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  • Superantigen-related Th2 CD4+ T Cells in Non-asthmatic Chronic Rhinosinusitis with Nasal Polyps
    J. Allergy Clin. Immunol. (IF 14.110) Pub Date : 2020-01-25
    Min-Seok Rha; Sang-Wook Kim; Dong-Yeop Chang; Jin-Ku Lee; Jihye Kim; Su-Hyung Park; Roza Khamulratova; Hee-Suk Lim; Kyoung Mi Eun; Seung-No Hong; Dae Woo Kim; Eui-Cheol Shin
    更新日期:2020-01-26
  • Charcot-Leyden Crystal Protein/Galectin-10 Interacts with Cationic Ribonucleases and is Required for Eosinophil Granulogenesis
    J. Allergy Clin. Immunol. (IF 14.110) Pub Date : 2020-01-23
    Milica M. Grozdanovic; Christine B. Doyle; Li Liu; Brian Maybruck; Mark A. Kwatia; Nethaji Thiyagarajan; K. Ravi Acharya; Steven J. Ackerman
    更新日期:2020-01-24
  • Long-term air pollution exposure is associated with increased severity of rhinitis in 2 European cohorts
    J. Allergy Clin. Immunol. (IF 14.110) Pub Date : 2020-01-23
    Emilie Burte; Bénédicte Leynaert; Alessandro Marcon; Jean Bousquet; Meriem Benmerad; Roberto Bono; Anne-Elie Carsin; Kees de Hoogh; Bertil Forsberg; Frederic Gormand; Joachim Heinrich; Jocelyne Just; Mark Nieuwenhuijsen; Isabelle Pin; Morgane Stempfelet; Jordi Sunyer; Simona Villani; Nino Künzli; Bénédicte Jacquemin

    Background Very few studies have examined the association between long-term outdoor air pollution and rhinitis severity in adults. Objective We sought to assess the cross-sectional association between individual long-term exposure to air pollution and severity of rhinitis. Methods Participants with rhinitis from 2 multicenter European cohorts (Epidemiological Study on the Genetics and Environment on Asthma and the European Community Respiratory Health Survey) were included. Annual exposure to NO2, PM10, PM2.5, and PMcoarse (calculated by subtracting PM2.5 from PM10) was estimated using land-use regression models derived from the European Study of Cohorts for Air Pollution Effects project, at the participants’ residential address. The score of rhinitis severity (range, 0-12), based on intensity of disturbance due to symptoms reported by questionnaire, was categorized into low (reference), mild, moderate, and high severity. Polytomous logistic regression models with a random intercept for city were used. Results A total of 1408 adults with rhinitis (mean age, 52 years; 46% men, 81% from the European Community Respiratory Health Survey) were included. The median (1st quartile-3rd quartile) score of rhinitis severity was 4 (2-6). Higher exposure to PM10 was associated with higher rhinitis severity (adjusted odds ratio [95% CI] for a 10 μg/m3 increase in PM10: for mild: 1.20 [0.88-1.64], moderate: 1.53 [1.07-2.19], and high severity: 1.72 [1.23-2.41]). Similar results were found for PM2.5. Higher exposure to NO2 was associated with an increased severity of rhinitis, with similar adjusted odds ratios whatever the level of severity. Adjusted odds ratios were higher among participants without allergic sensitization than among those with, but interaction was found only for NO2. Conclusions People with rhinitis who live in areas with higher levels of pollution are more likely to report more severe nasal symptoms. Further work is required to elucidate the mechanisms of this association.

    更新日期:2020-01-24
  • Exposure to diesel exhaust particles increases susceptibility to invasive pneumococcal disease
    J. Allergy Clin. Immunol. (IF 14.110) Pub Date : 2020-01-23
    Rebecca K. Shears; Laura C. Jacques; Georgia Naylor; Lisa Miyashita; Shadia Khandaker; Filipa Lebre; Ed C. Lavelle; Jonathan Grigg; Neil French; Daniel R. Neill; Aras Kadioglu
    更新日期:2020-01-23
  • Association of HLA-DRB1*09:01 with tIgE levels among African ancestry individuals with asthma
    J. Allergy Clin. Immunol. (IF 14.110) Pub Date : 2020-01-22
    Nicolas Vince; Sophie Limou; Michelle Daya; Wataru Morii; Nicholas Rafaels; Estelle Geffard; Venceslas Douillard; Alexandre Walencik; Meher Preethi Boorgula; Sameer Chavan; Candelaria Vergara; Victor E. Ortega; James G. Wilson; Leslie A. Lange; Harold Watson; Dan L. Nicolae; Deborah A. Meyers; Nadia N. Hansel; Pierre-Antoine Gourraud

    Background Asthma is a complex chronic inflammatory disease of the airways. Association studies between HLA and asthma were first reported in the 1970’s, and yet, the precise role of HLA alleles in asthma is not fully understood. Numerous genome-wide association studies were recently conducted on asthma, but were always limited to simple genetic markers (SNPs) and not complex HLA gene polymorphisms (alleles/haplotypes), therefore not capturing the biological relevance of this complex locus for asthma pathogenesis. Objective To run the first HLA-centric association study with asthma and specific asthma-related phenotypes in a large cohort of African ancestry individuals. Methods We collected high-density genomics data for the CAAPA participants (Consortium on Asthma among African-ancestry Populations in the Americas, N=4,993). Using computer-intensive machine-learning attribute bagging methods to infer HLA alleles, and Easy-HLA to infer HLA 5-gene haplotypes, we conducted a high-throughput HLA-centric association study of asthma susceptibility and total serum IgE levels (tIgE) in subjects with and without asthma. Results Among the 1,607 individuals with asthma, 972 had available tIgE levels with a mean tIgE level of 198.7 IU.ml-1. We could not identify any association with asthma susceptibility. However, we showed that HLA-DRB1*09:01 was associated with increased tIgE levels (P=8.5x10-4, weighted effect size 0.51 [0.15-0.87]). Conclusions We identified for the first time an HLA allele associated with tIgE levels in African ancestry individuals with asthma. Our report emphasizes that by leveraging powerful computational machine-learning methods, specific/extreme phenotypes, and population diversity, we can explore HLA gene polymorphisms in depth and reveal the full extent of complex disease associations.

    更新日期:2020-01-22
  • Sensitization to grass pollen allergen molecules in a birth cohort – Phl p 4 as early indicator of grass pollen allergy
    J. Allergy Clin. Immunol. (IF 14.110) Pub Date : 2020-01-17
    Marit Westman; Karin Åberg; Danijela Apostolovic; Christian Lupinek; Pia Gattinger; Irene Mittermann; Niklas Andersson; Erik Melén; Anna Bergström; Josep M. Antó; Jean Bousquet; Rudolf Valenta; Magnus Wickman; Marianne van Hage

    Background Grass pollen allergy is one of the most common allergies worldwide. Objective To evaluate the usefulness of grass pollen allergen molecules for prediction of grass pollen allergy during childhood up to adolescence. Method Questionnaire data and sera obtained at 4, 8 and 16 years from the population-based BAMSE birth cohort were used. Sera from 763 representative subjects with serum samples available at all three ages were analysed for IgE-reactivity to 8 Phleum pratense allergens (MeDALL-chip) and to timothy extract (ImmunoCAP). Allergic rhinitis to grass pollen (ARg) was defined as upper airway symptoms during grass pollen exposure. Results The prevalence of sensitization to any Phl p molecule was higher compared to timothy extract at all three ages; 4 (9.7% vs. 6.8%), 8 (28.4% vs 15.3%) and 16 (37.1% vs. 27.1%) years. General estimating equations (GEE) analyses revealed that among children sensitized at 4 years, the overall odds ratio (OR) of later ARg (up to 16 years) was increased only for IgE-reactivity to Phl p 1 (OR=4.9) and nPhl p 4 (OR=6.9). The likelihood of later symptoms increased with the number of allergen molecules; at 4 years ≥2 molecules predicted ARg to 78% and ≥3 molecules 95%. A positive test for timothy extract predicted ARg to 70%. Conclusions nPhl p 4 is a hitherto unrecognized early indicator of grass pollen allergy, in addition to Phl p 1. To identify grass pollen sensitization and predict later ARg, allergen molecules are of added value to timothy extract and may help clinicians improve prediction of grass pollen allergy.

    更新日期:2020-01-17
  • A role for early oral exposure to house dust mite allergens through breastmilk in IgE-mediated food allergy susceptibility
    J. Allergy Clin. Immunol. (IF 14.110) Pub Date : 2020-01-17
    Akila Rekima; Chrystelle Bonnart; Patricia Macchiaverni; Jessica Metcalfe; Meri K. Tulic; Nicolas Halloin; Samah Rekima; Jon Genuneit; Samantha Zanelli; Samara Medeiros; Debra J. Palmer; Susan Prescott; Valerie Verhasselt
    更新日期:2020-01-17
  • Vagal sensory neurons drive mucous cell metaplasia
    J. Allergy Clin. Immunol. (IF 14.110) Pub Date : 2020-01-16
    Sébastien Talbot; Benjamin Doyle; Junwei Huang; Jo-Chiao Wang; Maryam Ahmadi; David P. Roberson; Ajay Yekkirala; Simmie L. Foster; Liam E. Browne; Bruce P. Bean; Bruce D. Levy; Clifford J. Woolf

    Airway sensory neuron-produced Substance P heightens allergy-induced goblet cell hyperplasia and hypersecretion of Muc5AC, electrically silencing these overreactive neurons reduced these components of lung type 2 allergic inflammatory response.

