The Journal of Allergy and Clinical Immunology

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2012-02-01

Brief Overview of This Month's JACI

2012-02-01

Editorial Board

2012-02-01

Information for Readers

2012-02-01

News & Notes

2012-02-01

For this month's interview, we talked with Stuart L. Abramson, MD, PhD, AE-C, FAAAAI, the incoming chair of the Annual Meeting Program Committee (AMPC). Dr. Abramson leads the Allergy/Immunology Service at Shannon Medical Center in San Angelo, TX.

CME Activities Calendar

2012-02-01

▪ Online Teaching Slide Presentations

News Beyond Our Pages

Marc E. Rothenberg, Jean Bousquet — 2012-02-01

Previous research on reslizumab, an anti–IL-5 mAb, in asthmatic patients did not provide a clear clinical benefit; however, improvements were noted in small studies in subgroups of patients with eosinophilic asthma. Castro et al (Am J Respir Crit Care Med 2011;184:1125-32) investigated reslizumab's effectiveness in 106 patients with uncontrolled asthma with eosinophilia exclusively. The primary outcome (asthma control questionnaire) was not significantly improved. However, the authors found that airway function improved and sputum and blood eosinophilia decreased in the reslizumab-treated group. Moreover, they reported a novel finding. Patients with nasal polyposis had a statistically significant improvement in asthma control compared with those without polyposis. Thus there might be a subpopulation of patients with eosinophilic asthma whose symptoms can be controlled with anti–IL-5 consistent with other recent reports concerning another anti-IL-5 therapeutic.Lead author, Mario Castro, MD, at Washington University, St Louis, Mo, gave us this comment on their findings: “The results of this trial add to the growing body of evidence that there are sub-phenotypes of severe asthma that can be identified by combining clinical history with biomarkers, such as sputum eosinophils, to provide targeted therapy. These subgroups now need to be prospectively tested in randomized controlled trials with novel therapies to test their effectiveness and safety.”

A Special Thank-You to Our Reviewers

2012-02-01

Rob C. Aalberse∗ Jun Abe

Fungi and allergic lower respiratory tract diseases

2012-02-01

Asthma is a common disorder that in 2009 afflicted 8.2% of adults and children, 24.6 million persons, in the United States. In patients with moderate and severe persistent asthma, there is significantly increased morbidity, use of health care support, and health care costs. Epidemiologic studies in the United States and Europe have associated mold sensitivity, particularly to Alternaria alternata and Cladosporium herbarum, with the development, persistence, and severity of asthma. In addition, sensitivity to Aspergillus fumigatus has been associated with severe persistent asthma in adults. Allergic bronchopulmonary aspergillosis (ABPA) is caused by A fumigatus and is characterized by exacerbations of asthma, recurrent transient chest radiographic infiltrates, coughing up thick mucus plugs, peripheral and pulmonary eosinophilia, and increased total serum IgE and fungus-specific IgE levels, especially during exacerbation. The airways appear to be chronically or intermittently colonized by A fumigatus in patients with ABPA. ABPA is the most common form of allergic bronchopulmonary mycosis (ABPM); other fungi, including Candida, Penicillium, and Curvularia species, are implicated. The characteristics of ABPM include severe asthma, eosinophilia, markedly increased total IgE and specific IgE levels, bronchiectasis, and mold colonization of the airways. The term severe asthma associated with fungal sensitization (SAFS) has been coined to illustrate the high rate of fungal sensitivity in patients with persistent severe asthma and improvement with antifungal treatment. The immunopathology of ABPA, ABPM, and SAFS is incompletely understood. Genetic risks identified in patients with ABPA include HLA association and certain TH2-prominent and cystic fibrosis variants, but these have not been studied in patients with ABPM and SAFS. Oral corticosteroid and antifungal therapies appear to be partially successful in patients with ABPA. However, the role of antifungal and immunomodulating therapies in patients with ABPA, ABPM, and SAFS requires additional larger studies.

Fungi and allergic lower respiratory tract diseases

2012-02-01

Mendelian traits causing susceptibility to mucocutaneous fungal infections in human subjects

Karin R. Engelhardt, Bodo Grimbacher — 2012-02-01

Mucocutaneous candidiasis and dermatophyte infections occur either in isolation or alongside other symptoms in patients with various primary immunodeficiency diseases with diverse genetic defects, which result in impaired IL-17 immunity, IL-22 immunity, or both. In patients with chronic mucocutaneous candidiasis, disease-associated polymorphisms in DECTIN1 act on the level of fungal recognition, whereas mutations in caspase recruitment domain–containing protein 9 (CARD9) disturb the subsequent spleen tyrosine kinase 2–CARD9/BCL10/MALT1–driven signaling cascade, impairing nuclear factor κB–mediated maturation of antigen-presenting cells and priming of naive T cells to differentiate into the TH17 cell lineage. TH17-priming cytokines signal through the transcription factor signal transducer and activator of transcription (STAT) 3, which in turn induces the TH17 lineage–determining transcription factor retinoic acid–related orphan receptor γt. Dominant-negative mutations in STAT3 result in reduced numbers of TH17 cells, causing localized candidiasis in patients with hyper-IgE syndrome. In patients with chronic mucocutaneous candidiasis, gain-of-function STAT1 mutations shift the cellular response toward TH17 cell–inhibiting cytokines. TH17 cells secrete IL-17 and IL-22, which are cytokines with potent antifungal properties, including production of antimicrobial peptides and activation and recruitment of neutrophils. Neutrophils mediate microbial killing through phagocytosis, degranulation, and neutrophil extracellular traps. Mutations in IL17F and IL17R in patients with chronic mucocutaneous candidiasis, as well as neutralizing autoantibodies against IL-17 and IL-22 in patients with autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy, directly impair IL-17 and IL-22 immunity.

Mendelian traits causing susceptibility to mucocutaneous fungal infections in human subjects

2012-02-01

International consensus and practical guidelines on the gynecologic and obstetric management of female patients with hereditary angioedema caused by C1 inhibitor deficiency

2011-12-26

Background: There are a limited number of publications on the management of gynecologic/obstetric events in female patients with hereditary angioedema caused by C1 inhibitor deficiency (HAE-C1-INH).Objective: We sought to elaborate guidelines for optimizing the management of gynecologic/obstetric events in female patients with HAE-C1-INH.Methods: A roundtable discussion took place at the 6th C1 Inhibitor Deficiency Workshop (May 2009, Budapest, Hungary). A review of related literature in English was performed.Results: Contraception: Estrogens should be avoided. Barrier methods, intrauterine devices, and progestins can be used. Pregnancy: Attenuated androgens are contraindicated and should be discontinued before attempting conception. Plasma-derived human C1 inhibitor concentrate (pdhC1INH) is preferred for acute treatment, short-term prophylaxis, or long-term prophylaxis. Tranexamic acid or virally inactivated fresh frozen plasma can be used for long-term prophylaxis if human plasma-derived C1-INH is not available. No safety data are available on icatibant, ecallantide, or recombinant human C1-INH (rhC1INH). Parturition: Complications during vaginal delivery are rare. Prophylaxis before labor and delivery might not be clinically indicated, but pdhC1INH therapeutic doses (20 U/kg) should be available. Nevertheless, each case should be treated based on HAE-C1-INH symptoms during pregnancy and previous labors. pdhC1INH prophylaxis is advised before forceps or vacuum extraction or cesarean section. Regional anesthesia is preferred to endotracheal intubation. Breast cancer: Attenuated androgens should be avoided. Antiestrogens can worsen angioedema symptoms. In these cases anastrozole might be an alternative. Other issues addressed include special features of HAE-C1-INH treatment in female patients, genetic counseling, infertility, abortion, lactation, menopause treatment, and endometrial cancer.Conclusions: A consensus for the management of female patients with HAE-C1-INH is presented.

Fungal disease of the nose and paranasal sinuses

George R. Thompson, Thomas F. Patterson — 2011-12-30

Fungal infections of the nose and paranasal sinuses represent a spectrum of diseases ranging from colonization to invasive rhinosinusitis. Clinical manifestations are largely dependent on the immune status of the host, and given the ubiquitous nature of these organisms, exposure is unavoidable. Noninvasive disease includes asymptomatic fungal colonization, fungus balls, and allergic fungal rhinosinusitis. Invasive disease includes indolent chronic rhinosinusitis, granulomatous fungal sinusitis, and acute fulminant fungal rhinosinusitis. A differentiation of these somewhat overlapping syndromes and the disparate treatment regimens required for effective management are the focus of this review.

New approaches to personalized medicine for asthma: Where are we?

Scott T. Weiss — 2012-02-01

Access to an electronic medical record is essential for personalized medicine. Currently, only 40% of US physicians have such access, but this is rapidly changing. It is expected that 100,000 Americans will have their whole genome sequenced in 2012. The cost of such sequencing is rapidly dropping, and is estimated to be $1000 by 2013. These technological advances will make interpretation of whole genome sequence data a major clinical challenge for the foreseeable future. At present, a relatively small number of genes have been identified to determine drug treatment response phenotypes for asthma. It is anticipated that this will dramatically increase over the next 10 years as personalized medicine becomes more of a reality for asthma patients.

Advances in mechanisms of asthma, allergy, and immunology in 2011

Joshua A. Boyce, Bruce Bochner, Fred D. Finkelman, Marc E. Rothenberg — 2012-02-01

2011 was marked by rapid progress in the identification of basic mechanisms of allergic disease and the translation of these mechanisms into human cell systems. Studies published in the Journal of Allergy and Clinical Immunology this year provided new insights into the molecular determinants of allergenicity, as well as the environmental, cellular, and genetic factors involved in sensitization to allergens. Several articles focused on mechanisms of allergen immunotherapy and the development of novel strategies to achieve tolerance to allergens. Additional studies identified substantial contributions from TH17-type cells and cytokines to human disease pathogenesis. Finally, new therapeutic applications of anti-IgE were identified. The highlights of these studies and their potential clinical implications are summarized in this review.

