A molecular model of type I allergy: identification and characterization of a nonanaphylactic anti-human IgE antibody fragment that blocks the IgE-FcepsilonRI interaction and reacts with receptor-bound IgE.

BACKGROUND: The IgE-mediated activation of effector cells and antigen-presenting cells through the high-affinity receptor for IgE (FcepsilonRI) represents a key pathomechanism in type I allergy and many forms of asthma. OBJECTIVE: We sought to establish an in vitro molecular model for the interaction of human FcepsilonRI, IgE, and the corresponding allergen and to identify monoclonal anti-human IgE antibodies with a therapeutic profile different from previously established anti-IgE antibodies. METHODS: Human FcepsilonRI alpha chain, a human monoclonal allergen-specific IgE antibody (chimeric Bip 1), and the corresponding allergen, the major birch pollen allergen Bet v 1, were produced as recombinant proteins and analyzed by means of circular dichroism and native overlays, respectively. Using this molecular model, as well as negative stain immunoelectron microscopic analysis, and in vitro cultivated human basophils, we characterized mouse anti-human IgE antibodies. RESULTS: We established a molecular model for the interaction of human IgE with FcepsilonRI. Using this molecular model, we identified a nonanaphylactic anti-human IgE antibody fragment (Fab12), which blocked the IgE-FcepsilonRI interaction and reacted with effector cell-bound IgE. CONCLUSION: Fab12 represents a candidate molecule for therapy of atopy and asthma because it can be used for the depletion of circulating IgE antibodies, as well as for the depletion of IgE-bearing cells.     

Opposite gene by environment interactions in Karelia for CD14 and CC16 single nucleotide polymorphisms and allergy

Background:  Finnish Karelians have a higher prevalence of allergic disease than Russian Karelians. As both populations are generally from the same ethnic group, the Karelian population offers a unique opportunity to analyse genetic and allergic disease interactions between 'Western' and 'Eastern' environments.
Objectives:  We investigated associations between allergic diseases and CD14 and CC16 polymorphisms in Finnish vs Russian Karelian women.
Methods:  Adult female Karelians (330 Finnish and 274 Russian) were recruited, examined for a range of symptoms and conditions including rhinitis, itchy rash, asthma and atopy and genotyped for CD14 C-159T and CC16 A38G.
Results:  For both CD14 C-159T and CC16 A38G, the risk allele for atopic phenotypes in Finnish Karelia was the protective allele in Russian Karelia. For CD14 C-159T, an interactive effect on ever itchy rash ( P _interaction = 0.004), itchy rash <12 mo ( P _interaction = 0.001) and dry cough at night in the past 12 months (<12 months) ( P _interaction = 0.011) was found; the risk allele was C in Russians and T in Finns. For CC16 A38G, an interaction was significant for ever rhinitis ( P _interaction = 0.006), rhinitis <12 mo ( P _interaction = 0.004), and marginally significant for ever hayfever ( P _interaction = 0.07), allergic eye symptoms <12 mo ( P _interaction = 0.09); their risk allele was G in Russians and A in Finns.
Conclusion:  An Eastern vs Western environment appears to exert an effect via opposite alleles on risk of allergic diseases in adult women.     

A quantitative genetic analysis of intermediate asthma phenotypes

Aim:  To study the relative contribution of genetic and environmental factors to the correlation between exhaled nitric oxide (FeNO), airway responsiveness, airway obstruction, and serum total immunoglobulin E (IgE).
Methods:  Within a sampling frame of 21 162 twin subjects, 20–49 years of age, from the Danish Twin Registry, a total of 575 subjects (256 intact pairs and 63 single twins) who either themselves and/or their co-twins reported a history of asthma at a nationwide questionnaire survey, were clinically examined. Traits were measured using standard techniques. Latent factor models were fitted to the observed data using maximum likelihood methods.
Results:  Additive genetic factors explained 67% of the variation in FeNO, 43% in airway responsiveness, 22% in airway obstruction, and 81% in serum total IgE. In general, traits had genetically and environmentally distinct variance structures. The most substantial genetic similarity was observed between FeNO and serum total IgE, genetic correlation (ρ_A) = 0.37, whereas the strongest environmental resemblance was observed between airway responsiveness and airway obstruction, specific environmental correlation (ρ_E) = −0.46, and between FeNO and airway responsiveness, ρ_E = 0.34.
Conclusions:  Asthma is a complex disease characterized by a set of etiologically heterogeneous biomarkers, which likely constitute diverse targets of intervention.     

The size of the disease relevant IgE antibody fraction in relation to 'total-IgE' predicts the efficacy of anti-IgE (Xolair®) treatment

Background:  Some patients with allergic asthma treated with anti-IgE (Xolair^®) do not become symptom free. Better criteria for response assessment than allergy skin tests or IgE determination are needed. The impact of the size of the disease relevant allergen-specific IgE antibody fraction, i.e. the percentage of IgE antibody of total IgE, was evaluated in cat allergic patients treated with the recommended doses of Xolair^®. Results were measured as changes in basophil allergen threshold sensitivity (CD-sens).
Methods:  In a double-blind placebo controlled trial 20 patients with a high (>3.8%) and 18 with a low (<1%) percentage of IgE antibodies to cat were given Xolair^® for 16 weeks and the change in CD-sens was compared to 11 and 10 patients, respectively, in each group receiving placebo.
Results:  The CD-sens dropped significantly in both the high ( P  < 0.001) and low ( P  < 0.001) group on Xolair^® but did not change significantly after placebo. For Xolair^®-treated patients, at the end of the trial there was a highly significant ( P  < 0.001) difference in CD-sens between the high group, where no patients, and the low group, where 13/18 patients, had become negative.
Conclusions:  The currently recommended doses of Xolair^® very efficiently eliminate IgE antibodies if the IgE antibody fraction is <1% of total IgE but has not enough effect on allergen sensitivity if the fraction is >3–4%. Further studies will show if increased doses of Xolair^® would help also these patients, who seem to represent about 1/3 of the patient population.     

Relationship between pretreatment specific IgE and the response to omalizumab therapy

Background:  Omalizumab, an anti-IgE antibody, has proven efficacy in patients with moderate-to-severe and severe persistent allergic (IgE-mediated) asthma. While previous analyses have had some limited success in predicting which patients will gain greatest benefit based on pretreatment baseline characteristics, it remains important to try to improve this predictability.
Methods:  Following a run-in phase, patients (12–75 years) inadequately controlled despite current therapy were randomized to receive omalizumab or placebo for 28 weeks in a double-blind, parallel-group, multicenter study (INNOVATE). Univariate analyses were performed to assess whether pretreatment specific IgE serum levels and related variables could be identified that were predictive of a response to omalizumab patients ( n  = 337) enrolled in INNOVATE. Response was measured via variables including exacerbations, QoL, FEV₁ and physicians' overall assessment.
Results:  A total of 305 patients (90.5%) were sensitive to more than one allergen and the majority of patients were positive to D1 Dermatophagoides pteronyssinus and D2 Dermatophagoides farinae . Patients with relatively high values of D1 or D2, but with these making a relatively low contribution to total specific IgE load, appeared to attain most benefit from omalizumab. However, no consistent predictive effect for omalizumab response was observed either for total specific IgE or levels of IgEs specific for individual allergens.
Conclusions:  Based on these data, pretreatment allergen-specific IgE levels do not provide any better prediction of response to treatment as compared with pretreatment total IgE. At present, the most reliable method of identifying patients who respond to omalizumab treatment remains a physician's assessment.     

Common variants in FCER1A influence total serum IgE levels from cord blood up to six years of life

Background:  In a recent genome wide scan, a functional promoter variant (rs2251746) in the gene encoding the alpha chain of the high affinity receptor for immunoglobulin E (IgE) (FCER1A) was identified as major determinant of serum IgE levels.
Objective:  The aim of this study was to investigate the role of rs2251746 on total IgE levels measured at different stages of life from birth (cord blood) up to the age of 6 and to evaluate its interaction with the environmental influences in two German birth cohorts.
Method:  Data from two German birth cohorts were analysed ( n  = 1043 for the LISA cohort and n  = 1842 for the GINI cohort). In the studies, total serum IgE was measured from cord blood, and blood samples taken at the age of 2/3 and 6 years. In a subgroup of the LISA study, house dust samples were collected at age of 3 months and the amount of endotoxin was determined. Random effect models were used to analyse the longitudinal health outcomes.
Results:  In the two cohorts, the heterozygote and the rare homozygote of rs2251746 was consistently associated with lower total IgE levels from birth up to the age of 6 years with an allele-dose effect ( P  < 0.02 for blood samples taken at each time point in both cohorts). No interaction between the two FCER1A encoding gene and environmental exposures including endotoxin, worm infestation and day care centre attendance during early childhood were observed.
Conclusion:  Common variants in FCER1A strongly influence basal IgE production independently from environmental stimuli. These effects can be observed already in cord blood pointing to altered gene expression in foetus.     

Monomeric immunoglobulin E stabilizes FcεRIα from the human basophil cell line KU812 by protecting it from natural turnover

BACKGROUND: The high affinity IgE receptor (FcepsilonRI) on mast cells and basophils is up-regulated by its own ligand IgE; however, the mechanism is unknown. OBJECTIVE: To study the IgE-mediated effect on FcepsilonRI on basophils by using the human basophilic cell line KU812. METHODS: Expression of cell surface FcepsilonRI was assessed by flow cytometry. Western blot technique was used to illustrate tyrosine-phosphorylation and the Ca2+ level in KU812 was measured by fluorescence of Fura-2. Soluble specimens of the alpha-chain from FcepsilonRI (FcepsilonRIalpha) were obtained by lysing 107 KU812 pr. mL. FcepsilonRIalpha was detected by a sandwich immunoradiometric assay employing the IgE-binding capacity of FcepsilonRIalpha in conjunction with a monoclonal antibody. Polyclonal rabbit anti-FcepsilonRIalpha was used for detection of FcepsilonRIalpha by Western blotting. RESULTS: We found that monomeric IgE did not induce tyrosine-phosphorylation in KU812, which was the case when stimulating with IgE cross-linked by anti-IgE binding. Further, only cross-linking of IgE, but not monomeric IgE, increased the Ca2+ level. Using the immunoradiometric assay, we found a temperature dependent reduction in the amount of FcepsilonRIalpha. Samples incubated at 37 degrees C for 5 h displayed a 16-fold decrease in the FcepsilonRIalpha level compared with samples incubated at 4 degrees C. In the presence of IgE the reduction at 37 degrees C was only threefold. CONCLUSION: These results indicate that IgE does not induce intracellular signals in KU812, i.e., tyrosine-phosphorylation or Ca2+ release. Instead it appears that FcepsilonRIalpha is an unstable protein that IgE stabilizes and thereby protects from a temperature dependent turnover.     

Human dendritic cell 1 and dendritic cell 2 subsets express FcepsilonRI: correlation with serum IgE and allergic asthma

BACKGROUND: Type 1 dendritic cells (DC1) express the high-affinity IgE receptor (FcepsilonRI); however, the regulation of FcepsilonRI expression by DCs is not well understood. Type 2 DC (DC2) expression of FcepsilonRI has not been demonstrated. OBJECTIVE: We hypothesized that DC2 cellsalso express FcepsilonRI and that expression of FcepsilonRI by the DC1 and DC2 subsets correlates with serum IgE and allergic asthma disease status. METHODS: To test these hypotheses, we quantitated FcepsilonRI alpha chain expression by the peripheral blood precursor DC1 (pDC1) and pDC2 subsets by using flow cytometry. RESULTS: FcepsilonRI was expressed by the pDC1 and pDC2 subsets, as well as tissue DCs from tonsils. Relative FcepsilonRI expression by basophil, pDC1, and pDC2 subsets was 12:6.5:1, respectively. In both pDC subsets, FcepsilonRI expression was significantly greater in allergic asthmatic subjects than in nonatopic control subjects. pDC1 and pDC2 expression of FcepsilonRI was highly correlated to serum IgE concentration. The pDC1, pDC2, and basophil subsets demonstrated a similar magnitude of increase in FcepsilonRI expression relative to changes in serum IgE. CONCLUSIONS: FcepsilonRI expression is characteristic of both the DC1 and DC2 subsets. Furthermore, FcepsilonRI expression by these cells is highly correlated to serum IgE and to basophil FcepsilonRI expression and is greater in subjects with allergic asthma. These data support the concept that novel therapeutic approaches directly targeted at FcepsilonRI expression would affect both the sensitization and the effector phases of the allergen-specific immune response.     

After 6 years with Xolair; a 3-year withdrawal follow-up

Background:  This study reports the clinical and immunological state of patients 3 years after a 6-year period of Xolair treatment for severe allergic asthma.
Methods:  The patient's cat allergen sensitivity, measured as CD-sens, IgE and IgE- and IgG4 antibodies, was analysed and compared with asthma severity evaluated from FEV₁ and a questionnaire.
Results:  Three years after treatment with Xolair was stopped, 12/18 patients reported improved or unchanged asthma compared with ongoing Xolair treatment. Most of the patients were in a stable clinical condition, 16/18 had not increased nightly asthma attacks and 14/18 little or no increase in medication. The CD-sens to cat was still significantly lower ( P  < 0.02) than untreated patients with allergic asthma and lower than expected from their serum IgE antibody levels.
Conclusion:  Most of the patients in this study had, still 3 years after closing of 6 years Xolair treatment, a surprisingly mild and stable asthma. Interestingly, the observed, considerable, downregulation of basophil allergen sensitivity, CD-sens, most likely representing mast cell allergen sensitivity, contributed to the clinical results.     

Production of IgE-potentiating factor in man by T cell lines bearing Fc receptors for IgE

The regulation of human IgE production in vitro by soluble T cell factors was examined. T cells were isolated from the peripheral blood of 2 patients with the hyper-IgE syndrome on the basis of their expression of Fc receptors for human IgE (Fc epsilon R). The T cells were incubated with human myeloma IgE (10 micrograms/ml), washed, reacted with immunosorbent-purified goat anti-human IgE conjugated with fluorescein isothiocyanate, and then separated into Fc epsilon R+ and Fc epsilon R- T cells on the fluorescence-activated cell sorter. Fc epsilon R+ T cells and Fc epsilon R- T cells were propagated in culture using supernatants of phytohemagglutinin-stimulated peripheral blood mononuclear cells (PBMC) and irradiated autologous PBMC. Supernatants of Fc epsilon R+ T cell lines but not of Fc epsilon R- T cell lines selectively enhanced IgE synthesis in cultures of B cells obtained from patients with allergic rhinitis but not from normal nonallergic subjects. The surface phenotype of the Fc epsilon R+ T cell line was predominantly T3+, T4+, Ia+ with few (15%) T8+ cells. Two T cell clones were grown from the Fc epsilon R+ T cell line by limiting dilution (0.3 cells/well). These clones possessed the T4+ helper/inducer phenotype and secreted IgE-enhancing factor(s). The IgE-enhancing factor(s) which had affinity for insolubilized human IgE was sensitive to treatment with trypsin and neuraminidase, and had as its target an IgE-bearing B cell. These results suggest that a subset of human T cells bearing an Fc epsilon R secretes an IgE-binding glycoprotein which selectively enhances IgE synthesis by IgE-bearing B cells.     

Functional Changes of Human Peripheral B-Lymphocytes in Pre-Eclampsia

Problem  The aim of our study was to investigate the functional changes of human peripheral B-lymphocytes in healthy and pre-eclamptic pregnancies.
Method of study  Twenty patients with pre-eclampsia and 15 healthy third-trimester pregnant women were recruited in this study. Peripheral blood mononuclear cells (PBMCs) were isolated and directly stained with fluorescein isothiocyanate (FITC)-labeled anti-CD27 monoclonal antibody (mAb) and phycoerythrin (PE)-labeled anti-CD38 mAb. The percentages of the individual B-cell subsets were estimated out of total lymphocytes by flow cytometric analysis. Additionally, the enriched PBMCs were cultured with or without the stimulation of pokeweed mitogen (PWM) for 5 days. Then morphologic observation of plasma cells was analysed by Wright-Giemsa stain, and antibody-producing cells were detected by enzyme-linked immunospot assay.
Results  The percentage of CD27⁻CD38⁻ naïve B-cells and CD27⁻CD38⁺ plasma cells did not differ between study groups ( P  >   0.05). The percentage of CD27⁺CD38⁻ memory B-cells and CD27⁺CD38⁺ plasma cell pre-cursors increased in pre-eclamptic women compared with the controls ( P  <   0.05). Irrespective of whether the PBMCs were stimulated with or w/o PWM in vitro , the mean percentages of generated plasma cells were significantly higher in pre-eclamptic group than in the controls ( P  <   0.05). There were more antibody-producing cells in pre-eclamptic women following the activation of PWM than those in the controls ( P <  0.01).
Conclusion  Our findings implicate that the functional changes of human circulating B-cells might contribute to the etiology of pre-eclampsia.     

An IgE-dependent secretory response of mast cells can be induced by a glycosphingolipid-specific monoclonal antibody

The signal transduction pathway of the type 1 Fcepsilon receptor (FcepsilonRI) has been proposed to be spatially constrained to plasma membrane microdomains enriched in glycosphingolipids and cholesterol. These domains are proposed to serve as platforms that enhance the efficiency of the antigen-receptor stimulus-response coupling process. Here we describe a monoclonal antibody (mAb) designated 2B5, raised by immunizing mice with rat mucosal-type mast cell (line RBL-2H3) membranes, which binds to glycosphingolipids and causes a dose-dependent secretory response of these cells. This secretory response to mAb 2B5 requires binding of IgE to the FcepsilonRI on these cells, although direct interactions between IgE and mAb 2B5 are excluded. The bound IgE- or FcepsilonRI-specific mAb did not affect binding of mAb 2B5 or its Fab fragments to the RBL-2H3 cells and only a limited interference with the binding of IgE to the FcepsilonRI by mAb 2B5 was observed. Binding of mAb 2B5 to the RBL-2H3 cells induced a distribution of fluorescently labeled IgE similar to that produced by antigen-induced aggregation of the IgE-FcepsilonRI. Thus we suggest that mAb 2B5 binds to cell surface glycosphingolipids that are probably associated with the FcepsilonRI-IgE complexes and causes their aggregation, thereby initiating the cascade leading to the cell's secretory response.     

Allergen extract-induced interleukin-10 in human memory B cells inhibits immunoglobulin E production

Background Elevated specific IgE antibody levels are common in atopic individuals, caused by T-helper type 2-dominated B cell activation. The induction of antigen-specific IL-10 secreting T cells is discussed as an important mechanism during specific immunotherapy. By contrast the presence and function of B cell-derived IL-10 is not well defined yet.
Objective We investigated whether type-I allergen extracts induce IL-10 expression in human B cells and analysed its functional role on IgE production.
Methods Human peripheral B cells were stimulated with grass pollen, house dust mite (HDM) ( Dermatophagoides pteronyssimus ; Der p) and dog allergen extract. Expression of IL-10 by activated human B cells was determined by flow cytometric analysis and ELISA. Functional analysis considering immunoglobulin production was assayed by ELISA.
Results The allergen extracts studied induced IL-10 expression in B cells. However, the ability to induce IL-10 differed between the allergen extracts. The most potent allergen extract was dog (169±28 pg/mL), followed by grass pollen (141±10 pg/mL) and HDM allergen (125±11 pg/mL). Upon allergen extract stimulation only CD27 expressing memory B cells produced IL-10 and co-expressed the very early activation antigen CD69. The addition of allergen extracts to B cells activated by anti-CD40 and IL-4 selectively inhibited IgE which was dependent on allergen extract-induced IL-10. By contrast the other immunoglobulin subclasses like IgA, IgG or IgM were not altered upon allergen extract challenge.
Conclusion Our data indicate that allergen-activated memory B cells can modulate IgE production through secretion of IL-10.     

Association between Asymmetric Dimethylarginine and Neopterin in Patients with and without Angiographic Coronary Artery Disease

The increase of circulating asymmetric dimethylarginine (ADMA) concentrations, a competitive inhibitor of the nitric oxide synthases, is associated with an increased cardiovascular risk and is considered to play a role in endothelial dysfunction. Recently, ADMA production was observed in stimulated human peripheral mononuclear cells. In this study, we examined a potential relationship between concentrations of ADMA and of the immune activation marker neopterin in patients scheduled for coronary angiography. In a cross-sectional approach, blood concentrations of ADMA, homocysteine, neopterin, folic acid and vitamins B6 and B12 were compared in 2030 patients, which were recruited as participants of the LUdwigshafen RIsk and Cardiovascular Health (LURIC) study. ADMA concentrations did not differ between patients with coronary artery disease (CAD) (mean ± SD: 0.82 ± 0.15 μmol/l) and controls (0.81 ± 0.14 μmol/l; Welch's t- test: P  = n.s.). ADMA concentrations correlated with homocysteine ( r _s = 0.207) and vitamin B6 ( r _s = −0.190), and an even stronger correlation with neopterin ( r _s = 0.276; all P  < 0.0001) was observed. In conclusion, increased ADMA concentrations in patients at risk for atherosclerosis are associated with increased neopterin concentrations. Data suggest that immune activation may contribute to increased ADMA production in CAD patients.     

Longitudinal trends of total and allergen-specific IgE throughout childhood

Background:  The development and the quantitative relationship between allergen-specific IgE (S-IgE) responses and total IgE (T-IgE), during childhood and adolescence have not been described and understood in detail. The objective of this study was to describe and compare the longitudinal trends of serum levels of S-IgE and T-IgE during childhood.
Methods:  We analysed data from participants in the MAS birth cohort study at 2, 5, 7 and 10 years of age ( n  = 273) and at 1, 3, 5, 6, 7, 10 and 13 years ( n  = 84). Total-IgE and the overall level of specific-IgE against nine locally relevant airborne and food allergens were determined by FEIA (ImmunoCAP). Allergic rhino-conjunctivitis and asthma were ascertained by questionnaires.
Results:  Longitudinal patterns of T-IgE levels from age 1 to 13 years were highly heterogeneous (declining, flat or increasing with different profiles). From 5 years of age, logarithmic (log₁₀) transformed values of T-IgE and of S-IgE levels tend to follow a parallel trend, so that their relation remained constant throughout school age. A flat trend of T-IgE vs a constantly increasing trend of T-IgE was associated with a low or, respectively, high rate of wheezing at 13 years of age.
Conclusions:  Beginning at the age of 5 years, total serum IgE levels in children from an industrialized country evolved in parallel with overall S-IgE levels. Therefore, variations in T-IgE levels at school age closely reflect variations in overall S-IgE levels. Further studies are required to strengthen the biological and clinical implication of this novel finding.     

Regulation of surface FcepsilonRI expression on human eosinophils by IL-4 and IgE

BACKGROUND: Recent studies have demonstrated that eosinophils from allergic patients express low levels of FcepsilonRI on their surface, but the regulatory mechanisms of eosinophil surface FcepsilonRI expression are not fully understood. We investigated whether IL-4 and IgE, which are reported to regulate surface FcepsilonRI expression on human mast cells, are able to affect surface FcepsilonRI expression in normal human eosinophils. METHODS: Eosinophils purified from peripheral blood were cultured with IL-5 and with or without IL-4 and/or IgE, and surface FcepsilonRI expression was analyzed by flow cytometry using an anti-FcepsilonRI mAb, CRA-1. RESULTS: Apparent FcepsilonRI expression (approximately 1% of mast cell FcepsilonRI levels) was observed in eosinophils cultured with both IL-4 and IgE. A combination of IL-4 (>or=1 ng/ml) and IgE (>or= 0.5 microg/ml) was necessary for the maximal induction of surface FcepsilonRI expression. In the presence of IL-4 and IgE, eosinophils cultured for 2 days demonstrated low but statistically significant levels of surface FcepsilonRI, which reached a plateau after 7 days of culture. However, cross-linkage of surface FcepsilonRI molecules by CRA-1 or anti-IgE did not induce any eosinophil activation. CONCLUSIONS: IL-4 and IgE can affect the levels of surface FcepsilonRI on normal human eosinophils. FcepsilonRI expression on eosinophils may be regulated by a mechanism similar to that in mast cells.     

Genetic variation in CRTh2 influences development of allergic phenotypes

Background:  Allergic disorders are characterized by an increase in the Th2 cytokines IL-4, IL-5 and IL-13, produced primarily by Th2 cells. These cells are marked by the expression of CRTh2 ( c hemoattractant r eceptor-homologous molecule expressed on Th2 cells), a receptor for prostaglandin D₂. As genetic variation plays a significant role in the predisposition for allergic disorders, we investigated the influence of single nucleotide polymorphisms (SNPs) in CRTh2.
Methods:  In a large study population of German children ( n  = 4264) from the International Study of Asthma and Allergy in Children (ISAAC II), six polymorphisms in CRTh2 were genotyped. Statistical analyses were performed using single SNP and haplotype analyses.
Results:  Uncorrected associations among −6373G>A, +1431G>C and +1538A>G were observed with a number of allergic phenotypes ( P  < 0.05). After correction, association between +1431C and specific IgE to food allergens remained significant ( P  = 0.04). Associations of haplotype (H)3 (containing +1538G) with reduced risk for asthma and H2 (containing +1431C) with increased risk for specific IgE to food allergens also remained significant after correction for multiple testing ( P  = 0.004).
Conclusions:  Genetic variation within CRTh2 modifies the development of allergic sensitization and asthma in a population of German children.     

Immunogenic Versus Tolerogenic Dendritic Cells: A Matter of Maturation

Allergic diseases result from the interaction with IgE bound to cell surface receptors. Therefore, rational therapeutic approaches to allergic diseases would be aimed at decreasing IgE and/or at blocking the binding of IgE to effector cells such as mast cells and monocytes. Our investigation of the mechanism of IgE synthesis in man shows that IgE synthesis by peripheral blood mononuclear cells (PBMC) absolutely requires the presence of IL-4 and requires endogenous IL-6, because antibody to IL-6 inhibits IgE production completely. IgE synthesis requires T/B cell contact and involves interactions between B cell surface MHC Class II molecules and T cell surface receptors, as antibodies to both of these cell surface molecules inhibit IgE synthesis. Furthermore, alloreactive T cell clones which are unable to engage the B cell MHC Class II molecules fail to induce IgE synthesis in spite of their ability to secrete IL-4.

Studies on the immunoglobulin sites that are involved in IgE binding to high affinity receptors on mast cells and basophils have used recombinant fragments of IgE to block mast cell binding. These studies suggest that a stretch of 76 amino acids which straddles the C?2 and C?3 domains is essential for this binding. Parallel studies on IgE binding to low affinity receptors on monocyles and B cells suggest that sequences within C?3 are involved in this binding. Peptides or analogues that inhibit IgE binding to its cellular receptors may be useful in the treatment of allergic diseases.     

The increased histamine release in ischaemic heart disease patients undergoing coronaroangiography is not mediated by specific IgE

Background:  The release of histamine by iodinated contrast media (ICM) is higher in coronary artery disease patients than in noncoronary patients during coronary angiogram.
Methods:  Eighty-eight patients who underwent a coronary angiography were classified either as having coronary artery disease or as noncoronary patients. Histamine concentration was higher than the 6.8 nM upper limit in 7 cases (group 1), of whom six were coronary artery disease patients. We compared the IgE and complement fractions in plasma of these patients to two control groups with normal histamine blood level, one (group 2) with and the other (group 3) without coronary artery disease.
Results:  No difference of total IgE and C _3c and C ₄ complement fractions was found among the three groups. Anti-ioxaglate IgE-RIA was positive in only one patient from group 1. The affinity of drug-IgE binding in the serum of this patient was very low (Kd: 18.7 mM). The level of anti-ICM IgE detected by ioxitalamate- and iomeprol-Sepharose RIA was significantly higher in groups 2 and 3 than in group 1.
Conclusions:  The higher histamine release in ischaemic heart disease patients undergoing coronaroangiography is not mediated by IgE or complement activation. Further studies are needed to investigate the implication of histamine release factors.