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  • Self-reported adverse food reactions and anaphylaxis in the SchoolNuts study: A population-based study of adolescents
    J. Allergy Clin. Immunol. (IF 13.081) Pub Date : 2017-11-23
    Vicki L. McWilliam, Jennifer J. Koplin, Michael J. Field, Mari Sasaki, Shyamali C. Dharmage, Mimi L.K. Tang, Susan M. Sawyer, Rachel L. Peters, Katrina J. Allen

    Background Adolescents are at the highest risk of death from anaphylaxis, yet few population-based studies have described the frequencies and risk factors for allergic reactions caused by accidental allergen ingestion in this group. Methods We describe the prevalence, frequency, and associated risk factors for recent adverse food reactions in 10- to 14-year-olds in Melbourne, Australia, recruited from a stratified, random, population-based sample of schools (SchoolNuts, n = 9663; 48% response rate). Self-reported food allergy and adverse reaction details, including anaphylaxis, were identified by using a student questionnaire over the past year. Results Of 547 students with possible IgE-mediated food allergy, 243 (44.4%; 95% CI, 40.3% to 48.7%) reported a reaction to a food. Fifty-three (9.7%; 95% CI, 7.2% to 12.2%) students reported 93 anaphylaxis episodes. Peanut and tree nuts were the most common food triggers. Among students with current IgE-mediated food allergy, those with resolved or current asthma (adjusted odds ratio [aOR], 1.9 [95% CI, 1.1-1.3] and 1.7 [95% CI, 1.1-2.6]) and those with more than 2 food allergies (aOR, 1.9 [95% CI, 1.1-3.1]) were at greatest risk of any adverse food reaction, and those with nut allergy were most at risk of severe reactions (aOR, 2.9 [95% CI, 1.1-4.4]). Resolved or current asthma was not associated with increased risk of severe reactions (aOR, 0.8 [95% CI, 0.3-2.2] and 1.6 [95% CI, 0.7-3.7]). Conclusions Adolescents with food allergy are frequently exposed to food allergens. Those with asthma and more than 2 food allergies were at the greatest risk for adverse food reactions. Those with nut allergies were most at risk of severe reactions.

    更新日期:2017-11-23
  • Food Allergy: A review and update on epidemiology, pathogenesis, diagnosis, prevention and management
    J. Allergy Clin. Immunol. (IF 13.081) Pub Date : 2017-11-21
    Scott H. Sicherer, Hugh A. Sampson

    This review provides general information to serve as a primer for those embarking on understanding food allergy and also details advances and updates in epidemiology, pathogenesis, diagnosis and treatment that have occurred over the four years since our last comprehensive review. Although firm prevalence data are lacking, there is a strong impression that food allergy has increased, and rates as high as ∼10% have been documented. Genetic, epigenetic and environmental risk factors are being increasingly elucidated, opening the potential for improved prevention and treatment strategies targeted to those at risk. Insights on pathophysiology are revealing a complex interplay of epithelial barrier, mucosal and systemic immune response, route of exposure and microbiome among other influences resulting in allergy or tolerance. The diagnosis of food allergy is largely reliant on the medical history, tests for sensitization, and oral food challenges, but emerging use of component resolved diagnostics are improving diagnostic accuracy. Additional novel diagnostics such as basophil activation tests, determination of epitope binding, DNA methylation signatures and bioinformatics approaches will further change the landscape. A number of prevention strategies are under investigation, but early introduction of peanut has been advised as a public health measure based on existing data. Management remains largely based on allergen avoidance, but a panoply of promising treatment strategies are in phase 2 and 3 studies, giving immense hope that better treatment will be imminently and widely available, while numerous additional promising treatments are in the preclinical and clinical pipeline.

    更新日期:2017-11-21
  • Endolysosomal protease susceptibility of Amb a 1 as a determinant of allergenicity
    J. Allergy Clin. Immunol. (IF 13.081) Pub Date : 2017-11-20
    Martin Wolf, Lorenz Aglas, Teresa E. Twaroch, Markus Steiner, Sara Huber, Michael Hauser, Maria A. Parigiani, Heidi Hofer, Christof Ebner, Barbara Bohle, Peter Briza, Angela Neubauer, Frank Stolz, Michael Wallner, Fatima Ferreira

    In the absence of extrinsic adjuvants, purified Amb a 1 induced a strong Th2-polarized immune response in mice. This high allergenic activity seems to be linked to the allergen’s susceptibility to endolysosomal proteolysis.