    更新日期:2020-01-17
  • CRISPR gene-engineered CYBBko THP-1 cell lines highlight the crucial role of NADPH-induced reactive oxygen species for regulating inflammasome activation
    J. Allergy Clin. Immunol. (IF 14.110) Pub Date : 2020-01-15
    Aissa Benyoucef; Lorie Marchitto; Fabien Touzot

    CRISPR-Cas9 engineered CYBBko THP-1 cell lines display an inflammatory profile with increased IL-1β, IL-6 and TNF-α secretion as consequence of NADPH-induced ROS deficiency. This phenotype is reminiscent of the one observed in phagocytes from CGD patients.

    更新日期:2020-01-15
  • Nasal DNA methylation profiling of asthma and rhinitis
    J. Allergy Clin. Immunol. (IF 14.110) Pub Date : 2020-01-14
    Cancan Qi; Yale Jiang; Ivana V. Yang; Erick Forno; Ting Wang; Judith M. Vonk; Ulrike Gehring; Henriëtte A. Smit; Edith B. Milanzi; Orestes A. Carpaij; Marijn Berg; Laura Hesse; Sharon Brouwer; Jonathan Cardwell; Cornelis J. Vermeulen; Edna Acosta-Pérez; Glorisa Canino; Nadia Boutaoui; Gerard H. Koppelman

    Background Epigenetic signatures in the nasal epithelium, which is a primary interface with the environment and an accessible proxy for the bronchial epithelium, might provide insights into mechanisms of allergic disease. Objective We aimed to identify and interpret methylation signatures in nasal epithelial brushes associated with rhinitis and asthma. Methods Nasal epithelial brushes were obtained from 455 children at the 16 year follow-up of the Dutch PIAMA birth cohort study. Epigenome-wide association studies (EWAS) were performed on asthma, rhinitis and asthma and/or rhinitis (AsRh) using logistic regression, and top results were replicated in two independent cohorts of African American and Puerto Rican children. Significant CpG sites (CpGs) were related to environmental exposures (pets, active and passive smoking and molds) during secondary school, and correlated to gene expression by RNA-sequencing (n=244). Results The EWAS identified CpGs significantly associated with rhinitis (n=81) and AsRh (n=75), but not with asthma. We significantly replicated 62 /81 CpGs with rhinitis, and 60/75 with AsRh, as well as one CpG with asthma. Methylation of cg03565274 was negatively associated with AsRh, and positively associated with pets exposure during secondary school. DNA methylation signals associated with AsRh were mainly driven by specific IgE positive subjects. DNA methylation related to gene transcripts that were enriched for immune pathways, and expressed in immune and epithelial cells. Nasal CpGs performed well in predicting AsRh. Conclusions We identified replicable DNA methylation profiles of asthma and rhinitis in nasal brushes. Pets exposure may affect nasal epithelial methylation in relation to asthma and rhinitis.

    更新日期:2020-01-14
  • Lymphocyte DNA methylation mediates genetic risk at shared immune mediated disease loci
    J. Allergy Clin. Immunol. (IF 14.110) Pub Date : 2020-01-13
    Alexander D. Clark; Nisha Nair; Amy E. Anderson; Nishanthi Thalayasingam; Najib Naamane; Andrew J. Skelton; Julie Diboll; Anne Barton; Stephen Eyre; John D. Isaacs; Arthur G. Pratt; Louise N. Reynard
    更新日期:2020-01-14
  • Genotype and functional correlates of disease phenotype in deficiency of adenosine deaminase 2 (DADA2)
    J. Allergy Clin. Immunol. (IF 14.110) Pub Date : 2020-01-13
    Pui Y. Lee; Erinn S. Kellner; Yuelong Huang; Elissa Furutani; Zhengping Huang; Wayne Bainter; Mohammed F. Alosaimi; Kelsey Stafstrom; Craig D. Platt; Tali Stauber; Somech Raz; Irit Tirosh; Aaron Weiss; Michael B. Jordan; Christa Krupski; Despina Eleftheriou; Paul Brogan; Ali Sobh; Qing Zhou
    更新日期:2020-01-14
  • Food aversion and poor weight gain in food protein-induced enterocolitis syndrome: a retrospective study
    J. Allergy Clin. Immunol. (IF 14.110) Pub Date : 2020-01-12
    Kuan-Wen Su; Sarita U. Patil; Jennifer L. Stockbridge; Victoria M. Martin; Yamini V. Virkud; Jing-Long Huang; Wayne G. Shreffler; Qian Yuan

    Background Food protein-induced enterocolitis syndrome (FPIES) is a form of non-IgE mediated gastrointestinal food allergy. Insufficient data exist in regards to gastrointestinal history and outcome, particularly comorbidity, family history, food aversion, and poor body weight gain. Objective To identify the gastrointestinal outcomes and related risk factors in FPIES. Methods We analyzed the clinical features and gastrointestinal outcomes of FPIES patients retrospectively at four hospitals in Boston. Results Two hundred and three FPIES patients were identified, including 180 only with acute FPIES, 8 with chronic FPIES, and 15 with both. Oat (34.5%), rice (29.6%), and cow’s milk (19.2%) were the most common food triggers. The prevalence of personal history with allergic proctocolitis (23.2%) and family history with inflammatory bowel diseases (9.4%) and celiac disease (7.3%) were higher than the general population. Compared to the FPIES patients triggered by 1 or 2 foods, the risk of developing food aversion increased in cases triggered by 3 or more foods (adjusted odds ratio (OR) = 3.07 [95% confidence interval (CI), 1.38 – 6.82], P = .006). The risk of poor body weight gain increased in FPIES triggered by cow’s milk (adjusted OR = 3.41 [95% CI, 1.21 – 9.63], P = .02) and banana (adjusted OR = 7.63, [95% CI, 2.10 – 27.80], P = .002). Conclusion Gastrointestinal comorbidities and family history were common in FPIES patients. FPIES patients with 3 or more triggers were at risk of food aversion. Patients with cow’s milk and banana triggered FPIES were at risk of poor body weight gain.

    更新日期:2020-01-13
  • Prevalence and impact of comorbid laryngeal dysfunction in asthma: A systematic review and meta-analysis
    J. Allergy Clin. Immunol. (IF 14.110) Pub Date : 2020-01-12
    Ji-Hyang Lee; Jin An; Ha-Kyeong Won; Yewon Kang; Hyouk-Soo Kwon; Tae-Bum Kim; You Sook Cho; Hee-Bom Moon; Woo-Jung Song; James H. Hull

    Background Laryngeal or vocal cord dysfunction has long been regarded as a mimic of asthma; however recent evidence indicates that it may be a significant comorbid condition in asthmatics. Objective We aimed to systematically estimate the prevalence of comorbid laryngeal dysfunction (LD) in asthmatic adults and to characterize its clinical impact on asthma. Methods Electronic databases were searched for relevant studies published until June 2019. Studies were included if LD was objectively defined by direct visualization of laryngeal movement. Outcomes included the prevalence of LD and its association with clinical asthma indicators, such as severity, control and quality of life. Random effects meta-analyses were performed to calculate the estimates. Results A total of 21 studies involving 1,637 patients were identified. Overall, the pooled prevalence of LD in asthmatic adults was 25% (95% CI: 15-37%; I2=96%). Prevalence estimates differed according to the diagnostic test utilized with lowest overall prevalence (4%; 95% CI: 0-10%; I2=90%) seen when LD was diagnosed by resting laryngoscopy without external stimuli; however, it was much higher in laryngoscopy studies utilizing external trigger, such as exercise (38%, 95% CI: 24-53; I2=90%) or in those using a CT-based diagnostic protocol (36%; 95% CI: 24-49; I2=78%). Only seven studies reported the associations between LD and clinical asthma indicators; inconsistencies between studies limited meaningful conclusions. Conclusion LD may be a common comorbidity in asthma, affecting about 25% of adult patients. Further prospective studies are needed to better characterize its clinical impact and benefits of detecting and managing LD in asthmatic patients.

    更新日期:2020-01-13
  • Interleukin-32γ suppressed atopic dermatitis through inhibition of miR-205 expression via inactivation of nuclear factor-kappa B
    J. Allergy Clin. Immunol. (IF 14.110) Pub Date : 2020-01-10
    Yong Sun Lee; Sang-Bae Han; Hyeon Joo Ham; Ju Ho Park; Jong Sung Lee; Dae Yeon Hwang; Young Suk Jung; Do Young Yoon; Jin Tae Hong

    Background Interleukin 32 (IL-32) is a novel cytokine involved in many inflammatory diseases. However, the role of IL-32γ, an isotype of IL-32, in atopic dermatitis has not been reported. Objective We investigated the effects of IL-32γ on the atopic dermatitis development and its action mechanisms. Methods We used phthalic anhydride (PA) and MC903-inudced atopic dermatitis model using wild type and IL-32γ transgenic mice. We conducted the therapy experiments using recombinant IL-32γ protein in reconstructed human skin model and PA-induced model. We conducted the receive operating characteristic analysis of IL-32γ with new atopic dermatitis biomarkers, IL-31 and IL-33, in serum from atopic dermatitis patients. Results Dermatitis severity and epidermal thickness were significantly reduced in PA and MC903-induced IL-32γ transgenic mice compared to wild type mice. The concentration of AD-related cytokines was reduced in PA and MC903-induced IL-32γ transgenic mice compared to wild type mice. Subsequent analysis showed that IL-32γ inhibits miR-205 expression in PA and MC903-induced skin tissues and TNF-α/IFN-γ-treated HaCaT cells. IL-32γ reduced NF-κB activity in skin tissues from PA and MC903-induced mice and TNF-α/IFN-γ-treated HaCaT cells. NF-κB inhibitor treatment with IL-32γ expression further suppressed expression of inflammatory mediators as well as miR-205 in TNF-α/IFN-γ-treated HaCaT cells. Furthermore, recombinant IL-32γ protein alleviated atopic dermatitis-like inflammation in in vivo and reconstructed human skin model. Spearman’s correlation analysis showed that serum levels of IL-32γ and miR-205 were significantly concordant in patients with atopic dermatitis. Conclusion Our results indicate that IL-32γ reduces atopic dermatitis through the inhibition of miR-205 expression via inactivation of NF-κB.

