The Journal of Allergy and Clinical Immunology - Articles in Press

Apolipoprotein A-IV is a candidate target molecule for the treatment of seasonal allergic rhinitis - Corrected Proof

2010-09-01

Background: Allergic rhinitis is a global health problem that causes major illnesses and disability worldwide. Allergen-specific immunotherapy (SIT) is the only available treatment that can alter the natural course of allergic disease. However, the precise mechanism underlying allergen-SIT is not well understood.Objective: The aim of the current study was to identify protein expression signatures reflective of allergen-SIT—more specifically, sublingual immunotherapy (SLIT).Methods: Serum was taken twice from patients with seasonal allergic rhinitis caused by Japanese cedar: once before the pollen season and once during the season. A total of 25 patients was randomly categorized into a placebo-treated group and an active-treatment group. Their serum protein profiles were analyzed by 2-dimensional electrophoresis.Results: Sixteen proteins were found to be differentially expressed during the pollen season. Among the differentially expressed proteins, the serum levels of complement C4A, apolipoprotein A-IV (apoA-IV), and transthyretin were significantly increased in SLIT-treated patients but not in placebo-treated patients. Among these proteins, the serum levels of apoA-IV correlated with the clinical symptom-medication scores (r = –0.635; P < .05) and with quality of life scores (r = –0.516; P < .05) in the case of SLIT-treated patients. The amount of histamine released from the basophils in vitro was greatly reduced after the addition of recombinant apoA-IV in the medium (P < .01).Conclusion: Our data will increase the understanding of the mechanism of SLIT and may provide novel insights into the treatment of allergic rhinitis.

Presence of IL-5 protein and IgE antibodies to staphylococcal enterotoxins in nasal polyps is associated with comorbid asthma - Corrected Proof

2010-09-01

Background: Nasal polyps often are associated with asthma. The phenotype of these patients is unknown.Objective: To identify the mucosal factors associated with asthma comorbidity, we analyzed the inflammatory patterns of nasal polyps.Methods: Nasal polyps from 70 Belgian patients, 34% with asthma, were analyzed for type of inflammation, T-cell cytokines, and IgE antibodies to Staphylococcus aureus enterotoxins. The same investigations were repeated in 93 Chinese patients with polyps, a group with a low asthma comorbidity rate (8%).Results: In Belgian patients with polyps, 54% of samples showed eosinophilic inflammation. A classification tree evaluation identified IL-5 as the main positive determinant. Enterotoxin IgE in tissue (37%) was associated with significantly increased total IgE and eosinophil cationic protein concentrations. Expression of enterotoxin IgE, total IgE at greater than 1,442 kU/L, and eosinophil cationic protein at greater than 17,109 μg/L in samples with a total IgE concentration of greater than 246 kU/L significantly predicted asthma (odds ratio, 5.8-13). Only 7.5% of the samples from Chinese patients with polyps showed eosinophilic inflammation. IL-5 was confirmed as a positive determinant of eosinophilic inflammation, and enterotoxin IgE in tissue (17% of patients) was associated with significantly increased total IgE and eosinophil cationic protein concentrations. The expression of IL-5 or total IgE at greater than 790 kU/L in samples with an IL-5 concentration of greater than 194 pg/mL significantly predicted comorbid asthma (odds ratio, 17.2-96).Conclusion: Mucosal inflammation in nasal polyps orchestrated by TH2 cytokines and amplified by S aureus enterotoxins is characterized by an increased eosinophilic inflammation and formation of IgE antibodies. This phenotype is associated with comorbid asthma in white and Asian patients with nasal polyps.

ALOX5AP and LTA4H polymorphisms modify augmentation of bronchodilator responsiveness by leukotriene modifiers in Latinos - Corrected Proof

2010-09-01

Background: Understanding the effects of interactions between multiple genes and asthma medications may aid in the understanding of the heterogeneous response to asthma therapies.Objective: To identify modulating effects of arachidonate 5-lipoxygenase-activating protein (ALOX5AP) and leukotriene A4 hydrolase (LTA4H) gene polymorphisms on the drug-drug interaction between leukotriene modifiers and albuterol in Mexicans and Puerto Ricans.Methods: In a cross-sectional study of 293 Mexicans and 356 Puerto Ricans with asthma, ALOX5AP and LTA4H genes were sequenced, and interactions between gene polymorphisms and bronchodilator responsiveness to albuterol were compared between leukotriene modifier users and nonusers.Results: In heterozygotes and homozygotes for the minor allele at LTA4H single nucleotide polymorphism (SNP) rs2540491 and heterozygotes for the major allele at LTA4H SNP rs2540487, leukotriene modifier use was associated with a clinically significant increase in percent change in FEV1 after albuterol administration of 7.10% (P = .002), 10.06% (P = .001), and 10.03% (P < .001), respectively. Presence of the major allele at ALOX5AP SNP rs10507391 or the minor allele at ALOX5AP SNP rs9551963 augmented this response. When stratified by ethnicity, these findings held true for Puerto Ricans but not Mexicans.Conclusion: LTA4H and ALOX5AP gene polymorphisms modify the augmentation of bronchodilator responsiveness by leukotriene modifiers in Puerto Ricans but not Mexicans with asthma.

Mepolizumab as a corticosteroid-sparing agent in lymphocytic variant hypereosinophilic syndrome - Corrected Proof

2010-09-01

Background: Mepolizumab, a monoclonal anti–IL-5 antibody, is an effective corticosteroid-sparing agent for patients with Fip1-like 1/platelet-derived growth factor receptor α fusion (F/P)–negative hypereosinophilic syndrome (HES). Lymphocytic variant hypereosinophilic syndrome (L-HES) is characterized by marked overproduction of IL-5 by dysregulated T cells.Objective: To determine whether patients with L-HES respond to mepolizumab in terms of corticosteroid tapering and eosinophil depletion to the same extent as corticosteroid-responsive F/P-negative patients with HES and a normal T-cell profile.Methods: Patients enrolled in the mepolizumab trial were evaluated for L-HES on the basis of T-cell phenotyping and T-cell receptor gene rearrangement patterns, and their serum thymus-and-activation-regulated chemokine (TARC) levels were measured. Response to treatment was compared in patient subgroups based on results of these analyses.Results: Lymphocytic variant HES was diagnosed in 13 of 63 patients with HES with complete T-cell assessments. The ability to taper corticosteroids on mepolizumab was similar in patients with L-HES and those with a normal T-cell profile, although a lower proportion of patients with L-HES maintained eosinophil levels below 600/μL. Increased serum TARC levels (>1000 pg/mL) had no significant impact on the ability to reduce corticosteroid doses, but a lower proportion of patients with elevated TARC achieved eosinophil control on mepolizumab.Conclusion: Mepolizumab is an effective corticosteroid-sparing agent for patients with L-HES. In some cases however, eosinophil levels remain above 600/μL, suggesting incomplete neutralization of overproduced IL-5 or involvement of other eosinophilopoietic factors.

Fatal consequence of allergic rhinitis - Corrected Proof

Sheldon L. Spector, Ricardo A. Tan — 2010-09-01

To the Editor: Although it is accepted that allergic rhinitis significantly affects quality of life, it can also have tragic consequences. Our patient was a 43-year-old woman who was referred for allergy evaluation. Eight months before the consult, she had a sneezing episode with closing of her eyes while driving at 40 miles per hour with her daughter and crashed into another vehicle, killing the other driver. She sustained ankle and foot fractures.

Safety and efficacy of measles, mumps, and rubella vaccine in patients with DiGeorge syndrome - Corrected Proof

2010-09-01

To the Editor: DiGeorge syndrome is the most common cause of T-cell lymphocytopenia in infants, affecting 1 in 3000 children. More than 90% of these patients have a microdeletion in 22q11.2 chromosome, which can cause an array of clinical features, including cardiac and neurologic anomalies in addition to an underdeveloped thymus gland.