    更新日期:2017-11-20
  • Enhancement of cutaneous immunity during ageing by blocking p38 MAPkinase induced inflammation
    J. Allergy Clin. Immunol. (IF 13.081) Pub Date : 2017-11-17
    Milica Vukmanovic-Stejic, Emma S. Chambers, Mayte Suarez- Farinas, Daisy Sandhu, Judilyn Fuentes-Duculan, Neil Patel, Elaine Agius, Katie E. Lacy, Carolin T. Turner, Anis Larbi, Veronique Birault, Mahdad Noursadeghi, Neil A. Mabbott, Malcolm H.A. Rustin, James Krueger, Arne N. Akbar

    Background Immunity declines with age that leads to re-activation of varicella zoster virus (VZV). In humans, age associated immune changes are usually measured in blood leukocytes however this may not reflect alterations in tissue-specific immunity. Objectives We used a VZV antigen challenge system in the skin to investigate changes in tissue specific mechanisms involved in the decreased response to this virus during ageing. Methods We assessed cutaneous immunity by the extent of erythema and induration after intradermal VZV antigen injection. We also performed immune histology and transcriptomic analyses on skin biopsies taken from the site of challenge in young (<40 yrs) and old (>65 yrs) subjects. Results Old humans exhibited decreased erythema and induration, CD4+ and CD8+ T cell infiltration and attenuated global gene activation at the site of cutaneous VZV antigen challenge compared to young subjects. This was associated with elevated sterile inflammation in the skin in the same subjects, related to p38 MAPK-related pro-inflammatory cytokine production (p <0.0007). We inhibited systemic inflammation in old subjects by pre-treatment with an oral small molecule p38 MAP kinase inhibitor (Losmapimod), which reduced both serum C reactive protein (CRP) and peripheral blood monocyte secretion of IL-6 and TNF-α. In contrast, cutaneous responses to VZV antigen challenge was significantly increased in the same individuals (p <0.0006). Conclusion Excessive inflammation in the skin early after antigen challenge retards antigen-specific immunity. However this can be reversed by inhibition of inflammatory cytokine production that may be utilized to promote vaccine efficacy and the treatment of infections and malignancy during ageing.

    更新日期:2017-11-20
  • Vascular endothelial specific IL-4Rα–ABL1 kinase signaling axis regulates severity of IgE-mediated anaphylactic reactions
    J. Allergy Clin. Immunol. (IF 13.081) Pub Date : 2017-11-17
    Amnah Yamani, David Wu, Lisa Waggoner, Taeko Noah, Anthony J. Koleske, Fred Finkelman, Simon P. Hogan

    Background Severe IgE-mediated, food-induced anaphylactic reactions are characterized by pulmonary venous vasodilatation and fluid extravasation, which is thought to lead to the life-threatening anaphylactic phenotype. The underlying immunological and cellular processes involved in driving fluid extravasation and the severe anaphylactic phenotype are not fully elucidated. Objective To define the interaction and requirement of IL-4 and vascular endothelial (VE) IL-4Rα chain signaling in histamine-ABL1–mediated VE dysfunction and fluid extravasation in the severity of IgE-mediated anaphylactic reactions in mice. Methods Mice deficient in VE IL-4Rα and models of passive and active oral antigen– and IgE-induced anaphylaxis were employed to define the requirements of VE IL-4Rα and ABL1 pathway in severe anaphylactic reactions. Human VE cell line (EA.hy926 cells) and pharmacologic (imatinib) and genetic approaches (shRNA knockdown of IL4RA and ABL1) were used to define the requirement of this pathway in VE barrier dysfunction. Results IL-4 exacerbation of histamine-induced hypovolemic shock in mice was dependent on VE expression of the IL-4Rα. IL-4 and histamine induced ABL1 activation in human VE cells and VE barrier dysfunction was ABL1 dependent. Development of severe IgE-mediated hypovolemia and shock required VE-restricted ABL1 expression. Treatment of mice with a history of food-induced anaphylaxis with the ABL kinase inhibitor imatinib protected the mice from developing severe IgE-mediated anaphylaxis. Conclusion IL-4 amplifies IgE- and histamine-induced VE dysfunction, fluid extravasation, and severity of anaphylaxis via a VE IL-4Rα-ABL1–dependent mechanism. These studies implicate an important contribution by the VE compartment in the severity of anaphylaxis and identify a new