    更新日期:2020-01-11
  • Evolving Concepts in how Viruses Impact Asthma
    J. Allergy Clin. Immunol. (IF 14.110) Pub Date : 2020-01-09
    Matthew C. Altman; Avraham Beigelman; Christina Ciaccio; James E. Gern; Peter W. Heymann; Daniel J. Jackson; Joshua L. Kennedy; Kirsten Kloepfer; Robert F. Lemanske; Laurie M. McWilliams; Lyndsey Muehling; Christy Nance; R. Stokes Peebles

    Over the last decade, there have been substantial advances in our understanding about how viral infections regulate asthma (Table 1). Important lessons have been learned from birth cohort studies examining viral infections and subsequent asthma, understanding the relationships between host genetics and viral infections, the contributions of respiratory viral infections to patterns of immune development, the impact of environmental exposure on severity of viral infections, and how the viral genome influences host immune responses to viral infections. Further, there has been major progress in our knowledge about how bacteria regulate host immune responses in asthma pathogenesis. In this article, we also examine the dynamics of respiratory tract bacterial colonization during viral upper respiratory tract infection, in addition to the relationship of the gut and respiratory microbiomes with respiratory viral infections. Finally, we focus on potential interventions that could decrease virus-induced wheezing and asthma. There are emerging therapeutic options to decrease severity of wheezing exacerbations caused by respiratory viral infections. Primary prevention is a major goal and a strategy toward this end is considered.

    更新日期:2020-01-09
  • Diagnosis and treatment of eosinophilic esophagitis
    J. Allergy Clin. Immunol. (IF 14.110) Pub Date : 2020-01-03
    Nirmala P. Gonsalves; Seema S. Aceves

    Eosinophilic esophagitis (EoE) is an eosinophil-rich, TH2 antigen–mediated disease of increasing pediatric and adult worldwide prevalence. Diagnosis requires greater than or equal to 15 eosinophils per high-power field on light microscopy. Symptoms reflect esophageal dysfunction, and typical endoscopic features include linear furrows, white plaques, and concentric rings. Progressive disease leads to pathologic tissue remodeling, with ensuing esophageal rigidity and loss of luminal diameter caused by strictures. Therapies include proton pump inhibitors, elimination diets, and topical corticosteroids. Effective treatment can reverse tissue fibrosis in some patients, as well as decrease the rate of food impactions. Esophageal dilation might be required to increase luminal patency. The chronic nature of EoE necessitates long-term therapy to avoid disease recurrence and complications. This review serves the function of providing the current state-of-the-art diagnostic criteria and disease management for adult and pediatric EoE.

    更新日期:2020-01-04
  • The genetic etiology of eosinophilic esophagitis
    J. Allergy Clin. Immunol. (IF 14.110) Pub Date : 2020-01-03
    Leah C. Kottyan; Sreeja Parameswaran; Matthew T. Weirauch; Marc E. Rothenberg; Lisa J. Martin

    Eosinophilic esophagitis (EoE) is a chronic allergic disease associated with marked mucosal eosinophil accumulation. Multiple studies have reported a strong familial component to EoE, with the presence of EoE increasing the risk for other family members with EoE. Epidemiologic studies support an important role for environmental risk factors as modulators of genetic risk. In a small percentage of cases, including patients who have Mendelian diseases with co-occurrent EoE, rare genetic variation with large effect sizes could mediate EoE and explain multigenerational incidence in families. Common genetic risk variants mediate genetic risk for the majority of patients with EoE. Across the 31 reported independent EoE risk loci (P < 10−5), most of the EoE risk variants are located in between genes (36.7%) or within the introns of genes (42.4%). Although some variants do change the amino acid sequence of genes (2.2%), only 3 of the 31 EoE risk loci harbor an amino acid–changing variant. Thus most EoE risk loci are outside of the coding regions of genes, suggesting a key role for gene regulation in patients with EoE, which is consistent with most other complex diseases.

    更新日期:2020-01-04
  • The microbiome and inflammatory bowel disease
    J. Allergy Clin. Immunol. (IF 14.110) Pub Date : 2020-01-03
    Kerri L. Glassner; Bincy P. Abraham; Eamonn M.M. Quigley

    Inflammatory bowel disease (IBD) is a chronic immune-mediated disease affecting the gastrointestinal tract. IBD consists of 2 subtypes: ulcerative colitis and Crohn disease. IBD is thought to develop as a result of interactions between environmental, microbial, and immune-mediated factors in a genetically susceptible host. Of late, the potential role of the microbiome in the development, progression, and treatment of IBD has been a subject of considerable interest and enquiry. Indeed, studies in human subjects have shown that the gut microbiome is different in patients with IBD compared with that in healthy control subjects. Other evidence in support of a fundamental role for the microbiome in patients with IBD includes identification of mutations in genes involved in microbiome-immune interactions among patients with IBD and epidemiologic observations implicating such microbiota-modulating risk factors as antibiotic use, cigarette smoking, levels of sanitation, and diet in the pathogenesis of IBD. Consequently, there has been much interest in the possible benefits of microbiome-modulating interventions, such as probiotics, prebiotics, antibiotics, fecal microbiota transplantation, and gene manipulation in the treatment of IBD. In this review we will discuss the role of the gut microbiome in patients with IBD; our focus will be on human studies.

    更新日期:2020-01-04
  • Staphylococcus aureus internalization in mast cells in nasal polyps: Characterization of interactions and potential mechanisms
    J. Allergy Clin. Immunol. (IF 14.110) Pub Date : 2019-06-27
    Stephen M. Hayes; Timothy C. Biggs; Simon P. Goldie; Philip G. Harries; Andrew F. Walls; Raymond N. Allan; Sylvia L.F. Pender; Rami J. Salib
    更新日期:2020-01-04
  • The IL-37–Mex3B–Toll-like receptor 3 axis in epithelial cells in patients with eosinophilic chronic rhinosinusitis with nasal polyps
    J. Allergy Clin. Immunol. (IF 14.110) Pub Date : 2019-07-19
    Jin-Xin Liu; Bo Liao; Qi-Hong Yu; Hai Wang; Yi-Bo Liu; Cui-Lian Guo; Zhi-Chao Wang; Zhi-Yong Li; Zhe-Zheng Wang; Jian-Wen Ruan; Li Pan; Yin Yao; Cai-Ling Chen; Heng Wang; Yuxia Liang; Guohua Zhen; Zheng Liu
    更新日期:2020-01-04
  • Genetic ancestry does not explain increased atopic dermatitis susceptibility or worse disease control among African American subjects in 2 large US cohorts
    J. Allergy Clin. Immunol. (IF 14.110) Pub Date : 2019-07-29
    Katrina Abuabara; Yue You; David J. Margolis; Thomas J. Hoffmann; Neil Risch; Eric Jorgenson
    更新日期:2020-01-04
  • A novel knock-in mouse model of cryopyrin-associated periodic syndromes with development of amyloidosis: Therapeutic efficacy of proton pump inhibitors
    J. Allergy Clin. Immunol. (IF 14.110) Pub Date : 2019-06-10
    Arinna Bertoni; Sonia Carta; Chiara Baldovini; Federica Penco; Enrica Balza; Silvia Borghini; Marco Di Duca; Emanuela Ognio; Alessio Signori; Paolo Nozza; Francesca Schena; Patrizia Castellani; Claudia Pastorino; Carola Perrone; Laura Obici; Alberto Martini; Isabella Ceccherini; Marco Gattorno; Sabrina Chiesa
    更新日期:2020-01-04
  • How does parental history of atopic disease predict the risk of atopic dermatitis in a child? - a systematic review and meta-analysis
    J. Allergy Clin. Immunol. (IF 14.110) Pub Date : 2019-12-28
    Nina H. Ravn; Anne-Sofie Halling; Aviva G. Berkowitz; Maria R. Rinnov; Jonathan I. Silverberg; Alexander Egeberg; Jacob P. Thyssen

    Background Parental history of atopic disease is a well-established risk factor for development of atopic dermatitis (AD), but several aspects of this association remain unclear. Objective To determine the association of parental history of atopic disease with AD in offspring. Methods We searched PubMed and EMBASE through June 2018 for relevant records and adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. . Pooled odds ratios (OR) with 95% confidence intervals (CI) were calculated using random-effects models. Results 163 records covering 149 unique studies were included. Of these, 119 studies were included in the meta-analysis. Individuals with parental history of atopic disease had increased odds of AD (OR 1.81, 95% CI 1.65-1.99). Parental asthma (OR 1.56, 95% CI 1.18-2.05) and allergic rhinitis (OR 1.68, 95% CI 1.34-2.11) had a smaller effect than AD (OR 3.30, 95% CI 2.46-4.42). The effect of maternal and paternal history was comparable for all atopic diseases. An increase in odds was observed when comparing the effect of having one (OR 1.30, 95% CI 1.15-1.47) or two atopic parents (OR 2.08, 95% CI 1.83-2.36), as well as having a parent with one (OR 1.49, 95% CI 1.28-1.74) or more atopic diseases (OR 2.32, 95% CI 1.92-2.81). Conclusions This study provides evidence-based risk estimates that may guide physicians, who counsel parents with a history of atopic disease about their children’s risk of AD. This information is of particular importance for future efforts towards establishing prophylactic interventions for AD on a general population level.