Advances in basic and clinical immunology in 2011

Javier Chinen, William T. Shearer — 2011-12-30

Investigations of basic immunologic mechanisms and clinical studies of primary immunodeficiencies were most prevalent in 2011. Significant progress was achieved in the characterization of TH17 cell differentiation and associated cytokines in the setting of inflammatory disorders, HIV infection, and immunodysregulation disorders. The role of transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI) mutations in the pathogenesis of CVID was further described and reported to be likely mediated by impaired TACI expression affecting B-cell function. The frequency of autoimmunity in patients with partial DiGeorge syndrome was estimated at 8.5%, predominantly resulting in blood cytopenias and hypothyroidism. Several reports emphasized the presentation of neoplasias, most often lymphomas, as the first manifestation of several primary immunodeficiencies. Novel strategies for newborn screening of B-cell lymphopenia by measuring immunoglobulin κ chain–deletion recombinant excision circles and for adenosine deaminase deficiency using tandem mass spectrometry were demonstrated to be feasible at a large scale. Progress in the treatment of primary immunodeficiencies included increased success with unrelated HLA-compatible donors for hematopoietic stem cell transplantation and the development of new gene therapy approaches with improved safety features. Induced pluripotent stem cells were developed from patients with primary immunodeficiencies, providing a virtually unlimited resource for pathophysiology and gene correction studies. New findings in several of the uncommon immunodeficiencies, such as the increased susceptibility to severe viral infections caused by defects in the activation of the Toll-like receptor 3 pathway, overall contributed to the understanding of their immunologic basis and provided for the design of effective diagnostic and therapeutic strategies.

The Editors’ Choice

Donald Y.M. Leung, Stanley J. Szefler, Associate Editors of the JACI — 2012-02-01

Allergic rhinitis or hay fever is a common disease caused by environmental allergens, such as pollens and animal dander, in allergic persons. Characteristic symptoms include runny nose, nasal itching, sneezing, and congestion. Antihistamines that block the first of 4 different receptors, molecules that mediate the effects of histamine released during allergies, are available over the counter and by prescription. These antihistamines are effective in treating allergic rhinitis–associated itching, runny nose, and sneezing but are not very effective against nasal congestion, often the most bothersome symptom. A number of decongestants are available either alone or in combination with these antihistamines, but they are not completely effective in treating nasal congestion either, and they often have side effects of insomnia, jitteriness, and hypertension. On the basis of these concerns, Stokes et al (p 409) studied the effects of a novel type of antihistamine, PF-03654746, which targets the third of 4 histamine receptors thought to be important in causing nasal congestion. These investigators found that PF-03654746, used in combination with fexofenadine, blocked nasal symptoms, including congestion, after an acute allergic reaction to ragweed better than fexofenadine plus decongestant (see Figure) These novel antihistamines, in combination with traditional antihistamines, might be a better strategy to treat allergic rhinitis.

Airway remodeling and inflammation in competitive swimmers training in indoor chlorinated swimming pools

2011-12-26

Background: Airway disorders are common in regular chlorinated swimming pool attendees, particularly competitive athletes, but the impact of intense swimming training on airway function and structure remains unclear.Objective: This study aimed to evaluate airway inflammation and remodeling in elite swimmers.Methods: Twenty-three elite swimmers were tested during off-training season. All had exhaled nitric oxide measurement, methacholine test, eucapnic voluntary hyperpnea challenge, allergy skin prick tests, and bronchoscopy with bronchial biopsies. Clinical data and tissues from 10 age-matched mild-asthmatic and 10 healthy nonallergic subjects were used for comparison.Results: Swimmers had increased airway mucosa eosinophil and mast cell counts than did controls (P < .05). They had more goblet cell hyperplasia and higher mucin expression than did healthy or asthmatic subjects (P < .05). A greater submucosal type I and III collagen expression and tenascin deposition was also observed in swimmers than in controls (P < .05). Neither exhaled nitric oxide nor airway responsiveness to methacholine or eucapnic voluntary hyperpnea challenge correlated with these inflammatory and remodeling changes.Conclusion: Intense, long-term swimming training in indoor chlorinated swimming pools is associated with airway changes similar to those seen in mild asthma, but with higher mucin expression. These changes were independent from airway hyperresponsiveness. The long-term physiological and clinical consequences of these changes remain to be clarified.

The effect of single and multiple infections on atopy and wheezing in children

2011-10-31

Background: The current epidemic of asthma and atopy has been explained by alterations in immune responses related to reduction in childhood infections. However, the findings of epidemiologic studies investigating the association between infection with atopy and asthma have been inconsistent.Objective: We sought to investigate the effect of single or multiple infections (pathogen burden) on atopy and wheeze in urban children from Latin America.Methods: Specific IgE against aeroallergens (sIgE) and skin prick test (SPT) reactivity for the most common local allergens were measured in 1128 children aged 4 to 11 years. Data on wheezing and potential confounders were collected by questionnaire. Infections by 8 pathogens were assessed by using serology and stool examination. Associations of wheeze and atopic outcomes with single and multiple infections were analyzed by means of logistic regression.Results: Negative results for Toxoplasma gondii were associated with a higher prevalence of sIgE (≥0.70 kU/L), whereas negative results for Ascaris lumbricoides, T gondii, herpes simplex virus, and EBV were associated with a higher prevalence of SPT reactivity. Children with 3 or fewer infection markers had a higher prevalence of sIgE and SPT reactivity compared with those with 4 or more infection markers. However, isolated infections or pathogen burden were not associated with the prevalence of atopic or nonatopic wheeze.Conclusion: The findings provide support for the idea that the hygiene hypothesis is operating in an urban Latin American context, but its expression is thus far restricted to the atopic status of patients and not the perceived asthma symptoms.

Genome-wide association study reveals class I MHC–restricted T cell–associated molecule gene (CRTAM) variants interact with vitamin D levels to affect asthma exacerbations

2011-11-03

Background: It has recently been shown that vitamin D deficiency can increase asthma development and severity and that variations in vitamin D receptor genes are associated with asthma susceptibility.Objective: We sought to find genetic factors that might interact with vitamin D levels to affect the risk of asthma exacerbation.Methods: We conducted a genome-wide study of gene–vitamin D interaction on asthma exacerbations using population-based and family-based approaches on 403 subjects and trios from the Childhood Asthma Management Program. Twenty-three polymorphisms with significant interactions were studied in a replication analysis in 584 children from a Costa Rican cohort.Results: We identified 3 common variants in the class I MHC–restricted T cell–associated molecule gene (CRTAM) that were associated with an increased rate of asthma exacerbations based on the presence of a low circulating vitamin D level. These results were replicated in a second independent population (unadjusted combined interaction, P = .00028-.00097; combined odds ratio, 3.28-5.38). One variant, rs2272094, is a nonsynonymous coding polymorphism of CRTAM. Functional studies on cell lines confirmed the interaction of vitamin D and rs2272094 on CRTAM expression. CRTAM is highly expressed in activated human CD8+ and natural killer T cells, both of which have been implicated in asthmatic patients.Conclusion: The findings highlight an important gene-environment interaction that elucidates the role of vitamin D and CD8+ and natural killer T cells in asthma exacerbation in a genome-wide gene-environment interaction study that has been replicated in an independent population. The results suggest the potential importance of maintaining adequate vitamin D levels in subsets of high-risk asthmatic patients.

Interaction between filaggrin null mutations and tobacco smoking in relation to asthma

2011-11-17

Background: The mechanisms underlying the association between filaggrin (FLG) deficiency and asthma are not known. It has been hypothesized that FLG deficiency leads to enhanced percutaneous exposure to environmental substances that might trigger immune responses. We hypothesized that interactions between FLG deficiency and environmental exposures play a role in asthma development.Objective: We sought to investigate possible interactions between FLG null mutations and tobacco smoking in relation to asthma.Methods: A total of 3471 adults from a general population sample participated in a health examination. Lung function and serum specific IgE levels to inhalant allergens were measured, and information on asthma and smoking was obtained by means of questionnaire. Participants were genotyped for the 2 most common FLG null mutations in white subjects: R501X and 2282del4. Another Danish population was used for replication.Results: The FLG null mutation genotype was significantly associated with a higher prevalence of asthma and decreased FEV1/forced vital capacity ratio. In logistic regression analyses with asthma as the outcome, a significant interaction was found between FLG null mutations and smoking status (P = .02). This interaction was confirmed, although it was not statistically significant, in another Danish population study. Interactions between FLG genotype and cumulated smoking exposure were found in relation to asthma (P = .03) and decreased FEV1/forced vital capacity ratio (P = .03). A 3-way interaction was found among FLG genotype, smoking, and asthma, suggesting that the FLG-smoking interaction mainly played a role in nonatopic subjects.Conclusion: FLG null mutations modified the effects of smoking on the risk of asthma. This finding might have implications for risk stratification of the population.

The role of the small airways in the clinical expression of asthma in adults

2011-12-22

Background: The clinical relevance of increased ventilation heterogeneity, a marker of small-airways disease, in asthmatic patients is unclear. Ventilation heterogeneity is an independent determinant of airway hyperresponsiveness (AHR), improves with bronchodilators and inhaled corticosteroids (ICSs), and worsens during exacerbations, but its relationship to asthma control is unknown.Objective: We sought to determine the association between ventilation heterogeneity and current asthma control before and after ICS treatment.Methods: Adult subjects with asthma had lung function and asthma control (5-item Asthma Control Questionnaire [ACQ-5 score] ≥1.5 = poorly controlled, ACQ-5 score ≤0.75 = well controlled) measured at baseline. A subgroup with AHR had repeat measurements after 3 months of high-dose ICS treatment. The indices of ventilation heterogeneity in the regions of the lung where gas transport occurs predominantly through convection (ventilation heterogeneity in convection-dependent airways [Scond]) and through diffusion (ventilation heterogeneity in diffusion-dependent airways [Sacin]) were derived by using the multiple-breath nitrogen washout technique.Results: At baseline (n = 105), subjects with poorly controlled asthma had worse FEV1, fraction of exhaled nitric oxide measured at 200 mL/s (Feno), Scond, and Sacin values. In the treatment group (n = 50) spirometric, Feno, residual volume (RV)/total lung capacity (TLC), AHR, and Scond values significantly improved. Asthma control also improved (mean ACQ-5 score, 1.3-0.7; P < .0001). The change in ACQ-5 score correlated with changes in Feno (rs = 0.31, P = .03), Sacin (rs = 0.32, P = .02), and Scond (rs = 0.41, P = .003) values. The independent predictors of a change in asthma control were changes in Scond and Sacin values (model r2 = 0.20, P = .005).Conclusions: Current asthma control is associated with markers of small-airways disease. Improvements in ventilation heterogeneity with anti-inflammatory therapy are associated with improvements in symptoms. Sensitive measures of small-airway function might be useful in monitoring the response to therapy in asthmatic subjects.