    更新日期:2017-11-20
  • ORAI1 mutations abolishing store-operated Ca2+ entry cause anhidrotic ectodermal dysplasia with immunodeficiency (EDA-ID)
    J. Allergy Clin. Immunol. (IF 13.081) Pub Date : 2017-11-16
    Jayson Lian, Mario Cuk, Sascha Kahlfuss, Lina Kozhaya, Martin Vaeth, Frédéric Rieux-Laucat, Capucine Picard, Melina J. Benson, Antonia Jakovcevic, Karmen Bilic, Iva Martinac, Peter Stathopulos, Imre Kacskovics, Thomas Vraetz, Carsten Speckmann, Stephan Ehl, Thomas Issekutz, Derya Unutmaz, Stefan Feske

    Background Store-operated Ca2+ entry (SOCE) through Ca2+ release-activated Ca2+ (CRAC) channels is an essential signaling pathway in many cell types. CRAC channels are formed by ORAI1, ORAI2 and ORAI3 proteins and activated by stromal interaction molecule 1 (STIM1) and STIM2. Mutations in ORAI1 and STIM1 genes that abolish SOCE cause a combined immunodeficiency (CID) syndrome that is accompanied by autoimmunity and non-immunological symptoms. Objective Molecular and immunological analysis of patients with CID, anhidrosis and ectodermal dysplasia of unknown etiology. Methods DNA sequencing of ORAI1 gene, modeling of mutations on ORAI1 crystal structure, analysis of ORAI1 mRNA and protein expression, measurements of SOCE, immunological analysis of peripheral blood lymphocyte populations by flow cytometry, histological and ultrastructural analysis of patient tissues. Results We identified 3 novel autosomal recessive mutations in ORAI1 in unrelated kindreds with CID, autoimmunity, ectodermal dysplasia with anhidrosis (EDA) and muscular dysplasia. The patients were homozygous for p.V181SfsX8, p.L194P and p.G98R mutations in the ORAI1 gene that suppressed ORAI1 protein expression and SOCE in the patients' lymphocytes and fibroblasts. Besides impaired T cell cytokine production, ORAI1 mutations were associated with strongly reduced numbers of invariant natural killer (iNKT) and regulatory T (Treg) cells, and altered composition of γδ T cell and NK cell subsets. Conclusion ORAI1 null mutations are associated with reduced numbers of iNKT and Treg cells that likely contribute to the patients' immunodeficiency and autoimmunity. ORAI1 deficient patients suffer from dental enamel defects and anhidrosis representing a new form of anhidrotic ectodermal dysplasia with immunodeficiency (EDA-ID) that is distinct from previously reported patients with EDA-ID due to mutations in the NF-kB signaling pathway (IKBKG and NFKBIA).

    更新日期:2017-11-17
  • Type I IFN related NETosis in Ataxia Telangiectasia and Artemis deficiency
    J. Allergy Clin. Immunol. (IF 13.081) Pub Date : 2017-11-16
    Ersin Gul, Esra Hazar Sayar, Bilgi Gungor, Fehime Kara Eroglu, Naz Surucu, Sevgi Keles, Sukru Nail Guner, Sıddıka Fındık, Esin Alpdündar, Ihsan Cihan Ayanoglu, Basak Kayaoglu, Busra Nur Geçkin, Hatice Asena Sanli, Tamer Kahraman, Cengiz Yakicier, Meltem Muftuoglu, Berna Oguz, Deniz Nazire Cagdas Ayvaz, Ihsan Gursel, Seza Ozen, Ismail Reisli, Mayda Gursel