    更新日期:2019-12-29
  • Progression of acute-to-chronic atopic dermatitis is associated with quantitative rather than qualitative changes in cytokine responses
    J. Allergy Clin. Immunol. (IF 14.110) Pub Date : 2019-12-28
    Lam C. Tsoi; Elke Rodriguez; Dora Stölzl; Ulrike Wehkamp; Jingru Sun; Sascha Gerdes; Mrinal K. Sarkar; Matthias Hübenthal; Chang Zeng; Ranjitha Uppala; Xianying Xing; Frederieke Thielking; Allison C. Billi; William R. Swindell; Alanna Shefler; Jiahan Chen; Matthew T. Patrick; Paul W. Harms; Stephan Weidinger

    Background While multiple studies have assessed molecular changes in chronic atopic dermatitis (AD) lesions, little is known about the transition from acute to chronic disease stages, and the factors and mechanisms that shape chronic inflammatory activity. Objectives We sought to assess the global transcriptome changes that characterize the progression from acute to chronic stages of AD. Methods We analyzed transcriptome changes in paired non-lesional skin, acute and chronic AD lesions from 11 patients and 38 healthy controls by RNA-seq, and conducted in vivo and histological assays to evaluate findings. Results Our data demonstrate that ∼74% of the genes dysregulated in acute lesions remain or are further dysregulated in chronic lesions, whereas only 34% of genes dysregulated in chronic lesions are altered already in the acute stage. Non-lesional AD skin exhibited enrichment of TNF, Th1, Th2, and Th17 response genes. Acute lesions showed marked dendritic cell signatures and a prominent enrichment of Th1, Th2 and Th17 responses, along with increased IL-36 and TSLP expression, which were further heightened in chronic lesions. In addition, genes involved in skin barrier repair, keratinocyte proliferation, wound healing and negative regulation of T cell activation showed a significant dysregulation in the chronic versus acute comparison. Furthermore, our data show progressive changes in vasculature and maturation of dendritic cell subsets with chronicity, with FOXK1 acting as immune regulator. Conclusions Our results show that the changes accompanying the transition from non-lesional to acute to chronic inflammation in AD are quantitative rather than qualitative, with chronic AD having heightened Th2, Th1, Th17, and IL36 responses and skin barrier repair mechanisms. These findings provide novel insights and highlight underappreciated pathways in AD pathogenesis that may be amenable to therapeutic targeting.

    更新日期:2019-12-29
  • Long-term outcome of LRBA deficiency in 76 patients after various treatment modalities as evaluated by the immune deficiency and dysregulation activity (IDDA) score
    J. Allergy Clin. Immunol. (IF 14.110) Pub Date : 2019-12-27
    Victoria Katharina Tesch; Hassan Abolhassani; Bella Shadur; Joachim Zobel; Yuliya Mareika; Svetlana Sharapova; Elif Karakoc-Aydiner; Jacques G. Rivière; Marina Garcia-Prat; Nicolette Moes; Filomeen Haerynck; Luis I. Gonzales- Granado; Juan Luis Santos Pérez; Anna Mukhina; Anna Shcherbina; Asghar Aghamohammadi; Lennart Hammarström; Figen Dogu; Markus G. Seidel

    Background Recent findings strongly support hematopoietic stem cell transplantation (HSCT) in patients with severe presentations of lipopolysaccharide-responsive beige-like anchor protein (LRBA) deficiency, but long-term follow-up and survival data for non-transplanted patients beyond previous patient reports or meta-reviews are scarce. Objective This international, retrospective study was conducted to elucidate the longitudinal clinical course of transplanted and non-transplanted LRBA-deficient patients. Methods We assessed disease burden and treatment responses with a specially developed immune deficiency and dysregulation activity (IDDA) score, reflecting the sum and severity of organ involvement and infections, days of hospitalization, supportive care requirements, and performance indices. Results Twenty-four of 76 LRBA-deficient patients from 29 centers (10 years median follow-up, range: 1–52) underwent HSCT from 2005 to 2019. Overall survival after HSCT (median follow-up 20 months) was 70.8% (17/24 patients); all deaths were due to non-specific, early, transplant-related mortality. Currently, 82.7% (43/52) of non-transplanted patients (aged 3-69 years) are alive. Of 17 HSCT survivors, seven are in complete and five in good partial remission without treatment (12/17, 70.6%). Only five of 43 non-transplanted patients (11.6%) are without immunosuppression. IDDA scores were significantly lower in patients who survived HSCT than in those receiving conventional treatment (P=0.005) or in patients who received abatacept or sirolimus as compared to other therapies, and in patients with residual LRBA expression. Higher disease burden, longer duration before HSCT, and lung involvement were associated with poor outcome. Conclusions The life-long disease activity, implying a need for immunosuppression and risk of malignancy, must be weighed against the risks of HSCT.

    更新日期:2019-12-27
  • Allergen-specific IgG+ memory B cells are temporally linked to IgE memory responses
    J. Allergy Clin. Immunol. (IF 14.110) Pub Date : 2019-12-27
    Ilka Hoof; Veronique Schulten; Janice A. Layhadi; Thomas Stranzl; Lars H. Christensen; Sara Herrera de la Mata; Grégory Seumois; Pandurangan Vijayanand; Claus Lundegaard; Kristoffer Niss; Anders Lund; Johanne Ahrenfeldt; Jens Holm; Esther Steveling; Hanisah Sharif; Stephen R. Durham; Björn Peters; Mohamed H. Shamji; Peter S. Andersen
    更新日期:2019-12-27
  • Short-term transcriptional response to IL-17 Receptor-A antagonism in the treatment of Psoriasis
    J. Allergy Clin. Immunol. (IF 14.110) Pub Date : 2019-12-27
    Lewis E. Tomalin; Chris B. Russell; Sandra Garcet; David Adrian Ewald; Paul Klekotka; Ajay Nirula; Hanne Norsgaard; Mayte Suarez-Farinas; James G. Krueger
    更新日期:2019-12-27
  • Natural language processing to advance EHR-based clinical research in Allergy, Asthma, and Immunology
    J. Allergy Clin. Immunol. (IF 14.110) Pub Date : 2019-12-26
    Young Juhn; Hongfang Liu

    The wide adoption of electronic health record systems (EHRs) in health care generates big real-world data that opens new venues to conduct clinical research. As a large amount of valuable clinical information is locked in clinical narratives, natural language processing (NLP) techniques as an artificial intelligence approach have been leveraged to extract information from clinical narratives in EHRs. This capability of NLP potentially enables automated chart review for identifying patients with distinctive clinical characteristics in clinical care and reduces methodological heterogeneity in defining phenotype obscuring biological heterogeneity in research concerning allergy, asthma, and immunology. This brief review discusses the current literature on the secondary use of EHR data for clinical research concerning allergy, asthma, and immunology and highlights the potential, challenges, and implications of NLP techniques.

    更新日期:2019-12-27
  • Treatment with Rapamycin Can Restore Regulatory T Cell Function in IPEX Patients
    J. Allergy Clin. Immunol. (IF 14.110) Pub Date : 2019-12-23
    Laura Passerini; Federica Barzaghi; Rosalia Curto; Claudia Sartirana; Graziano Barera; Francesca Tucci; Luca Albarello; Alberto Mariani; Pier AlbertoTestoni; Elena Bazzigaluppi; Emanuele Bosi; Vito Lampasona; Olaf Neth; Daniele Zama; Manfred Hoenig; Ansgar Schulz; Markus G. Seidel; Ivana Rabbone; Rosa Bacchetta
    更新日期:2019-12-23
  • BMP7 aberrantly induced in the psoriatic epidermis instructs inflammation-associated Langerhans cells
    J. Allergy Clin. Immunol. (IF 14.110) Pub Date : 2019-12-21
    Izabela Borek; René Köffel; Julia Feichtinger; Melanie Spies; Elisabeth Glitzner-Zeis; Mathias Hochgerner; Tommaso Sconocchia; Corinna Krump; Carmen Tam-Amersdorfer; Christina Passeger; Theresa Benezeder; Julia Tittes; Anna Redl; Clemens Painsi; Gerhard G. Thallinger; Peter Wolf; Georg Stary; Maria Sibilia; Herbert Strobl

