Advances and Highlights in Allergen Immunotherapy: On the way to sustained clinical and immunologic tolerance J. Allergy Clin. Immunol. (IF 13.081) Pub Date : 2017-09-20 Margot Berings, Cagatay Karaaslan, Can Altunbulakli, Philippe Gevaert, Mübeccel Akdis, Claus Bachert, Cezmi A. Akdis
Allergen immunotherapy (AIT) is an effective treatment strategy for allergic diseases and has been used for more than 100 years. In recent years, however, the expectations on concepts, conduct, statistical evaluation and reporting have been significantly developed. Products have undergone dose-response and confirmative studies in adults and children to provide evidence for the optimal dosage, safety and efficacy of AIT vaccines using subcutaneous and sublingual delivery pathways in large patient cohorts, ensuring solid conclusions to be drawn from them for the advantage of patients and societies alike. Those standards should be followed today, and products answering to them should be preferred over others lacking optimization and proof of efficacy and safety. Molecular and cellular mechanisms of AIT include early mast cell and basophil desensitization effects, regulation of T and B cell responses, regulation of IgE and IgG4 production and inhibition of responses from eosinophils, mast cells and basophils in the affected tissues. There were many developments to improve vaccination strategies, demonstration of new molecules involved in molecular mechanisms and demonstration of new biomarkers for AIT during the last few years. The combination of probiotics, vitamins and biologicals with AIT are highlighting current advances. Development of allergoids, recombinant and hypoallergenic vaccines to skew the immune response from IgE to IgG4 and regulation of dendritic cell, mast cell, basophil, innate lymphoid cell, T and B cell responses to allergens are also discussed in detail.
High prevalence of severe asthma in a large random population study J. Allergy Clin. Immunol. (IF 13.081) Pub Date : 2017-09-20 Roxana Mincheva, Linda Ekerljung, Apostolos Bossios, Bo Lundbäck, Jan Lötvall
Th1 Signatures Are Present in the Lower Airways of Children with Severe Asthma, Regardless of Allergic Status J. Allergy Clin. Immunol. (IF 13.081) Pub Date : 2017-09-20 Julia A. Wisniewski, Lyndsey M. Muehling, Jacob D. Eccles, Brian J. Capaldo, Rachana Agrawal, Debbie-Ann Shirley, James T. Patrie, Lisa J. Workman, Alexander J. Schuyler, Monica G. Lawrence, W. Gerald Teague, Judith A. Woodfolk
Human CD40L-expressing type 3 innate lymphoid cells induce IL-10-producing immature transitional regulatory B cells J. Allergy Clin. Immunol. (IF 13.081) Pub Date : 2017-09-20 Zsolt István Komlósi, Nóra Kovács, Willem van de Veen, Anna Kirsch, Heinz Benedikt Fahrner, Marcin Wawrzyniak, Ana Rebane, Barbara Stanic, Oscar Palomares, Beate Rückert, Günter Menz, Mübeccel Akdis, György Losonczy, Cezmi A. Akdis
TLR7/8 agonists stimulate plasmacytoid dendritic cells to initiate a Th17-deviated acute contact dermatitis in humans J. Allergy Clin. Immunol. (IF 13.081) Pub Date : 2017-09-19 Natalie Garzorz-Stark, Felix Lauffer, Linda Krause, Jenny Thomas, Anne Atenhan, Regina Franz, Sophie Roenneberg, Alexander Boehner, Manja Jargosch, Richa Batra, Nikola S. Mueller, Stefan Haak, Christina Groß, Olaf Groß, Claudia Traidl-Hoffmann, Fabian J. Theis, Carsten B. Schmidt-Weber, Tilo Biedermann, Stefanie Eyerich, Kilian Eyerich
Background A standardized human model to study early pathogenic events in psoriasis is missing. Activation of Toll-like receptor 7/8 by topical application of imiquimod is the most commonly used mouse model of psoriasis. Objective To investigate the potential of a human imiquimod patch test model to resemble human psoriasis. Methods Imiquimod (Aldara® 5% cream) was applied twice a week onto the back of volunteers (n=18) and the development of skin lesions was monitored over a time period of four weeks. Consecutive biopsies were taken for whole genome expression analysis, histology and T cell isolation. pDC were isolated from whole blood, stimulated with TLR7 agonist and analysed by extracellular flux analysis and real time PCR. Results We demonstrate imiquimod induces a monomorphic and self-limited inflammatory response in healthy individuals as well as psoriasis or eczema patients, respectively. The clinical and histologic phenotype as well as transcriptome of imiquimod-induced inflammation in human skin resembles an acute contact dermatitis rather than psoriasis. Nevertheless, the imiquimod model mimics hallmarks of psoriasis. Namely, plasmacytoid dendritic cells (pDC) are primary sensors of imiquimod, responding with production of pro-inflammatory and Th17-skewing cytokines. This results in a Th17 immune response with IL-23 as a key driver. In a proof-of-concept setting, systemic treatment with ustekinumab diminished the imiquimod-induced inflammation. Conclusion In humans, imiquimod induces contact dermatitis with the distinctive feature that pDC are the primary sensors, leading to an IL-23/Th17 deviation. Despite these shortcomings, the human imiquimod model might be useful to investigate early pathogenic events and prove molecular concepts in psoriasis.
Early-life home environment and risk of asthma among inner-city children J. Allergy Clin. Immunol. (IF 13.081) Pub Date : 2017-09-19 George T. O'Connor, Susan V. Lynch, Gordon R. Bloomberg, Meyer Kattan, Robert A. Wood, Peter J. Gergen, Katy F. Jaffee, Agustin Calatroni, Leonard B. Bacharier, Avrahman Beigelman, Megan T. Sandel, Christine C. Johnson, Ali Faruqi, Clark Santee, Kei E. Fujimura, Douglas Fadrosh, Homer Boushey, Cynthia M. Visness, James E. Gern
BackgroundEnvironmental exposures in early life appear to play an important role in the pathogenesis of childhood asthma, but the potentially modifiable exposures that lead to asthma remain uncertain.ObjectiveWe sought to identify early-life environmental risk factors for childhood asthma in a birth cohort of high-risk inner-city children.MethodsWe examined the relationship of prenatal and early-life environmental factors to the occurrence of asthma at 7 years of age among 442 children.ResultsHigher house dust concentrations of cockroach, mouse, and cat allergens in the first 3 years of life were associated with lower risk of asthma (for cockroach allergen: odds ratio per interquartile range increase in concentration, 0.55; 95% CI, 0.36-0.86; P < .01). House dust microbiome analysis using 16S ribosomal RNA sequencing identified 202 and 171 bacterial taxa that were significantly (false discovery rate < 0.05) more or less abundant, respectively, in the homes of children with asthma. A majority of these bacteria were significantly correlated with 1 of more allergen concentrations. Other factors associated significantly positively with asthma included umbilical cord plasma cotinine concentration (odds ratio per geometric SD increase in concentration, 1.76; 95% CI, 1.00-3.09; P = .048) and maternal stress and depression scores.ConclusionAmong high-risk inner-city children, higher indoor levels of pet or pest allergens in infancy were associated with lower risk of asthma. The abundance of a number of bacterial taxa in house dust was associated with increased or decreased asthma risk. Prenatal tobacco smoke exposure and higher maternal stress and depression scores in early life were associated with increased asthma risk.
A novel role for cilia function in atopy: ADGRV1 and DNAH5 interactions J. Allergy Clin. Immunol. (IF 13.081) Pub Date : 2017-09-18 Pierre-Emmanuel Sugier, Myriam Brossard, Chloé Sarnowski, Amaury Vaysse, Andréanne Morin, Lucile Pain, Patricia Margaritte-Jeannin, Marie-Hélène Dizier, William O.C.M. Cookson, Mark Lathrop, Miriam F. Moffatt, Catherine Laprise, Florence Demenais, Emmanuelle Bouzigon
Background Atopy, an endotype underlying allergic diseases, has a substantial genetic component. Objective Our goal was to identify novel genes associated with atopy in asthma-ascertained families. Methods We implemented a three-step analysis strategy in three datasets: The Epidemiological study on the Genetics and Environment of Asthma (EGEA) dataset: 1,660 subjects; The Saguenay-Lac-Saint-Jean (SLSJ) dataset: 1,138 subjects; and The Medical Research Council (MRC) dataset: 446 subjects). This strategy included a single-SNP genome-wide association study (GWAS), the selection of related gene pairs based on statistical filtering of GWAS results and text-mining filtering using GRAIL and SNP-SNP interaction analysis of selected gene pairs. Results We identified the 5q14 locus, harboring the adhesion G protein-coupled receptor V1 (ADGRV1) gene, that showed genome-wide significant association with atopy (rs4916831; Pmeta=6.8x10-9). Statistical filtering of GWAS results followed by text-mining filtering revealed relationships between ADGRV1 and three genes showing suggestive association with atopy (P≤10-4). SNP-SNP interaction analysis between ADGRV1 and these three genes showed significant interaction between ADGRV1 rs17554723 and two correlated SNPs (rs2134256 and rs1354187) within dynein axonemal heavy chain 5 (DNAH5) gene (Pmeta-int=3.6x10-5 and 6.1x10-5, that met the multiple-testing corrected threshold of 7.3x10-5). Further conditional analysis indicated that rs2134256 alone accounted for the interaction signal with rs17554723. Conclusion As both DNAH5 and ADGRV1 contribute to function of cilia, this study suggests that cilia dysfunction may represent a novel mechanism underlying atopy. Combining GWAS and epistasis analysis driven by statistical and knowledge-based evidence represents a promising approach for identifying new genes involved in complex traits.
Mast Cell Chymase Decreases The Severity Of Group B Streptococcus Infections J. Allergy Clin. Immunol. (IF 13.081) Pub Date : 2017-09-12 Claire Gendrin, Nicholas J. Shubin, Erica Boldenow, Sean Merillat, Morgan Clauson, Danny Power, Kelly S. Doran, Magnus Abrink, Gunnar Pejler, Lakshmi Rajagopal, Adrian M. Piliponsky
BackgroundGroup B Streptococcus (GBS) or Streptococcus agalactiae are ß-hemolytic, Gram-positive bacteria that colonize the lower genital tract of women and are frequently associated with infections during pregnancy. Innate immune defenses are critical for controlling GBS dissemination and systemic infection. Mast cells are resident sentinel cells that come into contact with pathogens early during colonization and infection.ObjectiveWe aimed to investigate the contribution of chymase to systemic GBS infection and rates of preterm birth.MethodsPharmacological and genetic approaches using mice deficient in mast cell protease (MCPT)4, the mouse functional homolog of human chymase, were employed.ResultsOur studies show that, in response to GBS, mast cells release a protease with chymotrypsin-like cleavage specificity. Additionally, increased GBS systemic infection and preterm births were observed in MCPT4-deficient mice vs. MCPT4 sufficient mice. We further observed that proteolytic cleavage of the host extracellular matrix protein fibronectin by peritoneal cell-derived mast cell (PCMC) lysates diminished GBS adherence. Consistent with this observation, the increase in GBS dissemination and preterm births observed in MCPT4-deficient mice was abolished when GBS were deficient in expression of the fibronectin binding protein, SfbA.ConclusionsTaken together, our results suggest that the protective effect of MCPT4 against GBS dissemination and preterm labor can in part be attributed to MCPT4-mediated proteolysis of fibronectin. Our studies reveal a novel role of mast cells in defense against bacterial infections.