    Background Pathological inflammatory syndromes of unknown etiology are commonly observed in Ataxia telangiectasia (AT) and Artemis deficiency. Similar inflammatory manifestations also exist in STING-associated vasculopathy in infancy (SAVI) patients. Objective To test the hypothesis that the inflammation associated manifestations observed in AT and Artemis deficient patients stem from increased type I IFN signature leading to neutrophil mediated pathological damage. Methods Cytokine/protein signatures were determined by ELISA, cytometric bead array or by qPCR. Stat1 phosphorylation levels were determined by flow cytometry. DNA species accumulating in the cytosol of patients’ cells was quantified microscopically and flow cytometrically. Propensity of isolated polymorhonuclear granulocytes to form neutrophil extracellular traps (NETs) was determined using fluorescence microscopy and picogreen assay. Neutrophil reactive oxygen species levels and mitochondrial stress were assayed using fluorogenic probes, microscopy and flow cytometry. Results Type-I and III interferon signatures were elevated in plasma and peripheral blood cells of AT, Artemis deficient and SAVI patients. Chronic interferon production stemmed from accumulation of DNA in cytoplasm of AT and Artemis deficient cells. Neutrophils isolated from patients spontaneously produced neutrophil extracellular traps (NETs) and displayed indicators of oxidative and mitochondrial stress, supportive of their NETotic tendencies. A similar phenomenon was also observed in neutrophils from healthy controls exposed to patient plasma samples or exogeneous IFNα. Conclusion Type I IFN-mediated neutrophil activation and NET formation may contribute to inflammatory manifestations observed in AT, Artemis deficient and SAVI patients. Thus, neutrophils represent a promising target to manage inflammatory syndromes in diseases with active type I IFN signature.

    更新日期:2017-11-17
  • Targeting of Rac1 prevents bronchoconstriction and airway hyperresponsiveness
    J. Allergy Clin. Immunol. (IF 13.081) Pub Date : 2017-11-16
    Gwennan André-Grégoire, Florian Dilasser, Julie Chesné, Faouzi Braza, Antoine Magnan, Gervaise Loirand, Vincent Sauzeau

    Background The molecular mechanisms responsible for airway smooth muscle cells (aSMC) contraction and proliferation in airway hyperresponsiveness (AHR) associated with asthma are still largely unknown. The small GTPases of the Rho family (RhoA, Rac1 and Cdc42) play a central role in SMC functions including migration, proliferation and contraction. Objective The objective of this study is to identify the role of Rac1 in aSMC contraction and to investigate its involvement in AHR associated with allergic asthma. Methods To define the role of Rac1 in aSMC, ex- and in vitro analyses of bronchial reactivity were performed on bronchi from smooth muscle (SM)-specific Rac1 knockout mice (SM-Rac1-KO) and human individuals. In addition, this murine model was exposed to allergens (ovalbumin or house dust mite extract) to decipher in vivo the implication of Rac1 in AHR. Results The specific SMC deletion or pharmacological inhibition of Rac1 in mice prevented the bronchoconstrictor response to methacholine. In human bronchi a similar role of Rac1 was observed during bronchoconstriction. We further demonstrated that Rac1 activation is responsible for bronchoconstrictor-induced increase in intracellular Ca2+ concentration and contraction both in murine and human bronchial aSMC, through its association with phospholipase C β2 and the stimulation of inositol 1,4,5-trisphosphate production. In vivo, Rac1 deletion in SMC or pharmacological Rac1 inhibition by nebulization of NSC23766 prevented AHR in murine models of allergic asthma. Moreover, nebulization of NSC23766 decreased eosinophil and neutrophil populations in bronchoalveolar lavages from asthmatic mice. Conclusion Our data reveal an unexpected and essential role of Rac1 in the regulation of intracellular Ca2+ and contraction of aSMC, and the development of AHR. Rac1 thus appears as an attractive therapeutic target in asthma, with a combined beneficial action on both bronchoconstriction and pulmonary inflammation.

    更新日期:2017-11-17
  • RASGRP1 mutation in autoimmune lymphoproliferative syndrome-like disease
    J. Allergy Clin. Immunol. (IF 13.081) Pub Date : 2017-11-15
    Huawei Mao, Wanling Yang, Sylvain Latour, Jing Yang, Sarah Winter, Jian Zheng, Ke Ni, Minmin Lv, Chenjing Liu, Hongmei Huang, Koon-Wing Chan, Pamela Pui-Wah Lee, Wenwei Tu, Alain Fischer, Yu-Lung Lau