    Background Epidermal hyperplasia represents a morphologic hallmark of psoriatic skin lesions. Langerhans cells (LCs) in the psoriatic epidermis engage with keratinocytes (KCs) in tight physical interactions; moreover, they induce T cell-mediated immune responses critical to psoriasis. Objective Epidermal factors in psoriasis pathogenesis remain poorly understood. Methods We phenotypically characterized BMP7-LCs vs. TGF-β1-LCs and analyzed their functional properties using flow cytometry, cell kinetic studies, co-culture with CD4 T-cells and cytokine measurements. Furthermore, immunohistology of healthy and psoriatic skin was performed. Additionally, in vivo experiments with Junf/fJunBf/fK5creER mice were carried out to assess the role of BMP signaling in psoriatic skin inflammation. Results Here we identified a KC-derived signal, i.e. bone morphogenetic protein (BMP) signaling, to promote epidermal changes in psoriasis. Whereas BMP7 is strictly confined to the basal KC layer in the healthy skin, it is expressed at high levels throughout the lesional psoriatic epidermis. BMP7 instructs precursor cells to differentiate into LCs that phenotypically resemble psoriatic LCs. These BMP7-LCs exhibit proliferative activity and increased sensitivity to bacterial stimulation. Moreover, aberrant high BMP signaling in the lesional epidermis is mediated by a KC intrinsic mechanism, as suggested from murine data and clinical outcome after topical anti-psoriatic treatment in human patients. Conclusion Our data indicate that available TGF-β family members within the lesional psoriatic epidermis preferentially signal through the canonical BMP signaling cascade to instruct inflammatory-type LCs and to promote psoriatic epidermal changes. Targeting BMP signaling might allow to therapeutically interfere with cutaneous psoriatic manifestations.

    更新日期:2019-12-21
  • Defining challenge-proven coexistent nut and sesame seed allergy: A prospective multicenter European study
    J. Allergy Clin. Immunol. (IF 14.110) Pub Date : 2019-12-20
    Helen A. Brough; Jean-Christoph Caubet; Angel Mazon; Diab Haddad; Marcel M. Bergmann; Jacqueline Wassenberg; Valentina Panetta; Rosalynd Gourgey; Suzana Radulovic; Maria Nieto; Alexandra F. Santos; Antonio Nieto; Gideon Lack; Philippe A. Eigenmann
    更新日期:2019-12-20
  • An Expert Consensus Framework for Asthma Remission as a Treatment Goal
    J. Allergy Clin. Immunol. (IF 14.110) Pub Date : 2019-12-19
    Andrew Menzies-Gow; Mona Bafadhel; William W. Busse; Thomas B. Casale; Janwillem W.H. Kocks; Ian D. Pavord; Stanley J. Szefler; Prescott G. Woodruff; Alexander de Giorgio-Miller; Frank Trudo; Malin Fageras; Christopher S. Ambrose

    With novel therapies in development, there is an opportunity to consider asthma remission as a treatment goal. In this Rostrum, we present a generalized framework for clinical and complete remission in asthma, on and off treatment, developed based on medical literature and expert consensus. A modified Delphi survey approach was used to ascertain expert consensus on core components of asthma remission as a treatment target. Phase 1 identified other chronic inflammatory diseases with remission definitions. Phase 2 evaluated components of those definitions as well as published definitions of spontaneous asthma remission. Phase 3 evaluated a remission framework created using consensus findings. Clinical remission comprised ≥12 months with 1) absence of significant symptoms by validated instrument, 2) lung function optimization/stabilization, 3) patient/provider agreement regarding remission, and 4) no use of systemic corticosteroids. Complete remission was defined as clinical remission plus objective resolution of asthma-related inflammation and, if appropriate, negative bronchial hyperresponsiveness. Remission off treatment required no asthma treatment for ≥12 months. The proposed framework is a first step toward developing asthma remission as a treatment target and should be refined through future research, patient input, and clinical study.

    更新日期:2019-12-20
  • Vaccine against peanut allergy based on engineered Virus-Like-Particles displaying single major peanut allergens
    J. Allergy Clin. Immunol. (IF 14.110) Pub Date : 2019-12-19
    Federico Storni; Andris Zeltins; Ina Balke; Matthew D. Heath; Matthias F. Kramer; Murray A. Skinner; Lisha Zha; Elisa Roesti; Paul Engeroff; Lukas Muri; Diego von Werdt; Thomas Gruber; Mark Cragg; Margrit Mlynarczyk; Thomas M. Kündig; Monique Vogel; Martin F. Bachmann

    Background Peanut allergy is a severe and increasingly frequent disease with high medical, psychosocial and economical burden for affected patients. A causal, safe and effective therapy is not available. Objective We aimed to develop an immunogenic, protective and non-reactogenic vaccine candidate against peanut allergy based on Virus-like Particles (VLPs) coupled to single peanut allergens. Methods To generate vaccine candidates, extracts of roasted peanut (Ara R) or the single allergens Ara h 1 or Ara h 2 were coupled to immunologically optimized Cucumber Mosaic Virus-derived VLPs (CuMVtt). BALB/c mice were sensitized intraperitoneally with peanut extract absorbed to Alum. Immunotherapy consisted of one single subcutaneous injection of CuMVtt coupled to Ara R, Ara h 1 or Ara h 2. Results The vaccines CuMVtt-Ara R, CuMVtt-Ara h 1 and CuMVtt-Ara h 2 protected peanut sensitized mice against anaphylaxis after i.v. challenge with the whole peanut extract. Vaccines did not cause allergic reactions in sensitized mice. CuMVtt-Ara h 1 was able to induce specific IgG antibodies, diminished local reactions after skin-prick-tests and reduced the infiltration of the gastrointestinal tract by eosinophils and mast cells after oral challenge with peanut. The ability of CuMVtt-Ara h 1 to protect against challenge with the whole extract was mediated by IgG, as shown via passive IgG transfer. FcγRIIb was required for protection, indicating that immune-complexes with single allergens were able to block the allergic response against the whole extract, consisting of a complex allergen mixture. Conclusion Our data suggest that vaccination using single peanut allergens displayed on CuMVtt may represent a novel and safe therapy against peanut allergy.

    更新日期:2019-12-20
  • Reduction in mouse allergen exposure is associated with greater lung function growth
    J. Allergy Clin. Immunol. (IF 14.110) Pub Date : 2019-12-19
    Torie Grant; Wanda Phipatanakul; Matthew Perzanowski; Susan Balcer-Whaley; Roger D. Peng; Jean Curtin-Brosnan; Michelle Newman; Amparito Cunningham; Adnan Divjan; Mary E. Bollinger; Robert A. Wise; Elizabeth C. Matsui
    更新日期:2019-12-19
  • Safety of Live Attenuated Influenza Vaccine in Children with Moderate-Severe Asthma
    J. Allergy Clin. Immunol. (IF 14.110) Pub Date : 2019-12-18
    Paul J. Turner; Louise Fleming; Sejal Saglani; Jo Southern; Nick J. Andrews; Elizabeth Miller

    Background Live attenuated influenza vaccine (LAIV) is recommended for annual influenza vaccination in children from age 2 years. However, some guidelines recommend against its use in children with asthma or recurrent wheeze due to concerns over its potential to induce wheezing. Objective To assess the safety of LAIV in children with moderate-severe asthma, and in preschool children with recurrent wheeze. Methods Prospective, multi-center, open label, phase IV intervention study in 14 specialist UK clinics. LAIV was administered under medical supervision, with follow-up of asthma symptoms 72 hours and 4 weeks late, using validated questionnaires. ClinicalTrials.gov registration NCT02866942, EU Clinical Trials registration 2016-002352-24. Results 478 young people (median 9.3, range 2–18 years) with physician-diagnosed asthma or recurrent wheeze were recruited, including 208 (44%) prescribed high-dose inhaled corticosteroids and 122 (31%) with severe asthma. There was no significant change in asthma symptoms in the 4 weeks following administration (median change 0, P=.26, McNemar’s test), with no impact of level of baseline asthma control/symptoms in predicting either a worsening of asthma or exacerbation following LAIV using a regression model. 47 subjects (14.7%, 95%CI 11% to 19.1%) reported a severe asthma exacerbation in the four weeks following immunization, requiring short course of systemic corticosteroids; in four cases, this occurred within 72 hours of vaccine. No association with asthma severity, baseline lung function or asthma control was identified. Conclusions LAIV appears to be well-tolerated in the vast majority of children with asthma or recurrent wheeze, including those whose asthma is categorized as severe or poorly controlled.

    更新日期:2019-12-19
  • Time to Develop More Clinician Educators in Allergy and Immunology
    J. Allergy Clin. Immunol. (IF 14.110) Pub Date : 2019-12-18
    Lily C. Pien; Colleen Y. Colbert

    Clinician educators in the field of allergy and immunology (A/I) in the U.S. teach and assess trainees (medical students, residents, fellows), provide professional development to primary care physicians and advance practice providers, and are essential in developing a pipeline of academic A/I specialists. The U.S. appears to be facing a shortage of clinician educators and academic allergists in A/I, based upon data from Doximity and the Association of American Medical Colleges. Without adequate numbers of A/I specialists focused on medical education, institutions will find it difficult to train fellows and introduce the field of A/I to medical students and residents. It is now imperative that the field focus on empowering more A/I specialists to become clinical teachers and clinician educators. There are specific strategies which individuals, as active agents in their own development, can take in planning for this rewarding and fulfilling career. Individuals can pursue professional development opportunities, join medical education communities of practice, seek education mentors, and join in scholarship activities. It is also essential that systems-level support be provided for clinician educators, given the increasing business pressures in medicine. Academic institutions, national organizations, and professional societies can provide resources, including structured programs in medical education, protected time, and grants. This article outlines strategies for individuals, institutions and professional organizations that will promote the development of the next generation of A/I clinician educators.

    更新日期:2019-12-19
  • Hypomorphic variants in AK2 reveal the contribution of mitochondrial function to B cell activation
    J. Allergy Clin. Immunol. (IF 14.110) Pub Date : 2019-12-17
    Janet Chou; Anas M. Alazami; Faris Jaber; Rodrigo Hoyos-Bachiloglu; Jennifer Jones; Sabrina Weeks; Mohammed F. Alosaimi; Wayne Bainter; Brittney Cangemi; Yousef R. Badran; Reem Mohammed; Fayhan Alroqi; Abduarahman Almutairi; Noufa Al-Onazi; Sulaiman AlAjaji; Bander Al-Saud; Rand Arnaout; Megan Elkins; Hamoud Al-Mousa

    Background AK2 encodes the phosphotransferase adenylate kinase 2 (AK2). Human variants in AK2 cause reticular dysgenesis, a severe combined immunodeficiency with agranulocytosis, lymphopenia, and sensorineural deafness that requires hematopoietic stem cell transplantation for survival. Objective We investigated the mechanisms underlying recurrent sino-pulmonary infections and hypogammaglobulinemia in 15 patients, ranging from three to 34 years of age, from nine kindreds. Only two patients, both of whom had mildly impaired T cell proliferation, each had a single clinically significant opportunistic infection. Methods Patient cells were studied with next-generation DNA sequencing, tandem mass spectrometry, and assays of lymphocyte and mitochondrial function. Results We identified two different homozygous variants in AK2. AK2G100S and AK2A182D permit residual protein expression, enzymatic activity, and normal numbers of neutrophils and lymphocytes. All but one patient have intact hearing. The patients’ B cells had severely impaired proliferation and in vitro immunoglobulin secretion. With activation, the patients’ B cells exhibit defective mitochondrial respiration and impaired regulation of mitochondrial membrane potential and quality. Although activated T cells from the patients with opportunistic infections demonstrated impaired mitochondrial function, the mitochondrial quality in T cells was preserved. Consistent with the capacity of activated T cells to utilize non-mitochondrial metabolism, these findings reveal a less strict cellular dependence of T cell function on AK2 activity. Chemical inhibition of ATP synthesis in control T and B cells similarly demonstrated the greater dependency of B cells on mitochondrial function. Conclusions Our patients demonstrate the in vivo sequelae of the cell-specific requirements for the functions of AK2 and mitochondria, particularly in B cell activation and antibody production.

    更新日期:2019-12-18
  • Non-canonical autophagy in dermal dendritic cells mediates immunosuppressive effects of UV exposure
    J. Allergy Clin. Immunol. (IF 14.110) Pub Date : 2019-12-16
    Payel Sil; Jutamas Suwanpradid; Ginger Muse; Artiom Gruzdev; Liwen Liu; David L. Corcoran; Cynthia J. Willson; Kyathanahalli Janardhan; Sara Grimm; Page Myers; Laura Miller Degraff; Amanda S. MacLeod; Jennifer Martinez
    更新日期:2019-12-17
  • Dual transcriptomic and epigenomic study of reaction severity in peanut allergic children
    J. Allergy Clin. Immunol. (IF 14.110) Pub Date : 2019-12-12
    Anh N. Do; Corey T. Watson; Ariella T. Cohain; Robert S. Griffin; Alexander Grishin; Robert A. Wood; Wesley A. Burks; Stacie M. Jones; Amy Scurlock; Donald Y.M. Leung; Hugh A. Sampson; Scott H. Sicherer; Andrew J. Sharp; Eric E. Schadt; Supinda Bunyavanich
    更新日期:2019-12-13
  • Cost-effectiveness of implementing objective diagnostic verification of asthma in the United States
    J. Allergy Clin. Immunol. (IF 14.110) Pub Date : 2019-12-11
    Mohsen Yaghoubi, Amin Adibi, Zafar Zafari, J Mark FitzGerald, Shawn D. Aaron, Kate M. Johnson, Mohsen Sadatsafavi

    Background Asthma diagnosis in the community is often made without objective testing. Objective The aim of this study was to evaluate the cost-effectiveness of implementing a stepwise objective diagnostic verification algorithm among patients with community-diagnosed asthma in the United States (US). Methods We developed a probabilistic time-in-state cohort model that compared a stepwise asthma verification algorithm based on spirometry and methacholine challenge test against the current standard of care over 20 years. Model input parameters were informed from the literature and with original data analyses when required. The target population was US adults (≥15 y/o) with physician-diagnosed asthma. The final outcomes were costs (in 2018 $) and quality-adjusted life years (QALYs), discounted at 3% annually. Deterministic and probabilistic analyses were undertaken to examine the effect of alternative assumptions and uncertainty in model parameters on the results. Results In a simulated cohort of 10,000 adults with diagnosed asthma, the stepwise algorithm resulted in the removal of diagnosis in 3,366. This was projected to be associated with savings of $36.26 million in direct costs and a gain of 4,049.28 QALYs over 20 years. Extrapolating these results to the US population indicated an undiscounted potential savings of $56.48 billion over 20 years. Results were robust against alternative assumptions and plausible changes in values of input parameters. Conclusion Implementation of a simple diagnostic testing algorithm to verify asthma diagnosis might result in substantial savings and improvement in patients’ quality of life.

    更新日期:2019-12-11
  • Rapid desensitization of humanized mice with anti-human FcεRIα monoclonal antibodies
    J. Allergy Clin. Immunol. (IF 14.110) Pub Date : 2019-12-11
    Marat V. Khodoun, Suzanne C. Morris, Elizabeth Angerman, Crystal Potter, Richard Schuman, Mark Wunderlich, Joseph J. Maciag, Kathryn C. Sullivan Locker, James C. Mulloy, Andrew B. Herr, Fred D. Finkelman

    Background Anaphylaxis is classically mediated by allergen crosslinking of IgE bound to the α chain of FcεRI, the mast cell/basophil high affinity IgE receptor. Allergen crosslinking of the IgE/FcεRI complex activates these cells, inducing release of disease-causing mediators, cytokines and enzymes. We previously demonstrated that IgE-mediated anaphylaxis could be safely prevented in wild-type BALB/c mice by rapid desensitization with anti-mouse FcεRIα monoclonal antibody (mAb). Objective Use humanized mice to extend these results to humans. Methods We actively immunized huFcεRIα/F709 mice, which express human (hu) instead of mouse FcεRIα and a mutant IL-4 receptor that lacks inhibitory function. We passively immunized huFcεRIα mice, as well as human cord blood-reconstituted reNSGS mice, which are immune-deficient, produce mast cell-stimulating human cytokines and develop numerous human mast cells. For desensitization, we used anti-huFcεRIα mAbs that bind FcεRIα regardless of its association with IgE (non-competing mAbs), and/or mAbs that compete with IgE for huFcεRIα binding (competing mAbs). Anaphylaxis was induced by intravenous injection of antigen or anti-huIgE mAb. Results Anti-huFcεRIα mAb rapid desensitization was safer and more effective than allergen rapid desensitization and suppressed anaphylaxis more rapidly than omalizumab or ligelizumab. Rapid desensitization of naïve, IgE-sensitized huFcεRIα mice and egg-allergic huFcεRIα/F709 mice with anti-FcεRIα mAbs safely removed >98% of IgE from peritoneal mast cells and completely suppressed IgE-mediated anaphylaxis. Rapid desensitization of reNSGS mice with anti-FcεRIα mAbs also safely removed ∼98% of mast cell IgE and prevented IgE-mediated anaphylaxis. Conclusion Rapid desensitization with anti-FcεRIα mAbs may be a safe, effective, and practical way to prevent IgE-mediated anaphylaxis.

    更新日期:2019-12-11
  • NLRP3-associated autoinflammatory diseases: phenotypic and molecular characteristics of germline versus somatic mutations
    J. Allergy Clin. Immunol. (IF 14.110) Pub Date : 2019-12-06
    Camille Louvrier, Eman Assrawi, Elma El Khouri, Isabelle Melki, Bruno Copin, Emmanuelle Bourrat, Noémie Lachaume, Bérengère Cador-Rousseau, Philippe Duquesnoy, William Piterboth, Fawaz Awad, Claire Jumeau, Marie Legendre, Gilles Grateau, Sophie Georgin-Lavialle, Sonia A. Karabina, Serge Amselem, Irina Giurgea

    Background NLRP3-associated autoinflammatory diseases (NLRP3-AIDs) include conditions of various severities, due to germline or somatic mosaic NLRP3 mutations. Objective To identify mosaic-specific versus germline-specific NLRP3 mutations’ characteristics, we reinterpreted all the mutations reported in NLRP3-AIDs and performed an in-depth study of three novel patients. Methods The pathogenicity of all reported mosaic/germline mutations was re-assessed according to international recommendations and their location on the NLRP3 3D-structure. Deep-targeted sequencing and NLRP3 inflammasome-activation assays were used to identify the disease-causing mutation in three patients. Results We identified, in three patients, mosaic mutations affecting the same NLRP3 aminoacid (Glu569). This residue belongs to one of the two mosaic mutational hotspots that face each other in the core of the NLRP3 ATPase domain. The review of the 90 NLRP3 mutations identified in 277 patients revealed that those hotspots account for 68.5% (37/54) of patients with mosaic mutations. Glu569 is affected in 22% (12/54) of the patients with mosaic mutations and in 0.4% (1/223) of those with germline mutations. Only 8/90 mutations were found in mosaic and germinal state. All of the germline mutations were associated with a severe phenotype. These data suggest that mutations found only in mosaic state could be incompatible with life if present in germinal state. None of the five most frequent germline mutations was identified in mosaic state. Mutations found only in germinal state could, therefore, be asymptomatic in mosaic state. Conclusion The phenotypic spectrum of NLRP3-AIDs appears to be related to the germinal/mosaic status and localization of the underlying mutations.

    更新日期:2019-12-07
  • Abnormal Peyer’s patch development and B cell gut homing drive IgA deficiency in Kabuki syndrome
    J. Allergy Clin. Immunol. (IF 14.110) Pub Date : 2019-12-06
    Genay O. Pilarowski, Tareian Cazares, Li Zhang, Joel S. Benjamin, Ke Liu, Sajjeev Jagannathan, Nadeem Mousa, Jennifer Kasten, Artem Barski, Andrew W. Lindsley, Hans T. Bjornsson

    Background Kabuki syndrome (KS) is commonly caused by mutations in the histone modifying enzyme KMT2D. Immune dysfunction is frequently observed in individuals with KS, but the role of KMT2D in immune system function has not been identified. Objective We sought to understand mechanisms driving Kabuki syndrome associated immune deficiency (hypogammaglobulinemia [low IgA], splenomegaly, and diminished immunization responses). Methods We performed a comprehensive evaluation of humoral immunity and secondary lymphoid tissues in an established KS (Kmt2d+/βGeo) mouse model and validated select findings in a patient with Kabuki syndrome. Results Compared to wildtype littermates, Kmt2d+/βGeo mice demonstrated deficiencies in multiple B cell lineages and reduced serum IgA and elevated IgM levels across multiple ages. Kmt2d+/βGeo bone marrow, spleen, and intestine contained diminished numbers of IgA-secreting cells, while elevated germinal center B cells were found in mesenteric lymph node and Peyer’s patches. Kmt2d+/βGeo mice have decreased size and numbers of Peyer’s patches, a finding confirmed in human samples. We identified deficiency of Itgb7 RNA and protein expression, a gene encoding an adhesion protein that mediates intestinal homing, and we demonstrated KMT2D-dependent control of ITGB7 expression in a human cell line. Conclusions Kmt2d haploinsufficiency has broad deleterious effects on B cell differentiation, specifically hampering gut lymphocyte homing and IgA+ plasma cell differentiation. Intestinal lymphoid defects caused by ITGB7 deficiency have not previously been recognized in KS and these results provide new mechanistic insights into the pathogenesis of Kabuki associated immune deficiency.

    更新日期:2019-12-07
  • Effects of myeloid and plasmacytoid dendritic cells on ILC2s in patients with allergic rhinitis
    J. Allergy Clin. Immunol. (IF 14.110) Pub Date : 2019-12-05
    Ya-Qi Peng, Zi-Li Qin, Shu-Bin Fang, Zhi-Bin Xu, Hong-Yu Zhang, Dong Chen, Zheng Liu, Joseph A. Bellanti, Song Guo Zheng, Qing-Ling Fu
    更新日期:2019-12-05
  • Inhibiting eicosanoid degradation exerts antifibrotic effects in a pulmonary fibrosis mouse model and human tissue
    J. Allergy Clin. Immunol. (IF 14.110) Pub Date : 2019-12-05
    Thomas Bärnthaler, Anna Theiler, Diana Zabini, Sandra Trautmann, Elvira Stacher-Priehse, Ilse Lanz, Walter Klepetko, Katharina Sinn, Holger Flick, Stefan Scheidl, Dominique Thomas, Horst Olschewski, Grazyna Kwapiszewska, Rufina Schuligoi, Akos Heinemann
    更新日期:2019-12-05
  • The role of the changing human microbiome in the asthma pandemic
    J. Allergy Clin. Immunol. (IF 14.110) Pub Date : 2019-12-04
    Timothy C. Borbet, Xiaozhou Zhang, Anne Müller, Martin J. Blaser

    Asthma and allergy incidence continue to increase globally. We have made significant strides in treating disease, but it is becoming more apparent that we need to advance our knowledge into the origins of asthmatic disease. Much recent work has indicated that microbiome composition influences immune regulation and that multiple health care factors have driven a loss in microbiome diversity in modern human populations. Evidence is growing of microbiota-driven influences on immune development, asthma susceptibility, and asthma pathogenesis. The focus of this review is to highlight the strides the field has made in characterizing the constituents of the human gastrointestinal microbiota, such as Helicobacter pylori, other members of the neonatal intestinal microbiota, and microbial peptides and metabolites that influence host immunity and immune response to allergens. As we delve further into this field of research, the goal will be to find actionable and clinical interventions to identify at-risk populations earlier to prevent disease onset. Manipulation of the host microbial community during infancy might be an especially promising approach.

    更新日期:2019-12-04
  • Food allergy and the microbiome: Current understandings and future directions
    J. Allergy Clin. Immunol. (IF 14.110) Pub Date : 2019-12-04
    Supinda Bunyavanich, M. Cecilia Berin

    Growing evidence points to an important role for the commensal microbiota in susceptibility to food allergy. Epidemiologic studies demonstrate associations between exposures known to modify the microbiome and risk of food allergy. Direct profiling of the gut microbiome in human cohort studies has demonstrated that individuals with food allergy have distinct gut microbiomes compared to healthy control subjects, and dysbiosis precedes the development of food allergy. Mechanistic studies in mouse models of food allergy have confirmed that the composition of the intestinal microbiota can imprint susceptibility or resistance to food allergy on the host and have identified a unique population of microbially responsive RORγt-positive FOXp3-positive regulatory T cells as critical for the maintenance of tolerance to foods. Armed with this new understanding of the role of the microbiota in food allergy and tolerance, therapeutics aimed at modifying the gastrointestinal microbiota are in development. In this article we review key milestones in the development of our current understanding of how the gastrointestinal microbiota contributes to food allergy and discuss our vision for the future of the field.

    更新日期:2019-12-04
  • Effect of sleep deprivation and exercise on reaction threshold in adults with peanut allergy: A randomized controlled study
    J. Allergy Clin. Immunol. (IF 14.110) Pub Date : 2019-07-15
    Shelley Dua, Monica Ruiz-Garcia, Simon Bond, Stephen R. Durham, Ian Kimber, Clare Mills, Graham Roberts, Isabel Skypala, James Wason, Pamela Ewan, Robert Boyle, Andrew Clark
    更新日期:2019-12-04
  • Factors influencing adherence in a trial of early introduction of allergenic food
    J. Allergy Clin. Immunol. (IF 14.110) Pub Date : 2019-12-04
    Michael R. Perkin, Henry T. Bahnson, Kirsty Logan, Tom Marrs, Suzana Radulovic, Rebecca Knibb, Joanna Craven, Carsten Flohr, E.N. Mills, Serge A. Versteeg, Ronald van Ree, Gideon Lack
    更新日期:2019-12-04
  • Efficacy of the Enquiring About Tolerance (EAT) study among infants at high risk of developing food allergy
    J. Allergy Clin. Immunol. (IF 14.110) Pub Date : 2019-12-04
    Michael R. Perkin, Kirsty Logan, Henry T. Bahnson, Tom Marrs, Suzana Radulovic, Joanna Craven, Carsten Flohr, E.N. Mills, Serge A. Versteeg, Ronald van Ree, Gideon Lack
    更新日期:2019-12-04
  • Challenges experienced with early introduction and sustained consumption of allergenic foods in the Enquiring About Tolerance (EAT) study: A qualitative analysis
    J. Allergy Clin. Immunol. (IF 14.110) Pub Date : 2019-12-04
    Paula Voorheis, Sadie Bell, Laura Cornelsen, Matthew Quaife, Kirsty Logan, Tom Marrs, Suzana Radulovic, Joanna Craven, Carsten Flohr, Gideon Lack, Michael R. Perkin
    更新日期:2019-12-04
  • Reduced genetic potential for butyrate fermentation in the gut microbiome of infants who develop allergic sensitization
    J. Allergy Clin. Immunol. (IF 14.110) Pub Date : 2019-07-03
    Alissa Cait, Erick Cardenas, Pedro A. Dimitriu, Nelly Amenyogbe, Darlene Dai, Jessica Cait, Hind Sbihi, Leah Stiemsma, Padmaja Subbarao, Piush J. Mandhane, Allen B. Becker, Theo J. Moraes, Malcolm R. Sears, Diana L. Lefebvre, Meghan B. Azad, Tobias Kollmann, Stuart E. Turvey, William W. Mohn
    更新日期:2019-12-04
  • The ORMDL3 asthma susceptibility gene regulates systemic ceramide levels without altering key asthma features in mice
    J. Allergy Clin. Immunol. (IF 14.110) Pub Date : 2019-07-20
    Nincy Debeuf, Assem Zhakupova, Regula Steiner, Sofie Van Gassen, Kim Deswarte, Farzaneh Fayazpour, Justine Van Moorleghem, Karl Vergote, Benjamin Pavie, Kelly Lemeire, Hamida Hammad, Thorsten Hornemann, Sophie Janssens, Bart N. Lambrecht
    更新日期:2019-12-04
  • Reference intervals for lymphocyte subsets in preterm and term neonates without immune defects
    J. Allergy Clin. Immunol. (IF 14.110) Pub Date : 2019-06-18
    George S. Amatuni, Stanley Sciortino, Robert J. Currier, Stanley J. Naides, Joseph A. Church, Jennifer M. Puck