Successful engraftment of donor marrow after allogeneic hematopoietic cell transplantation in autosomal-recessive hyper-IgE syndrome caused by dedicator of cytokinesis 8 deficiency - Corrected Proof

2010-09-01

To the Editor: The hyper-IgE syndromes are rare combined immune deficiencies associated with marked elevations in plasma IgE levels and eosinophilia. An autosomal-dominant form of hyper-IgE syndrome caused by mutations in signal transducer and activator of transcription 3 is characterized by elevated IgE, eosinophilia, eczema, recurrent skin and pulmonary infections, and skeletal abnormalities. Recently, an autosomal recessive form of hyper-IgE syndrome caused by mutations in the dedicator of cytokinesis 8 (DOCK8) gene has been identified and is characterized by elevated IgE levels, eosinophilia, atopic dermatitis, asthma, food allergies, recurrent upper and lower respiratory tract infections, and unusual susceptibility to infections with herpesvirus family members (herpes simplex virus, human papilloma virus) and molluscum contagiosum. Cutaneous infections with human papilloma virus have progressed to squamous cell carcinomas in some cases. Immunologic evaluation of DOCK8-deficient patients has revealed T-cell lymphopenia with impaired proliferative responses of both CD4+ and CD8+ T cells as well as impaired differentiation of TH17 T cells.

The effect of aspirin desensitization on novel biomarkers in aspirin-exacerbated respiratory diseases - Corrected Proof

2010-08-23

Background: Patients with aspirin-exacerbated respiratory disease have been shown to benefit clinically from aspirin desensitization followed by chronic high-dose aspirin therapy. However, the mechanism of this phenomenon is still unclear.Objective: The aim of this study was to characterize the airway inflammatory response to aspirin desensitization and after treatment with high-dose aspirin for 6 months.Methods: Twenty-one adult patients with asthma, chronic polypoid sinusitis, and a convincing history of acute respiratory reaction to the ingestion of aspirin or nonsteroidal anti-inflammatory drugs were selected. These patients underwent an oral desensitization to aspirin over a 2-day period, followed by daily ingestion of aspirin 650 mg twice daily. Induced sputum samples and exhaled nitric oxide measurements were taken before the procedure, during the second day of the procedure, and after 6 months of treatment.Results: There was a significant elevation in both the exhaled nitric oxide level (P = .03) and sputum tryptase level (P = .05) during the desensitization process. After 6 months of aspirin treatment, sputum IL-4 (P = .0007) and matrix metalloproteinase 9 (MMP-9; P = .05) decreased significantly compared with baseline. Predesensitization to postdesensitization changes in MMP-9 and tissue inhibitors of metalloproteinases 1 were highly correlated (r = 0.79; P = .0003). Immediately after the desensitization, MMP-9 and tryptase were correlated (r = 0.82; P = .001), whereas IL-4 was inversely related with FMS-like tyrosine kinase 3 ligand (FLT3-L) (r = –0.79; P = .0008). There was a significant decrease in the average symptom score at 6 months.Conclusion: Consistent with previous reports, acute aspirin desensitization in patients with aspirin-exacerbated respiratory disease involves mast cell degranulation. In contrast, long-term treatment with aspirin involves suppression of IL-4 as well as downregulation of proinflammatory MMP-9 while Th1 marker FLT3-L increases.

Exosomes from human macrophages and dendritic cells contain enzymes for leukotriene biosynthesis and promote granulocyte migration - Corrected Proof

2010-08-23

Background: Leukotrienes (LTs) are potent proinflammatory lipid mediators with key roles in the pathogenesis of asthma and inflammation. Recently, nanovesicles (exosomes), released from macrophages and dendritic cells (DCs), have become increasingly appreciated as messengers in immunity.Objective: We investigated whether exosomes from human macrophages, DCs, and plasma contain enzymes for LT biosynthesis and studied potential roles for exosomes in transcellular LT metabolism and granulocyte chemotaxis.Methods: The presence of LT pathway enzymes and LT biosynthesis in exosomes and cells was analyzed by Western blot, immunoelectron microscopy, and enzyme activity assays. Surface marker expression was evaluated by flow cytometry, and granulocyte migration was assessed in a multiwell chemotaxis system.Results: Exosomes from macrophages and DCs contain functional enzymes for LT biosynthesis. After incubation of intact cells with the LT biosynthesis intermediate LTA4, LTB4 was the major product of macrophages, whereas DCs primarily formed LTC4. However, in exosomes from both cell types, LTC4 was the predominant LTA4 metabolite. Exosomal LTC4 formation (per milligram protein) exceeded that of cells. In macrophages and DCs, TGF-β1 upregulated LTA4 hydrolase along with increased LTB4 formation also in the exosomes. Moreover, TGF-β1 modified the expression of surface marker proteins on cells and exosomes and reduced the exosome yield from macrophages. On Ca2+-ionophore and arachidonic acid stimulation, exosomes produced chemotactic eicosanoids and induced granulocyte migration. Interestingly, active LTA4 hydrolase and LTC4 synthase were present also in exosomes from human plasma.Conclusion: Our findings indicate that exosomes can contribute to inflammation by participation in LT biosynthesis and granulocyte recruitment.

Levels of circulating IL-33 and eosinophil cationic protein in patients with hypereosinophilia or pulmonary eosinophilia - Corrected Proof

2010-08-18

To the Editor: IL-33, a member of the IL-1 family, induces eosinophilia in mice and is involved in eosinophilic inflammation, as well as production of IL-5, a major cytokine that can lead to eosinophilia. ST2, the IL-33 receptor, is expressed on eosinophils and TH2 cells and is necessary for induction of TH2 responses by IL-33. Previous studies reported increased levels of a soluble form IL-33 receptor (soluble form ST2, sST2) during asthma exacerbation and in a case of eosinophilic pneumonia. Currently, no clinical evidence exists that shows altered levels of circulating IL-33 in patients with hypereosinophilia.

Invariant natural killer T cells and asthma: Immunologic reality or methodological artifact? - Corrected Proof

2010-08-18

To the Editor: A role for invariant natural killer T (iNKT) cells in the cause of asthma has been shown in mice, but the evidence in human subjects is equivocal. Matangkasombut et al, in a recent issue of the Journal, provided further evidence of higher iNKT cell numbers (up to 64% of all CD3+ T cells) in bronchoalveolar lavage fluid of subjects with severe asthma compared with those seen in subjects with well-controlled asthma, who in turn had higher numbers than seen in nonasthmatic subjects. If true, this might have major implications for our understanding of asthma's pathology.

Added value of IgE detection to rApi m 1 and rVes v 5 in patients with Hymenoptera venom allergy - Corrected Proof

2010-08-18

To the Editor: Diagnosis of Hymenoptera venom allergy is based on a history of anaphylactic sting reactions, positive skin test responses, and/or detection of specific IgE to honeybee venom or Vespula species venom (VV). Positive results in skin and serologic tests with conventional venom extracts do not always reflect genuine sensitizations but are frequently caused by antibodies cross-reactive to homologous peptide sequences in protein allergens (eg, hyaluronidases and dipeptidyl peptidase IV homologs) or to cross-reactive carbohydrate determinants (CCDs), which are present in the majority of Hymenoptera venom allergens. Double positivity (DP) to both bee venom (BV) and VV in patients who have not identified the culprit insect necessitates additional laboratory tests (eg, IgE inhibition assays) to distinguish genuine double sensitization from cross-reactivity. These tests are expensive, time-consuming, difficult to interpret, and therefore rarely used in the clinical routine. Here we assessed whether the routine use of recombinant species-specific major allergens (SSMA) of honeybee venom (rApi m 1) and VV (rVes v 5), both devoid of CCD reactivity in a novel ImmunoCAP solid-phase assay (Phadia, Uppsala, Sweden), improves the diagnosis of Hymenoptera venom allergy and facilitates the discrimination between genuine double sensitization and cross-reactivity.