    Background Autoimmune lymphoproliferative syndrome (ALPS) is a genetic disorder of lymphocyte homeostasis due to impaired apoptosis. It was initially regarded as a very rare disease, but recent studies show it may be more common than previously thought. Defects in a couple of genes have been identified in a proportion of ALPS patients, but around one third of such patients remain undefined genetically. Objective We described two siblings presenting with ALPS-like disease. This study aimed to identify the genetic cause responsible for this phenotype. Methods Whole exome sequencing, molecular and functional analyses were used to identify and characterize the genetic defect. Clinical and immunological analysis was also performed and reported. Results The two patients presented with chronic lymphadenopathy, hepatosplenomegaly, autoimmune hemolytic anemia, immune thrombocytopenia, presence of ANA and other autoantibodies, but normal double negative T cells. They also suffered from recurrent infections. Novel compound heterozygous mutations of RASGRP1 encoding Ras guanyl nucleotide releasing protein 1 were identified in the two siblings. The mutations impaired TCR signaling, leading to defective T cell activation and proliferation, as well as impaired activation-induced cell death of T cells. Conclusion This study shows for the first time that RASGRP1 mutation should be considered in patients with ALPS-like disease. We also propose to investigate the intracellular proteins involved in the TCR signaling pathway in similar patients but with unknown genetic cause.

    更新日期:2017-11-17
  • 14-3-3z sequesters cytosolic T-bet, up-regulating IL-13 in Tc2 and scleroderma CD8+ lymphocytes
    J. Allergy Clin. Immunol. (IF 13.081) Pub Date : 2017-11-15
    Sandra Cascio, Thomas A. Medsger Jr., William F. Hawse, Simon C. Watkins, Christine Milcarek, Larry W. Moreland, Robert A. Lafyatis, Patrizia Fuschiotti

    Background Interleukin(IL)-13-producing CD8+ T cells have been implicated in the pathogenesis of type-2 driven inflammatory human conditions. We have shown that CD8+IL-13+ cells play a critical role in cutaneous fibrosis, the most characteristic feature of systemic sclerosis (scleroderma; SSc). However, the molecular mechanisms underlying IL-13 and other type-2 cytokine production by CD8+ T cells remain unclear. Objective Establish the molecular basis of IL-13 over-production by SSc CD8+ T cells, focusing on T-bet modulation of GATA-3 activity, which we showed to underlie IL-13 over-production in SSc CD8+IL-13+ cells. Methods Biochemical and biophysical methods were employed to determine expression and association of T-bet, GATA-3 and regulatory factors in CD8+ T cells isolated from the blood and lesional skin of SSc patients with severe skin thickening. ChIP analysis determined GATA-3 binding to the IL-13 promoter. ImageStream analysis and confocal microscopy visualized the subcellular localization of T-bet and GATA-3. Transcript levels were decreased by small interfering RNAs. Results The interaction of T-bet with the adaptor protein 14-3-3z in the cytosol of SSc CD8+ T cells reduces T-bet translocation into the nucleus and its ability to associate with GATA-3, allowing more GATA-3 to bind to the IL-13 promoter and inducing IL-13 up-regulation. Strikingly, we show that this mechanism is also found during type-2 polarization of healthy donor CD8+ T cells (Tc2). Conclusions We identified a novel molecular mechanism underlying type-2 cytokine production by CD8+ T cells revealing a more complete picture of the complex pathway leading to SSc disease pathogenesis.

    更新日期:2017-11-17
  • Predicting the atopic march: Results from the Canadian Healthy Infant Longitudinal Development Study
    J. Allergy Clin. Immunol. (IF 13.081) Pub Date : 2017-11-15

    BackgroundThe atopic march describes the progression from atopic dermatitis during infancy to asthma and allergic rhinitis in later childhood. In a Canadian birth cohort we investigated whether concomitant allergic sensitization enhances subsequent development of these allergic diseases at age 3 years.MethodsChildren completed skin prick testing at age 1 year. Children were considered sensitized if they produced a wheal 2 mm or larger than that elicited by the negative control to any of 10 inhalant or food allergens. Children were also assessed for atopic dermatitis by using the diagnostic criteria of the UK Working Party. At age 3 years, children were assessed for asthma, allergic rhinitis, food allergy, and atopic dermatitis. Data from 2311 children were available.ResultsAtopic dermatitis without allergic sensitization was not associated with an increased risk of asthma at age 3 years after adjusting for common confounders (relative risk [RR], 0.46; 95% CI, 0.11-1.93). Conversely, atopic dermatitis with allergic sensitization increased the risk of asthma more than 7-fold (RR, 7.04; 95% CI, 4.13-11.99). Atopic dermatitis and allergic sensitization had significant interactions on both the additive (relative excess risk due to interaction, 5.06; 95% CI, 1.33-11.04) and multiplicative (ratio of RRs, 5.80; 95% CI, 1.20-27.83) scales in association with asthma risk. There was also a positive additive interaction between atopic dermatitis and allergic sensitization in their effects on food allergy risk (relative excess risk due to interaction, 15.11; 95% CI, 4.19-35.36).ConclusionsAtopic dermatitis without concomitant allergic sensitization was not associated with an increased risk of asthma. In combination, atopic dermatitis and allergic sensitization had strong interactive effects on both asthma and food allergy risk at age 3 years.