    Background In 6.5 years of newborn screening for severe combined immunodeficiency in California, 3,252,156 infants had DNA from dried blood spots (DBSs) assayed for T-cell receptor excision circles. Infants with T-cell receptor excision circle values of less than a designated cutoff on a single DBS, 2 DBS samples with insufficient PCR amplification, or known genetic risk of immunodeficiency had peripheral blood complete blood counts and lymphocyte subsets assayed in a single flow cytometry laboratory. Cases in which immune defects were ruled out were available for analysis. Objective We sought to determine reference intervals for lymphocyte subsets in racially/ethnically diverse preterm and term newborns who proved to be unaffected by any T-lymphopenic immune disorder. Methods Effective gestational age (GA) was defined as GA at birth plus postnatal age at the time of sample collection. After determining exclusion criteria, we analyzed demographic and clinical information, complete and differential white blood cell counts, and lymphocyte subsets for 301 infants, with serial measurements for 33 infants. Lymphocyte subset measurements included total T cells, helper and cytotoxic T-cell subsets, naive and memory phenotype of each T-cell subset, B cells, and natural killer cells. Results Reference intervals were generated for absolute numbers and lymphocyte subsets from infants with effective GAs of 22 to 52 weeks. Sex and ethnicity were not significant determinants of lymphocyte subset counts in this population. Lymphocyte counts increased postnatally. Conclusion This study provides a baseline for interpreting comprehensive lymphocyte data in preterm and term infants, aiding clinicians to determine which newborns require further evaluations for immunodeficiency.

    更新日期:2019-12-04
  • Sex differences in academic rank in allergy/immunology
    J. Allergy Clin. Immunol. (IF 14.110) Pub Date : 2019-07-03
    Kimberly G. Blumenthal, Emily M. Huebner, Aleena Banerji, Aidan A. Long, Nate Gross, Neena Kapoor, Daniel M. Blumenthal

    Background Female physicians are significantly less likely than male physicians to be full professors, even after accounting for age, experience, specialty, and measures of research and clinical productivity. Objective We sought to evaluate sex differences in academic rank in the allergy and immunology workforce. Methods We used a cross-sectional physician data set containing the allergist's sex, age, years since residency, faculty appointment, authored publications, National Institutes of Health (NIH) funding, clinical trial investigation, and Medicare reimbursement to investigate sex differences in the academic allergy and immunology workforce using multilevel logistic regression models. Results Among 507 academic allergists (9.3% of practicing US allergists in 2014), 323 (63.7%) were men, and 184 (36.3%) were women. Female allergists were younger (47.9 vs 56.9 years, P < .001), had fewer total (12.5 vs 28.7, P < .001) and first/last author (8.0 vs 21.5, P < .001) average publications, were less likely to have NIH funding (13.0% vs 23.5%, P = .004), were less frequently a clinical trial investigator (10.3% vs 16.1%, P = .07), and generated less average annual Medicare revenue ($44,000 vs $23,000, P = .10). Of 152 (30.0%) full professors, 126 (82.9%) were male, and 26 (17.0%) were female. After multivariable adjustment, rates of full professorship among female and male allergists were not significantly different (absolute adjusted difference for female vs male allergists, 6.0%; 95% CI, −8.3% to 20.2%). Conclusions Among allergists with US medical school faculty appointments, men and women were similarly likely to be full professors after accounting for factors influencing promotion. Underlying differences in research productivity and NIH funding not explained by age differences alone warrant additional investigation.

    更新日期:2019-12-04
  • Prenatal polyunsaturated fatty acids and child asthma: effect modification by maternal asthma and child sex
    J. Allergy Clin. Immunol. (IF 14.110) Pub Date : 2019-12-03
    Maria José Rosa, Terryl J. Hartman, Margaret Adgent, Kourtney Gardner, Tebeb Gebretsadik, Paul E. Moore, Robert L. Davis, Kaja Z. LeWinn, Nicole R. Bush, Frances Tylavsky, Rosalind J. Wright, Kecia N. Carroll
    更新日期:2019-12-04
  • Sustained Successful Peanut Oral Immunotherapy Associated with Low Basophil Activation and Peanut-Specific IgE
    J. Allergy Clin. Immunol. (IF 14.110) Pub Date : 2019-12-02
    Mindy Tsai, Kaori Mukai, R. Sharon Chinthrajah, Kari C. Nadeau, Stephen J. Galli

    Background Oral immunotherapy (OIT) can successfully desensitize many peanut allergic subjects, but clinical tolerance diminishes over time upon discontinuation, or low dose maintenance, of peanut. Therefore, in order to improve the efficacy and sustainability of such therapy, we sought to identify biomarkers and clinical tools that can predict therapeutic outcomes and monitor treatment responses. Objective We evaluated whether basophil activation in whole blood, and plasma levels of peanut-specific immunoglobulins, are useful biomarkers for peanut OIT. Methods We longitudinally measured, before, during and after OIT, basophil activation in whole blood ex vivo in response to peanut stimulation, and peanut-specific IgE and IgG4, in a large, single-site, double-blind, randomized, placebo-controlled, phase 2 peanut OIT study. We compared basophil responsiveness and peanut specific immunoglobulins between those who were clinically reactive vs. tolerant to peanut oral challenges. Results Peanut OIT significantly decreased basophil activation, peanut-specific, Ara h 1, Ara h 2 and Ara h 3 IgEs, and sIgE/total IgE, but increased sIgG4/sIgE. Participants who became reactive to 4 g of peanut 13 weeks off active OIT exhibited higher peanut-induced basophil activation ex vivo and higher peanut-specific IgEs and sIgE/total IgE, but lower sIgG4/sIgE. Notably, participants entering the study with low basophil responsiveness were more likely to achieve treatment success. Substantial suppression of basophil activation was required to maintain long-term clinical tolerance after peanut OIT. Conclusion Assessments of peanut-specific basophil activation and peanut-specific immunoglobulins can help to predict treatment outcomes, and to differentiate transient desensitization vs. sustained unresponsiveness after OIT.

    更新日期:2019-12-02
  • IL-13 and IL-4, but not IL-5 nor IL-17A, induce hyperresponsiveness in isolated human small airways
    J. Allergy Clin. Immunol. (IF 14.110) Pub Date : 2019-12-02
    Martijn L. Manson, Jesper Säfholm, Anna James, Anna-Karin Johnsson, Per Bergman, Mamdoh Al-Ameri, Ann-Charlotte Orre, Carina Kärrman Mårdh, Sven-Erik Dahlén, Mikael Adner
    更新日期:2019-12-02
  • Upadacitinib in Adults With Moderate-to-Severe Atopic Dermatitis: 16-Week Results From a Randomized, Placebo-Controlled Trial
    J. Allergy Clin. Immunol. (IF 14.110) Pub Date : 2019-11-29
    Emma Guttman-Yassky, Diamant Thaçi, Aileen L. Pangan, H. Chih-ho Hong, Kim A. Papp, Kristian Reich, Lisa A. Beck, Mohamed-Eslam F. Mohamed, Ahmed A. Othman, Jaclyn K. Anderson, Yihua Gu, Henrique D. Teixeira, Jonathan I. Silverberg

    Background Atopic dermatitis is a chronic inflammatory skin disease characterized by pruritic skin lesions. Objective This study evaluated the safety and efficacy of multiple doses of the selective Janus kinase 1 inhibitor upadacitinib in patients with moderate-to-severe atopic dermatitis. Methods In the 16-week, double-blind, placebo-controlled, parallel-group, dose-ranging portion of this 88-week trial in 8 countries (ClinicalTrials.gov, NCT02925117; ongoing, not recruiting), adults with moderate-to-severe disease and inadequate control by topical treatment were randomized 1:1:1:1, using an interactive response system and stratified geographically, to once-daily upadacitinib oral monotherapy 7.5, 15, or 30 mg or placebo. The primary endpoint was percentage improvement in Eczema Area and Severity Index from baseline at week 16. Efficacy was analyzed by intention-to-treat in all randomized patients. Safety was analyzed in all randomized patients who received study medication, based on actual treatment. Results Patients (N=167) enrolled from November 21, 2016, to April 20, 2017. All were randomized and analyzed for efficacy (each upadacitinib group, n=42; placebo, n=41); 166 were analyzed for safety (each upadacitinib group, n=42; placebo, n=40). The mean (standard error) primary efficacy endpoint was 39% (6.2%), 62% (6.1%), and 74% (6.1%) for the upadacitinib 7.5-, 15-, and 30-mg groups, respectively, versus 23% (6.4%) for placebo (P=0.03, <0.001, and <0.001). Serious adverse events occurred in 4.8% [2/42], 2.4% [1/42], 0% [0/42] of upadacitinib groups (vs 2.5% [1/40] for placebo). Conclusion A dose-response relationship was observed for upadacitinib efficacy; the 30-mg once-daily dose showed the greatest clinical benefit. Dose-limiting toxicity was not observed.

    更新日期:2019-11-29
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