Acinar effect of inhaled steroids evidenced by exhaled nitric oxide - Corrected Proof

Alain Van Muylem, Yannick Kerckx, Alain Michils — 2010-08-16

Background: The effects of inhaled corticosteroids (ICSs) on distal lung inflammation, as assessed by alveolar nitric oxide concentration (CANO), are a matter of debate. Recently, a theoretic study suggested that acinar airway obstruction that is relieved by ICS treatment and associated with a decrease in fraction of exhaled nitric oxide (FeNO) concentration might, paradoxically, increase CANO. This increase could be a hallmark effect of ICSs at the acinar level.Objective: In the light of this new hypothesis, we studied changes in CANO and FeNO after administration of ICSs.Methods: CANO and FeNO were measured before and after ICS treatment of 38 steroid-naive patients with uncontrolled asthma who showed clinical improvement after ICS therapy.Results: The average FeNO decreased from 78.3 to 28.9 ppb (P < .001); CANO decreased from 7.7 to 4.3 ppb (P = .009). In 14 subjects (low-slope group), slope (= ΔCANO/ΔFeNO) values (Δ = post-ICS − pre-ICS value) were less than the 95% normal CI (average ΔFeNO = −32.7 ppb and average ΔCANO= +2.9 ppb). In this group, baseline CANO was abnormally low when FeNO was taken into account. In 11 subjects (the high-slope group), the slope was above the normal interval (average ΔFeNO = −42.5 ppb and average ΔCANO = −14.7 ppb).Conclusion: Opposite patterns (one that was predicted) can indicate peripheral actions of ICSs; this difference might account for conflicting data reported from studies using CANO to determine the peripheral action of ICSs. We show that a low CANO does not preclude distal inflammation.

The role of the T cell in asthma - Corrected Proof

Douglas S. Robinson — 2010-08-16

Since the initial detection of TH2 cytokines in asthmatic airways, our understanding of the complexity of T-cell subtypes and flexibility and of the potential role of airway structural cells in the immunopathology of asthma has increased. Cytokines derived from airway epithelium, including IL-25, IL-33, and thymic stromal lymphopoietin, might be important drivers of TH2-type inflammation in asthma. The balance between effector TH2 cells and suppressive regulatory T cells is skewed toward a proinflammatory TH2 response in atopy and asthma, and there is much interest in how to redress this equilibrium. Novel T-cell subsets, including TH17, TH9, and TH22, have been described, although their role in asthma remains unclear. Other T cells, including natural killer T cells, γδ T cells, and CD8 T cells, have also been implicated in asthma, although their importance remains to be confirmed. Therapeutic strategies aimed at TH2 cytokines are beginning to bear fruit in patients with asthma, although like many biologic agents, these might need specific targeting at subgroups of patients. Strategies directed specifically at the T cells are currently being evaluated, including novel forms of allergen immunotherapy. T cells remain an exciting potential target for new treatments in patients with asthma.

The prostaglandin D2 receptor CRTH2 is important for allergic skin inflammation after epicutaneous antigen challenge - Corrected Proof

2010-08-16

Background: Cutaneous prostaglandin (PG) D2 levels increase after scratching. Chemoattractant receptor–homologous molecule expressed on receptor on TH2 cells (CRTH2) mediates chemotaxis to PGD2 and is expressed on TH2 cells and eosinophils, which infiltrate skin lesions in patients with atopic dermatitis.Objective: We sought to examine the role of CRTH2 in a murine model of atopic dermatitis.Methods: CRTH2−/− mice and wild-type control animals were epicutaneously sensitized by means of repeated application of ovalbumin (OVA) to tape-stripped skin for 7 weeks and then challenged by means of OVA application to tape-stripped previously unsensitized skin for 1 week. Skin histology was assessed by means of hematoxylin and eosin staining and immunohistochemistry. Cytokine mRNA expression was examined by means of quantitative RT-PCR. Levels of PGD2, antibody, and cytokines were measured by means of ELISA.Results: PGD2 levels significantly increased in skin 24 hours after tape stripping, although not in skin subjected to repeated sensitization with OVA. Allergic skin inflammation developed normally at sites of chronic epicutaneous sensitization with OVA in CRTH2−/− mice but was severely impaired in previously unsensitized skin challenged with OVA, as evidenced by significantly decreased skin infiltration with eosinophils and CD4+ cells and impaired TH2 cytokine mRNA expression. Impaired skin inflammation at sites of acute OVA challenge in CRTH2−/− mice was not due to an impaired systemic response to epicutaneous sensitization because OVA-specific IgG1 and IgE antibody levels and OVA-driven splenocyte secretion of cytokines in these mice were comparable with those seen in wild-type control animals.Conclusions: CRTH2 promotes allergic skin inflammation in response to cutaneous exposure to antigen in previously sensitized mice.

Are rhinoviral proteinases responsible for mixed Th1 and Th2 immunity in chronic obstructive pulmonary disease? - Corrected Proof

John W. Upham, Antonia Pritchard — 2010-08-16

To the Editor: We read with interest the article by Dr Singh et al in the June issue of the Journal. Rhinoviruses are thought to play an important role in acute exacerbations of chronic obstructive pulmonary disease (COPD), and in this study, the authors have highlighted the role of immunity to rhinovirus proteinases, particularly proteinase 2A.

Reply - Corrected Proof

Farrah Kheradmand, David B. Corry — 2010-08-16

To the Editor: Professors Upham and Pritchard raise 2 very interesting and interrelated questions about our recent work published in the Journal. The first concern relates to the perceived lack of information in Fig 4 regarding the source of cells used in the coculture experiments in which we measured cytokine responses of T cells activated with monocyte-derived dendritic cells. We should note that the data presented in Fig 4 are based on coculture of the conditioned monocyte-derived dendritic cells (the source of which is described in Fig 3) and autologous T cells; thus, the source of T cells and monocyte-derived dendritic cells is the same patient for each coculture. To avoid redundant information, we did not give demographics of T cells because they are identical to the source of cells shown in Fig 3 and instead described monocyte-derived dendritic cell–induced T-cell activation in the Methods section. We hope that this information clarifies any confusion regarding the source of cells used in Fig 4. Regarding differences in the assays performed in Figs 3 and 4 between control subjects and subjects with chronic obstructive pulmonary disease, none were observed, which is why we combined results from the 2 groups.

The US Food and Drug Administration and long-acting β2-agonists: The importance of striking the right balance between risks versus benefits of therapy? - Corrected Proof

Robert F. Lemanske, William W. Busse — 2010-08-09

“When E. F. Hutton speaks, people listen” was the catchy and memorable slogan of this brokerage house decades ago and was based on the premise that E. F. Hutton knew what he was speaking about: “Well, my broker is E. F. Hutton, and he says….” The same can be said for the US Food and Drug Administration (FDA). The FDA must protect the public by initially and then prospectively evaluating and monitoring the safety of medications, thereby providing a trusted service to clinicians and patients alike. Because of their knowledge, experience, and access to information, clinicians and the public listen closely when the FDA speaks.

The diagnosis and management of anaphylaxis practice parameter: 2010 Update - Corrected Proof

2010-08-09

These parameters were developed by the Joint Task Force on Practice Parameters, representing the American Academy of Allergy, Asthma & Immunology (AAAAI); the American College of Allergy, Asthma & Immunology (ACAAI); and the Joint Council of Allergy, Asthma and Immunology.The AAAAI and the ACAAI have jointly accepted responsibility for establishing “The Diagnosis and Management of Anaphylaxis Practice Parameter: 2010 Update.” This is a complete and comprehensive document at the current time. The medical environment is a changing environment, and not all recommendations will be appropriate for all patients. Because this document incorporated the efforts of many participants, no single individual, including those who served on the Joint Task Force, is authorized to provide an official AAAAI or ACAAI interpretation of these practice parameters. Any request for information about or an interpretation of these practice parameters by the AAAAI or ACAAI should be directed to the Executive Offices of the AAAAI, the ACAAI, or the Joint Council of Allergy, Asthma and Immunology. These parameters are not designed for use by pharmaceutical companies in drug promotion.

Prescribing practices and asthma control with hydrofluoroalkane-beclomethasone and fluticasone: A real-world observational study - Corrected Proof

2010-08-09

Background: Long-term randomized trials comparing asthma outcomes between inhaled corticosteroids in real-world populations are lacking. As such, rigorously conducted observational studies to complement the findings of randomized trials are needed.Objective: We sought to compare asthma-related outcomes over 1 year as recorded in a large primary care database for patients aged 5 to 60 years receiving a first prescription (initiation population) or dose increase (step-up population) of hydrofluoroalkane (HFA)-beclomethasone or fluticasone.Methods: We used a retrospective matched cohort study in which patients were matched on baseline demographic and disease severity measures. Coprimary outcomes were asthma control (a composite measure comprising no unplanned visit or hospitalization for asthma, oral corticosteroids, or antibiotics for lower respiratory tract infection) and exacerbation rate.Results: More than 80% of patients in each population achieved asthma control; 10% and 16% of patients in the initiation and step-up populations, respectively, received add-on or combination therapy during the year. Fluticasone was prescribed at significantly higher doses than HFA-beclomethasone for both populations (P ≤ .001). In the initiation population (n = 1319 in each cohort) the adjusted odds ratio for achieving asthma control with HFA-beclomethasone was 1.30 (95% CI, 1.02-1.65) relative to fluticasone. In the step-up population (cohorts: n = 250) the adjusted odds ratio for achieving asthma control with HFA-beclomethasone was 1.22 (95% CI, 0.66-2.26). Exacerbation rates were similar between cohorts.Conclusions: In a real-world setting patients receiving HFA-beclomethasone had a similar or better chance of achieving asthma control at lower prescribed doses than with fluticasone.

Are free light chain immunoglobulins related to nasal local allergic rhinitis? - Corrected Proof

Carmen Rondón, Gabriela Canto, Javier Fernández, Miguel Blanca — 2010-08-09

To the Editor: The study by Powe et al is the first to demonstrate the localization of free light chains (FLCs) in patients with allergic and nonallergic rhinitis in both tissue and nasal secretions by using immunohistochemical and ELISA techniques and opens up new avenues for the study of the nasal local hypersensitivity response.

Reply - Corrected Proof

2010-08-09

To the Editor: We acknowledge the suggestion made by Rondón et al that some of the patients with nonallergic rhinitis investigated in our study might have “entopy” (local mucosal allergy), and for clarity, this will be defined. Entopy is the presence of local mucosal allergy in the absence of systemic markers of atopy, and although it is commonly interpreted that this is IgE mediated, our original report does not implicitly specify this. Accordingly, although patients with allergic rhinitis undoubtedly have a local nasal mucosal IgE production component that might or might not contribute to the expression of atopy, they do not satisfy the definition of entopy because they are atopic.

Asthma in the elderly: Diagnosis and management - Corrected Proof

Charles E. Reed — 2010-08-05

The National Asthma Education and Prevention Program's “Expert Panel Report 3: Guidelines for the Diagnosis and Management of Asthma” apply to all ages. This review discusses additional specific points for elderly patients. These patients are very heterogeneous. Their asthma can have begun at any time and can vary greatly in severity. It is frequently associated not only with any of the diseases that affect older persons but also with comorbid lung diseases. Many patients have irreversible airway obstruction, which is due to severe airway remodeling, chronic obstructive pulmonary disease, or bronchiectasis. Diagnosis should include chest radiography and computed tomographic scanning to diagnose other lung diseases if FEV1 remains low after treatment. Asthma pathogenesis includes not only IgE-mediated allergy but also innate immune inflammation from endotoxin and trypsin-like proteases, and therefore evaluation and control of environmental exposures is an important part of management. Pharmacologic treatment, too, is adjusted to achieve and maintain control and is basically the same for all ages, except that elderly patients have reduced response to bronchodilators and increased side effects from beta adrenergic agonists and glucocorticoids. Many elderly patients have difficulty inhaling aerosols, and therefore nebulizers might be a better delivery system. Oral medications have the benefit of greater ease of administration and greater efficacy on the peripheral airways. Leukotriene antagonists and low-dose theophylline are often helpful additives to aerosol glucocorticoids. Oral glucocorticoids might be indicated for severe asthma.

Dual-specificity phosphatase 1 as a pharmacogenetic modifier of inhaled steroid response among asthmatic patients - Corrected Proof

2010-08-05

Background: Inhaled corticosteroids (ICSs) are considered first-line treatment for persistent asthma, yet there is significant variability in treatment response. Dual-specificity phosphatase 1 (DUSP1) appears to mediate the anti-inflammatory action of corticosteroids.Objective: We sought to determine whether variants in the DUSP1 gene are associated with clinical response to ICS treatment.Methods: Study participants with asthma were drawn from the following multiethnic cohorts: the Genetics of Asthma in Latino Americans (GALA) study; the Study of African Americans, Asthma, Genes & Environments (SAGE); and the Study of Asthma Phenotypes and Pharmacogenomic Interactions by Race-ethnicity (SAPPHIRE). We screened GALA study participants for genetic variants that modified the relationship between ICS use and bronchodilator response. We then replicated our findings in SAGE and SAPPHIRE participants. In a group of SAPPHIRE participants treated with ICSs for 6 weeks, we examined whether a DUSP1 polymorphism was associated with changes in FEV1 and self-reported asthma control.Results: The DUSP1 polymorphisms rs881152 and rs34507926 localized to different haplotype blocks and appeared to significantly modify the relationship between ICS use and bronchodilator response among GALA study participants. This interaction was also seen for rs881152 among SAPPHIRE but not SAGE participants. Among the group of SAPPHIRE participants prospectively treated with ICSs for 6 weeks, rs881152 genotype was significantly associated with changes in self-reported asthma control but not FEV1.Conclusion: DUSP1 polymorphisms were associated with clinical response to ICS therapy and therefore might be useful in the future to identify asthmatic patients more likely to respond to this controller treatment.

Nasal application of rBet v 1 or non–IgE-reactive T-cell epitope–containing rBet v 1 fragments has different effects on systemic allergen-specific antibody responses - Corrected Proof

2010-08-05

To the Editor: Allergen-specific IgE antibodies are key elements in allergic inflammation and in the immunoregulation of allergic disease. Mucosal allergen contact induces allergic inflammation and also boosts systemic allergen-specific IgE production, which leads to increased sensitivity of mast cells and basophils, to the upregulation of Fcε receptor expression on allergic effector cells and antigen-presenting cells, and thus to increased T-cell activation. Increases in allergen-specific IgE levels are also associated with increased clinical sensitivity and aggravation of symptoms.

Interferon response factor 3 is essential for house dust mite–induced airway allergy - Corrected Proof

2010-08-05

Background: Pattern-recognition receptors (PRRs) are critically involved in the pathophysiology of airway allergy, yet most of the signaling pathways downstream of PRRs implicated in allergic airway sensitization remain unknown.Objective: We sought to study the effects of genetic depletion of interferon response factor (IRF) 3 and IRF7, important transcription factors downstream of various PRRs, in a murine model of house dust mite (HDM)–induced allergic asthma.Methods: We compared HDM-induced allergic immune responses in IRF3-deficient (IRF3−/−), IRF7−/−, and wild-type mice.Results: Parameters of airway allergy caused by HDM exposure were strongly attenuated in IRF3−/−, but not IRF7−/−, mice compared with those in wild-type mice. Indeed, in HDM-exposed IRF3−/− mice HDM-specific TH2 cell responses did not develop. This correlated with impaired maturation and migration of IRF3−/− lung dendritic cells (DCs) on HDM treatment. Furthermore, adoptive transfer of HDM-loaded DCs indicated that IRF3−/− DCs had an intrinsic defect rendering them unable to migrate and to prime HDM-specific TH2 responses. Intriguingly, we also show that DC function and allergic airway sensitization in response to HDM were independent of signaling by type I interferons, the main target genes of IRF3.Conclusion: Through its role in DC function, IRF3, mainly known as a central activator of antiviral immunity, is essential for the development of TH2-type responses to airway allergens.

MiR-155 is overexpressed in patients with atopic dermatitis and modulates T-cell proliferative responses by targeting cytotoxic T lymphocyte–associated antigen 4 - Corrected Proof

2010-08-05

Background: MicroRNAs (miRNAs) are short noncoding RNAs that suppress gene expression at the posttranscriptional level. Atopic dermatitis is a common chronic inflammatory skin disease characterized by the presence of activated T cells within the skin.Objective: We sought to explore the role of miRNAs in the pathogenesis of atopic dermatitis.Methods: Global miRNA expression in healthy and lesional skin of patients with atopic dermatitis was compared by using TaqMan MicroRNA Low Density Arrays. miR-155 expression in tissues and cells was quantified by means of quantitative real-time PCR. The cellular localization of miR-155 was analyzed by means of in situ hybridization. The regulation of cytotoxic T lymphocyte–associated antigen (CTLA-4) by miR-155 was investigated by using luciferase reporter assays and flow cytometry. CTLA-4 expression and functional assays were performed on TH cells overexpressing miR-155.Results: miR-155 was one of the highest-ranked upregulated miRNAs in patients with atopic dermatitis. In the skin miR-155 was predominantly expressed in infiltrating immune cells. miR-155 was upregulated during T-cell differentiation/activation and was markedly induced by T-cell activators in PBMCs in vitro and by superantigens and allergens in the skin in vivo. CTLA-4, an important negative regulator of T-cell activation, was identified as a direct target of miR-155. Overexpression of miR-155 in TH cells resulted in decreased CTLA-4 levels accompanied by an increased proliferative response.Conclusion: miR-155 is significantly overexpressed in patients with atopic dermatitis and might contribute to chronic skin inflammation by increasing the proliferative response of TH cells through the downregulation of CTLA-4.

Serum amyloid P attenuates M2 macrophage activation and protects against fungal spore–induced allergic airway disease - Corrected Proof

2010-08-05

Background: Aspergillus fumigatus conidia aggravate asthmatic responses. Lung macrophages normally kill fungal conidia, but the presence of type 2 cytokines during asthma contributes to the alternative (or M2) activation of these cells, which secrete proallergic factors and exhibit impaired innate immunity.Objective: Considering that pentraxins modulate macrophage function, we examined the effect of C-reactive protein (CRP) and serum amyloid P (SAP) in an experimental model of A fumigatus–induced allergic airway disease.Methods: The effects of SAP and CRP on M2 macrophage differentiation were examined in vitro, and the in vivo effects of these pentraxins were analyzed in the asthma model.Results: SAP inhibited the generation of M2 markers, such as arginase and the chitinase Ym-1, through an FcγR-dependent mechanism in cultured macrophages. This effect correlated with a decrease in signal transducer and activator of transcription 6 (STAT6) phosphorylation in SAP-treated M2 macrophages. In vivo treatment with SAP significantly decreased methacholine-induced bronchial resistance, mucus cell metaplasia, the number of “found in inflammatory zone 1” (FIZZ1)–positive cells in the lungs, and collagen deposition compared with the control group. CRP had a modest effect on M2 differentiation, and in vivo treatment with CRP had a minor effect or exacerbated A fumigatus–induced lung disease. Finally, the adoptive transfer of SAP-pretreated M2 macrophages into allergic mice significantly attenuated disease when compared with nontransferred or M2-transferred control groups.Conclusions: These findings demonstrate that SAP is a potent inhibitor of M2 macrophage differentiation and represents a novel therapy in A fumigatus–induced allergic disease.

Exposure of rye (Secale cereale) cultivars to elevated ozone levels increases the allergen content in pollen - Corrected Proof

2010-08-05

To the Editor: The increase of air pollution because of climate change and global warming represents a major challenge for humankind in this century. Changes in climate and air pollution have also been suggested to be potential factors behind the increasing prevalence of allergic diseases. In this context, it has been shown that particular matter (eg, diesel exhaust particles) can act as carriers and adjuvant for allergens, thereby enhancing the allergic immune response and promoting airway inflammation. Furthermore, it has been demonstrated that rising concentrations of CO2 increase the production of ragweed pollen and their major allergen contents. Environmental effects caused by the air pollutant ozone (O3) may occur at 2 levels. On the one hand, depletion of ozone in the stratosphere results in increased UV exposure. On the other hand, new low-level ozone is formed by the photochemical dissociation of nitrogen dioxide in the troposphere and has been reported to have adverse effects on human health. The latter ozone, which is a major component of photochemical smog, is particularly produced during the summer months in urban settings. Evidence has been provided that it may increase the content of a particular allergen (ie, group 5 allergen) in rye grass pollen.

Efficacy of sublingual immunotherapy with grass allergens for seasonal allergic rhinitis: A systematic review and meta-analysis - Corrected Proof

2010-08-05

Background: The benefit of sublingual immunotherapy (SLIT) with grass allergens for seasonal allergic rhinitis has been extensively studied, but data on efficacy are still equivocal.Objective: To assess the effectiveness of SLIT with grass allergens in the reduction of symptoms and medication in patients with seasonal allergic rhinitis to grass pollen.Methods: Computerized bibliographic searches of MEDLINE (1995-2010) were supplemented by hand searches of reference lists. Studies were included if they were double-blind randomized controlled trials (RCTs) comparing SLIT to placebo and if they included patients with history of allergy to grass pollen treated with natural grass pollen extracts. Nineteen RCTs with 2971 patients were analyzed. The outcomes assessed were symptom and medication scores.Results: Using a random-effects model, SLIT with grass allergens significantly reduces both symptoms (standardized mean difference, –0.32; 95% CI, –0.44 to –0.21) and medication use (standardized mean difference, –0.33; 95% CI, –0.50 to –0.16) compared with placebo. The treatment is more efficacious in adults than in children. Prolonging duration of preseasonal treatment for more than 12 weeks improves the treatment efficacy.Conclusion: This meta-analysis found that SLIT with grass allergens is effective in patients with seasonal allergic rhinitis compared with placebo. The benefit is clinically modest, and criteria are needed to identify patients most likely to benefit from SLIT.

Successful use of omalizumab for prevention of fire ant anaphylaxis - Corrected Proof

Hana M. Tartibi, Amee R. Majmundar, David A. Khan — 2010-08-05

To the Editor: Imported fire ant (IFA) anaphylaxis is a common cause of insect sting anaphylaxis in the United States, accounting for the majority of insect hypersensitivity in the southeastern United States (including Texas). Standard and rush immunotherapy with IFA whole-body extract (WBE) have been used successfully for the prevention of subsequent anaphylaxis in patients with allergy. The current standard of care for individuals with systemic reactions to IFA stings is WBE immunotherapy at a maintenance dose of 0.5 mL of a 1:100 wt/vol with higher dosing considered for the rare treatment failures. We report a case of a patient who failed to respond to higher than conventional doses of IFA WBE immunotherapy who was treated with omalizumab with protection against subsequent IFA sting reactions.

Ciliary dysfunction and ultrastructural abnormalities are features of severe asthma - Corrected Proof

2010-08-05

Background: Epithelial dysfunction has been implicated in asthma pathophysiology, but no studies have directly assessed ciliary function in asthma.Objective: To study the ciliary function and epithelial ultrastructure of patients with asthma and healthy controls.Methods: We studied ciliary beat frequency and beat pattern by using digital high-speed video imaging and ultrastructure by transmission electron microscopy of bronchial epithelial strips from 7 subjects with mild, 7 with moderate, and 19 with severe asthma and 9 healthy controls.Results: The median (interquartile range) ciliary beat frequency was decreased in moderate (6.5 [4.4-8.5] Hz) and severe asthma (6.7 [6.1-7.6] Hz) compared with controls (10.5 [9.7-11.8] Hz; P < .01). Dyskinesia and immotility indices were higher in severe asthma (65% [43%-75%]; 6.3% [1%-9.5%], respectively) compared with controls (4% [0%-6.7%; 0%, respectively; P < .01). These abnormalities were related to disease severity (ciliary beat frequency, rs = –0.68; dyskinesia index, rs = 0.86; immotility index, rs = 0.65; P < .0001). The ultrastructure of the epithelium was abnormal in severe asthma with a reduction in ciliated cells, an increase in dead cells, and ciliary disorientation compared with all other groups (P < .05). Compared with patients with mild asthma and healthy controls, patients with severe asthma showed increased ciliary depletion, microtubular defects, mitochondrial damage, and cytoplasmic blebbing (P < .01). All of these changes were related to disease severity.Conclusion: Ciliary dysfunction and ultrastructural abnormalities are closely related to asthma severity. Ciliary dysfunction is a feature of moderate to severe asthma, and profound ultrastructural abnormalities are restricted to severe disease. Whether these changes contribute to the development of severe asthma phenotype remains to be determined.

Effective treatment of therapy-resistant chronic spontaneous urticaria with omalizumab - Corrected Proof

2010-08-05

To the Editor: Chronic urticaria is a severe skin disease characterized by itchy wheals and/or angioedema with an estimated lifetime prevalence of 3% to 5% in the general population. The current European Academy of Allergy and Clinical Immunology (EAACI)/Global Allergy and Asthma European Network (GA2LEN)/European Dermatology Forum (EDF)/World Allergy Organization (WAO) treatment guidelines recommend nonsedating H1-antihistamines as first-line treatment, increasing their dosage as second-line treatment, and switching to another such antihistamine or adding a leukotriene antagonist as the third-line treatment. Thereafter, among several other fourth-line options including cyclosporine A, the guidelines suggest the possibility of using omalizumab, a humanized mAb that blocks the IgE receptor.

Transplantation of hematopoietic stem cells and long-term survival for primary immunodeficiencies in Europe: Entering a new century, do we do better? - Corrected Proof

2010-08-05

Background: Hematopoietic stem cell transplantation remains the only treatment for most patients with severe combined immunodeficiencies (SCIDs) or other primary immunodeficiencies (non-SCID PIDs).Objective: To analyze the long-term outcome of patients with SCID and non-SCID PID from European centers treated between 1968 and 2005.Methods: The product-limit method estimated cumulative survival; the log-rank test compared survival between groups. A Cox proportional-hazard model evaluated the impact of independent predictors on patient survival.Results: In patients with SCID, survival with genoidentical donors (n = 25) from 2000 to 2005 was 90%. Survival using a mismatched relative (n = 96) has improved (66%), similar to that using an unrelated donor (n = 46; 69%; P = .005). Transplantation after year 1995, a younger age, B+ phenotype, genoidentical and phenoidentical donors, absence of respiratory impairment, or viral infection before transplantation were associated with better prognosis on multivariate analysis. For non-SCID PID, in contrast with patients with SCID, we confirm that, in the 2000 to 2005 period, using an unrelated donor (n = 124) gave a 3-year survival rate similar to a genoidentical donor (n = 73), 79% for both. Survival was 76% in phenoidentical transplants (n = 23) and worse in mismatched related donor transplants (n = 47; 46%; P = .016).Conclusion: This is the largest cohort study of such patients with the longest follow-up. Specific issues arise for different patient groups. Patients with B-SCID have worse survival than other patients with SCID, despite improvements in each group. For non-SCID PID, survival is worse than SCID, although more conditions are now treated. Individual disease categories now need to be analyzed so that disease-specific prognosis may be better understood and the best treatments planned.

In utero smoke exposure and impaired response to inhaled corticosteroids in children with asthma - Corrected Proof

2010-08-05

Background: Few studies have examined the effects of in utero smoke exposure (IUS) on lung function in children with asthma, and there are no published data on the impact of IUS on treatment outcomes in children with asthma.Objectives: To explore whether IUS exposure is associated with increased airway responsiveness among children with asthma and whether IUS modifies the response to treatment with inhaled corticosteroids (ICSs).Methods: To assess the impact of parent-reported IUS exposure on airway responsiveness in childhood asthma, we performed a repeated-measures analysis of methacholine PC20 data from the Childhood Asthma Management Program, a 4-year, multicenter, randomized, double-masked, placebo-controlled trial of 1041 children age 5 to 12 years comparing the long-term efficacy of ICS with mast cell stabilizing agents or placebo.Results: Although improvement was seen in both groups, children with asthma and IUS exposure had on average 26% less of an improvement in airway responsiveness over time compared with unexposed children (P = .01). Moreover, while children who were not exposed to IUS who received budesonide experienced substantial improvement in PC20 compared with untreated children (1.25-fold increase; 95% CI, 1.03-1.50; P = .02), the beneficial effects of budesonide were attenuated among children with a history of IUS exposure (1.04-fold increase, 95% CI, 0.65-1.68; P = .88).Conclusion: In utero smoke exposure reduces age-related improvements in airway responsiveness among children with asthma. Moreover, IUS appears to blunt the beneficial effects of ICS use on airways responsiveness. These results emphasize the importance of preventing this exposure through smoking cessation counseling efforts with pregnant women.

Genetic influence on the age at onset of asthma: A twin study - Corrected Proof

Simon Francis Thomsen, David Lorenzo Duffy, Kirsten Ohm Kyvik, Vibeke Backer — 2010-08-05

Background: Although the genetics of asthma susceptibility have been frequently explored, little is known about genetic factors that influence the age at onset of asthma.Objective: To study the variation in the age at onset of asthma attributable to genetic and environmental factors.Methods: Data on the age at onset and predictors of asthma were collected in 2002 via a multidisciplinary questionnaire study of 34,782 Danish twins 20 to 71 years of age. Survival analytic methods were applied to partition variation in the age at onset of asthma into genetic and environmental components.Results: Sex, hay fever, atopic dermatitis, smoking, and exposure to passive smoking in childhood were significant risk factors, whereas BCG vaccination was protective for asthma. The risk of asthma in the co-twin of an affected twin was higher in monozygotic than in dizygotic twins (hazard ratio, 2.59; 95% CI, 1.83-3.68; P < .001). The risk of asthma in the co-twin decreased with increasing age at onset of asthma in the index twin (hazard ratio per ten years, 0.86; 95% CI, 0.76-0.98; P = .019). The effect was attenuated in dizygotic twins relative to monozygotic twins (P = .005). Genetic factors explained 34% of the variation in the age at onset of asthma, and environmental factors accounted for 66%.Conclusion: Host-related differences in genetic make-up cause different individuals to develop asthma at different ages. Better understanding of the causes for variation in the age at onset of disease may ultimately lead the way to targeted treatments.

Resurrection men and the FEF25-75 - Corrected Proof

E.R. McFadden — 2010-08-05

The movement of medicine toward a scientific foundation in the late 18th and early 19th centuries had the unexpected effect of creating a cottage industry called “body snatching.” Corpses were disinterred from graveyards, sold to medical schools and private institutions, and recycled for anatomic dissection. This process was dubbed “resurrectionism,” and the practitioners were called “resurrection men” because they caused the dead to rise again. In a sense, Simon et al in the current issue of the Journal are also “resurrection men” who are giving a new purpose to a lung function test long considered dead and buried.

Forced expiratory flow between 25% and 75% of vital capacity and FEV1/forced vital capacity ratio in relation to clinical and physiological parameters in asthmatic children with normal FEV1 values - Corrected Proof

2010-07-20

Background: The assumption that the assessment of forced expiratory flow between 25% and 75% of vital capacity (FEF25-75) does not provide additional information in asthmatic children with normal FEV1 percent predicted has not been adequately tested.Objective: We sought to determine whether the measurement of FEF25-75 percent predicted offers advantages over FEV1 percent predicted and FEV1/forced vital capacity (FVC) percent predicted for the evaluation of childhood asthma.Methods: This is a secondary analysis of data from the Pediatric Asthma Controller Trial and the Characterizing the Response to a Leukotriene Receptor Antagonist and Inhaled Corticosteroid trials. Pearson correlation coefficients, Pearson partial correlation coefficients, canonical correlations, and receiver operating characteristic (ROC) curves were constructed.Results: Among 437 children with normal FEV1 percent predicted, FEF25-75 percent predicted, and FEV1/FVC percent predicted were (1) positively correlated with log2 methacholine PC20, (2) positively correlated with morning and evening peak expiratory flow percent predicted, and (3) negatively correlated with log10 fraction of exhaled nitric oxide and bronchodilator responsiveness. Pearson partial correlations and canonical correlations indicated that FEF25-75 percent predicted was better correlated with bronchodilator responsiveness and log2 methacholine PC20 than were FEV1 percent predicted or FEV1/FVC percent predicted. In the ROC curve analysis, FEF25-75 at 65% of predicted value had a 90% sensitivity and a 67% specificity for detecting a 20% increase in FEV1 after albuterol inhalation.Conclusion: FEF25-75 percent predicted was well correlated with bronchodilator responsiveness in asthmatic children with normal FEV1. FEF25-75 percent predicted should be evaluated in clinical studies of asthma in children and might be of use in predicting the presence of clinically relevant reversible airflow obstruction.

Stable hematopoietic cell engraftment after low-intensity nonmyeloablative conditioning in patients with immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome - Corrected Proof

2010-07-20

Background: Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome is characterized by severe systemic autoimmunity caused by mutations in the forkhead box protein 3 (FOXP3) gene. Hematopoietic cell transplantation is currently the only viable option for long-term survival, but patients are frequently very ill and may not tolerate traditional myeloablative conditioning regimens.Objective: Here we present the outcome of hematopoietic cell transplantation using a low-intensity, nonmyeloablative conditioning regimen in 2 patients with IPEX syndrome and significant pretransplant risk factors.Methods: Two high-risk patients with IPEX syndrome received HLA-matched related bone marrow or unrelated peripheral blood stem cell grafts following conditioning with 90 mg/m2 fludarabine and 4 Gy total body irradiation. Postgrafting immunosuppression consisted of mycophenolate mofetil and cyclosporine. Immune reconstitution and immune function was evaluated by measurement of donor chimerism, regulatory T-cell numbers, absolute lymphocyte subsets, and T-cell proliferation assays.Results: Both patients experienced minimal conditioning toxicity and successfully engrafted after hematopoietic cell transplantation. With a follow-up of 4 and 1 years, respectively, patients 1 and 2 have full immune function and normal FOXP3 protein expression.Conclusion: A low-intensity, nonmyeloablative conditioning regimen can establish stable engraftment and correct the life-threatening immune deficiency and enteropathy of IPEX syndrome despite the presence of comorbidities that preclude conventional hematopoietic cell transplantation.

Hypoallergenic derivatives of the major birch pollen allergen Bet v 1 obtained by rational sequence reassembly - Corrected Proof

2010-07-20

Background: At least 100 million patients suffer from birch pollen allergy.Objective: Rational design of recombinant derivatives of the major birch pollen allergen, Bet v 1, characterized by reduced IgE reactivity, preservation of sequences relevant for the induction of allergen-specific blocking IgG, and maintenance of T-cell epitopes for immunotherapy of birch pollen allergy.Methods: Three recombinant mosaic proteins derived from Bet v 1 were generated by reassembly of codon-optimized genes coding for Bet v 1 fragments containing the elements for the induction of allergen-specific blocking IgG antibodies and the major T-cell epitopes. The proteins were expressed in Escherichia coli as recombinant mosaic molecules and compared with the Bet v 1 wild-type protein by chemical and structural methods, regarding IgE-binding and IgG-binding capacity, in basophil activation assays and tested for the in vivo induction of IgG responses.Results: Three recombinant Bet v 1 (rBet v 1) mosaic proteins with strongly reduced IgE reactivity and allergenic activity were expressed and purified. Immunization with the recombinant hypoallergens induced IgG antibodies that inhibited IgE reactivity of patients with allergy to Bet v 1 comparable to those induced with the rBet v 1 wild-type allergen.Conclusion: We report the generation and preclinical characterization of 3 hypoallergenic rBet v 1 derivatives with suitable properties for immunotherapy of birch pollen allergy.

Application of genetic/genomic approaches to allergic disorders - Corrected Proof

Tesfaye M. Baye, Lisa J. Martin, Gurjit K. Khurana Hershey — 2010-07-20

Completion of the human genome project and rapid progress in genetics and bioinformatics have enabled the development of large public databases, which include genetic and genomic data linked to clinical health data. With the massive amount of information available, clinicians and researchers have the unique opportunity to complement and integrate their daily practice with the existing resources to clarify the underlying cause of complex phenotypes, such as allergic diseases. The genome itself is now often used as a starting point for many studies, and multiple innovative approaches have emerged applying genetic/genomic strategies to key questions in the field of allergy and immunology. There have been several successes that have uncovered new insights into the biologic underpinnings of allergic disorders. Herein we will provide an in-depth review of genomic approaches to identifying genes and biologic networks involved in allergic diseases. We will discuss genetic and phenotypic variation, statistical approaches for gene discovery, public databases, functional genomics, clinical implications, and the challenges that remain.

Impaired TH2 response in patients with Vav1-deficient common variable immunodeficiency with T-cell defects - Corrected Proof

2010-07-20

To the Editor: Common variable immunodeficiency (CVID) is a primary immune disorder including a heterogeneous group of diseases with the unifying feature of hypogammaglobulinemia. Defects not only in B cells, which are directly responsible for antibody production, but also in other immune cells involved in the generation of an effective humoral response, including antigen-presenting cells and TH cells, represent the molecular basis of CVID.

The T-cell response to Amb a 1 is characterized by 3 dominant epitopes and multiple MHC restriction elements - Corrected Proof

2010-07-20

To the Editor: Common ragweed (Ambrosia artemisiifolia) represents the most prominent seasonal allergen in North America and Mexico. The plant has also been introduced into parts of Europe and Asia, and the prevalence of sensitization to ragweed pollen has been increasing steadily. Ragweed pollen contains several allergens, of which Amb a 1, a 38-kd protein belonging to the pectate-lyase protein family, is the most important. More than 90% of ragweed-sensitized subjects react to Amb a 1 in skin prick tests, and at least 90% of the allergenic activity in ragweed pollen can be attributed to this protein. The dominance of 1 major allergen makes ragweed pollen allergy especially suitable for new molecule-based immunotherapeutic strategies. Pollinosis to ragweed can be cured by specific immunotherapy (SIT) using vaccines that contain solely the major allergen or hypoallergenic variants thereof. In fact, conjugates containing purified natural Amb a 1 showing reduced IgE binding have been used successfully in clinical trials, indicating that the single major ragweed allergen can replace the pollen extract in SIT.

Lymphoid neogenesis in the giant papillae of patients with chronic allergic conjunctivitis - Corrected Proof

2010-07-20

To the Editor: Lymphoid neogenesis (tertiary lymphoid organ [TLO]) resembles a secondary lymphoid organ (eg, the lymph node) and is observed in patients with chronic inflammatory diseases. TLOs play roles in immune responses against persistent antigens; however, they can also induce severe tissue damage. It has also been reported that the germinal centers and follicular dendritic cell (FDC) networks in TLOs relate to class-switch recombination. In this study we examined the lymphoid neogenesis and lymphatic vessel formation in patients with atopic keratoconjunctivitis (AKC) and vernal keratoconjunctivitis (VKC), severe chronic forms of allergic conjunctivitis. AKC and VKC are often accompanied by giant papillae formation in tarsal conjunctivae and/or marked inflammatory cell infiltration in the limbal region, with prominent TH2 cytokine profiles. We found various degrees of lymphoid neogenesis in the giant papillae with B-cell clusters, FDCs, and a marginal T-cell zone essential for TLO formation.

Raman profiles of the stratum corneum define 3 filaggrin genotype–determined atopic dermatitis endophenotypes - Corrected Proof

2010-07-12

Background: Filaggrin (FLG) has a central role in the pathogenesis of atopic dermatitis (AD). FLG is a complex repetitive gene; highly population-specific mutations and multiple rare mutations make routine genotyping complex. Furthermore, the mechanistic pathways through which mutations in FLG predispose to AD are unclear.Objectives: We sought to determine whether specific Raman microspectroscopic natural moisturizing factor (NMF) signatures of the stratum corneum could be used as markers of FLG genotype in patients with moderate-to-severe AD.Methods: The composition and function of the stratum corneum in 132 well-characterized patients with moderate-to-severe AD were assessed by means of confocal Raman microspectroscopy and measurement of transepidermal water loss (TEWL). These parameters were compared with FLG genotype and clinical assessment.Results: Three subpopulations closely corresponding with FLG genotype were identified by using Raman spectroscopy. The Raman signature of NMF discriminated between FLG-associated AD and non–FLG-associated AD (area under the curve, 0.94; 95% CI, 0.91-0.99). In addition, within the subset of FLG-associated AD, NMF distinguished between patients with 1 versus 2 mutations. Five novel FLG mutations were found on rescreening outlying patients with Raman signatures suggestive of undetected mutations (R3418X, G1138X, S1040X, 10085delC, and L2933X). TEWL did not associate with FLG genotype subgroups.Conclusions: Raman spectroscopy permits rapid and highly accurate stratification of FLG-associated AD. FLG mutations do not influence TEWL within established moderate-to-severe AD.

Arabinogalactan isolated from cowshed dust extract protects mice from allergic airway inflammation and sensitization - Corrected Proof

2010-07-12

Background: Extract from cowshed dust (CDE) is a source of immunomodulating substances. We have previously shown that such substances protect from experimental allergic disorders in a mouse model of asthma.Objective: The objective of this study was to identify immunomodulatory molecules in extracts of dust from an allergy protective farming environment.Methods: Polysaccharides were isolated from CDE and plants by chromatography and precipitation with specific reagents. Polysaccharides were then characterized by nuclear magnetic resonance spectroscopy. Subsequently, the allergy-protective potential of isolated polysaccharides was tested in a mouse model of asthma.Results: The authors demonstrate that plant arabinogalactans are contained in CDE in high concentrations. The source of this arabinogalactan is fodder, in particular a prevalent grass species known as Alopecurus pratensis. Treatment of murine dendritic cells with grass arabinogalactan resulted in autocrine IL-10 production. Interestingly, these dendritic cells were not able to induce an allergic immune response. Furthermore, intranasal application of grass arabinogalactan protected mice from developing atopic sensitization, allergic airway inflammation and airway hyperreactivity in a mouse model of allergic asthma. This allergy-protective effect is specific for grass arabinogalactan because control experiments with arabinogalactan from gum arabic and larch revealed that these molecules do not show allergy-protective properties. This is likely because of structural differences because we were able to show by nuclear magnetic resonance spectroscopy that although they are predominantly composed of arabinose and galactose, the molecules differ in structure.Conclusions: The authors conclude that grass arabinogalactans are important immunomodulatory substances that contribute to the protection from allergic airway inflammation, airway hyperresponsiveness, and atopic sensitization in a mouse model of asthma.

Steroid-sparing effects with allergen-specific immunotherapy in children with asthma: A randomized controlled trial - Corrected Proof

Stefan Zielen, Peter Kardos, Enzo Madonini — 2010-07-12

Background: Asthma control is now recognized as the main goal of asthma therapy. Guidelines recommend finding the lowest effective dose of inhaled corticosteroids in children with persistent asthma.Objective: The aim of this study was to investigate the efficacy of an allergen-specific immunotherapy with a high-dose hypoallergenic mite preparation (allergoid) as steroid-sparing agent in children with allergic asthma.Methods: Sixty-five children with asthma (Global Initiative for Asthma treatment levels II and III; 6-17 years old), after reaching asthma control with inhaled steroids during a 5-month baseline period, were randomized for subcutaneous mite allergoid immunotherapy (SCIT) plus fluticasone propionate (FP) or FP therapy alone for 2 years. During 2 subsequent 5-month winter periods, steroid therapy was adjusted according to predefined dose steps, determining and comparing the changes in FP dosages and the lowest FP dose sufficient to maintain asthma control. Immunologic and functional investigations were also carried out.Results: Children treated with house dust mite SCIT plus FP were able to significantly reduce the FP dose by more steps (P < .05), compared with the control group on FP alone. The mean daily dose in the immunotherapy group decreased from 330.3 μg in the baseline period to 151.5 μg after 2 treatment years, whereas in the control group the dose decreased from 290.6 μg to 206.3 μg. Compared with the control group, significant improvement was also observed in morning peak expiratory flow (P = .0315). Significantly increased levels of specific IgG1 (P = .0001) and IgG4 (P < .0001) were also observed.Conclusion: Adding a mite allergoid SCIT to pharmacologic treatment is an effective and safe strategy to reduce corticosteroid doses while maintaining disease control in children with mite-induced allergic asthma.

Phl p 5 resorption in human oral mucosa leads to dose-dependent and time-dependent allergen binding by oral mucosal Langerhans cells, attenuates their maturation, and enhances their migratory and TGF-β1 and IL-10–producing properties - Corrected Proof

2010-06-28

Background: Sublingual immunotherapy (SLIT) is safe and effective as treatment of allergic rhinitis and mild asthma. Oral mucosal Langerhans cells (oLCs) play a central role. However, little is known about allergen binding by oLCs during mucosal allergen resorption and its impact on oLC functions.Objective: Binding of Phl p 5 to oLCs was studied in a standardized ex vivo model to investigate mechanisms important for SLIT.Methods: Human oral mucosal biopsies were incubated with the grass pollen allergen Phl p 5. Migration, binding of Phl p 5, phenotype and cytokine production, and T-cell priming of Phl p 5–binding oLCs were analyzed.Results: Significant uptake required more than 5 minutes, and dose-dependent binding of Phl p 5 to oLCs was saturated at 100 μg/mL Phl p 5. Furthermore, Phl p 5 significantly increased the migratory capacity of oLCs but attenuated their maturation and strongly promoted the release of TGF-β1 and IL-10 by oLCs themselves as well as by cocultured T cells.Conclusion: Oral mucosal Langerhans cells bind Phlp5 in a dose-dependent and time-dependent manner, leading to an increased production of tolerogenic cytokines and an enhanced migratory capacity but decelerated maturation of oLCs.

Symptom-pattern phenotype and pulmonary function in preschool wheezers - Corrected Proof

2010-06-25

Background: Pulmonary function in preschool wheezing phenotypes based on wheeze onset and duration and atopic status has been extensively described but has not been studied in symptom-pattern phenotypes of episodic (viral) and multiple-trigger wheeze.Objective: We investigated whether multiple-trigger wheezers were more likely to have abnormal pulmonary function and increased fraction of exhaled nitric oxide (FeNO) than episodic (viral) wheezers and whether multiple-breath wash-out was more sensitive at detecting abnormal pulmonary function than specific airways resistance (sRaw) in preschool wheezers.Methods: FeNO, multiple-breath wash-out indices (lung clearance index [LCI] and conductive airways ventilation inhomogeneity [Scond]) and sRaw were measured in healthy children and those with recurrent wheeze aged 4 to 6 years. Subgroup analysis was performed according to current symptom-pattern (multiple-trigger vs episodic [viral]), atopic status (atopic vs nonatopic), and wheeze status (currently symptomatic vs asymptomatic).Results: Seventy-two control subjects and 62 wheezers were tested. Multiple-trigger wheezers were associated with an average increase of 11% (95% CI, 7% to 18%; P < .001) in LCI, 211% (95% CI, 70% to 470%; P < .001) in Scond, and 15% (95% CI, 3% to 28%; P = .01) in sRaw compared with episodic (viral) wheezers. Pulmonary function in episodic (viral) wheezers did not differ significantly from control subjects. The presence of current atopy or wheeze was associated with higher FeNO (P = .05) but did not influence pulmonary function significantly. On average, LCI was abnormal in 39% (95% CI, 32% to 45%), Scond was abnormal in 68% (95% CI, 61% to 74%), and sRaw was abnormal in 26% (95% CI, 16% to 35%) of multiple-trigger wheezers.Conclusions: Multiple-trigger wheeze is associated with pulmonary function abnormalities independent of atopic and current wheeze status. Scond is the most sensitive indicator of abnormal pulmonary function in preschool wheezers.

Safety of small-particle inhaled corticosteroids in infants - Corrected Proof

H. William Kelly — 2010-06-25

To the Editor: Amirav et al provided an excellent review of the delivery of inhaled corticosteroids (ICSs) in infants and young children. They provided some compelling arguments for considering the use of devices that generate small particles, such as hydrofluoroalkane (HFA)–propelled beclomethasone dipropionate (BDP) and ciclesonide metered-dose inhalers (MDIs) with a spacer and appropriate facemasks. However, the potential for risks from this increased delivery of ICSs to infants was given short shrift, primarily because there are few data on which to draw. It would be a mistake not to take this into greater consideration because studies of larger-particle MDIs and nebulized ICSs have clearly demonstrated efficacy and safety in children 1 to 4 years of age. The authors cited 2 studies on growth in older children as suggesting that small-particle MDIs were safe in this group. However, neither of these studies demonstrate improved safety.