    更新日期:2017-11-16
  • Pathogenic Th17 inflammation is sustained in the lungs by conventional dendritic cells and TLR4 signaling
    J. Allergy Clin. Immunol. (IF 13.081) Pub Date : 2017-11-14
    Karim H. Shalaby, Miranda R. Lyons-Cohen, Gregory S. Whitehead, Seddon Y. Thomas, Immo Prinz, Hideki Nakano, Donald N. Cook

    BackgroundMechanisms that elicit mucosal Th17 cell responses have been described, yet how these cells are sustained in chronically inflamed tissues remains unclear.ObjectiveWe sought to understand whether the maintenance of lung Th17 inflammation requires environmental agents in addition to antigen, and to identify the lung antigen-presenting cell types (APCs) that sustain the self-renewal of Th17 cells.MethodsAnimals were repeatedly exposed to aspiration of ovalbumin alone, or together with environmental adjuvants, including extracts of common house dust (HDE), to test their role in maintaining lung inflammation. Alternatively, antigen-specific effector/memory Th17 cells, generated in culture using CD4+ T cells from Il17a fate-mapping mice, were adoptively transferred to assess their persistence in genetically modified animals lacking distinct lung APC subsets or cell-specific TLR4 signaling. Th17 cells were also co-cultured with lung APC subsets to determine which of these could revive their expansion and activation.ResultsTh17 cells and consequent neutrophilic inflammation were poorly sustained by inhaled antigen alone, but were augmented by inhalation of antigen together with HDE. This was associated with weight loss and changes in lung physiology consistent with interstitial lung disease. The effect of HDE required TLR4 signaling predominantly in lung hematopoietic cells, including CD11c+ cells. CD103+ and CD11b+ conventional dendritic cells (cDCs) directly interacted with Th17 cells in situ and revived the clonal expansion of Th17 cells ex vivo and in vivo, whereas lung macrophages and B cells could not.ConclusionTh17-dependent inflammation in the lungs can be sustained by persistent TLR4-mediated activation of lung cDCs.

    更新日期:2017-11-15
  • Early life innate immune signatures of persistent food allergy
    J. Allergy Clin. Immunol. (IF 13.081) Pub Date : 2017-11-14
    Melanie R. Neeland, Jennifer J. Koplin, Thanh D. Dang, Shyamali C. Dharmage, Mimi L. Tang, Susan L. Prescott, Richard Saffery, David J. Martino, Katrina J. Allen

    BackgroundFood allergy naturally resolves in a proportion of food allergic children without intervention, however the underlying mechanisms governing the persistence or resolution of food allergy in childhood are not understood.ObjectivesThis study aimed to define the innate immune profiles associated with egg allergy at one year of age, determine the phenotypic changes that occur with the development of natural tolerance in childhood and explore the relationship between early life innate immune function and serum vitamin D.MethodsThis study used longitudinally collected PBMC samples from a population-based cohort of challenge-confirmed egg allergic infants with either persistent or transient egg allergy outcomes in childhood to phenotype and quantify the functional innate immune response associated with clinical phenotypes of egg allergy.ResultsWe show that infants with persistent egg allergy exhibit a unique innate immune signature, characterised by increased numbers of circulating monocytes and dendritic cells that produce more inflammatory cytokines both at baseline and following endotoxin exposure when compared to infants with transient egg allergy. Follow up analysis revealed that this unique innate immune signature continues into childhood in those with persistent egg allergy and that increased serum vitamin D levels correlate with changes in innate immune profiles observed in children who developed natural tolerance to egg.ConclusionEarly life innate immune dysfunction may represent a key immunological driver and predictor of persistent food allergy in childhood. Serum vitamin D may play an immune-modulatory role in the development of natural tolerance.

    更新日期:2017-11-15
  • Obstruction phenotype as a predictor of asthma severity and instability in children
    J. Allergy Clin. Immunol. (IF 13.081) Pub Date : 2017-11-14
    Ronald L. Sorkness, Edward M. Zoratti, Meyer Kattan, Peter J. Gergen, Michael D. Evans, Cynthia M. Visness, Michelle Gill, Gurjit K. Khurana Hershey, Carolyn M. Kercsmar, Andrew H. Liu, George T. O'Connor, Jacqueline A. Pongracic, Dinesh Pillai, Christine A. Sorkness, Alkis Togias, Robert A. Wood, William W. Busse

    BackgroundSmall airways instability, resulting in premature airway closure, has been recognized as a risk for asthma severity and poor control. Although spirometry has limited sensitivity for detecting small airway dysfunction, a focus on the air-trapping component of obstruction may identify a risk factor for asthma instability.ObjectiveTo use spirometric measurements to identify patterns of airway obstruction in children, and define obstruction phenotypes that relate to asthma instability.MethodsPre- and post-bronchodilation spirometry data were obtained from 560 children in the Asthma Phenotypes in the Inner City study. An air-trapping obstruction phenotype (A Trpg) was defined as forced vital capacity (FVC) Z-score < -1.64, or an increase of FVC ≥ 10% predicted with bronchodilation. The airflow limitation phenotype (A Limit) had forced expiratory volume in 1 s (FEV1)/FVC Z-score < -1.64, but not A Trpg. The None phenotype had neither A Trpg nor A Limit. The 3 obstruction phenotypes were assessed as predictors of number of exacerbations, asthma severity, and airway lability.ResultsThe A Trpg phenotype (14% of the cohort) had more exacerbations during the 12-month study, compared with the A Limit (P<0.03) and the None (P<0.001) phenotypes. The A Trpg phenotype also had the highest Composite Asthma Severity Index, the highest asthma treatment step, the greatest variability in FEV1 over time, and the greatest sensitivity to methacholine challenge.ConclusionsA Trpg and A Limit patterns of obstruction, defined with routine spirometric measurements, can identify obstruction phenotypes that are indicators of risk for asthma severity and instability.

    更新日期:2017-11-14
  • Autoinflammatory phenotypes in Aicardi-Goutières syndrome with interferon upregulation and serological autoimmune features
    J. Allergy Clin. Immunol. (IF 13.081) Pub Date : 2017-11-11
    Yuji Sugawara, Kohsuke Imai, Ayako Kashimada, Kengo Moriyama, Shimpei Baba, Ryuta Nishikomori, Mizuho Motegi, Yasuo Takeuchi, Tomohiro Morio

    In an Aicardi-Goutières syndrome patient, cimetidine successfully controlled periodic fever with improved serum autoimmune marker levels, suggesting the presence of crosstalk between autoinflammation and autoimmunity in type I interferonopathy.

    更新日期:2017-11-11
  • Allergy terminology: towards a common language and shared understanding
    J. Allergy Clin. Immunol. (IF 13.081) Pub Date : 2017-11-10
    Michael Levin

    Terminology that is used in an inconsistent and ambiguous way by allergists includes the term “cross reactivity” and the use of the word “positive” when referring to allergy tests. This may have serious potential for miscommunication and adversely affect patient care.

    更新日期:2017-11-11
  • The XTEND-CIU study: long term use of Omalizumab in Chronic Idiopathic Urticaria
    J. Allergy Clin. Immunol. (IF 13.081) Pub Date : 2017-11-10
    Marcus Maurer, Allen Kaplan, Karin Rosén, Michael Holden, Ahmar Iqbal, Benjamin L. Trzaskoma, Ming Yang, Thomas B. Casale

    These data support omalizumab safety and efficacy in patients with antihistamine-resistant CIU/CSU to 48 weeks and provide evidence of omalizumab re-treatment efficacy and safety.

    更新日期:2017-11-11
  • Influenza-derived peptides cross-react with allergens and provide asthma protection
    J. Allergy Clin. Immunol. (IF 13.081) Pub Date : 2017-11-10
    Chrysanthi Skevaki, