Terumi Midoro-Horiuti

Environmental estrogens induce mast cell degranulation and enhance IgE-mediated release of allergic mediators

Background Prevalence and morbidity of allergic diseases have increased over the last decades. Based on the recently recognized differences in asthma prevalence between the sexes, we have examined the effect of endogenous estrogens on a key element of the allergic response. Some lipophilic pollutants have estrogen-like activities and are termed environmental estrogens. These pollutants tend to degrade slowly in the environment and to bioaccumulate and bioconcentrate in the food chain; they also have long biological half-lives. Objectives Our goal in this study was to identify possible pathogenic roles for environmental estrogens in the development of allergic diseases. Methods We screened a number of environmental estrogens for their ability to modulate the release of allergic mediators from mast cells. We incubated a human mast cell line and primary mast cell cultures derived from bone marrow of wild type and estrogen receptor α (ER-α )–deficient mice with environmental estrogens with and without estradiol or IgE and allergens. We assessed degranulation of mast cells by quantifying the release of β -hexosaminidase. Results All of the environmental estrogens tested caused rapid, dose-related release of β -hexosaminidase from mast cells and enhanced IgE-mediated release. The combination of physiologic concentrations of 17β -estradiol and several concentrations of environmental estrogens had additive effects on mast cell degranulation. Comparison of bone marrow mast cells from ER-α –sufficient and ER-α –deficient mice indicated that much of the effect of environmental estrogens was mediated by ER-α . Conclusions Our findings suggest that estrogenic environmental pollutants might promote allergic diseases by inducing and enhancing mast cell degranulation by physiologic estrogens and exposure to allergens.

Maternal bisphenol a exposure promotes the development of experimental asthma in mouse pups

Background We recently reported that various environmental estrogens induce mast cell degranulation and enhance IgE-mediated release of allergic mediators in vitro. Objectives We hypothesized that environmental estrogens would enhance allergic sensitization as well as bronchial inflammation and responsiveness. To test this hypothesis, we exposed fetal and neonatal mice to the common environmental estrogen bisphenol A (BPA) via maternal loading and assessed the pups’ response to allergic sensitization and bronchial challenge. Methods Female BALB/c mice received 10 μg/mL BPA in their drinking water from 1 week before impregnation to the end of the study. Neonatal mice were given a single 5 μg intraperitoneal dose of ovalbumin (OVA) with aluminum hydroxide on postnatal day 4 and 3% OVA by nebulization for 10 min on days 13, 14, and 15. Forty-eight hours after the last nebulization, we assessed serum IgE antibodies to OVA by enzyme-linked immunosorbent assay (ELISA) and airway inflammation and hyperresponsiveness by enumerating eosinophils in bronchoalveolar lavage fluid, whole-body barometric plethysmography, and a forced oscillation technique. Results Neonates from BPA-exposed mothers responded to this “suboptimal” sensitization with higher serum IgE anti-OVA concentrations compared with those from unexposed mothers (p < 0.05), and eosinophilic inflammation in their airways was significantly greater. Airway responsiveness of the OVA-sensitized neonates from BPA-treated mothers was enhanced compared with those from unexposed mothers (p < 0.05). Conclusions Perinatal exposure to BPA enhances allergic sensitization and bronchial inflammation and responsiveness in a susceptible animal model of asthma.

Pathogenesis-related proteins of plants as allergens

OBJECTIVE Many pathogenesis-related (PR) proteins from plants are allergenic. We review the evidence that PR proteins represent an increasingly important group of plant-derived allergens. DATA SOURCES A detailed literature search was conducted through PubMed and GenBank databases. STUDY SELECTION All reports in PubMed and GenBank related to PR protein allergens for which at least partial amino acid sequence is known were included. RESULTS Production of PR proteins by plants is induced in plants by stress. Members of PR-protein groups 2, 3, 4, 5, 8, 10, and 14 have demonstrated allergenicity. PR2-, 3-, 4-, and 8-homologous allergens are represented by the latex allergens. Cross-reactivity of PR3 latex allergen, Hev b 6.02, with some fruit allergens may be a reflection of the representation of homologous PR proteins among varied plants. The expression of one of the representative PR5-homologous cedar pollen allergens, Jun a 3, is highly variable across years and geographic areas, possibly because of variable induction of this PR protein by environmental factors. PR10-homologous birch pollen allergen, Bet v 1, is structurally similar to and cross-reacts with PR10 proteins from fruits (eg, Mal d 1) which cause oral allergy syndrome. PR14 allergens (eg, Zea m 14) consist of lipid transfer proteins found in grains and fruits and are inducers of anaphylaxis. CONCLUSIONS PR-homologous allergens are pervasive in nature. Similarity in the amino acid sequences among members of PR proteins may be responsible for cross-reactivity among allergens from diverse plants. Induced expression of PR-homologous allergens by environmental factors may explain varying degrees of allergenicity. Man-made environmental pollutants may also alter the expression of some PR protein allergens.

Estrogen effects in allergy and asthma

Purpose of reviewAsthma prevalence and severity are greater in women than in men, and mounting evidence suggests this is in part related to female steroid sex hormones. Of these, estrogen has been the subject of much study. This review highlights recent research exploring the effects of estrogen in allergic disease. Recent findingsEstrogen receptors are found on numerous immunoregulatory cells and estrogens actions skew immune responses toward allergy. It may act directly to create deleterious effects in asthma, or indirectly via modulation of various pathways including secretory leukoprotease inhibitor, transient receptor potential vanilloid type 1 ion channel and nitric oxide production to exert effects on lung mechanics and inflammation. Not only do endogenous estrogens appear to play a role, but environmental estrogens have also been implicated. Environmental estrogens (xenoestrogens) including bisphenol A and phthalates enhance allergic sensitization in animal models and may enhance development of atopic disorders like asthma in humans. SummaryEstrogens role in allergic disease remains complex. As allergic diseases continue to increase in prevalence and affect women disproportionately, gaining a fuller understanding of its effects in these disorders will be essential. Of particular importance may be effects of xenoestrogens on allergic disease.

Variable expression of pathogenesis-related protein allergen in mountain cedar (Juniperus ashei) pollen

Allergic diseases have been increasing in industrialized countries. The environment is thought to have both direct and indirect modulatory effects on disease pathogenesis, including alterating on the allergenicity of pollens. Certain plant proteins known as pathogenesis-related proteins appear to be up-regulated by certain environmental conditions, including pollutants, and some have emerged as important allergens. Thus, the prospect of environmentally regulated expression of plant-derived allergens becomes yet another potential environmental influence on allergic disease. We have identified a novel pathogenesis-related protein allergen, Jun a 3, from mountain cedar (Juniperus ashei) pollen. The serum IgE from patients with hypersensitivity to either mountain cedar or Japanese cedar were shown to bind to native and recombinant Jun a 3 in Western blot analysis and ELISA. Jun a 3 is homologous to members of the thaumatin-like pathogenesis-related (PR-5) plant protein family. The amounts of Jun a 3 extracted from mountain cedar pollen varied up to 5-fold in lots of pollen collected from the same region in different years and between different regions during the same year. Thus, Jun a 3 may contribute not only to the overall allergenicity of mountain cedar pollen, but variable levels of Jun a 3 may alter the allergenic potency of pollens produced under different environmental conditions.

A structural basis for food allergy: the role of cross-reactivity.

Purpose of reviewImmunologic cross-reactivity, which is important in many aspects of host defense and immune-mediated diseases, is a prominent feature of allergic disorders. The goal of this article is to define allergenic cross-reactivity and its role in food allergy, review current understanding of mechanisms of cross-reactivity, and consider how advances in our ability to predict cross-reactivity can impact diagnosis and treatment of food allergy. Recent findingsRecent evidence suggests that specific T cells, in addition to IgE, developed in response to inhaled allergens can cross-react with related food allergens, leading to distinct clinical reactions. Several new cross-reactivities have been identified, including food–food, pollen–food, and latex–venom associations. Debate continues regarding prediction of allergenicity based on protein structure, and clinical relevance of in-vitro testing. Cross-reactivity is also being used to develop specific immunotherapy for treatment of food allergy. SummaryA thorough understanding of immunologic cross-reactivity is essential to advancing our knowledge about food allergy. This knowledge will help elucidate the pathogenesis of the disorder and prevent exposures to allergenic, genetically engineered foods. New insight will allow for better utilization of current diagnostic tools and the development of more accurate tests and therapies for food allergy.

Homology modeling and characterization of IgE binding epitopes of mountain cedar allergen Jun a 3.

The Jun a 3 protein from mountain cedar (Juniperus ashei) pollen, a member of group 5 of the family of plant pathogenesis-related proteins (PR-proteins), reacts with serum IgE from patients with cedar hypersensitivity. We used the crystal structures of two other proteins of this group, thaumatin and an antifungal protein from tobacco, both approximately 50% identical in sequence to Jun a 3, as templates to build homology models for the allergen. The in-house programs EXDIS and FANTOM were used to extract distance and dihedral angle constraints from the Protein Data Bank files and determine energy-minimized structures. The mean backbone deviations for the energy-refined model structures from either of the templates is <1 A, their conformational energies are low, and their stereochemical properties (determined with PROCHECK) are acceptable. The circular dichroism spectrum of Jun a 3 is consistent with the postulated beta-sheet core. Tryptic fragments of Jun a 3 that reacted with IgE from allergic patients all mapped to one helical/loop surface of the models. The Jun a 3 models have features common to aerosol allergens from completely different protein families, suggesting that tertiary structural elements may mediate the triggering of an allergic response.

Molecular cloning of the mountain cedar (Juniperus ashei) pollen major allergen, Jun a 1.

BACKGROUND Cedar pollens cause allergic disease in diverse geographic areas. We have recently purified and characterized the major mountain cedar (Juniperus ashei) pollen allergen, Jun a 1. OBJECTIVE A full-length complementary DNA for Jun a 1 was cloned and sequenced, and the recombinant protein was expressed. METHODS Messenger RNA from mountain cedar pollen was purified and Jun a 1 sequences were established with use of reverse transcriptase-PCR and primers based on the N-terminal amino acid sequence of Jun a 1 and the homologous protein Cry j 1. Portions of the nucleotide sequence were confirmed by comparison with N-terminal amino acid sequencing of the intact tryptic fragments of the purified native protein. Recombinant Jun a 1 was cloned into pET 30, expressed in BL21, and purified by HPLC, and its allergenicity was analyzed by Western blotting with patient sera. RESULTS Jun a 1 possesses a high level of amino acid sequence homology with Cha o 1 and Cry j 1, the major allergens of Japanese cypress and Japanese cedar. The amino acid sequence of a region with putative pectate lyase activity was identical to that of Cry j 1 and Cha o 1. Jun a 1 contained 2 potential N-glycosylation sites that were distinct from those found in Cry j 1. The IgE from patient sera bound recombinant Jun a 1 in Western blot analysis. CONCLUSION The high degree of homology of Jun a 1 with Cha o 1 and Cry j 1 may explain the cross-reactivity of conifer pollens. Differences in N-glycosylation suggest little overlap of glycopeptide epitopes.

Major linear IgE epitopes of mountain cedar pollen allergen Jun a 1 map to the pectate lyase catalytic site.

Resolution of the 3D structures and IgE epitopes of allergens may identify common or conserved features of allergens. Jun a 1, the predominant allergen in mountain cedar pollen, was chosen as a model for identifying common structural and functional features among a group of plant allergens. In this study, synthetic, overlapping peptides of Jun a 1 and sera from patients allergic to mountain cedar pollen were used to identify linear epitopes. A 3D model of Jun a 1 was produced using the Bacillus subtiles pectate lyase (PL) as a template and validated with biophysical measurements. This allowed mappings of four IgE binding sites on Jun a 1. Two of the epitopes mapped to turns or loops on the surface of the model structure. The other two epitopes mapped to the beta-sheet region, homologous to the catalytic site of PL. This region of Jun a 1 is highly conserved in the group 1 allergens from other cedar trees as well as microbial PLs. The finding that two out of three major IgE epitopes map to highly conserved catalytic regions of group 1 cedar allergens may help to explain the high degree of cross-reactivity between cedar pollen allergens and might represent a pattern of reactivity common to other allergens with catalytic activity.

Isolation and characterization of native Cry j 3 from Japanese cedar (Cryptomeria japonica) pollen.

Background:  Japanese cedar (Cryptomeria japonica) pollinosis is the most prevalent allergy in Japan. Recently, the Japanese cedar pollen allergen Cry j 3 was cloned as a homologue of Jun a 3, which is a major allergen from mountain cedar (Juniperus ashei) pollen. However, native Cry j 3 has not been isolated and there are no reports on its allergenic activity. The aims of this study were to isolate native Cry j 3 and assess its immunoglobulin E (IgE)‐binding capacity in patients with Japanese cedar pollinosis.