Alveolar eosinophilia in current smokers with chronic obstructive pulmonary disease in the SPIROMICS cohort J. Allergy Clin. Immunol. (IF 13.081) Pub Date : 2017-09-12 Carlos H. Martinez, Sara X. Li, Andrew J. Hirzel, Valerie R. Stolberg, Neil E. Alexis, R. Graham Barr, Eugene R. Bleecker, Elizabeth E. Carretta, Stephanie A. Christenson, Christopher B. Cooper, David J. Couper, Claire M. Doerschuk, MeiLan K. Han, Nadia N. Hansel, Annette T. Hastie, Eric A. Hoffman, Robert J. Kaner, Fernando J. Martinez, Deborah A. Meyers, Wanda K. O’Neal, Robert Paine III, Nirupama Putcha, Stephen I. Rennard, Prescott G. Woodruff, Michelle Zeidler, Jeffrey L. Curtis, Christine M. Freeman
Active smoking in stable COPD subjects significantly increased eosinophil accumulation in the distal airspaces, but not in sputum or peripheral blood. Our findings support the need to investigate this cell-type as a potential driver of COPD symptomatology and progression.
Clinical, Immunological and Genetic Spectrum of 696 Patients with Combined Immunodeﬁciency J. Allergy Clin. Immunol. (IF 13.081) Pub Date : 2017-09-12 Hassan Abolhassani, Janet Chou, Wayne Bainter, Craig Platt, Mahmood Tavassoli, Toba Momen, Marzieh Tavakol, Mohammad Hossein Eslamian, Mohammad Gharagozlou, Masoud Movahedi, Mohsen Ghadami, Amir Ali Hamidieh, Gholamreza Azizi, Reza Yazdani, Mohsen Afarideh, Alireza Ghajar, Arash Havaei, Zahra Chavoushzadeh, Seyed Alireza Mahdaviani, Taher Cheraghi, Nasrin Behniafard, Reza Amin, Soheila Aleyasin, Reza Faridhosseini, Farahzad Jabbari-Azad, Mohammamd Nabavi, Mohammad Hassan Bemanian, Saba Arshi, Rasol Molatefi, Roya Sherkat, Mahboubeh Mansouri, Mehrnaz Mesdaghi, Delara Babaie, Iraj Mohammadzadeh, Javad Ghaffari, Alireza Shafiei, Najmeddin Kalantari, Hamid Ahanchian, Maryam Khoshkhui, Habib Soheili, Abbas Dabbaghzadeh, Afshin Shirkani, Rasoul Nasiri Kalmarzi, Seyed Hamidreza Mortazavi, Javad Tafaroji, Abbas Khalili, Javad Mohammadi, Babak Negahdari, Mohammad-Taghi Joghataei, Basel K. al-Ramadi
BackgroundCombined immunodeficiencies (CIDs) are diseases of defective adaptive immunity with diverse clinical phenotypes. Although CIDs are more prevalent in the Middle East than Western countries, the resources for genetic diagnosis are limited.ObjectivesThis study aims to characterize the categories of CID patients in Iran clinically and genetically.MethodsClinical and laboratory data were obtained from 696 patients with CIDs. Patients were subdivided into those with syndromic (344 patients) and non-syndromic CIDs (352 patients). Targeted DNA sequencing was performed on 243 patients (34.9%).ResultsThe overall diagnostic yield of the 243 sequenced patients was 77.8% (189 patients). The clinical diagnosis of HIES (p<0.001), onset of disease > 5y (p=0.02), and the absence of multiple affected family members (p=0.04), were significantly more frequent in the patients without a genetic diagnosis. An autosomal recessive disease was found in 62.9% of patients, reflecting the high rate of consanguinity in this cohort. Mutations impairing VDJ recombination and DNA repair were the most common underlying causes of CIDs. However, in patients with syndromic CIDs, autosomal recessive mutations in ATM, autosomal dominant mutations in STAT3 and microdeletions in 22q11.21 were the most commonly affected genomic loci. Patients with syndromic CIDs had a significantly lower five-year survival rate rather than those with non-syndromic CIDs.ConclusionsThis study provides proof of principle for the application of targeted next-generation sequencing panels in countries with limited diagnostic resources. The impact of genetic diagnosis on clinical care requires continued improvements in therapeutic resources for these patients.
Role of the IL-12/IL-35 balance in Sjögren’s syndrome J. Allergy Clin. Immunol. (IF 13.081) Pub Date : 2017-09-12 Olivier Fogel, Elodie Rivière, Raphaèle Seror, Gaetane Nocturne, Saida Boudaoud, Bineta Ly, Jacques-Eric Gottenberg, Véronique Le Guern, Jean-Jacques Dubost, Joanne Nititham, Kimberly E. Taylor, Philippe Chanson, Philippe Dieudé, Lindsey A. Criswell, Bernd Jagla, Alice Thai, Michael Mingueneau, Xavier Mariette, Corinne Miceli-Richard
BackgroundAn interferon (IFN) signature is involved in the pathogenesis of primary Sjögren’s syndrome (pSS), but whether the signature is type 1 or 2 remains controversial. Mouse models and genetic studies suggested the involvement of T helper 1 and type 2 IFN pathways. Likewise, polymorphisms of interleukin 12A gene (IL-12A), which encodes for IL-12p35, have been associated with pSS. IL-12p35 subunit is shared by 2 heterodimers, IL-12 and IL-35.ObjectiveTo confirm the genetic association of IL-12A polymorphism and pSS and elucidate the involvement of the IL-12/IL-35 balance in pSS by functional studies.MethodsThe genetic study involved 673 patients with pSS from 2 French pSS cohorts and 585 healthy French controls. Functional studies were performed on sorted monocytes, stimulated or not. IL-12A mRNA and IL-12 and IL-35 protein levels were assessed by qRT-PCR and by ELISA and a multiplex kit for IL-35 and IL-12, respectively.ResultsWe confirmed the association of the IL-12A rs485497 polymorphism and pSS and found an increased serum protein level of IL-12p70 in pSS patients carrying the risk allele (p=0.016). Serum level of IL-12p70 was greater in patients than controls (p=0.0001), especially patients with more active disease (p=0.05); conversely IL-35 level was decreased in patients (p=0.0001) especially in patients with a more active disease (p=0.05). In blood cellular subsets, both IL-12p35 and EBI-3 mRNAs were detected only in B cells with a trend toward a lower level among pSS patients.ConclusionOur findings emphasize the involvement of the IL-12/IL-35 balance in the pathogenesis of pSS. Serum IL-35 level was associated with low disease activity, in contrast to serum IL-12p70 level, which was rather associated with a more active disease.
Reduced risk of peanut sensitization following exposure through breast-feeding and early peanut introduction J. Allergy Clin. Immunol. (IF 13.081) Pub Date : 2017-09-12 Tracy J. Pitt, Allan B. Becker, Moira Chan-Yeung, Edmond S. Chan, Wade T.A. Watson, Rishma Chooniedass, Meghan B. Azad
Mesenchymal stem cells alleviate oxidative stress-induced mitochondrial dysfunction in the airways J. Allergy Clin. Immunol. (IF 13.081) Pub Date : 2017-09-11 Xiang Li, Charalambos Michaeloudes, Yuelin Zhang, Coen H. Wiegman, Ian M. Adcock, Qizhou Lian, Judith C.W. Mak, Pankaj K. Bhavsar, Kian Fan Chung
Background Oxidative stress-induced mitochondrial dysfunction may contribute to inflammation and remodeling in chronic obstructive pulmonary disease (COPD). Mesenchymal stem cells (MSCs) protect against lung damage in animal models of COPD. It is unknown whether these effects occur through attenuating mitochondrial dysfunction in airway cells. Objective To examine the effect of induced-pluripotent stem cell-derived MSCs (iPSC-MSCs) on oxidative stress-induce mitochondrial dysfunction in human airway smooth muscle cells (ASMCs) in vitro and in mouse lungs in vivo. Methods ASMCs were co-cultured with iPSC-MSCs in the presence of cigarette smoke medium (CSM), and mitochondrial reactive oxygen species (ROS), mitochondrial membrane potential (ΔΨm) and apoptosis were measured. Conditioned media from iPSC-MSCs and trans-well co-cultures were used to detect any paracrine effects. The effect of systemic injection of iPSC-MSCs on airway inflammation and hyper-responsiveness in ozone-exposed mice was also investigated. Results Co-culture of iPSC-MSCs with ASMCs attenuated CSM-induced mitochondrial ROS, apoptosis and ΔΨm loss in ASMCs. iPSC-MSC-conditioned media or trans-well co-cultures with iPSC-MSCs reduced CSM-induced mitochondrial ROS but not ΔΨm or apoptosis in ASMCs. Mitochondrial transfer from iPSC-MSCs to ASMCs was observed after direct co-culture and was enhanced by CSM. iPSC-MSCs attenuated ozone-induced mitochondrial dysfunction, airway hyper-responsiveness and inflammation in mouse lungs. Conclusion iPSC-MSCs offered protection against oxidative stress-induced mitochondrial dysfunction in human ASMCs and in mouse lungs, whilst reducing airway inflammation and hyper-responsiveness. These effects are, at least partly, dependent on cell-cell contact that allows for mitochondrial transfer, and paracrine regulation. Therefore, iPSC-MSCs show promise as a therapy for oxidative stress-dependent lung diseases such as COPD.
The effects of house dust mite sublingual immunotherapy (SLIT)-tablet effects on immunological biomarkers and nasal allergen challenge symptoms J. Allergy Clin. Immunol. (IF 13.081) Pub Date : 2017-09-11 Natasha C. Gunawardana, Qing Zhao, Leonidas N. Carayannopoulos, Kuenhi Tsai, Vladislav A. Malkov, Diana Selverian, Graham Clarke, Tim Mant, Brent Butts, Kaare Lund, Trevor T. Hansel, Hendrik Nolte
SQ HDM SLIT-tablet significantly increased serum HDM-specific IgG4 and IgE blocking factor, and significantly decreased early phase nasal symptoms after nasal allergen challenge. No significant effects on cytokines or gene expression in nasal mucosa were observed.
Role of B cells in T helper cell responses in a mouse model of asthma J. Allergy Clin. Immunol. (IF 13.081) Pub Date : 2017-09-07 Tomasz Piotr Wypych, Roberta Marzi, Gregory F. Wu, Antonio Lanzavecchia, Federica Sallusto
Ormdl3 Upregulates Airway Smooth Muscle Proliferation, Contraction, and Ca2+ Oscillations in Asthma J. Allergy Clin. Immunol. (IF 13.081) Pub Date : 2017-09-07 Jun Chen, Marina Miller, Hirotoshi Unno, Peter Rosenthal, Michael Sanderson, David H. Broide
Background Airway hyperresponsiveness (AHR) is a major feature of asthma attributed predominantly to an extrinsic immune/inflammatory response increasing airway smooth muscle (ASM) contractility. Objective We investigated whether increased ASM expression of ORMDL3, a gene on chromosome 17q21 highly linked to asthma, induced increased ASM proliferation and contractility in vitro, as well as influenced airway contractility and calcium flux in ASM in precision cut lung slices from WT and hORMDL3Zp3-Cre mice (which express increased levels of human ORMDL3). Methods Levels of ASM proliferation and contraction were assessed in ASM cells transfected with ORMDL3 in vitro. In addition, airway contractility and calcium oscillations were quantitated in ASM cells in precision cut lung slices derived from naïve WT and naïve hORMDL3Zp3-Cre mice which do not have a blood supply. Results Increased ASM expression of ORMDL3 in vitro resulted in increased ASM proliferation and contractility. Precision cut lung slices derived from naïve hORMDL3Zp3-Cre mice which do not have airway inflammation exhibit increased airway contractility with increased calcium oscillations in ASM cells. Increased ASM ORMDL3 increases ASM sarcoplasmic reticulum Ca2+ ATPase 2b (SERCA2b) which increases ASM proliferation and contractility. Conclusion Overall, these studies provide evidence that an intrinsic increase in ORMDL3 in ASM can induce increased ASM proliferation and contractility which may contribute to increased AHR in the absence of airway inflammation in asthma.
Siglec-8 is an activating receptor mediating β2 integrin-dependent function in human eosinophils J. Allergy Clin. Immunol. (IF 13.081) Pub Date : 2017-09-06 Daniela J. Carroll, Jeremy A. O’Sullivan, David B. Nix, Yun Cao, Michael Tiemeyer, Bruce S. Bochner
Background Siglec-8 is a CD33 subfamily cell surface receptor that is selectively expressed on human eosinophils. Following cytokine-priming, Siglec-8 mAb or glycan ligand binding causes eosinophil apoptosis associated with reactive oxygen species (ROS) production. Most CD33-related Siglecs function as inhibitory receptors, but the ability of Siglec-8 to stimulate eosinophil ROS production and apoptosis suggests that Siglec-8 may instead function as an activating receptor. Objective To determine the role of IL-5 priming and to identify the signaling molecules involved in Siglec-8 function for human eosinophils. Methods We used a mAb and/or a multimeric synthetic sulfated sialoglycan ligand recognizing Siglec-8, in combination with integrin blocking antibodies, pharmacological inhibitors, phosphoproteomics and western blot analysis, to define the necessity of various proteins involved in Siglec-8 function for human eosinophils. Results Cytokine priming was required to elicit the unanticipated finding that Siglec-8 engagement promotes rapid β2-integrin dependent eosinophil adhesion. Also novel was the finding that this adhesion was necessary for subsequent ROS production and apoptosis. Siglec-8-mediated ROS was generated via NADPH oxidase activation, because pretreatment of eosinophils with catalase (an extracellular superoxide scavenger) or NSC23766 (a Rac GTPase inhibitor) completely inhibited Siglec-8 mediated eosinophil apoptosis. Finally, engagement of Siglec-8 on IL-5 primed eosinophils resulted in increased phosphorylation of Akt, p38 and JNK1 that was also β2-integrin dependent; pharmacologic inhibition of these kinases completely prevented Siglec-8-mediated eosinophil apoptosis. Conclusions These data demonstrate that Siglec-8 uniquely functions as an activating receptor on IL-5 primed eosinophils via a novel pathway involving regulation of β2-integrin-dependent adhesion, NADPH oxidase and a subset of protein kinases.
TNFAIP3 levels in lung dendritic cells instruct Th2 or Th17 cell differentiation in eosinophilic or neutrophilic asthma J. Allergy Clin. Immunol. (IF 13.081) Pub Date : 2017-09-06 Heleen Vroman, Ingird M. Bergen, Jennifer .A.C. van Hulst, Memno van Nimwegen, Denise van Uden, Martin J. Schuijs, Saravanan Y. Pillai, Geert van Loo, Hamida Hammad, Bart N. Lambrecht, Rudi W. Hendriks, Mirjam Kool
Background It is currently unknown, why allergen exposure or environmental triggers in mild to moderate asthma patients results in Th2-mediated eosinophilic inflammation, whereas severe asthma patients often present with Th17-mediated neutrophilic inflammation. The activation state of dendritic cells (DCs) is crucial for both Th2 and Th17-cell differentiation, and is mediated through NF-κB activation. Ablation of TNFAIP3, one of the crucial negative regulators of NF-κB activation in myeloid cells and DCs was shown to control DC activation. Objective In this study we investigated the precise role of TNFAIP3 in myeloid cells for the development of Th2 and Th17-cell mediated asthma. Methods We exposed mice with conditional deletion of the Tnfaip3 gene in either myeloid cells (using the LysM promotor) or specifically in DCs (using the Cd11c promotor) to acute and chronic house dust mite (HDM)-driven asthma models. Results We demonstrated that reduced Tnfaip3 gene expression in DCs in either Tnfaip3CD11c or Tnfaip3LysM mice dose-dependently controlled development of Th17-mediated neutrophilic severe asthma in both acute and chronic HDM-driven models, whereas wildtype mice developed a purely Th2-mediated eosinophilic inflammation. TNFAIP3-deficient DCs induced HDM-specific Th17-cell differentiation, through increased expression of Th17-instructing cytokines, IL-1ß, IL-6 and IL-23, whereas HDM-specific Th2-cell differentiation was hampered by the increased IL-12 and IL-6 production. Conclusions These data show that the extent of TNFAIP3 expression in DCs controls Th2/Th17-cell differentiation. This implies that reducing DC activation could be a new pharmacological intervention to treat severe asthma patients that present with a Th17-mediated neutrophilic inflammation.
Critical role of mammalian target of rapamycin for IL-10 dendritic cell induction by a flagellin A conjugate in preventing allergic sensitization J. Allergy Clin. Immunol. (IF 13.081) Pub Date : 2017-09-05 Stefan Schülke, Anna-Helena Fiedler, Ann-Christine Junker, Adam Flaczyk, Sonja Wolfheimer, Andrea Wangorsch, Anke Heinz, Hendrik Beckert, Birgit Nagl, Barbara Bohle, Stefan Vieths, Masako Toda, Stephan Scheurer
Aspergillus fumigatus alkaline protease 1 (Alp1/Asp f13) in the airways correlates with asthma severity J. Allergy Clin. Immunol. (IF 13.081) Pub Date : 2017-09-04 Trisha Basu, Seyedmojtaba Seyedmousavi, Janyce A. Sugui, Nariman Balenga, Ming Zhao, Kyung Joo Kwon Chung, Sabrina Biardel, Michel Laviolette, Kirk M. Druey
A fungal protease (Alp1/Asp f13) from Aspergillus fumigatus was detected in the airways of subjects with asthma but not controls, which correlated strongly with disease severity, respiratory dysfunction, and steroid use.
Intestinal Microbiota in Infants at High-risk for Allergy: Effects of Prebiotics and Role in Eczema Development J. Allergy Clin. Immunol. (IF 13.081) Pub Date : 2017-09-01 Harm Wopereis, Kathleen Sim, Alexander Shaw, John O. Warner, Jan Knol, J. Simon Kroll
Natural protective immunity against grass pollen allergy is maintained by a diverse spectrum of response types J. Allergy Clin. Immunol. (IF 13.081) Pub Date : 2017-09-01 Almedina Kurtaj, Christoph Hillebrand, Gerda Fichtinger, Eva Hattinger, Melanie Lietzenmayer, Yoan Machado, Sandra Scheiblhofer, Angelika Stoecklinger, Theresa Thalhamer, Susanne Suessner, Martin Danzer, Sabine Keplinger, Johannes Weinberger, Susanne Schaller, Stephan Winkler, Christian Gabriel, Josef Thalhamer, Richard Weiss
Naturally acquired immunity against allergens utilizes a broad spectrum of response types besides T regulatory cells. Therapeutic concepts should not be limited to T regulatory cell induction, but take advantage of the diversity found in natural responses.
Efficacy and safety of 4 months of sublingual immunotherapy with recombinant Mal d 1 and Bet v 1 in patients with birch pollen-related apple allergy J. Allergy Clin. Immunol. (IF 13.081) Pub Date : 2017-09-01 Tamar Kinaciyan, Birgit Nagl, Sandra Faustmann, Florian Frommlet, Stephan Kopp, Martin Wolkersdorfer, Stefan Wöhrl, Katharina Bastl, Hans Huber, Uwe Berger, Barbara Bohle
Background Birch pollen-related apple allergy is among the most prevalent food allergies in adolescent/adult individuals and mainly results from sensitization to the major birch pollen allergen Bet v 1 and subsequent cross-reaction with the apple protein Mal d 1. However, specific immunotherapy with birch pollen has inconsistent effects on apple allergy. Objective To compare the safety and efficacy of sublingual immunotherapy (SLIT) with two formulations containing either recombinant (r) Mal d 1 or Bet v 1 on birch pollen-related apple allergy. Methods Sixty participants with birch pollen-related apple allergy were randomized to daily sublingual application of placebo (n=20), 25 μg of rMal d 1 (n=20) or rBet v 1 (n=20) for 16 weeks. Adverse events were regularly recorded. Sublingual challenges with standardized doses of rMal d 1, skin prick testing with recombinant allergens and measurements of allergen-specific IgE and IgG4 antibodies were performed before and after treatment. Results Both formulations caused comparable, mainly local adverse events. No systemic reactions occurred. Compared to the placebo and the rBet v 1-treated group SLIT with rMal d 1 reduced rMal d 1-induced oral symptoms (P=0.001 and P=0.038), accompanied by longitudinally reduced rMal d 1-specific cutaneous reactions (P=0.022) and enhanced IgG4/IgE ratios (P=0.012). SLIT with rBet v 1 neither improved the clinical reactivity to rMal d 1 nor enhanced rMal d 1-specific IgG4/IgE ratios. Participants receiving placebo showed no allergen-specific changes. Conclusion Sublingual treatment with a recombinant food allergen was safe and clinically effective as determined by standardized challenges. We present a promising approach for the effective treatment of birch pollen-related apple allergy.
IL-12 and IL-7 synergise to control MAIT cell cytotoxic responses to bacterial infection J. Allergy Clin. Immunol. (IF 13.081) Pub Date : 2017-09-01 Joshua C. Wallington, Anthony P. Williams, Karl J. Staples, Tom M.A. Wilkinson
Enhanced Plasmacytoid Dendritic Cell Antiviral Responses After Omalizumab J. Allergy Clin. Immunol. (IF 13.081) Pub Date : 2017-09-01 Michelle A. Gill, Andrew H. Liu, Agustin Calatroni, Rebecca Z. Krouse, Baomei Shao, Allison Schiltz, James E. Gern, Alkis Togias, William W. Busse
Background Atopy and viral respiratory infections synergistically promote asthma exacerbations. IgE cross-linking inhibits critical viral-induced IFNα responses of plasmacytoid dendritic cells (pDCs), which can be deficient in allergic asthma. Objective To determine whether reducing IgE in vivo with omalizumab treatment increases pDC antiviral IFNα responses in inner city children with asthma. Methods PBMCs and pDCs isolated from children with exacerbation-prone asthma before and during omalizumab treatment were stimulated ex vivo with rhinovirus and influenza in the presence or absence of IgE cross-linking. IFNα was measured in supernatants and mRNA of IFNα pathway genes determined by qRT-PCR in cell pellets. FcεRIα protein and mRNA expression were measured in unstimulated cells by flow cytometry and qRT-PCR respectively. Changes in these outcomes and associations with clinical outcomes were analyzed and statistical modeling utilized to identify risk factors for asthma exacerbations. Results Omalizumab treatment increased rhinovirus and influenza-induced PBMC and rhinovirus-induced pDC IFNα responses in the presence of IgE cross-linking, and reduced pDC surface FcεRIα expression. Omalizumab-induced reductions in pDC FcεRIα were significantly associated with lower asthma exacerbation rate during the outcome period and correlated with increases in PBMC IFNα responses. PBMC FcεRIα mRNA measured upon study entry significantly improved an existing model of exacerbation prediction. Conclusions These findings indicate that omalizumab treatment augments pDC IFNα responses and attenuates pDC FcεRIα protein expression, and provide evidence that these effects are related. These results support a potential mechanism underlying clinical observations that allergic sensitization is associated with increased susceptibility to virus-induced exacerbations of asthma.
Novel Stat1 Mutation Disrupts Small Ubiquitin-Related Modifier (Sumo) Conjugation Causing Gain Of Function J. Allergy Clin. Immunol. (IF 13.081) Pub Date : 2017-08-30 Elizabeth P. Sampaio, Li Ding, Stacey R. Rose, Phillip Cruz, Amy P. Hsu, Anuj Kashyap, Lindsey B. Rosen, Margery Smelkinson, Tatyana A. Tavella, Elise M.N. Ferre, Meredith K. Wierman, Christa S. Zerbe, Michail S. Lionakis, Steven M. Holland
Background Sumoylation is a post-translational reversible modification of cellular proteins by the conjugation of SUMO (small ubiquitin-related modifier) and comprises an important regulator of protein function. Objective To characterize the molecular mechanism of a novel mutation at the SUMO motif on STAT1. Methods STAT1 sequencing and functional characterization were performed in transfection experiments using immunoblotting and immunoprecipitation in STAT1-deficient cell lines. Transcriptional response and target gene activation were also investigated in peripheral blood mononuclear cells. Results We identified a novel STAT1 mutation (c.2114A>T, p.E705V), within the SUMO motif (702IKTE705), in a patient with disseminated Rhodococcus infection, Norwegian scabies, chronic mucocutaneous candidiasis, hypothyroidism and esophageal squamous cell carcinoma. The mutation is located in the tail segment and is predicted to disrupt STAT1 sumoylation. Immunoprecipitation experiments performed in transfected cells confirmed absent STAT1 sumoylation for E705V, while it was present in wild type (WT) STAT1 cells, as well as the loss of function (LOF) mutants L706S and Y701C. Further, stimulation with IFN-γ led to enhanced STAT1 phosphorylation, enhanced transcriptional activity and target gene expression in the E705V transfected compared to WT transfected cells. Computer modeling of WT and mutant STAT1 molecules showed variations in the accessibility of phosphorylation site Y701 that corresponded to the LOF and GOF variants. Conclusion This is the first report of a mutation in the STAT1 sumoylation motif associated with clinical disease. These data reinforce sumoylation as a key post-translational regulatory modification of STAT1 and identify a novel mechanism for GOF STAT1 disease in humans. Clinical Implications This mutation is the first pathologic identification of the critical role of sumoylation in STAT1 function and disease. The current data indicate a potential target for STAT1 therapeutic modulation in GOF disease.
Expansion of blood IgG4+ Bcells, Th2 and Tregulatory cells in IgG4-related disease J. Allergy Clin. Immunol. (IF 13.081) Pub Date : 2017-08-19 Jorn J. Heeringa, A. Faiz Karim, Jan A.M. van Laar, Robert M. Verdijk, Dion Paridaens, P. Martin van Hagen, Menno C. van Zelm
Background IgG4-related disease (IgG4-RD) is a systemic fibro-inflammatory condition affecting various organs and has a diverse clinical presentation. Fibrosis and accumulation of IgG4+ plasma cells in tissue are hallmarks of the disease and IgG4-RD is associated with elevated IgG4 serum levels. However, disease pathogenesis is still unclear and these cellular and molecular parameters are neither sensitive nor specific for diagnosis of IgG4-RD. Objective We here sought to develop a flowcytometric gating strategy to reliably identify blood IgG4+ B-cells to study their cellular and molecular characteristics and investigate their contribution in disease pathogenesis. Methods Sixteen patients with histologically confirmed IgG4-RD, 11 patients with sarcoidosis and 30 healthy individuals were included for 11-color flowcytometric analysis of peripheral blood for IgG4-expressing B cells and T-helper (Th) subsets. In addition, detailed analysis of activation markers and chemokine receptors was performed on IgG4-expressing B cells and IgG4 transcripts were analyzed for somatic hypermutations. Results Cellular and molecular analyses revealed increased numbers of blood IgG4+ memory B-cells in patients with IgG4-RD. These cells showed reduced expression of CD27 and CXCR5 and increased signs of antibody maturation. Furthermore, IgG4-RD patients, but not patients with sarcoidosis, had increased numbers of circulating plasma blasts and CD21low B-cells, as well as Th2 and regulatory T-cells, indicating of a common disease pathogenesis in IgG4-RD. Conclusion These results provide new insights into the dysregulated IgG4 response in patients with IgG4-RD. A specific “peripheral lymphocyte signature” observed in patients with IgG4-RD, could support diagnosis and treatment monitoring.
Advances in Basic and Clinical Immunology 2016 J. Allergy Clin. Immunol. (IF 13.081) Pub Date : 2017-08-19 Javier Chinen, Yousef Badran, Raif S. Geha, Janet S. Chou, Ari J. Fried
Advances in basic immunology in 2016 included studies that further characterized the role of different proteins in the differentiation of effector T cells and B cells, including cytokines and proteins involved in actin cytoskeleton. The regulation of granule formation and secretion in cytotoxic cells was also further described by examining patients with familial hemophagocytic lymphohystiocytosis. The role of prenylation in mevalonate kinase deficiency leading to inflammation has been established. We reviewed advances in clinical immunology as well as new approaches of whole genome sequencing and genes newly reported to be associated with immunodeficiency, such as linker of activation of T cells (LAT), B cell lymphoma 11B (BCL11B), RLTPR, moesin and JAK1. Trials of Hematopoietic stem cells transplantation and gene therapy for primary immunodeficiency have had relative success; the use of autologous viral specific cytotoxic T cells has proven effective. New medications are being explored, such as pioglitazone and its role in enhancing the oxidative burst in chronic granulomatous disease. Development of vaccines for HIV infection continues to provide insight into the immune response against a virus with an extraordinary mutation rate.
Combined immunodeficiency and atopy caused by a dominant negative mutation in CARD11 J. Allergy Clin. Immunol. (IF 13.081) Pub Date : 2017-08-19 Harjit Dadi, Tyler A. Jones, Daniele Merico, Nigel Sharfe, Adi Ovadia, Yael Schejter, Brenda Reid, Mark Sun, Linda Vong, Adelle Atkinson, Sasson Lavi, Joel L. Pomerantz, Chaim M. Roifman
Background Combined immunodeficiency is a T cell defect frequently presenting with recurrent infections as well as associated immune dysregulation manifesting as autoimmunity or allergic inflammation. Objective We sought to identify the genetic aberration in four related patients with combined immunodeficiency, early onset asthma, eczema and food allergies, as well as autoimmunity. Methods Whole exome sequencing (WES) followed by Sanger confirmation, assessment of the genetic variant impact on cell signaling and evaluation of the resultant immune function. Results A heterozygous novel c.C88T one base pair substitution resulting in the amino acid change R30W in CARD11 was identified by WES and segregated perfectly to family members with severe atopy only, but was not found in healthy individuals. We demonstrate that the R30W mutation results in a loss of function while also exerting a dominant negative effect on wild-type CARD11. The CARD11 defect altered the classical Nuclear Factor-κB (NF-κB) pathway, resulting in poor in vitro T cell responses to mitogens and antigens caused by reduced secretion of IFNγ and IL-2. Conclusion Unlike patients with biallelic mutations in CARD11 causing severe combined immunodeficiency, the R30W defect results in a less profound yet prominent susceptibility to infections as well as multi-organ atopy and autoimmunity.
Neutralization of interferon-γ reverts clinical and laboratory features in a mouse model of macrophage activation syndrome J. Allergy Clin. Immunol. (IF 13.081) Pub Date : 2017-08-12 Giusi Prencipe, Ivan Caiello, Antonia Pascarella, Alexei A. Grom, Claudia Bracaglia, Laurence Chatel, Walter G. Ferlin, Emiliano Marasco, Raffaele Strippoli, Cristina de Min, Fabrizio De Benedetti
Background The pathogenesis of macrophage activation syndrome (MAS) is not clearly understood: a large body of evidence supports the involvement of mechanisms similar to those implicated in primary hemophagocytic lymphohistiocytosis. Objective To investigate the pathogenic role of interferon-γ (IFNγ) and the therapeutic efficacy of IFNγ neutralization in an animal model of macrophage activation syndrome. Methods We used a MAS model established in mice transgenic for human interleukin-6 (IL-6TG) challenged with LPS (MAS mice). Levels of IFNγ and IFNγ-inducible chemokines were evaluated by real-time PCR in liver and spleen and by ELISA in plasma. IFNγ neutralization was achieved using the anti-IFNγ antibody XMG1.2 in vivo. Results MAS mice showed a significant upregulation of the IFNγ pathway, as demonstrated by increased mRNA levels of Ifnγ and by higher levels of phospho-STAT1 in liver and spleen and by increased expression of IFNγ-inducible chemokines Cxcl9 and Cxcl10 in liver and spleen as well as in plasma. A marked increase in Il-12a and Il-12b expression was also found in liver and spleen from MAS mice. In addition, MAS mice showed a significant increase in liver CD68 positive macrophages. MAS mice treated with an anti-IFNγ antibody showed a significant improvement in survival and in body weight recovery, associated to a significant amelioration of ferritin, fibrinogen and alanine aminotransferase levels. In MAS mice, treatment with the anti-IFNγ antibody significantly decreased circulating levels of CXCL9, CXCL10 and downstream proinflammatory cytokines. The decrease in CXCL9 and CXCL10 levels paralleled the decrease in the serum levels of proinflammatory cytokines and ferritin. Conclusion These results provide evidence for a pathogenic role of IFNγ in MAS.
Transient receptor potential vanilloid 4–expressing macrophages and keratinocytes contribute differentially to allergic and nonallergic chronic itch J. Allergy Clin. Immunol. (IF 13.081) Pub Date : 2017-08-11 Jialie Luo, Jing Feng, Guang Yu, Pu Yang, Madison R. Mack, Junhui Du, Weihua Yu, Aihua Qian, Yujin Zhang, Shenbin Liu, Shijin Yin, Amy Xu, Jizhong Cheng, Qingyun Liu, Roger G. O'Neil, Yang Xia, Liang Ma, Susan M. Carlton, Hongzhen Hu
Propagation of respiratory viruses in human airway epithelia reveals persistent virus-specific signatures J. Allergy Clin. Immunol. (IF 13.081) Pub Date : 2017-08-08 Manel Essaidi-Laziosi, Francisco Brito, Sacha Benaoudia, Léna Royston, Valeria Cagno, Mélanie Fernandes-Rocha, Isabelle Piuz, Evgeny Zdobnov, Song Huang, Samuel Constant, Marc-Olivier Boldi, Laurent Kaiser, Caroline Tapparel
Background Leading etiologies of acute illnesses, respiratory viruses typically cause self-limited diseases, though severe complications can occur in fragile patients. Rhinoviruses, respiratory enteroviruses, influenza virus, respiratory syncytial viruses and coronaviruses are highly prevalent respiratory pathogens, but due to the lack of reliable animal models, their differential pathogenesis remains poorly characterized. Objective To compare infections by respiratory viruses isolated from clinical specimens using reconstituted human airway epithelia. Methods Tissues were infected with rhinoviruses RV-A55, RV-A49, RV-B48, RV-C8 and RV-C15, respiratory enterovirus EV-D68, influenza virus H3N2, respiratory syncytial virus RSV-B and coronavirus HCoV-OC43. Replication kinetics, cell tropism, impact on tissue integrity and cytokine secretion were compared. Virus adaptation and tissue response were assessed through RNA-sequencing. Results Rhinoviruses, RSV-B and HCoV-OC43 infected ciliated cells and caused no major cell death while H3N2 and EV-D68 induced ciliated cell loss and tissue integrity disruption. H3N2 was also detected in rare goblet and basal cells. All viruses except RV-B48 and HCoV-OC43 altered cilia beating and MCC. H3N2 was the strongest cytokine-inducer and HCoV-OC43 the weakest. Persistent infection was observed in all cases. RNA-sequencing highlighted perturbation of tissue metabolism and induction of a transient but important immune response at 4-days post-infection. No majority mutations emerged in the viral population. Conclusion Our results highlight the differential in vitro pathogenesis of respiratory viruses during the acute infection-phase and their ability to persist under immune tolerance. These data help to appreciate the range of disease severity observed in vivo and the occurrence of chronic respiratory infections in immunocompromised hosts.
Prenatal fine particulate exposure and early childhood asthma: effect of maternal stress and fetal gender J. Allergy Clin. Immunol. (IF 13.081) Pub Date : 2017-08-08 Alison Lee, Hsiao-Hsien Leon Hsu, Yueh-Hsiu Mathilda Chiu, Sonali Bose, Maria José Rosa, Itai Kloog, Ander Wilson, Joel Schwartz, Sheldon Cohen, Brent A. Coull, Robert O. Wright, Rosalind J. Wright
Background The impact of prenatal ambient air pollution on child asthma may be modified by maternal stress, child sex and exposure dose and timing. Objective We prospectively examined associations between co-exposure to prenatal particulate matter with an aerodynamic diameter of less than 2.5 microns (PM2.5) and maternal stress on childhood asthma (n=736). Methods Daily PM2.5 exposure during pregnancy was estimated using a validated satellite-based spatio-temporally resolved prediction model. Prenatal maternal negative life events (NLEs) were dichotomized around the median (high: NLE ≥ 3; low: NLE<3). We employed Bayesian distributed lag interaction models (BDLIMs) to identify sensitive windows for prenatal PM2.5 exposure on children’s asthma by age 6, and determine effect modification by maternal stress and child sex. Results BDLIMs identified a critical window of exposure (19-23 weeks gestation, cumulative OR=1.15, 95%CI=1.03-1.26; per IQR (1.7 μg/m3) increase in prenatal PM2.5 level) during which children concomitantly exposed to prenatal PM2.5 and maternal stress had increased risk of asthma. No significant association was seen in children born to women reporting low prenatal stress. When examining modifying effects of prenatal stress and fetal sex, we found that boys born to mothers with higher prenatal stress were most vulnerable (19-21 weeks gestation, cumulative OR=1.28, 95%CI=1.15-1.41; per IQR increase in PM2.5). Conclusion Prenatal PM2.5 exposure during sensitive windows is associated with increased risk of child asthma, especially in boys concurrently exposed to elevated maternal stress.
MicroRNA-150 controls differentiation of intraepithelial lymphocytes via TGF-β receptor II regulation J. Allergy Clin. Immunol. (IF 13.081) Pub Date : 2017-08-07 Sang-Hwan Seo, Min Seong Jang, Doo-Jin Kim, Seok-Min Kim, Se-Chan Oh, Cho-Rok Jung, Yunji Park, Sang-Jun Ha, Haiyoung Jung, Young-Jun Park, Suk Ran Yoon, Inpyo Choi, Tae-Don Kim
More Than a Decade Follow-up in Severe or Difficult-to-Treat Asthma: TENOR II J. Allergy Clin. Immunol. (IF 13.081) Pub Date : 2017-08-07 Bradley E. Chipps, Tmirah Haselkorn, Brandee Paknis, Benjamin Ortiz, Eugene R. Bleecker, Farid Kianifard, Aimee J. Foreman, Stanley J. Szefler, Robert S. Zeiger,
Background The Epidemiology and Natural History of Asthma: Outcomes and Treatment Regimens (TENOR I) study demonstrated high morbidity in patients with severe/difficult-to-treat asthma, despite standard-of-care treatment. Objective To determine the long-term natural history of disease and outcomes in patients in TENOR I, after more than a decade. Methods TENOR I was a multicenter, observational study (2001–2004) of 4756 patients with severe/difficult-to-treat asthma. TENOR II was a follow-up study of TENOR I patients using a single, cross-sectional visit in 2013/2014. Overall, the sites participating in TENOR II originally enrolled 1230 patients in TENOR I. Clinical and patient-reported outcomes were assessed, including very poorly controlled (VPC) asthma based on National Heart, Lung, and Blood Institute (NHLBI) guidelines. Results A total of 341 (27.7%) patients were enrolled in TENOR II and were representative of the TENOR I cohort. Most frequent comorbidities were rhinitis (84.0%), sinusitis (47.8%) and gastroesophageal reflux disease (46.3%). Mean (SD) percent predicted pre- and post-bronchodilator FEV1 were 72.7% (21.4%) and 78.2% (20.7%), respectively. A total of 231/317 (72.9%) tested positive for ≥1 allergen-specific IgE. Mean (SD) blood eosinophil count was 200 μL (144). Eighty-eight (25.8%) patients experienced an asthma exacerbation in the prior 3 months requiring hospital attention and/or oral corticosteroids. Over half (197/339; 58.1%) had VPC asthma. Medication use suggested undertreatment. Conclusion TENOR II provides longitudinal data to characterize disease progression, heterogeneity and severity in severe/difficult-to-treat asthma. Findings show continued morbidity, including a high degree of comorbid conditions, allergic sensitization, exacerbations and VPC asthma, including reduced lung function.
Plasma cell deficiency in humans with heterozygous mutations in SEC61A1 J. Allergy Clin. Immunol. (IF 13.081) Pub Date : 2017-08-04 Desirée Schubert, Marie-Christine Klein, Sarah Hassdenteufel, Andrés Caballero-Oteyza, Linlin Yang, Michele Proietti, Alla Bulashevska, Janine Kemming, Johannes Kühn, Sandra Winzer, Stephan Rusch, Manfred Fliegauf, Alejandro A. Schäffer, Stefan Pfeffer, Roger Geiger, Adolfo Cavalié, Hongzhi Cao, Fang Yang, Bodo Grimbacher
Background Primary antibody deficiencies (PAD) are the most frequent primary immunodeficiencies in humans. The genetic causes for PADs are largely unknown. Sec61 translocon alpha 1 subunit (SEC61A1) is the major subunit of the Sec61 complex, which is the main polypeptide-conducting channel in the endoplasmic reticulum (ER) membrane. SEC61A1 is a target gene of XBP1s and strongly induced during plasma cell differentiation. Objective Characterization of a novel genetic defect and its pathological mechanism in eleven patients from two unrelated families with PAD. Methods Whole exome sequencing (WES) and targeted sequencing were conducted to identify novel genetic mutations. Functional studies were carried out ex vivo in primary cells of patients and in vitro in different cell lines to assess the effect of SEC61A1 mutations on B cell differentiation and survival. Results We investigated two families with patients suffering from hypogammaglobulinemia, severe recurrent respiratory tract infections and normal peripheral B- and T cell subpopulations. Upon in vitro stimulation, B cells showed an intrinsic deficiency to develop into plasma cells (PCs). Genetic analysis and targeted sequencing identified novel heterozygous missense (c.254T>A, p.V85D) and nonsense (c.1325G>T, p.E381*) mutations in SEC61A1, segregating with the disease phenotype. SEC61A1-V85D was deficient in co-translational protein translocation and it disturbed the cellular calcium homeostasis in HeLa cells. Moreover, SEC61A1-V85D triggered the terminal unfolded protein response (UPR) in multiple myeloma (MM) cell lines. Conclusion We describe a monogenic defect leading to a specific plasma cell deficiency in humans, expanding our knowledge about the pathogenesis of antibody deficiencies.
TCRαβ+ and CD19+ cell depleted Haploidentical and Mismatched Hematopoietic Stem Cell Transplantation in Primary Immune Deficiency J. Allergy Clin. Immunol. (IF 13.081) Pub Date : 2017-08-03 Ravi M. Shah, Reem Elfeky, Zohreh Nademi, Waseem Qasim, Persis Amrolia, Robert Chiesa, Kanchan Rao, Giovanna Lucchini, Juliana M.F. Silva, Austen Worth, Dawn Barge, David Ryan, Jane Conn, Andrew J. Cant, Roderick Skinner, Intan Juliana Abd Hamid, Terence Flood, Mario Abinun, Mary Slatter
Background Allogeneic hematopoietic stem cell transplantation (HSCT) is used as a therapeutic approach for primary immunodeficiencies (PIDs). The best outcomes have been achieved using HLA-matched donors, but when a matched donor is not available, a haploidentical or mismatched unrelated donor (mMUD) can be useful. Various strategies are used to mitigate the risk of graft versus host disease (GvHD) and rejection associated with such transplants. Objective We sought to evaluate the outcomes of haploidentical or mMUD HSCT after depleting GvHD causing TCRαβCD3+ cells from the graft. Methods CD3+TCRαβ+/CD19+ depleted grafts were given in conditioned (except three) children with PIDs. Treosulfan (busulfan in one), fludarabine, thiotepa and ATG or alemtuzumab conditioning was used in 77% cases, and all but four received GvHD prophylaxis. Results 25 patients with 12 types of PIDs received 26 HSCTs. Three were transplanted for refractory GvHD developing after first cord transplantation. At 20.8 months (5 month- 3.3 years) median follow up, 21/25 patients survived and were cured of underlying immunodeficiency. Overall and Event Free Survival at 3 years was 83.9% and 80.4% respectively. Cumulative incidence (CI) of Grade II-IV acute GvHD was 22±8.7%. No case of visceral or chronic GvHD was seen. CI of graft failure, CMV or/and adeno viral infections and transplant related mortality at 1 year were 4.2±4.1%, 58.8±9.8% and 16.1±7.4% respectively. Patients going into transplant with systemic viral infections had poor survival in comparison to those with absent or resolved infection (33.3% vs.100%). Conclusion CD3+TCRαβ+ and CD19+ depleted haploidentical or mMUD HSCT is a practical and viable alternative for children with a range of PIDs.
Vitiligo: Mechanistic Insights Lead to Novel Treatments J. Allergy Clin. Immunol. (IF 13.081) Pub Date : 2017-08-01 Michael L. Frisoli, John E. Harris
Vitiligo is an autoimmune disease of the skin characterized by patchy depigmentation. Current treatments are moderately effective at reversing disease by suppressing autoimmune inflammation in the skin and promoting the regeneration of melanocytes. Recent basic and translational research studies have significantly improved our understanding of disease pathogenesis, which is now leading to emerging treatment strategies based on targeted therapy. Here we discuss important clinical characteristics of vitiligo, current therapies, their limitations, advances in understanding disease pathogenesis, emerging targeted treatments, and strategies to optimize clinical trials to efficiently and effectively test these new treatments.
Prevalence of clinic-defined food allergy in early adolescence: The SchoolNuts study J. Allergy Clin. Immunol. (IF 13.081) Pub Date : 2017-07-26 Mari Sasaki, Jennifer J. Koplin, Shyamali C. Dharmage, Michael J. Field, Susan M. Sawyer, Vicki McWilliam, Rachel L. Peters, Lyle C. Gurrin, Peter J. Vuillermin, Jo Douglass, Angela Pezic, Maia Brewerton, Mimi L.K. Tang, George C. Patton, Katrina J. Allen
Background Rising rates of food-induced anaphylaxis have recently been shown in the adolescent age group, following earlier descriptions of a rise in children younger than 5 years. However, few population-based studies have examined the prevalence of food allergy in adolescence using objective measures such as oral food challenge (OFC). Objective We sought to determine the prevalence of food allergy among a population-based sample of 10- to 14-year-old adolescents using clinical evaluation including OFC to confirm the diagnosis. Methods Schools were randomly selected from greater metropolitan Melbourne, Australia. Students aged 10 to 14 years, and their parents, were asked to complete a questionnaire regarding the adolescent's food allergy or food-related reactions. Clinic evaluation, which consisted of skin prick tests and OFC where eligible, was undertaken if students were suspected to have current food allergy from parent response. Among 9816 students assessed, 5016 had complete parent response and clinic evaluation when eligible. An additional 4800 students had student questionnaires only. Results The prevalence of clinic-defined current food allergy based on history, sensitization data, and OFC results was 4.5% (95% CI, 3.9-5.1), with the most common food triggers being peanut, 2.7% (95% CI, 2.3-3.2), and tree nut, 2.3% (95% CI, 1.9-2.8). Among the additional group of 4800 adolescents who had only self-reported food allergy status available, the prevalence of self-reported current food allergy was 5.5% (95% CI, 4.9-6.2), with peanut, 2.8% (95% CI, 2.3-3.3), and tree nut, 2.3% (95% CI, 1.9-2.8), the most common. Conclusions Approximately 1 in 20 10- to 14-year-old school students in Melbourne has current food allergy. This high prevalence suggests that the previously reported rise in food-induced anaphylaxis in this age group may reflect an increasing prevalence of food allergy rather than simply increased reporting of anaphylaxis.
Pathway discovery using transcriptomic profiles in adult-onset severe asthma J. Allergy Clin. Immunol. (IF 13.081) Pub Date : 2017-07-26 Pieter-Paul Hekking, Matt J. Loza, Stelios Pavlidis, Bertrand De Meulder, Diane Lefaudeux, Fred Baribaud, Charles Auffray, Ariane H. Wagener, Paul Brinkman, Rene. Lutter, ArunaT. Bansal, Ana R. Sousa, Steve. Bates, Yannis Pandis, Louise J. Fleming, Dominique E. Shaw, Stephen J. Fowler, Y. Guo, Peter J. Sterk
Inflammatory mediators mediate airway smooth muscle contraction through a G protein-coupled receptor–transmembrane protein 16A–voltage-dependent Ca2+ channel axis and contribute to bronchial hyperresponsiveness in asthma J. Allergy Clin. Immunol. (IF 13.081) Pub Date : 2017-07-25 Pei Wang, Wei Zhao, Jie Sun, Tao Tao, Xin Chen, Yan-Yan Zheng, Cheng-Hai Zhang, Zhong Chen, Yun-Qian Gao, Fan She, Ye-Qiong Li, Li-Sha Wei, Ping Lu, Cai-Ping Chen, Ji Zhou, Da-Quan Wang, Liang Chen, Xiao-Hao Shi, Min-Sheng Zhu
Sputum autoantibodies in patients with severe eosinophilic asthma J. Allergy Clin. Immunol. (IF 13.081) Pub Date : 2017-07-24 Manali Mukherjee, David C. Bulir, Katherine Radford, Melanie Kjarsgaard, Chynna Margaret Huang, Elizabeth A. Jacobsen, Sergei I. Ochkur, Ana Catuneanu, Hanah Lamothe-Kipnes, James Mahony, James J. Lee, Paige Lacy, Parameswaran K. Nair
Background The persistence of eosinophils in sputum despite high doses of corticosteroids indicates disease severity in asthmatic patients. Chronic inflamed airways can lose tolerance over time to immunogenic entities released on frequent eosinophil degranulation, which further contributes to disease severity and necessitates an increase in maintenance corticosteroids. Objectives We sought to investigate the possibility of a polyclonal autoimmune event in the airways of asthmatic patients and to identify associated clinical and molecular characteristics. Methods The presence of autoantibodies against eosinophil peroxidase (EPX) and anti-nuclear antibodies was investigated in patients with eosinophilic asthma maintained on high-dose corticosteroids, prednisone, or both. The ability of sputum immunoglobulins to induce eosinophil degranulation in vitro was assessed. In addition, the associated inflammatory microenvironment in patients with detectable autoantibodies was examined. Results We report a “polyclonal” autoimmune event occurring in the airways of prednisone-dependent asthmatic patients with increased eosinophil activity, recurrent pulmonary infections, or both, as evident by the concomitant presence of sputum anti-EPX and anti-nuclear antibodies of the IgG subtype. Extensive cytokine profiling of sputum revealed a TH2-dominated microenvironment (eotaxin-2, IL-5, IL-18, and IL-13) and increased signalling molecules that support the formation of ectopic lymphoid structures (B-cell activating factor and B cell–attracting chemokine 1). Immunoprecipitated sputum immunoglobulins from patients with increased autoantibody levels triggered eosinophil degranulation in vitro, with release of extensive histone-rich extracellular traps, an event unsuppressed by dexamethasone and possibly contributing to the steroid-unresponsive nature of these eosinophilic patients. Conclusion This study identifies an autoimmune endotype of severe asthma that can be identified by the presence of sputum autoantibodies against EPX and autologous cellular components.
Omalizumab treatment in patients with chronic inducible urticaria: A systematic review of published evidence J. Allergy Clin. Immunol. (IF 13.081) Pub Date : 2017-07-24 Marcus Maurer, Martin Metz, Randolf Brehler, Uwe Hillen, Thilo Jakob, Vera Mahler, Claudia Pföhler, Petra Staubach, Regina Treudler, Bettina Wedi, Markus Magerl
Background Omalizumab, a recombinant anti-IgE antibody, effectively treats chronic spontaneous urticaria. Evidence is lacking in patients with chronic inducible urticarias (CIndUs), which are frequently H1-antihistamine resistant. Objective From the current published literature, we aimed to determine the strength of evidence for omalizumab efficacy and safety in the treatment of CIndUs. Methods We performed a PubMed search to identify evidence on omalizumab use in the following 9 CIndU subtypes: symptomatic dermographism, cold urticaria, delayed-pressure urticaria, solar urticaria, heat urticaria, vibratory angioedema, cholinergic urticaria, contact urticaria, and aquagenic urticaria. Results Forty-three trials, case studies, case reports, and analyses were identified. Our review indicates that omalizumab has substantial benefits in patients with various CIndUs. The evidence is strongest for symptomatic dermographism, cold urticaria, and solar urticaria. Little/no evidence was available on vibratory angioedema and aquagenic and contact urticaria. Our review supports rapid onset of action demonstrated through early symptom control in most cases, sometimes within 24 hours. Many patients gained complete/partial symptom relief and substantially improved quality of life. Adverse events were generally low, with omalizumab being well tolerated by most patients, including children. Conclusions A strong body of evidence supports the use of omalizumab in the treatment of patients with therapy-refractory CIndU. More data from randomized controlled studies are warranted.
Genetic and epigenetic regulation of YKL-40 in childhood J. Allergy Clin. Immunol. (IF 13.081) Pub Date : 2017-07-21 Stefano Guerra, Erik Melén, Jordi Sunyer, Cheng-Jian Xu, Iris Lavi, Marta Benet, Mariona Bustamante, Anne-Elie Carsin, Carlota Dobaño, Mònica Guxens, Christina Tischer, Martine Vrijheid, Inger Kull, Anna Bergström, Ashish Kumar, Cilla Söderhäll, Ulrike Gehring, Dorieke J. Dijkstra, Gerard H. Koppelman
Background Circulating levels of the chitinase-like protein YKL-40 are influenced by genetic variation in its encoding gene (chitinase 3–like 1 [CHI3L1]) and are increased in patients with several diseases, including asthma. Epigenetic regulation of circulating YKL-40 early in life is unknown. Objective We sought to determine (1) whether methylation levels at CHI3L1 CpG sites mediate the association of CHI3L1 single nucleotide polymorphisms (SNPs) with YKL-40 levels in the blood and (2) whether these biomarkers (CHI3L1 SNPs, methylation profiles, and YKL-40 levels) are associated with asthma in early childhood. Methods We used data from up to 2405 participants from the Spanish Infancia y Medio Ambiente; the Swedish Barn/Children, Allergy, Milieu, Stockholm, Epidemiological survey; and the Dutch Prevention and Incidence of Asthma and Mite Allergy birth cohorts. Associations between 68 CHI3L1 SNPs, methylation levels at 14 CHI3L1 CpG sites in whole-blood DNA, and circulating YKL-40 levels at 4 years of age were tested by using correlation analysis, multivariable regression, and mediation analysis. Each of these biomarkers was also tested for association with asthma at 4 years of age by using multivariable logistic regression. Results YKL-40 levels were significantly associated with 7 SNPs and with methylation at 5 CpG sites. Consistent associations between these 7 SNPs (particularly rs10399931 and rs4950928) and 5 CpG sites were observed. Alleles linked to lower YKL-40 levels were associated with higher methylation levels. Participants with high YKL-40 levels (defined as the highest YKL-40 tertile) had increased odds for asthma compared with subjects with low YKL-40 levels (meta-analyzed adjusted odds ratio, 1.90 [95% CI, 1.08-3.36]). In contrast, neither SNPs nor methylation levels at CpG sites in CHI3L1 were associated with asthma. Conclusions The effects of CHI3L1 genetic variation on circulating YKL-40 levels are partly mediated by methylation profiles. In our study YKL-40 levels, but not CHI3L1 SNPs or methylation levels, were associated with childhood asthma.
Promising approaches for the treatment and prevention of viral respiratory illnesses J. Allergy Clin. Immunol. (IF 13.081) Pub Date : 2017-07-21 Nikolaos G. Papadopoulos, Spyridon Megremis, Nikolaos A. Kitsioulis, Olympia Vangelatou, Peter West, Paraskevi Xepapadaki
Viral respiratory tract infections are the most common human ailments, leading to enormous health and economic burden. Hundreds of viral species and subtypes have been associated with these conditions, with influenza viruses, respiratory syncytial virus, and rhinoviruses being the most frequent and with the highest burden. When considering prevention or treatment of viral respiratory tract infections, potential targets include the causative pathogens themselves but also the immune response, disease transmission, or even just the symptoms. Strategies targeting all these aspects are developing concurrently, and several novel and promising approaches are emerging. In this perspective we overview the entire range of options and highlight some of the most promising approaches, including new antiviral agents, symptomatic or immunomodulatory drugs, the re-emergence of natural remedies, and vaccines and public health policies toward prevention. Wide-scale prevention through immunization appears to be within reach for respiratory syncytial virus and promising for influenza virus, whereas additional effort is needed in regard to rhinovirus, as well as other respiratory tract viruses.
Toll-like receptor 3 blockade in rhinovirus-induced experimental asthma exacerbations: A randomized controlled study J. Allergy Clin. Immunol. (IF 13.081) Pub Date : 2017-07-20 Philip E. Silkoff, Susan Flavin, Robert Gordon, Mathew J. Loza, Peter J. Sterk, Rene Lutter, Zuzana Diamant, Ronald B. Turner, Brian J. Lipworth, David Proud, Dave Singh, Andreas Eich, Vibeke Backer, James E. Gern, Christian Herzmann, Scott A. Halperin, Tjeert T. Mensinga, Alfred M. Del Vecchio, Sebastian L. Johnston
Background Human rhinoviruses (HRVs) commonly precipitate asthma exacerbations. Toll-like receptor 3, an innate pattern recognition receptor, is triggered by HRV, driving inflammation that can worsen asthma. Objective We sought to evaluate an inhibitory mAb to Toll-like receptor 3, CNTO3157, on experimental HRV-16 inoculation in healthy subjects and asthmatic patients. Methods In this double-blind, multicenter, randomized, parallel-group study in North America and Europe, healthy subjects and patients with mild-to-moderate stable asthma received single or multiple doses of CNTO3157 or placebo, respectively, and were then inoculated with HRV-16 within 72 hours. All subjects were monitored for respiratory symptoms, lung function, and nasal viral load. The primary end point was maximal decrease in FEV1 during 10 days after inoculation. Results In asthmatic patients (n = 63) CNTO3157 provided no protection against FEV1 decrease (least squares mean: CNTO3157 [n = 30] = −7.08% [SE, 8.15%]; placebo [n = 25] = −5.98% [SE, 8.56%]) or symptoms after inoculation. In healthy subjects (n = 12) CNTO3157 versus placebo significantly attenuated upper (P = .03) and lower (P = .02) airway symptom scores, with area-under-the-curve increases of 9.1 (15.1) versus 34.9 (17.6) and 13.0 (18.4) versus 50.4 (25.9) for the CNTO3157 (n = 8) and placebo (n = 4) groups, respectively, after inoculation. All of the severe and 4 of the nonserious asthma exacerbations occurred while receiving CNTO3157. Conclusion In summary, CNTO3157 was ineffective in attenuating the effect of HRV-16 challenge on lung function, asthma control, and symptoms in asthmatic patients but suppressed cold symptoms in healthy subjects. Other approaches, including blockade of multiple pathways or antiviral agents, need to be sought for this high unmet medical need.
Gamma tocopherol-enriched supplement reduces sputum eosinophilia and endotoxin-induced sputum neutrophilia in volunteers with asthma J. Allergy Clin. Immunol. (IF 13.081) Pub Date : 2017-07-20 Allison J. Burbank, Charity G. Duran, Yinghao Pan, Patricia Burns, Susan Jones, Qing Jiang, Chao Yang, Sha’Leema Jenkins, Heather Wells, Neil Alexis, Mehmet Kesimer, William D. Bennett, Haibo Zhou, David B. Peden, Michelle L. Hernandez
Background We and others have shown that the gamma tocopherol (γT) isoform of vitamin E has multiple anti-inflammatory and antioxidant actions and that γT supplementation reduces eosinophilic and endotoxin (LPS)-induced neutrophilic airway inflammation in animal models and healthy human volunteers. Objective We sought to determine whether γT supplementation reduces eosinophilic airway inflammation and acute neutrophilic response to inhaled LPS challenge in volunteers with asthma. Methods Participants with mild asthma were enrolled in a double-blinded, placebo-controlled crossover study to assess the effect of 1200 mg of γT daily for 14 days on sputum eosinophils, mucins, and cytokines. We also assessed the effect on acute inflammatory response to inhaled LPS challenge following γT treatment, focusing on changes in sputum neutrophilia, mucins, and cytokines. Mucociliary clearance was measured using gamma scintigraphy. Results Fifteen subjects with mild asthma completed both arms of the study. Compared with placebo, γT notably reduced pre-LPS challenge sputum eosinophils and mucins, including mucin 5AC and reduced LPS-induced airway neutrophil recruitment 6 and 24 hours after challenge. Mucociliary clearance was slowed 4 hours postchallenge in the placebo group but not in the γT treatment group. Total sputum mucins (but not mucin 5AC) were reduced at 24 hours postchallenge during γT treatment compared with placebo. Conclusions When compared with placebo, γT supplementation for 14 days reduced inflammatory features of asthma, including sputum eosinophils and mucins, as well as acute airway response to inhaled LPS challenge. Larger scale clinical trials are needed to assess the efficacy of γT supplements as a complementary or steroid-sparing treatment for asthma.
Leveraging Siglec-8 endocytic mechanisms to kill human eosinophils and malignant mast cells J. Allergy Clin. Immunol. (IF 13.081) Pub Date : 2017-07-20 Jeremy A. O'Sullivan, Daniela J. Carroll, Yun Cao, Adriano N. Salicru, Bruce S. Bochner
Background Sialic acid–binding immunoglobulin-like lectin (Siglec)-8 is a cell-surface protein expressed selectively on human eosinophils, mast cells, and basophils, making it an ideal target for the treatment of diseases involving these cell types. However, the effective delivery of therapeutic agents to these cells requires an understanding of the dynamics of Siglec-8 surface expression. Objectives We sought to determine whether Siglec-8 is endocytosed in human eosinophils and malignant mast cells, identify mechanisms underlying its endocytosis, and demonstrate whether a toxin can be targeted to Siglec-8–bearing cells to kill these cells. Methods Siglec-8 surface dynamics were examined by flow cytometry using peripheral blood eosinophils, mast cell lines, and Siglec-8–transduced cells in the presence of inhibitors targeting components of endocytic pathways. Siglec-8 intracellular trafficking was followed by confocal microscopy. The ribosome-inhibiting protein saporin was conjugated to a Siglec-8–specific antibody to examine the targeting of an agent to these cells through Siglec-8 endocytosis. Results Siglec-8 endocytosis required actin rearrangement, tyrosine kinase and protein kinase C activities, and both clathrin and lipid rafts. Internalized Siglec-8 localized to the lysosomal compartment. Maximal endocytosis in Siglec-8–transduced HEK293T cells required an intact immunoreceptor tyrosine-based inhibitory motif. Siglec-8 was also shuttled to the surface via a distinct pathway. Sialidase treatment of eosinophils revealed that Siglec-8 is partially masked by sialylated cis ligands. Targeting saporin to Siglec-8 consistently caused extensive cell death in eosinophils and the human mast cell leukemia cell line HMC-1.2. Conclusions Therapeutic payloads can be targeted selectively to eosinophils and malignant mast cells by exploiting this Siglec-8 endocytic pathway.
Differential connectivity of gene regulatory networks distinguishes corticosteroid response in asthma J. Allergy Clin. Immunol. (IF 13.081) Pub Date : 2017-07-20 Weiliang Qiu, Feng Guo, Kimberly Glass, Guo Cheng Yuan, John Quackenbush, Xiaobo Zhou, Kelan G. Tantisira
Sleep deprivation predisposes allergic mice to neutrophilic lung inflammation J. Allergy Clin. Immunol. (IF 13.081) Pub Date : 2017-07-19 Jethe O.F. Nunes, Juliana de Souza Apostolico, David A.G. Andrade, Francieli S. Ruiz, Edgar R. Fernandes, Monica L. Andersen, Alexandre C. Keller, Daniela S. Rosa
Background Although different studies associated sleep deprivation (SD) with systemic inflammatory changes, the effect of sleep duration on the pathology of allergic chronic diseases is poorly understood. Objective We sought to evaluate the influence of SD on allergen-induced pulmonary inflammation. Methods Ovalbumin (OVA)–sensitized C57BL/6 mice were exposed to a first set of intranasal OVA challenge under SD or healthy sleep (HS) conditions, followed by a second OVA challenge, 1 week apart. Some groups were subjected to corticosteroid treatment with dexamethasone. Results OVA-sensitized mice with SD had more severe airway inflammation than the allergic group with HS. Analysis of lung parenchyma revealed that the inflammation in allergic mice with SD was marked by an influx of neutrophils (mainly) and eosinophils and secretion of IL-6, TNF-α, and IL-17 in contrast to the eosinophilic inflammation and IL-4 production observed in allergic mice with HS. The same cytokine profile was observed in ex vivo culture of cervical lymph node cells and splenocytes, indicating that in allergic mice SD favors immune responses toward a proinflammatory TH17 profile. This idea is supported by the fact that disruption of IL-17 signaling (IL-17 receptor A−/−) prevented airway neutrophilia in allergic mice with SD. Furthermore, allergic mice with SD became refractory to corticosteroid treatment in contrast to the allergic group with HS. Conclusion Collectively, our data show that sleep quality participates in the progression of allergen-induced eosinophilic lung inflammation to corticosteroid-refractory neutrophilic manifestation.
Phosphatase wild-type p53-induced phosphatase 1 controls the development of TH9 cells and allergic airway inflammation J. Allergy Clin. Immunol. (IF 13.081) Pub Date : 2017-07-19 Peng Wang, Huiting Su, Lianjun Zhang, Hui Chen, Xuelian Hu, Fan Yang, Jun Lv, Lianfeng Zhang, Yong Zhao
Airway microbiota signals anabolic and catabolic remodeling in the transplanted lung J. Allergy Clin. Immunol. (IF 13.081) Pub Date : 2017-07-18 Stéphane Mouraux, Eric Bernasconi, Céline Pattaroni, Angela Koutsokera, John-David Aubert, Johanna Claustre, Christophe Pison, Pierre-Joseph Royer, Antoine Magnan, Romain Kessler, Christian Benden, Paola M. Soccal, Benjamin J. Marsland, Laurent P. Nicod,
Respiratory Virus prior to Hematopoietic Cell Transplantation is associated with allo-immune mediated lung syndromes J. Allergy Clin. Immunol. (IF 13.081) Pub Date : 2017-07-15 Birgitta Versluys, Marc Bierings, Jean Luc Murk, Tom Wolfs, Caroline Lindemans, Kors vd Ent, Jaap Jan Boelens
Maternal asthma severity and control during pregnancy and risk of offspring asthma J. Allergy Clin. Immunol. (IF 13.081) Pub Date : 2017-07-13 Xiaoqin Liu, Esben Agerbo, Vivi Schlünssen, Rosalind J. Wright, Jiong Li, Trine Munk-Olsen
Background Severe and uncontrolled asthma during pregnancy has been linked to several unfavorable perinatal outcomes. However, current knowledge on the association between the severity and control of maternal asthma and offspring asthma is sparse. Objective We sought to investigate the extent to which offspring asthma is influenced by maternal asthma severity and control during pregnancy. Methods We performed a prospective population-based cohort study. Using linkage of Danish national registers, we constructed a cohort of 675,379 singletons, of which 15,014 children were born to asthmatic mothers. Among them, 7,188 children were born to mothers with active asthma during pregnancy. We categorized mothers with active asthma into 4 groups based on dispensed antiasthma prescriptions and on use of medical services: mild controlled, mild uncontrolled, moderate-to-severe controlled, and moderate-to-severe uncontrolled asthma. The outcomes were offspring early-onset transient, early-onset persistent, and late-onset asthma. We estimated prevalence ratios (PRs) of each phenotype of asthma using a log-binomial model with 95% CIs. Results Higher prevalence of early-onset persistent asthma was observed among children of asthmatic mothers with mild uncontrolled (PR, 1.19; 95% CI, 1.05-1.35), moderate-to-severe controlled (PR, 1.33; 95% CI, 1.09-1.63), and moderate-to-severe uncontrolled asthma (PR, 1.37; 95% CI, 1.17-1.61) compared with those of mothers with mild controlled asthma. A borderline increased prevalence of early-onset transient asthma was observed among children of mothers with uncontrolled asthma. Conclusion Maternal uncontrolled asthma increases the risk of early-onset persistent and transient asthma. If replicated, this could suggest that maintaining asthma control in pregnancy is an area for possible prevention of specific phenotypes of offspring asthma.
Specific allergen profiles of peanut foods and diagnostic or therapeutic allergenic products J. Allergy Clin. Immunol. (IF 13.081) Pub Date : 2017-07-12 Stephanie Filep, Denise S. Block, Bryan R.E. Smith, Eva M. King, Scott Commins, Michael Kulis, Brian P. Vickery, Martin D. Chapman
Background Generic immunoassays for peanut cannot discriminate between allergen levels in peanut-derived food products or therapeutics. Clinical trials of oral immunotherapy (OIT) are strengthened by using standardized peanut preparations with defined doses of major allergens. Objective This article describes measurement of Ara h 1, Ara h 2, and Ara h 6 in peanut foods and in peanut flour extracts used for allergy diagnosis and OIT. Methods Monoclonal antibody–based enzyme immunoassays for Ara h 1, Ara h 2, and Ara h 6 were used to compare allergen levels in peanut (n = 16) and tree nut (n = 16) butter, peanut flour (n = 11), oils (n = 8), extracts used for diagnosis and OIT (n = 5), and the National Institute for Standards and Technology Peanut Butter Standard Reference Material 2387. Results Roasted peanut butters contained 991 to 21,406 μg/g Ara h 1 and exceeded Ara h 2 and Ara h 6 levels by 2- to 4-fold. Similarly, National Institute for Standards and Technology Peanut Butter Standard Reference Material 2387 contained 11,275 μg/g Ara h 1, 2,522 μg/g Ara h 2, and 2,036 μg/g Ara h 6. In contrast, peanut flours contained 787 to 14,631 μg/g Ara h 2 and exceeded Ara h 1 levels by 2- to 20-fold. Flour extracts used for OIT contained 394 to 505 μg/mL Ara h 1, 1,187 to 5,270 μg/mL Ara h 2, and 1,104 to 8,092 μg/mL Ara h 6. In most cases specific peanut allergens were not detected in tree nut butters or peanut oils. Conclusions The results show marked differences in specific peanut allergen profiles in peanut butter and flour and peanut preparations for clinical use. Roasting can increase Ara h 1 levels in peanut butter. Variability in allergen levels could affect the outcome of clinical trials of peanut OIT, especially with respect to Ara h 1. Specific allergen measurements will improve standardization and provide accurate dosing of peanut preparations that are being used for OIT.
Advances in Asthma 2016: Designing Individualized Approaches to Management J. Allergy Clin. Immunol. (IF 13.081) Pub Date : 2017-07-12 William C. Anderson, Andrea Apter, Cullen M. Dutmer, Daniel A. Searing, Stanley J. Szefler
In this years Advances in Asthma review we discuss viral infections in asthma and potential therapeutic agents, the microbiome, novel genetic associations with asthma, air quality and climate effects on asthma, exposures during development and long term sequelae of childhood asthma, patient centered outcome research, and precision medicine. In addition, we discuss application of biomarkers to precision medicine, and new information on asthma medications. New evidence indicates that rhinovirus-triggered asthma exacerbations become more severe as the degree of sensitization to dust mite and mouse increase. The two biggest drivers of asthma severity were an allergy pathway starting with allergic sensitization and an environmental tobacco smoke pathway. In addition, allergic sensitization and blood eosinophils can be used to select medications for management of early asthma in young children. These current findings, among others covered in this review, represent significant steps towards addressing rapidly advancing areas of knowledge that have implications for asthma management.
Results from the 5-year SQ grass sublingual immunotherapy tablet asthma prevention (GAP) trial in children with grass pollen allergy J. Allergy Clin. Immunol. (IF 13.081) Pub Date : 2017-07-06 Erkka Valovirta, Thomas H. Petersen, Teresa Piotrowska, Mette K. Laursen, Jens S. Andersen, Helle F. Sørensen, Rabih Klink
Functional role of kynurenine and aryl hydrocarbon receptor axis in chronic rhinosinusitis with nasal polyps J. Allergy Clin. Immunol. (IF 13.081) Pub Date : 2017-07-06 Heng Wang, Danh C. Do, Jinxin Liu, Baofeng Wang, Jingjing Qu, Xia Ke, Xiaoyan Luo, Ho Man Tang, Ho Lam Tang, Chengping Hu, Mark E. Anderson, Zheng Liu, Peisong Gao
Background Chronic rhinosinusitis with nasal polyps (CRSwNP) is associated with mast cell–mediated inflammation and heightened oxidant stress. Kynurenine (KYN), an endogenous tryptophan metabolite, can promote allergen-induced mast cell activation through the aryl hydrocarbon receptor (AhR). Objectives We sought to determine the role of the KYN/AhR axis and oxidant stress in mast cell activation and the development of CRSwNP. Methods We measured the expression of indoleamine 2,3-dioxygenase 1, tryptophan 2,3-dioxygenase, KYN, and oxidized calmodulin-dependent protein kinase II (ox-CaMKII) in nasal polyps and controls. KYN-potentiated ovalbumin (OVA)-induced ROS generation, cell activation, and ox-CaMKII expression were investigated in wild-type and AhR-deficient (AhR−/−) mast cells. The role of ox-CaMKII in mast cell activation was further investigated. Results Nasal polyps in CRSwNP showed an increased expression of indoleamine 2,3-dioxygenase 1, tryptophan2,3-dioxygenase, and KYN compared with controls. AhR was predominantly expressed in mast cells in nasal polyps. Activated mast cells and local IgE levels were substantially increased in eosinophilic polyps compared with noneosinophilic polyps and controls. Furthermore, KYN potentiated OVA-induced ROS generation, intracellular Ca2+ levels, cell activation, and expression of ox-CaMKII in wild-type, but not in AhR−/− mast cells. Compared with noneosinophilic polyps and controls, eosinophilic polyps showed increased expression of ox-CaMKII in mast cells. Mast cells from ROS-resistant CaMKII MMVVδ mice or pretreated with CaMKII inhibitor showed protection against KYN-promoted OVA-induced mast cell activation. Conclusions These studies support a potentially critical but previously unidentified function of the KYN/AhR axis in regulating IgE-mediated mast cell activation through ROS and ox-CaMKII in CRSwNP.
Peanut-specific type 1 regulatory T cells induced in vitro from allergic subjects are functionally impaired J. Allergy Clin. Immunol. (IF 13.081) Pub Date : 2017-07-06 Laurence Pellerin, Jennifer Anne Jenks, Sharon Chinthrajah, Tina Dominguez, Whitney Block, Xiaoying Zhou, Arram Noshirvan, Silvia Gregori, Maria Grazia Roncarolo, Kari Christine Nadeau, Rosa Bacchetta
Reduced need for surgery in severe nasal polyposis with mepolizumab: Randomized trial J. Allergy Clin. Immunol. (IF 13.081) Pub Date : 2017-07-04 Claus Bachert, Ana R. Sousa, Valerie J. Lund, Glenis K. Scadding, Philippe Gevaert, Shuaib Nasser, Stephen R. Durham, Marjolein E. Cornet, Harsha H. Kariyawasam, Jane Gilbert, Daren Austin, Aoife C. Maxwell, Richard P. Marshall, Wytske J. Fokkens
Background Patients with eosinophilic nasal polyposis frequently require surgery, and recurrence rates are high. Objective We sought to assess the efficacy and safety of mepolizumab versus placebo for severe bilateral nasal polyposis. Methods This randomized, double-blind, placebo-controlled trial recruited patients aged 18 to 70 years with recurrent nasal polyposis requiring surgery. Patients received 750 mg of intravenous mepolizumab or placebo every 4 weeks for a total of 6 doses in addition to daily topical corticosteroid treatment. The primary end point was the number of patients no longer requiring surgery at Week 25 based on a composite end point of endoscopic nasal polyp score and nasal polyposis severity visual analog scale (VAS) score. Secondary end points included change in nasal polyposis severity VAS score, endoscopic nasal polyp score, improvement in individual VAS symptoms (rhinorrhea, mucus in throat, nasal blockage, and sense of smell), patient-reported outcomes, and safety. Results One hundred five patients received mepolizumab (n = 54) or placebo (n = 51). A significantly greater proportion of patients in the mepolizumab group compared with the placebo group no longer required surgery at Week 25 (16 [30%] vs 5 [10%], respectively; P = .006). There was a significant improvement in nasal polyposis severity VAS score, endoscopic nasal polyp score, all individual VAS symptom scores, and Sino-Nasal Outcome Test patient-reported outcome score in the mepolizumab compared with placebo groups. Mepolizumab's safety profile was comparable with that of placebo. Conclusion In patients with recurrent nasal polyposis receiving topical corticosteroids who required surgery, mepolizumab treatment led to a greater reduction in the need for surgery and a greater improvement in symptoms than placebo.
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