic. The number of CD4+ NT cells was higher in atopics than in nonatopics (P=0.009). This number was correlated to the total IgE levels (r = 0.34, P = 0.03). In addition, the number of CD4 + NT cells, but also of CD8 + NT cells, was correlated to the levels of IL-4 (r=0.71, P=0.01, and r=0.6, P=0.03, respectively). CONCLUSIONS: These results show that the number of NT cells, particularly the CD4+ subset, is related to atopy, IL-4 production, and IgE levels. Therefore, this population of T cells is likely to play a role in the Th2 commitment initiating atopic diseases.     

Rare TLR2 mutations reduce TLR2 receptor function and can increase atopy risk

Background: Common genetic variations in toll‐like receptor 2 (TLR2), an innate pathogen recognition receptor, may influence the development of atopic diseases. So far, very little is known about the role of rare TLR2 mutations in these diseases. Objective: We investigated the functional properties of six rare amino acid changes in TLR2 (and one amino acid change in a TLR2 pseudogene) and studied their effect on atopic sensitization and disease. Methods: We identified rare TLR2 mutations leading to amino acid changes from databases. Functional effects of TLR2 variants were analyzed by NF‐κB‐dependent luciferase reporter assay and interleukin‐8 enzyme linked immunosorbent assay in vitro. The frequency of these mutations was determined in a random sample of the general population (n = 368). Association with atopic diseases were studied in a cross sectional German study population (n = 3099). Results: Three out of six mutations in the TLR2 gene altered receptor activity in vitro. Out of these, only the minor allele of R753Q occurred reasonably frequent in the German population (minor allele frequency 3%). The risk to develop atopy increased by 50% in carriers of the 753Q allele (P = 0.021) and total (P = 0.040) as well as allergen specific serum IgE levels (P = 0.011) were significantly elevated. Conclusion: The rare but functionally relevant mutation R753Q in TLR2 may significantly affect common conditions such as atopic sensitization in the general population.     

Early life markers of atopy and asthma

Since early intervention could modulate the natural course of atopic disease, the availability of predictive markers is of considerable interest. As long as specific genetic markers are not available, early IgE-responses (hen's egg) together with a positive family history of atopy can be proposed as highly specific and predictive markers, which could define subgroups as potential candidates for secondary prevention.     

Sequence variants of the secreted phosphoprotein 1 gene are associated with total serum immunoglobulin E levels in a Japanese population

BACKGROUND: Secreted phosphoprotein 1 (SPP1) is a cytokine with pleiotrophic immunological activities, including activation of macrophage chemotaxis and T-helper type 1 (Th1) immune responses. SPP1 gene polymorphisms have been shown to be associated with several immune inflammatory diseases including multiple sclerosis (MS), which is characterized by fewer allergic symptoms and lower numbers of allergen sensitizations. OBJECTIVE: The present study examined whether SPP1 gene polymorphisms are associated with total serum IgE levels, atopy and asthma in a Japanese population. METHODS: This case-control association analysis examined 611 subjects, including 268 subjects with asthma. We genotyped three promoter and two exon polymorphisms at SPP1: -1687A/G; -381T/C; -94 deletion/G; 5891C/T; and 7052T/C. Results Association analyses of SPP1 polymorphisms showed that homozygosities for the 5891T allele (P=0.009) and 7052C allele (P=0.001) were significantly associated with increased levels of total IgE in non-asthmatic subjects. However, these variants were not associated with asthma and atopy. Interestingly, individuals carrying the 5891C allele, which is more prevalent in patients with MS in Japanese populations, displayed significantly lower levels of total serum IgE. Individuals homozygous for the 7052C allele, which is associated with development of systemic lupus erythematosus, displayed significantly higher total serum IgE levels. CONCLUSION: These findings suggest that genetic polymorphisms in SPP1 may play a role in controlling basal levels of total serum IgE, independent of atopy.     

Maternal atopy and changes in parity

BACKGROUND: Atopic women tend to have fewer children, although atopy may favour conception. OBJECTIVE: To assess whether atopy is associated with the number of new births and whether changes in parity are associated with a change in atopy in a cohort of young women. METHODS: Women had atopy (defined as the presence of serum-specific IgE against common aeroallergens) measured in the European Community Respiratory Health Study during the years 1991--92 (n=4580). About 9 years later, 2844 (62.1%) were recontacted and 2414 (52.7%) had atopy measured again. RESULTS: Atopic women had fewer children at baseline than non-atopic women but the association disappeared at the end of the follow-up. Atopy tended to increase parity during the follow-up, but in a non-statistically significant way (relative risk=1.08; 0.86-1.35, after adjusting for number of children at baseline, age, length of follow-up, education or social class). Prevalence of atopy during the follow-up changed by the same magnitude whatever the birth cohort and the change in the number of children (P for interaction >0.7). CONCLUSION: Atopic women did not have a significantly higher fertility rate but they may postpone having their first child compared with non-atopic women. We are unable to confirm the hypothesis that atopy in women may decrease with successive pregnancies.     

Molecular variations in the promoter and coding regions of human Tim-1 gene and their association in Koreans with asthma

The family of T-cell immunoglobulin domain and mucin domain (TIM) proteins is identified to be expressed on T cells. A member of Tim family, TIM-1, was considered as a membrane protein that is associated with the development of helper T cell (Th2) biased immune responses, and may be selectively expressed on Th2 cells. In the present study we performed single nucleotide polymorphism (SNP) scanning of the coding and promoter regions of human Tim-1 gene. We identified a total of ten SNPs including five novel SNPs (-1166C>G, -416G>C, -232A>G, 5365C>T, and 5529A>G) in the coding and promoter regions, one novel variation site (-2278_-2276dupATT) in the promoter region and three variations (5383_5397del, 5387_5389insAAC, and 5509_5511delCAA) in exon 4 of human Tim-1 gene. Our results suggest that the exon 4 variation site in human Tim-1 gene is associated with the susceptibility of allergic disease.     

Mutation screening of interferon regulatory factor 1 gene (IRF-1) as a candidate gene for atopy/asthma.

BACKGROUND: IL-4 gene cluster on chromosome 5 contains several candidate genes for atopy and asthma. Several independent studies have shown evidence for linkage between the markers flanking IL-4 gene cluster and asthma and/or asthma-related traits. Interferon regulatory factor 1 (IRF-1) is located approximately 300 kb telomeric to IL-4 and recent study reveals that IRF-1 deficiency results in an elevated production of Th2-related cytokines and a compensatory decrease in the expression of native cell- and Th1-related cytokines. OBJECTIVE: To determine if there are any mutations associated with the development of atopy and asthma present in the coding exons and 5' flanking region of the IRF-1 gene. METHODS AND RESULTS: We have screened the promoter and coding regions of the IRF-1 gene in atopic asthmatics and controls by SSCP method. We found three novel nuclear variants (the -300G/T and 4396 A/G polymorphisms and the 6355G > A rare variant) in the IRF-1 gene. No variants causing amino acid alterations of IRF-1 were detected. The -300G/T polymorphism was in nearly complete linkage disequilibrium with the 4396 A/G polymorphism. An association between the 4396 A > G polymorphism and atopy/asthma was examined by transmission disequilibrium test in 81 asthmatic families. Either of 4396 A or 4396G alleles was not significantly preferentially transmitted to atopy- or asthma-affected children. CONCLUSION: The IRF-1 gene is less likely to play a substantial role in the development of atopy and asthma in the Japanese population.     

Low molecular weight PTP–IL-4RA interaction in atopy predisposition

We recently described a protective effect of the low molecular weight protein tyrosine phosphatase (LMPTP) BC genotype, associated with the highest total enzymatic activity, against high serum IgE levels both in the English and the Italian populations. Here we test the hypothesis of a role of LMPTP in the negative modulation of IL-4 signal transduction checking for genetic interaction between interleukin-4 receptor alpha chain (IL-4RA) genetic polymorphisms and LMPTP polymorphism in the predisposition to high total IgE levels in the English population. We find a significant interaction between LMPTP polymorphism and the intracellular Gln/Arg polymorphism in position 551 of IL-4RA. Our data support the hypothesis of a direct or indirect biochemical interaction between LMPTP and IL-4RA resulting in different modulation of IL-4 signal transduction among joint genotypes.     

IgE antibodies to Hymenoptera venoms in the serum are common in the general population and are related to indications of atopy

Determination of Hymenoptera venom (HV)-specific serum IgE antibodies is a useful diagnostic method in patients with systemic anaphylactic reaction (SAR) to Hymenoptera stings. In a general population cohort, we determined the prevalence of SAR and HV-specific IgE antibodies and assessed parameters associated with the latter. A total of 277 voluntarily participating inhabitants of rural Bavaria (Germany) (232 adults, mean age 38.0 years; 45 children, mean age 8.4 years) were investigated for a history of atopic disease or SAR to insect stings; in 258 of these, total IgE and specific IgE antibodies to HV ( Apis mellifera, Vespula vulgaris/germanica ) and four common aeroallergens (birch pollen, grass pollen, house-dust mite, and cat dander) in the serum were determined. Nine (3.3%) subjects reported SAR to insect stings. In 27.1% of the sera, specific IgE antibodies to HV were found, to bee venom in 24.8%, and to wasp venom in 8.5% ( P <0.0001). Of those exhibiting HV-specific IgE, 7.1% reported SAR to insect stings. A personal history of atopic disease (hay fever, asthma, or atopic eczema) was present in 16.7%, specific IgE to common aeroallergens was found in 32.6%, and total IgE> 100 kU/1 was found in 22.5%. Specific serum IgE to HV was significantly associated with male sex (female vs. male, OR = 0.47; CI 0.25–0.86), young age (children vs. adults, OR = 2.80; CI 1.25–6.28), a history of SAR to insect stings (OR = 4.16; CI 1.15–15.03), total slgE>100kU/l (OR = 3.88; CI 1.98–7.60), and specific IgE antibodies to three of the four aeroallergens (grass pollen, OR = 7.24 CI 3.66–14.38; birch pollen, OR = 3.67 CI 1.54–8.81; and house-dust mite, OR = 4.61 CI 2.08–10.32). It is concluded that immunologic sensitization to HV is common in the general population and is associated with atopy-related humoral IgE hyperresponsiveness.