Airway TGF-β1 and oxidant stress in children with severe asthma: Association with airflow limitation

2011-12-30

Background: TGF-β1 is thought to play a role in airway remodeling in asthmatic subjects. TGF-β1 expression might be mediated by an excessive burden of reactive oxygen species and oxidant stress.Objective: Given the profound airway oxidant stress we have previously observed in children with severe asthma, we sought to (1) quantify TGF-β1 protein and mRNA gene expression in the airways of children with mild-to-moderate and severe atopic asthma and (2) determine the relationship of airway TGF-β1 concentrations to oxidant burden (ie, lipid peroxidation), TH2-mediated eosinophilic inflammation, and airflow limitation.Methods: Bronchoalveolar lavage fluid was collected from 68 atopic children with asthma (severe asthma, n = 28) and 12 atopic adult control subjects. Airway TGF-β1 expression and activation were assessed in relation to airway IL-13, 8-isoprostane, and malondialdehyde concentrations. The relationship of airway TGF-β1 expression to airflow limitation in children with asthma was also assessed.Results: Children with severe asthma had higher total airway concentrations of TGF-β1 that were associated with increased protein and mRNA expression of TGF-β1 in airway macrophages and an increase in concentrations of the lipid peroxidation biomarkers 8-isoprostanes and malondialdehyde. TGF-β1 activation was also greater in children with severe asthma and was associated with higher airway 8-isoprostane, malondialdehyde, and IL-13 concentrations. Total airway TGF-β1 concentrations were further associated with airflow limitation.Conclusions: Children with severe asthma have increased airway TGF-β1 expression and activation associated with an increased airway oxidant burden. Oxidant stress might mediate the effects of TGF-β1 and promote airway remodeling in children with severe asthma.

Addendum

2012-02-01

With regard to the August 2011 article entitled “Tiotropium is noninferior to salmeterol in maintaining improved lung function in B16-Arg/Arg patients with asthma” (J Allergy Clin Immunol 2011;128:315-22), a full list of the investigators and other important participants who contributed to the study has been added to the article’s Supplemental Materials section on the Journal’s Web site (www.jacionline.org).

Prediction of the incidence and persistence of allergic rhinitis in adolescence: A prospective cohort study

2011-09-19

Background: Predictive models have rarely been used in allergy research and practice. However, they might support physicians in advising patients.Objective: The aim of this study was to create predictive models for the incidence and persistence of allergic rhinitis (AR) during adolescence.Methods: A prospective population-based cohort study was conducted starting at age 9 to 11 years. Potential risk factors for atopic diseases obtained at baseline in 2810 subjects were used to create predictive logistic regression models for the incidence and persistence of physician-diagnosed AR with current symptoms at age 15 to 18 years.Results: Positive skin prick test responses to outdoor allergens at baseline were the most important determinant for both the incidence and persistence of AR until follow-up. For the incidence of AR, positive skin prick test responses to indoor allergens, parental history of asthma, female sex, and not having been breast-fed exclusively for 2 or more months were additional statistically significant independent risk factors. Depending on the number of risk factors present, the probability of the incidence of AR increased from 2% (no risk factors present) to 72% (full model; 95% CI, 58% to 85%). The probability of persistence of AR ranged from 33% (no risk factors present) to 83% (full model; 95% CI, 70% to 97%).Conclusion: The course of AR over puberty can be predicted using risk factors that are easy to determine in childhood. Sensitization to outdoor allergens seems to play a much greater role for disease development than sensitization to indoor allergens. This might help pediatricians in advising patients.

Natural course and comorbidities of allergic and nonallergic rhinitis in children

2011-11-07

Background: Not much data are available from large, unselected, birth cohort studies on the natural course and comorbidities of rhinitis in children.Objective: To study phenotypes of rhinitis in relation to the natural course and comorbidities of allergic diseases in preschool-age and early school-age children.Methods: We analyzed data from a birth cohort of 2024 children, for whom information on IgEs against 8 common inhaled allergens was available, collected at age 4 and 8 years. The children were assigned to groups of allergic rhinitis (rhinitis with sensitization to allergens), nonallergic rhinitis (rhinitis without sensitization), allergic sensitization but no rhinitis, or neither rhinitis nor sensitization.Results: The proportion of children with allergic rhinitis increased from 5% to 14% from age 4 to 8 years, whereas the proportion of children with nonallergic rhinitis decreased slightly over the same period of development, from 8% to 6%. Of the children with allergic rhinitis when they were 4 years old, 12% underwent remission by the time they were 8 years old; of the children with nonallergic rhinitis, 73% underwent remission during this period of development. Among 4-year-olds without rhinitis who were sensitized to allergen, 56% had allergic rhinitis when they were 8 years old. Among 4- and 8-year-olds, allergic rhinitis and nonallergic rhinitis were associated with asthma, eczema, and food hypersensitivity. Twenty-five percent of 8-year-olds with allergic rhinitis also had oral allergy syndrome.Conclusions: Fewer preschool-age children with allergic rhinitis undergo remission than do those with nonallergic rhinitis. Sensitization to inhaled allergens at an early age (4 years) precedes the development of allergic rhinitis, whereas symptoms of rhinitis do not. Oral allergy syndrome is common among 8-year-olds with allergic rhinitis.

The effects of an H3 receptor antagonist (PF-03654746) with fexofenadine on reducing allergic rhinitis symptoms

2011-12-26

Background: Nasal H3 receptors might have a role in mediating the effects of histamine in patients with allergic rhinitis.Objective: This study explored the effect of the potent oral H3 receptor antagonist PF-03654746 in combination with an oral H1 receptor antagonist on the objective (acoustic rhinometry) and subjective (symptoms) responses to nasal allergen challenge.Methods: Twenty patients with out-of-season allergic rhinitis displaying a 30% or greater decrease in minimum nasal cross-sectional area (Amin) after bolus (ragweed) complete nasal allergen challenge at screening were studied by using a randomized, double-blind, single-dose, 4-way crossover design. Treatments included 10 mg of PF-03654746 plus 60 mg of fexofenadine (group 1), 1 mg of PF-03654746 plus 60 mg of fexofenadine (group 2), 60 mg of fexofenadine/120 mg of pseudoephedrine (group 3), and placebo (group 4). After dosing, subjects underwent complete nasal allergen challenge. Nasal symptom scores (no. of sneezes and 0- to 5-point scores for severity of congestion, itching, and rhinorrhea), Amin (in square centimeters), and nasal volume (in cubic centimeters) were recorded 15, 30, 45, and 60 minutes after allergen. There was a minimum 10-day washout between periods.Results: The following symptom scores were significantly (P ≤ .05) reduced by active treatments versus placebo: group 1, congestion of −0.7 (SE, 0.3), itching of −1.0 (SE, 0.3), rhinorrhea of −1.3 (SE, 0.3), and sneeze of −8.8 (SE, 1.5); group 2, itching of −0.6 (SE, 0.3), rhinorrhea of −0.8 (SE, 0.3), and sneeze of −9.1 (SE, 1.5); and group 3, rhinorrhea of −0.7 (SE, 0.3) and sneeze of −7.0 (SE, 1.5). There was no significant effect of any treatment on mean Amin proportion or nasal volume proportion after nasal allergen challenge.Conclusions: In combination with fexofenadine, single doses of PF-03654746 caused a reduction in allergen-induced nasal symptoms. H3 receptor antagonism might be a novel therapeutic strategy to further explore in patients with allergic rhinitis.

Association of subcutaneous allergen-specific immunotherapy with incidence of autoimmune disease, ischemic heart disease, and mortality

Allan Linneberg, Rikke Kart Jacobsen, Lasse Jespersen, Steen Z. Abildstrøm — 2011-10-17

Background: Subcutaneous allergen-specific immunotherapy (SCIT) is a well-documented treatment of IgE-mediated allergic disease. Little is known about potential effects of SCIT on the risk of other chronic immune-related diseases. Over the years, a few casuistic reports have caused concern that SCIT might act as a trigger of autoimmune disease.Objective: We aimed to investigate the association of SCIT with the incidence of autoimmune disease and ischemic heart disease (IHD), as well as all-cause mortality.Methods: All Danish citizens without other known diseases were linked and followed through central registries on medications and hospital admissions. Persons receiving SCIT and persons receiving conventional allergy treatment (CAT; nasal steroids or oral antihistamines) were compared with regard to mortality and development of autoimmune diseases, acute myocardial infarction (AMI), and IHD. Cox regression (survival analysis) with age as the underlying time scale was used to estimate relative risks (hazard ratios [HRs] with 95% CIs) associated with SCIT compared with CAT adjusted for age, sex, vocational status, and income.Results: During the 10-year study period (1997-2006), a total of 18,841 and 428,484 persons were followed in the SCIT and CAT groups, respectively. Receiving SCIT was associated with lower mortality (HR, 0.71; 95% CI, 0.62-0.81) and lower incidence of AMI (HR, 0.70; 95% CI, 0.52-0.93), IHD (HR, 0.88; 95% CI, 0.73-1.05), and autoimmune disease (HR, 0.86; 95% CI, 0.74-0.99).Conclusion: In this registry-based observational study, receiving SCIT compared with CAT was associated with lower risk of autoimmune disease and AMI, as well as decreased all-cause mortality.

Risk factors for new-onset cat sensitization among adults: A population-based international cohort study

2011-12-12

Background: Cat exposure during childhood has been shown to increase the risk of developing cat sensitization, while the effect of cat exposure in adulthood has not yet been established.Objective: To evaluate new-onset sensitization to cat in adulthood in relation to changes in cat keeping.Methods: A total of 6292 European Community Respiratory Health Survey I (ECRHS I) participants aged 20 to 44 years from 28 European centers, who were not sensitized to cat, were reevaluated 9 years later in ECRHS II. Present and past cat ownership and total and specific IgE levels were assessed in both surveys. Allergen-specific sensitization was defined as a specific serum IgE level of 0.35 kU/L or more.Results: A total of 4468 subjects did not have a cat in ECRHS I or ECRHS II, 473 had a cat only at baseline, 651 acquired a cat during the follow-up, and 700 had a cat at both evaluations. Two hundred thirty-one subjects (3.7%) became sensitized to cat. In a 2-level multivariable Poisson regression model, cat acquisition during follow-up was significantly associated with new-onset cat sensitization (relative risk = 1.85, 95% CI 1.23-2.78) when compared with those without a cat at both surveys. Preexisting sensitization to other allergens, a history of asthma, nasal allergies and eczema, and high total IgE level were also significant risk factors for developing cat sensitization, while cat ownership in childhood was a significant protective factor.Conclusion: Our data support that acquiring a cat in adulthood nearly doubles the risk of developing cat sensitization. Hence, cat avoidance should be considered in adults, especially in those sensitized to other allergens and reporting a history of allergic diseases.

IL-31 regulates differentiation and filaggrin expression in human organotypic skin models

2011-12-19

Background: Atopic dermatitis (AD) is an inflammatory skin disease affecting 10% to 20% of children and 1% to 3% of adults in industrialized countries. Enhanced expression of IL-31 is detected in skin samples of patients with AD, but its physiological relevance is not known.Objective: We sought to determine the role of IL-31 in skin differentiation.Methods: We used human 3-dimensional organotypic skin models with either primary keratinocytes or HaCaT keratinocytes with inducible IL-31 receptor α to evaluate the effect of IL-31. The consequences were studied by using histology, the expression of markers analyzed by immunofluoresence and quantitative RT-PCR, and gene expression arrays.Results: We observed that IL-31 interferes with keratinocyte differentiation. Gene expression analysis revealed a limited set of genes deregulated in response to IL-31, including IL20 and IL24. In HaCaT keratinocytes with inducible IL-31 receptor α, IL-31 inhibited proliferation upon induction of IL-31 receptor α by inducing cell cycle arrest. As in primary cells, IL-31–treated HaCaT cells elicited a differentiation defect in organotypic skin models, associated with reduced epidermal thickness, disturbed epidermal constitution, altered alignment of the stratum basale, and poor development of the stratum granulosum. The differentiation defect was associated with a profound repression of terminal differentiation markers, including filaggrin, an essential factor for skin barrier formation, and a reduced lipid envelope. The highly induced proinflammatory cytokines IL-20 and IL-24 were responsible for part of the effect on FLG expression and thus for terminal differentiation.Conclusion: Our study suggests that IL-31 is an important regulator of keratinocyte differentiation and demonstrates a link between the presence of IL-31 in skin, as found in patients with AD, and filaggrin expression.

Low diversity of the gut microbiota in infants with atopic eczema

2011-12-08

Background: It is debated whether a low total diversity of the gut microbiota in early childhood is more important than an altered prevalence of particular bacterial species for the increasing incidence of allergic disease. The advent of powerful, cultivation-free molecular methods makes it possible to characterize the total microbiome down to the genus level in large cohorts.Objective: We sought to assess microbial diversity and characterize the dominant bacteria in stool during the first year of life in relation to atopic eczema development.Methods: Microbial diversity and composition were analyzed with barcoded 16S rDNA 454-pyrosequencing in stool samples at 1 week, 1 month, and 12 months of age in 20 infants with IgE-associated eczema and 20 infants without any allergic manifestation until 2 years of age (ClinicalTrials.gov ID NCT01285830).Results: Infants with IgE-associated eczema had a lower diversity of the total microbiota at 1 month (P = .004) and a lower diversity of the bacterial phylum Bacteroidetes and the genus Bacteroides at 1 month (P = .02 and P = .01) and the phylum Proteobacteria at 12 months of age (P = .02). The microbiota was less uniform at 1 month than at 12 months of age, with a high interindividual variability. At 12 months, when the microbiota had stabilized, Proteobacteria, comprising gram-negative organisms, were more abundant in infants without allergic manifestation (Empirical Analysis of Digital Gene Expression in R [edgeR] test: P = .008, q = 0.02).Conclusion: Low intestinal microbial diversity during the first month of life was associated with subsequent atopic eczema.

Bacterial identification and analytic challenges in clinical microbiome studies

J. Kirk Harris, Brandie D. Wagner — 2012-02-01

The importance of the human microbiome is rapidly emerging. Our bodies host complex communities of microbes with much greater genetic diversity than our own genome. This complexity is variable across subjects, and there is still much to learn about the processes that drive the establishment and maintenance of these communities. More importantly, these communities fundamentally affect the normal function of our bodies and thus are critical to understand as modifiers of human processes, including disease.

A protocol for risk stratification of patients with carboplatin-induced hypersensitivity reactions

2011-11-18

Background: Management of patients with carboplatin-induced hypersensitivity reactions (HSR) has been complicated by high false-negative rates of carboplatin skin test (ST) results. These patients might be at risk for future carboplatin-induced HSRs. In this article we identify a strategy to improve risk stratification of patients with a history of carboplatin-induced HSRs by using a protocol that includes repeat skin testing and drug desensitization.Objective: We sought to identify a management strategy for patients with a history of carboplatin-induced HSRs with negative carboplatin ST results.Methods: From 2008-2010, patients with carboplatin-induced HSR underwent risk stratification per a protocol using 3 repeat STs with intervening drug desensitizations.Results: Of the 44 patients with carboplatin-induced HSRs, 39 completed the protocol. Patients were classified as having positive ST results (n = 16), having negative ST results (n = 11), or ST converters when the ST result converted to positive after an initial negative result (n = 12). ST converters are more likely to have HSRs during subsequent desensitizations than patients with negative ST results (56.1% vs 4.5%, P < .001). ST converters had a significantly longer time interval between their initial HSR and initial ST evaluation compared with either patients with true-negative ST results (22.1 vs 6.0 months, P = .03) or patients with positive ST results (22.1 vs 1.8 months, P = .001).Conclusion: Our experience suggests that repeat STs are necessary for risk stratification in patients with a remote clinical history of HSR and an initial negative ST result because there is a significant rate of conversion to a positive ST result. ST converters have an increased risk of HSRs during subsequent carboplatin treatment.

The safety and efficacy of sublingual and oral immunotherapy for milk allergy

2011-12-01

Background: Oral immunotherapy (OIT) and sublingual immunotherapy (SLIT) are potential therapies for food allergy, but the optimal method of administration, mechanism of action, and duration of response remain unknown.Objective: We sought to explore the safety and efficacy of OIT and SLIT for the treatment of cow’s milk (CM) allergy.Methods: We randomized children with CM allergy to SLIT alone or SLIT followed by OIT. After screening double-blind, placebo-controlled food challenges and initial SLIT escalation, subjects either continued SLIT escalation to 7 mg daily or began OIT to either 1000 mg (the OITB group) or 2000 mg (the OITA group) of milk protein. They were challenged with 8 g of milk protein after 12 and 60 weeks of maintenance. If they passed the 60-week challenge, therapy was withdrawn, with challenges repeated 1 and 6 weeks later. Mechanistic correlates included end point titration skin prick testing and measurement of CM-specific IgE and IgG4 levels, basophil histamine release, constitutive CD63 expression, CD203c expression, and intracellular spleen tyrosine kinase levels.Results: Thirty subjects with CM allergy aged 6 to 17 years were enrolled. After therapy, 1 of 10 subjects in the SLIT group, 6 of 10 subjects in the SLIT/OITB group, and 8 of 10 subjects in the OITA group passed the 8-g challenge (P = .002, SLIT vs OIT). After avoidance, 6 of 15 subjects (3 of 6 subjects in the OITB group and 3 of 8 subjects in the OITA group) regained reactivity, 2 after only 1 week. Although the overall reaction rate was similar, systemic reactions were more common during OIT than during SLIT. By the end of therapy, titrated CM skin prick test results and CD63 and CD203c expression decreased and CM-specific IgG4 levels increased in all groups, whereas CM-specific IgE and spontaneous histamine release values decreased in only the OIT group.Conclusion: OIT was more efficacious for desensitization to CM than SLIT alone but was accompanied by more systemic side effects. Clinical desensitization was lost in some cases within 1 week off therapy.

Reslizumab in children and adolescents with eosinophilic esophagitis: Results of a double-blind, randomized, placebo-controlled trial

2011-12-30

Background: Eosinophilic esophagitis is a chronic allergic disease with insufficient treatment options. Results from animal studies suggest that IL-5 induces eosinophil trafficking in the esophagus.Objective: We sought to evaluate the effect of reslizumab, a neutralizing antibody against IL-5, in children and adolescents with eosinophilic esophagitis.Methods: Patients with symptom severity scores of moderate or worse and an esophageal biopsy specimen with 24 or more intraepithelial eosinophils per high-power field were randomly assigned to receive infusions of 1, 2, or 3 mg/kg reslizumab or placebo at weeks 0, 4, 8, and 12. The coprimary efficacy measures were changes in peak esophageal eosinophil count and the physician’s global assessment score at week 15 (end of therapy).Results: Two-hundred twenty-six patients received study medication. Median reductions from baseline to the end of therapy in peak esophageal eosinophil counts were 59%, 67%, 64%, and 24% in the 1, 2, and 3 mg/kg reslizumab (all P < .001) and placebo groups, respectively. All treatment groups, including the placebo group, showed improvements in physician’s global assessment scores; the differences between the reslizumab and placebo groups were not statistically significant. The most common adverse events in the reslizumab groups were headache, cough, nasal congestion, and upper respiratory tract infection. One patient in each reslizumab group and 2 in the placebo group had serious adverse events; none were considered related to the study medication.Conclusion: Reslizumab significantly reduced intraepithelial esophageal eosinophil counts in children and adolescents with eosinophilic esophagitis. However, improvements in symptoms were observed in all treatment groups and were not associated with changes in esophageal eosinophil counts.

Autoimmune regulator (AIRE) contributes to Dectin-1–induced TNF-α production and complexes with caspase recruitment domain–containing protein 9 (CARD9), spleen tyrosine kinase (Syk), and Dectin-1

2011-09-29

Background: Autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy (APECED) syndrome is a complex immunologic disease caused by mutation of the autoimmune regulator (AIRE) gene. Autoimmunity in patients with APECED syndrome has been shown to result from deficiency of AIRE function in transcriptional regulation of thymic peripheral tissue antigens, which leads to defective T-cell negative selection. Candidal susceptibility in patients with APECED syndrome is thought to result from aberrant adaptive immunity.Objective: To determine whether AIRE could function in anticandidal innate immune signaling, we investigated an extrathymic role for AIRE in the immune recognition of β-glucan through the Dectin-1 pathway, which is required for defense against Candida species.Methods: Innate immune signaling through the Dectin-1 pathway was assessed in both PBMCs from patients with APECED syndrome and a monocytic cell line. Subcellular localization of AIRE was assessed by using confocal microscopy.Results: PBMCs from patients with APECED syndrome had reduced TNF-α responses after Dectin-1 ligation but in part used a Raf-1–mediated pathway to preserve function. In the THP-1 human monocytic cell line, reducing AIRE expression resulted in significantly decreased TNF-α release after Dectin-1 ligation. AIRE formed a transient complex with the known Dectin-1 pathway components phosphorylated spleen tyrosine kinase and caspase recruitment domain–containing protein 9 after receptor ligation and localized with Dectin-1 at the cell membrane.Conclusion: AIRE can participate in the Dectin-1 signaling pathway, indicating a novel extrathymic role for AIRE and a defect that likely contributes to fungal susceptibility in patients with APECED syndrome.

Heterogeneous telomere defects in patients with severe forms of dyskeratosis congenita

2011-11-14

Background: Telomeres represent the tips of linear chromosomes. In human subjects telomere maintenance deficiency leads to dyskeratosis congenita (DC), a rare genetic disorder characterized by progressive bone marrow failure, accelerated aging, and cancer predisposition. Hoyeraal-Hreidarsson syndrome (HH) is a severe variant of DC in which an early onset of bone marrow failure leading to combined immunodeficiency is associated with microcephaly, cerebellar hypoplasia, and growth retardation.Objectives: Limited information is available on the cellular and molecular phenotypes of cells from patients with HH. We analyzed fibroblasts and whole blood cells from 5 patients with HH, 3 of them of unknown molecular origin.Methods: Telomere length, cellular senescence rate, telomerase activity, telomeric aberration, and DNA repair pathways were investigated.Results: Although patients’ cells exhibit dysfunctional telomeres, sharp differences in the telomeric aberrations and telomere lengths were noted among these patients. In some patients the dysfunctional telomere phenotype was unprecedented and associated with either normal telomere length or with telomeric aberrations akin to fragile telomeres. This result is of particular importance because the molecular diagnosis of these patients is primarily based on telomere length, which therefore misses a subset of patients with telomere dysfunction.Conclusion: These observations provide the notions that (1) various telomere defects can lead to similar clinical features, (2) telomere dysfunction in cells from patients with DC/HH is not always associated with short telomeres, and (3) additional factors, likely involved in telomere protection rather than in length regulation, are responsible for a subset of DC/HH.

Monocyte-derived dendritic cell recruitment and allergic TH2 responses after exposure to diesel particles are CCR2 dependent

Sharen Provoost, Tania Maes, Guy F. Joos, Kurt G. Tournoy — 2011-09-09

Background: The inhalation of diesel exhaust particles (DEPs) is associated with increased sensitization toward inhaled allergens. Dendritic cells (DCs) are important mediators in immune regulation. We previously showed that the inhalation of DEPs increased the accumulation of DCs in the lung and enhanced the TH2 response in the mediastinal lymph node.Objective: We hypothesized that CC chemokine receptors CCR2, CCR5, and CCR6 critically mediate the DC recruitment upon exposure to DEPs and that these CC chemokine receptors are important in the DEP-induced TH2 response.Methods: We exposed CCR2 knockout, CCR5 knockout, CCR6 knockout, and wild-type mice to DEPs and examined the pulmonary monocyte and DC accumulation. By an adoptive transfer experiment, we assessed the direct involvement of CCR2 and CCR6 in the recruitment of blood monocytes toward the lung upon exposure to DEPs. We also examined the TH2 cytokine production in the mediastinal lymph nodes of DEP-exposed CCR2 knockout and CCR6 knockout mice.Results: We observed that the DEP-induced monocyte and monocyte-derived DC recruitment was completely abolished in CCR2 knockout mice. CCR6 knockout mice also showed impaired monocyte recruitment upon exposure to DEPs. In contrast, monocyte and DC recruitment was comparable between DEP-exposed wild-type and CCR5 knockout mice. The impaired monocyte-derived DC recruitment in DEP-exposed CCR2 knockout, not CCR6 knockout, mice resulted in an abolished TH2 response in the mediastinal lymph node.Conclusion: These data suggest that monocyte-derived DCs, recruited in a CCR2-dependent manner, are critical in inducing TH2 responses upon inhalation of DEPs.

D-type prostanoid receptor enhances the signaling of chemoattractant receptor–homologous molecule expressed on TH2 cells

2011-09-20

Background: Prostaglandin (PG) D2 is substantially involved in allergic responses and signals through the 7 transmembrane–spanning/G protein–coupled receptors, chemoattractant receptor–homologous molecule expressed on TH2 cells (CRTH2), and D-type prostanoid (DP) receptor.Objective: Although the proinflammatory function of CRTH2 is well recognized and CRTH2 is hence considered an important emerging pharmacotherapeutic target, the role of the DP receptor in mediating the biological effects of PGD2 in patients with allergic inflammation has remained unclear.Methods: The cross-talk of CRTH2 and DP receptors was investigated by using both a recombinant HEK293 cell model and human eosinophils in Ca2+ mobilization assays, coimmunoprecipitation, Western blotting, radioligand binding, and immunofluorescence.Results: We show that CRTH2 and DP receptors modulate one another’s signaling properties and form CRTH2/DP heteromers without altering their ligand-binding capacities. We find that the DP receptor amplifies the CRTH2-induced Ca2+ release from intracellular stores and coincidentally forfeits its own signaling potency. Moreover, desensitization or pharmacologic blockade of the DP receptor hinders CRTH2-mediated signal transduction. However, CRTH2 internalization occurs independently of the DP receptor. In cells that express both receptors, pharmacologic blockade of Gαq/11 proteins abolishes the Ca2+ response to both CRTH2 and DP agonists, whereas inhibition of Gαi proteins selectively attenuates the CRTH2-mediated response but not the DP signal.Conclusion: Our data demonstrate the capacity of DP receptors to amplify the biological response to CRTH2 activation. Therefore the CRTH2/DP heteromer might not only represent a functional signaling unit for PGD2 but also a potential target for the development of heteromer-directed therapies to treat allergic diseases.

Uptake of blood coagulation factor VIII by dendritic cells is mediated via its C1 domain

2011-10-03

Background: The uptake and processing of blood coagulation factor VIII (FVIII) by antigen-presenting cells and the subsequent presentation of FVIII-derived peptides to CD4+ T cells direct the immune response to FVIII in patients with hemophilia A. Multiple receptors including mannose receptor and low-density lipoprotein receptor–related protein-1 (LRP1) have been implicated in FVIII uptake.Objective: This work studies the involvement of receptor candidates in FVIII uptake by dendritic cells (DCs). Furthermore, we explore FVIII residues that mediate endocytosis.Methods: FVIII uptake was performed with human monocyte–derived and murine bone marrow–derived DCs. To investigate FVIII endocytosis, competition assays with soluble receptor ligands, binding studies with recombinant receptor fragments, and small-interfering RNA–induced gene silencing were performed. In addition, FVIII-targeting monoclonal antibodies KM33 and VK34 were used. To confirm in vitro results, hemophilic E17 knockout mice were pretreated with antibodies prior to FVIII injections and anti-FVIII titers were determined.Results: Upon treatment of DCs with mannan or LRP ligand α2-macroglobulin, we observed only a minor decrease in FVIII internalization. In addition, small interfering RNA–mediated knockdown of LRP, mannose receptor, or DC-SIGN expression in monocyte-derived dendritic cells did not prevent FVIII uptake. Binding studies using Fc chimeras revealed that LRP, DC-SIGN, and mannose receptor can bind to FVIII; however, we did not observe a critical role for these receptors in FVIII uptake. Previous studies have shown that human antibodies targeting the C1 (KM33) and A2 (VK34) domains of FVIII interfere with binding to endocytic receptors. Preincubation of FVIII with VK34 did not influence FVIII uptake; however, KM33 completely inhibited FVIII endocytosis by both monocyte-derived dendritic cells and bone marrow-derived dendritic cells. Accordingly, anti-FVIII antibody titers were greatly reduced following the preadministration of KM33 in vivo.Conclusion: Together, our observations emphasize the physiological significance of KM33-targeted residues within the C1 domain in the uptake of FVIII by DCs in vitro and in vivo.

Induction and maintenance of allergen-specific FOXP3+ Treg cells in human tonsils as potential first-line organs of oral tolerance

2011-11-04

Background: Tonsils are strategically located in the gateway of both alimentary and respiratory tracts representing the first contact point of food and aeroallergens with the immune system. Tonsillectomy removes only the palatine tonsils and sometimes adenoids. Lingual tonsil is anatomically big and remains lifelong intact.Objective: The aim of this study was to demonstrate cellular and molecular mechanisms of oral tolerance induction to food and aeroallergens in human tonsils.Methods: Tonsil allergen-specific FOXP3+ regulatory T (Treg) cells, plasmacytoid dendritic cells (pDCs), and myeloid dendritic cells were characterized by flow cytometry and suppressive assays. Intracellular staining, [3H]-thymidine incorporation, and carboxy-fluorescein succinimidyl ester dilution experiments were performed. Tonsil biopsies were analyzed by confocal microscopy.Results: CD4+FOXP3+ Treg cells and pDCs constitute important T- and dendritic cell–compartments in palatine and lingual tonsils. Tonsil pDCs have the ability to generate functional CD4+CD25+CD127−FOXP3+ Treg cells with suppressive property from naive T cells. CD4+FOXP3+ Treg cells proliferate and colocalize with pDCs in vivo in T-cell areas of lingual and palatine tonsils. Tonsil T cells did not proliferate to common food and aeroallergens. Depletion of FOXP3+ Treg cells enables the allergen-induced proliferation of tonsil T cells, indicating an active role of Treg cells in allergen-specific T-cell unresponsiveness. High numbers of major birch pollen allergen, Bet v 1–specific CD4+FOXP3+ Treg cells, are identified in human tonsils compared with peripheral blood. A positive correlation between the percentages of FOXP3+ Treg cells and pDCs is observed in tonsils from nonatopic individuals.Conclusion: Functional allergen-specific Treg cells are identified both in lingual and in palatine tonsils.

CD4-mediated regulatory T-cell activation inhibits the development of disease in a humanized mouse model of allergic airway disease

2011-11-14

Background: Based on their potency to control allergic diseases, regulatory T (Treg) cells represent a promising target for novel strategies to interfere with allergic airway inflammation. We have previously demonstrated that stimulation of the CD4 molecule on human Treg cells activates their suppressive activity in vitro and in vivo.Objective: We sought to determine the effect of CD4-mediated Treg-cell activation on pulmonary inflammation in a humanized mouse model of allergic airway inflammation.Methods: PBMCs obtained from donors allergic to birch pollen or from healthy donors were injected into NOD-severe combined immunodeficiency γc−/− mice, followed by allergen airway challenges and analysis of airway responsiveness and inflammation. For Treg-cell activation, mice were treated with the CD4-binding, lck-activating recombinant HIV-1 surface protein gp120 after sensitization prior to allergen challenge. Control experiments with CD25-depleted PBMCs were performed to evaluate the role of Treg cells.Results: PBMCs from allergic donors but not from healthy donors induced airway inflammation and airway hyperresponsiveness. Treatment with gp120 prior to allergen challenge abrogated airway hyperresponsiveness and reduced the inflammatory immune response. In contrast, treatment had no effect on inflammation and airway hyperresponsiveness in mice that received CD25-depleted PBMCs, demonstrating Treg-cell dependency of disease prevention.Conclusion: Allergic airway inflammation can be prevented by stimulation of human Treg cells by CD4. These results suggest a clinical potential of Treg-cell activation by high-affinity CD4 ligands in allergic diseases.

Protease-activated receptor 2–dependent fluid secretion from airway submucosal glands by house dust mite extract

2011-12-26

Background: The submucosal gland (SMG) is important in the control of airway surface fluid. Protease-activated receptor (PAR) 2 contributes to the pathophysiology of allergies in response to nonspecific allergens bearing proteases and anion secretion. House dust mites (HDMs) have abundant proteases that can activate PAR2, but little is known about the direct effect of HDM on SMG secretion.Objective: The aim of this study was to investigate the effect of HDMs on glandular secretion and its mechanism in allergic patients, patients with chronic rhinosinusitis (CRS), or both.Methods: Inferior nasal turbinates were harvested from 55 patients and classified into 4 groups (the control, allergic rhinitis [AR], CRS, and AR+CRS groups). A microscope attached to a digital camera was used to quantify mucus bubbles from individual SMGs while stimulated with HDM extract, PAR2-activating peptide, and carbachol. PAR2 expression in the SMG was determined by means of immunostaining with anti-PAR2 mAb.Results: HDM induced a significantly higher secretion rate and number of responding glands in the AR and AR+CRS groups than in the control group. Interestingly, patients in the CRS group, who had no HDM-specific IgE antibody, showed a higher response than the control group, and its response was suppressed by a PAR2-selective antagonist. The responses to PAR2-activating peptide were similar to those to HDM, and their secretion rates positively correlated with HDM responses. PAR2 was highly expressed in all 3 disease groups with immunostaining.Conclusions: HDM allergens can induce glandular secretion in patients with AR, CRS, or both, and PAR2 represents a possible mechanism for nonspecific hyperreactivity in inflammatory airway diseases.

PGD2 induces eotaxin-3 via PPARγ from sebocytes: A possible pathogenesis of eosinophilic pustular folliculitis

2011-12-30

Background: Eosinophilic pustular folliculitis (EPF) is a chronic intractable pruritic dermatosis characterized by massive eosinophil infiltrates involving the pilosebaceous units. Recently, EPF has been regarded as an important clinical marker of HIV infection, and its prevalence is increasing in number. The precise mechanism by which eosinophils infiltrate into the pilosebaceous units remains largely unknown. Given that indomethacin, a COX inhibitor, can be successfully used to treat patients with EPF, we can assume that COX metabolites such as prostaglandins (PGs) are involved in the etiology of EPF.Objective: To determine the involvement of PGs in the pathogenesis of EPF.Methods: We performed immunostaining for PG synthases in EPF skin lesions. We examined the effect of PGD2 on induction of eotaxin, a chemoattractant for eosinophils, in human keratinocytes, fibroblasts, and sebocytes and sought to identify its responsible receptor.Results: Hematopoietic PGD synthase was detected mainly in infiltrating inflammatory cells in EPF lesions, implying that PGD2 was produced in the lesions. In addition, PGD2 and its immediate metabolite 15-deoxy-Δ 12,14-PGJ2 (15d-PGJ2) induced sebocytes to produce eotaxin-3 via peroxisome proliferator–activated receptor gamma. Consistent with the above findings, eotaxin-3 expression was immunohistochemically intensified in sebaceous glands of the EPF lesions.Conclusion: The PGD2/PGJ2-peroxisome proliferator–activated receptor gamma pathway induces eotaxin production from sebocytes, which may explain the massive eosinophil infiltrates observed around pilosebaceous units in EPF.

Differentiation stage determines pathologic and protective allergen-specific CD4+ T-cell outcomes during specific immunotherapy

2011-10-05

Background: The main obstacle to elucidating the role of CD4+ T cells in allergen-specific immunotherapy (SIT) has been the absence of an adequately sensitive approach to directly characterize rare allergen-specific T cells without introducing substantial phenotypic modifications by means of in vitro amplification.Objective: We sought to monitor, in physiological conditions, the allergen-specific CD4+ T cells generated during natural pollen exposure and during allergy vaccination.Methods: Alder pollen allergy was used as a model for studying seasonal allergies. Allergen-specific CD4+ T cells were tracked and characterized in 12 subjects with alder pollen allergy, 6 nonallergic subjects, and 9 allergy vaccine–treated subjects by using peptide–MHC class II tetramers.Results: Allergen-specific CD4+ T cells were detected in all of the subjects with alder pollen allergy and nonallergic subjects tested. Pathogenic responses—chemoattractant receptor homologous molecule expressed on TH2 lymphocytes (CRTH2) expression and TH2 cytokine production— are specifically associated with terminally differentiated (CD27−) allergen-specific CD4+ T cells, which dominate in allergic subjects but are absent in nonallergic subjects. In contrast, CD27+ allergen-specific CD4+ T cells are present at low frequencies in both allergic and nonallergic subjects and reflect classical features of the protective immune response with high expression of IL-10 and IFN-γ. Restoration of a protective response during SIT appears to be due to the preferential deletion of pathogenic (CD27−) allergen-specific CD4+ T cells accompanied by IL-10 induction in surviving CD27+ allergen-specific CD4+ T cells.Conclusions: Differentiation stage divides allergen-specific CD4+ T cells into 2 distinct subpopulations with unique functional properties and different fates during SIT.

CD27 expression on allergen-specific T cells: A new surrogate for successful allergen-specific immunotherapy?

Stefanie Gilles, Claudia Traidl-Hoffmann — 2012-02-01

To date, allergen-specific immunotherapy (ASIT) is the only causal treatment for allergic diseases. The principle of ASIT is to administer gradually increasing doses of allergen, either as allergen extracts or as recombinant allergen. The aim is to reprogram the allergen-specific immune response from a TH2-driven IgE-dominated response toward a tolerant state. By inducing immune tolerance to an allergen, diseases such as allergic rhinitis might even be prevented in progressing toward a severe chronic disorder, such as asthma. Although the concept of specific immunotherapy is more than 100 years old, our knowledge about the underlying immunologic mechanisms is limited (for overview, see ). Moreover, some patients are clinically unresponsive to ASIT, and the identification of solid predictors for successful ASIT remains an unmet clinical need.

Comparison of methacholine and mannitol bronchial provocation tests in workers with occupational asthma

2011-10-24

Although a specific substance is identified as the cause for the onset of occupational asthma (OA), the removal of this substance does not induce a remission of the disease in the vast majority of subjects. The assessment of impairment/disability of OA after removal from exposure is currently performed in the province of Quebec by performing spirometry and identifying airflow limitation through airway hyperresponsiveness (AHR) to methacholine, and assessing the need for asthma medication 2 years after the initial diagnosis of OA.

Urinary tetranor-PGDM concentrations in aspirin-intolerant asthma and anaphylaxis

2011-10-24

The “F-ring” urinary prostaglandin D2 (PGD2) metabolites—9α,11β-prostaglandin F2 (9α,11β-PGF2), 2,3-dinor-9α,11β-prostaglandin F2 (2,3-dinor-9α,11β-PGF2), and 9α,11β-dihydroxy-15-oxo-2,3,18,19-tetranorprost-5-ene-1,20-dioic acid—are useful biomarkers of mast cell activation. In an original article recently published in this Journal, we employed gas chromatography-mass spectrometry-negative ion chemical ionization for the quantification of 2,3-dinor-9α,11β-PGF2 in urine from subjects with anaphylaxis or with aspirin-intolerant asthma (AIA). When assessed by changes in the 2,3-dinor-9α,11β-PGF2 concentration, PGD2 generation was more obviously evident during the acute exacerbation of anaphylaxis or AIA. We thus provided further evidence that AIA reactions are triggered by the pharmacological effects of cyclooxygenase-1 (COX-1) inhibitors, which include cysteinyl-leukotrienes and even PGD2 release. Song et al recommended the measurement of the urinary 11,15-dioxo-9α-hydroxy-2,3,4,5-tetranorprostan-1,20-dioic acid (tetranor-PGDM) concentration, a “D-ring” urinary metabolite, as a sensitive biomarker of PGD2. The formation of “F-ring” and “D-ring” products from PGD2 is described in this article's Online Repository at www.jacionline.org. Unexpectedly, immediately after we submitted this original manuscript, an enzyme immunoassay (EIA) kit for tetranor-PGDM became commercially available (Cayman Chemical, Ann Arbor, Mich). It is currently unknown whether urinary tetranor-PGDM may be applied to allergic diseases, such as anaphylaxis and asthma. Thus, we applied the tetranor-PGDM determination method to the same samples that were stored in the freezer from the subjects with anaphylaxis or AIA.

Heterozygous signal transducer and activator of transcription 3 mutations in hyper-IgE syndrome result in altered B-cell maturation

2011-10-28

Heterozygous mutations in the transcription factor signal transducer and activator of transcription 3 (STAT3) have been identified in patients with autosomal dominant hyper-IgE syndrome (HIES). The clinical phenotype of STAT3-HIES is characterized by Staphylococcus aureus–induced skin abscesses, pneumonia with pneumatocele formation, mucocutaneous candidiasis, eczema, and skeletal and connective tissue abnormalities, suggesting a crucial role for STAT3 signaling in both innate and adaptive immunity. To address the effect of decreased STAT3 signaling on the B-cell compartment, we enrolled 25 patients with STAT3-HIES (age, 2.5-51 years) from 20 unrelated families (see in this article’s Online Repository at www.jacionline.org) and 30 healthy subjects (age, 18-72 years) and determined antibody responses to the T cell–dependent neoantigen bacteriophage phiX174 (phage), the composition of B-cell subpopulations and expression of B cell–activating factor of the TNF family (BAFF) receptor (BAFF-R), and plasma BAFF levels. Institutional review board approval and written informed consent were obtained. The mutations observed were reported previously. All patients older than 5 years (n = 22) had National Institutes of Health (NIH) HIES scores of greater than 40 points. Three patients 4 years of age or less had scores of less than 40 points (see ).

Hypersensitivity reactions due to nitrile gloves

2011-10-24

Nitrile gloves are the alternative for health professionals sensitized to latex in case of biological risk or managing of chemical substances with irritating or toxic properties. There are very few reactions published in the literature with the use of these gloves.

Oral food challenge practices among allergists in the United States

Jacqueline A. Pongracic, S. Allan Bock, Scott H. Sicherer — 2011-10-31

The recently published National Institute of Allergy and Infectious Diseases–sponsored “Guidelines for the diagnosis and management of food allergy in the United States” and the “Work group report” both state that oral food challenge (OFC) is a critical procedure for the evaluation of food allergy. Fleischer et al reported that OFCs were crucial in identifying children who were otherwise following unnecessary dietary restrictions based on the results of in vitro testing. A subgroup of the Adverse Reactions to Foods Committee of the American Academy of Allergy, Asthma & Immunology (AAAAI) conceived and designed a survey to collect data about allergists' use of this important diagnostic procedure.

Medical and economic impact of misdiagnosis of drug hypersensitivity in hospitalized patients

Joaquín Sastre, Luis Manso, Silvia Sanchez-García, Mar Fernández-Nieto — 2011-10-31

A substantial proportion of patients admitted to the hospital have a diagnosis of drug hypersensitivity (DH). However, this diagnosis may sometimes be inaccurate, causing deleterious medical and economic consequences. We report the results of a study whose objectives were to determine the frequency with which reports of DH in a tertiary university hospital bring about both changes in drug selection and increased costs and also to assess the validity of the initial DH diagnosis.

Predictors of neonatal production of IFN-γ and relation to later wheeze

Ufuk Sevgican, Janet Rothers, Debra A. Stern, I. Carla Lohman, Anne L. Wright — 2011-10-31

We have shown that IFN-γ production at 3 and 9 months is inversely associated with frequent wheeze in the first year of life and with wheeze up to age 13 years, respectively. If early-life IFN-γ production predicts later wheeze, it is important to consider whether there are prenatal predictors of IFN-γ and, if so, whether these factors might actually be the driving force for the relation with wheeze. For example, if parental smoking is associated with early IFN-γ production, an observed relation between IFN-γ production and wheeze could be attributable to passive smoke exposure. In addition, there appear to be sex-specific differences in both immune responses and prevalence of wheeze, suggesting that potential modifications of the IFN-γ–wheeze relation by sex should be investigated. Thus the objective of this study was to investigate the predictors of cord blood IFN-γ levels, to assess whether the relation of cord blood IFN-γ levels to early wheeze is actually attributable to these factors, and to determine whether sex affects these relations.

Genetic and histologic evidence for autophagy in asthma pathogenesis

2011-10-31

Asthma affects all age groups and presents itself as a spectrum of severity and symptoms. Reactive oxygen species (ROS) play a pivotal role in asthma pathogenesis. Exhaled levels of mediators associated with ROS positively correlate with asthma severity. Autophagy, the process of cellular waste disposal through lysosome-dependent pathways, is induced by ROS to remove oxidized proteins or organelles to minimize tissue damage. Although autophagy is augmented in the lungs of patients with chronic obstructive pulmonary disease compared with healthy control subjects, evidence for autophagy in asthmatic patients, particularly those with moderate-to-severe asthma, has not been reported. We hypothesize that autophagy is associated with asthma pathogenesis and sought to detect its presence using both genetic and histologic approaches.

Current practices among allergists on writing self-injectable epinephrine prescriptions for immunotherapy patients

Payel Gupta, Prianka K. Gerrish, Bernard Silverman, Arlene Schneider — 2011-10-31

Although allergen immunotherapy (IT) is generally safe, it carries a risk of systemic reactions (SRs); predicting which patients will have SRs has proven to be difficult. Self-injectable epinephrine (SIE) in the form of a device was first introduced in 1980 and allows physicians to give a potentially life-saving treatment to those patients at risk of having an SR. However, there is no current consensus regarding the use of SIE prescriptions for patients on IT and the decision to prescribe SIE falls on the physician administering IT. Our objective was to investigate current practices among allergists on SIE-prescribing habits for IT recipients.

IL-1 receptor–associated kinase 3 gene (IRAK3) variants associate with asthma in a replication study in the Spanish population

2011-11-10

Asthma is a chronic inflammatory disease associated with genetic and environmental factors. Although the 12q13-24 chromosome region had previously shown linkage to asthma, the IL-1 receptor–associated kinase 3 gene (IRAK3) has recently emerged as a susceptibility candidate for asthma as a result of positional cloning of persistent asthma with age of onset less than 13 years in Italian samples. IRAK3 encodes a protein that negatively regulates Toll-like receptor signaling pathways involved in innate host defense and in the control of adaptive immune responses. However, single nucleotide polymorphisms (SNPs) near IRAK3 have not reached the stringent significance thresholds in any of the genome-wide association studies (GWASs) performed in asthmatic patients. Here we aimed to replicate the association of IRAK3 genetic variants with susceptibility to asthma in a case-control study with unrelated Spanish subjects.

The C11orf30-LRRC32 region is associated with total serum IgE levels in asthmatic patients

2011-11-10

Asthma is a chronic inflammatory respiratory disease characterized by bronchial hyperresponsiveness, increased TH2 cytokine levels, and increased serum IgE levels. Atopic dermatitis or eczema is a chronic inflammatory skin disease characterized by epidermal barrier dysfunction and IgE-mediated sensitization. The only published genome-wide association study (GWAS) of atopic dermatitis identified rs7927894 on chromosome 11q13.5 between the chromosome 11 open reading frame 30 (C11orf30) and leucine-rich repeat containing 32 (LRRC32) genes. A replication study further confirmed the association of rs7927894 with childhood eczema. The same variant is also associated with Crohn disease, an inflammatory bowel disease. Increased total serum IgE levels are common in both patients with asthma and those with eczema, and therefore we studied whether the C11orf30-LRRC32 region is associated with total serum IgE levels and asthma in 3 independently ascertained non-Hispanic white populations: the National Heart, Lung, and Blood Institute (NHLBI)–funded Severe Asthma Research Program (SARP); the NHLBI’s Collaborative Studies on the Genetics of Asthma (CSGA) studies; and the Epidemiology and Natural History of Asthma: Outcomes and Treatment Regimens (TENOR) multicenter study. For additional information on the methods used, see the section in this article’s Online Repository at www.jacionline.org.

A rapid screening method to detect autosomal-dominant ectodermal dysplasia with immune deficiency syndrome

2011-11-14

A patient presented to us with autosomal-dominant anhidrotic ectodermal dysplasia with immune deficiency syndrome (EDA-ID). By using a rapid flow cytometric screening system, we detected a novel mutation of the IKBA gene in the patient.

Effect of Lactobacillus GG on tolerance acquisition in infants with cow's milk allergy: A randomized trial

2011-11-14

The possible effect of probiotics on tolerance acquisition in patients with cow's milk allergy (CMA) is a largely unexplored research area. The only previous study of the effect of probiotic strains (not including Lactobacillus GG [LGG]) on tolerance acquisition in children with CMA yielded negative results. Despite this finding and earlier conflicting results on probiotic use in patients with allergic disorders, we asked, given the well-documented link between LGG and the immune system, whether supplementation of an extensively hydrolyzed casein formula (EHCF) with LGG could affect tolerance acquisition to cow's milk protein (CMP).

A suspicion of antibiotic allergy in children is often incorrect

Marjolein Mattheij, Esther de Vries — 2011-12-26

With great interest we read the article “The role of penicillin in benign skin rashes in childhood: a prospective study based on drug rechallenge” by Caubet et al. The authors studied the etiology of delayed-onset rashes in children treated with β-lactam antibiotics. They state that β-lactam allergy is clearly overdiagnosed. They advise oral provocation in all children suspected of antibiotic allergy, a statement in concurrence with the policy of the European Network of Drug Allergy. The few available studies about children with a suspected antibiotic allergy confirm this. They show that intradermal skin testing can be used to demonstrate a direct hypersensitivity reaction, but not a delayed-onset reaction, and confirm a high number of false-negative reactions. IgE assays show low sensitivity and specificity. Oral provocation tests are considered the golden standard in proving antibiotic allergies.

Reply

Jean-Christoph Caubet, Philippe A. Eigenmann — 2011-12-26

We thank Drs Mattheij and de Vries for their interesting communication on the diagnosis of β-lactam allergy in children. These results support our findings that β-lactam allergy is clearly overdiagnosed among children developing a benign maculopapular or urticarial rash during β-lactam treatment. Indeed, these skin rashes are only rarely reproducible by a subsequent challenge, and most of them are probably of viral origin. In this situation, several studies including ours have shown that an oral challenge test without prior skin testing is a safe procedure and is currently the best diagnostic tool for confirming a causal relationship between drug administration and an adverse reaction. However, it is to be noted that the clinician should be certain that the initial reaction was a delayed benign rash. This degree of certainty is reached only if the clinician observed the reaction firsthand, or if there is clear documentation of the rash in the medical record. If there is any doubt about the nature of the previous reaction, intradermal skin tests should be performed, particularly to exclude an immediate allergy.

The mediating effect of microbial colonization on the effect of cesarean section delivery

2011-12-30

van Nimwegen et al report an intriguing set of results concerning the role of intestinal microbiota colonization in the relationship between mode and place of delivery on childhood risk of allergic disease. The possibility of cesarean section being a potential cause of asthma has received considerable attention, and although other hypotheses have been posed, the most often cited explanation for this association is reduced colonization with microbiota from the maternal gut and vagina. The authors observed that, of the measured microbiota, only colonization by Clostridium difficile was related to the risk of allergic disease. It is worth noting that this observation is slightly different from the initial interpretation of the hygiene hypothesis, which suggested that lack of colonization rather than increased colonization by particular organisms increased the risk of allergic disease. In fact, none of the organisms measured in this study were associated with a protective effect against allergic disease, possibly because of the lack of statistical power.

Reply

2011-12-30

We appreciate the comments by Lowe et al on our article entitled “Mode and place of delivery, gastrointestinal microbiota, and their influence on asthma and atopy.” The authors suggest that we “claim that C difficile might cause allergic disease.” In our article the only strong causal claim concerns the role of delivery: “The findings of mediation by C difficile strengthen the evidence for a causal role of birth mode on atopic manifestations through influencing the GM composition.” The term “birth mode” in this sentence might be confusing because it was meant to refer to both birth mode and place.

Correction

2012-02-01

With regard to the February 2011 article entitled “The burden of adult asthma in the United States: Evidence from the Medical Expenditure Panel Survey” (J Allergy Clin Immunol 2011;127:363-9.e3), several numbers need to be corrected. First, the initial sentence of the Results section, both in the abstract and in the body of the article, should read “Of 44,795 adults, 1,935 reported an encounter for asthma.” Second, in , the Proportion rows for all headings other than “Adult MEPS total” are incorrect as given. A corrected version of the Table appears below:

T cell–mediated acute localized exanthematous pustulosis caused by finasteride

2011-08-25

A 21-year-old man presented with multiple erythematous nonfollicular papules partially confluent to plaques on his breast and lower abdomen that had been present for 1 month. Grouped pustules were present under the right breast. The patient had been taking finasteride over the past 3 months for androgenetic alopecia. His medical history was negative for psoriasis. Our initial differential diagnosis included dyskeratosis follicularis Darier, allergic contact dermatitis, infectious folliculitis, varicella zoster virus infection, fixed drug eruption, and IgA pemphigus. The white blood cell count and differential were within the normal limits. Results of viral cultures and PCR, as well as bacterial and fungal cultures of skin lesions proved negative. A lesional biopsy specimen showed a slight psoriasiform acanthosis in association with spongiosis and infiltration of both the epidermis and dermis by neutrophils and eosinophils, resulting in formation of subcorneal, intraepidermal, and subepidermal pustules. The results of direct immunofluorescence were negative, excluding an IgA pemphigus. The result of a lymphocyte transformation test was positive for finasteride. On the basis of the time relationship between the administration of finasteride and the development of the skin disease in combination with symptoms resolution on cessation of the drug, the histologic findings, and the positive lymphocyte transformation test result, we consider this to be an unusual type of acute generalized exanthematous pustulosis defined as acute localized exanthematous pustulosis caused by finasteride. Within 4 weeks after withdrawal of finasteride, the rash resolved without any specific therapy. Transient discrete residual hyperpigmentation and scaling were present. The patient refused an oral provocation challenge.

The Journal of Allergy and Clinical Immunology

Cover 1

Brief Overview of This Month's JACI

Table of Contents

Editorial Board

Information for Readers

News & Notes

CME Activities Calendar

News Beyond Our Pages

A Special Thank-You to Our Reviewers

Fungi and allergic lower respiratory tract diseases

Fungi and allergic lower respiratory tract diseases

Mendelian traits causing susceptibility to mucocutaneous fungal infections in human subjects

Mendelian traits causing susceptibility to mucocutaneous fungal infections in human subjects

International consensus and practical guidelines on the gynecologic and obstetric management of female patients with hereditary angioedema caused by C1 inhibitor deficiency

Fungal disease of the nose and paranasal sinuses

New approaches to personalized medicine for asthma: Where are we?

Advances in mechanisms of asthma, allergy, and immunology in 2011

Advances in basic and clinical immunology in 2011

The Editors’ Choice

Airway remodeling and inflammation in competitive swimmers training in indoor chlorinated swimming pools

The effect of single and multiple infections on atopy and wheezing in children

Genome-wide association study reveals class I MHC–restricted T cell–associated molecule gene (CRTAM) variants interact with vitamin D levels to affect asthma exacerbations

Interaction between filaggrin null mutations and tobacco smoking in relation to asthma

The role of the small airways in the clinical expression of asthma in adults

Airway TGF-β1 and oxidant stress in children with severe asthma: Association with airflow limitation

Addendum

Prediction of the incidence and persistence of allergic rhinitis in adolescence: A prospective cohort study

Natural course and comorbidities of allergic and nonallergic rhinitis in children

The effects of an H3 receptor antagonist (PF-03654746) with fexofenadine on reducing allergic rhinitis symptoms

Association of subcutaneous allergen-specific immunotherapy with incidence of autoimmune disease, ischemic heart disease, and mortality

Risk factors for new-onset cat sensitization among adults: A population-based international cohort study

IL-31 regulates differentiation and filaggrin expression in human organotypic skin models

Low diversity of the gut microbiota in infants with atopic eczema

Bacterial identification and analytic challenges in clinical microbiome studies

A protocol for risk stratification of patients with carboplatin-induced hypersensitivity reactions

The safety and efficacy of sublingual and oral immunotherapy for milk allergy

Reslizumab in children and adolescents with eosinophilic esophagitis: Results of a double-blind, randomized, placebo-controlled trial

Autoimmune regulator (AIRE) contributes to Dectin-1–induced TNF-α production and complexes with caspase recruitment domain–containing protein 9 (CARD9), spleen tyrosine kinase (Syk), and Dectin-1

Heterogeneous telomere defects in patients with severe forms of dyskeratosis congenita

Monocyte-derived dendritic cell recruitment and allergic TH2 responses after exposure to diesel particles are CCR2 dependent

D-type prostanoid receptor enhances the signaling of chemoattractant receptor–homologous molecule expressed on TH2 cells

Uptake of blood coagulation factor VIII by dendritic cells is mediated via its C1 domain

Induction and maintenance of allergen-specific FOXP3+ Treg cells in human tonsils as potential first-line organs of oral tolerance

CD4-mediated regulatory T-cell activation inhibits the development of disease in a humanized mouse model of allergic airway disease

Protease-activated receptor 2–dependent fluid secretion from airway submucosal glands by house dust mite extract

PGD2 induces eotaxin-3 via PPARγ from sebocytes: A possible pathogenesis of eosinophilic pustular folliculitis

Differentiation stage determines pathologic and protective allergen-specific CD4+ T-cell outcomes during specific immunotherapy

CD27 expression on allergen-specific T cells: A new surrogate for successful allergen-specific immunotherapy?

Comparison of methacholine and mannitol bronchial provocation tests in workers with occupational asthma

Urinary tetranor-PGDM concentrations in aspirin-intolerant asthma and anaphylaxis

Heterozygous signal transducer and activator of transcription 3 mutations in hyper-IgE syndrome result in altered B-cell maturation

Hypersensitivity reactions due to nitrile gloves

Oral food challenge practices among allergists in the United States

Medical and economic impact of misdiagnosis of drug hypersensitivity in hospitalized patients

Predictors of neonatal production of IFN-γ and relation to later wheeze

Genetic and histologic evidence for autophagy in asthma pathogenesis

Current practices among allergists on writing self-injectable epinephrine prescriptions for immunotherapy patients

IL-1 receptor–associated kinase 3 gene (IRAK3) variants associate with asthma in a replication study in the Spanish population

The C11orf30-LRRC32 region is associated with total serum IgE levels in asthmatic patients

A rapid screening method to detect autosomal-dominant ectodermal dysplasia with immune deficiency syndrome

Effect of Lactobacillus GG on tolerance acquisition in infants with cow's milk allergy: A randomized trial

A suspicion of antibiotic allergy in children is often incorrect

Reply

The mediating effect of microbial colonization on the effect of cesarean section delivery

Reply

Correction

T cell–mediated acute localized exanthematous pustulosis caused by finasteride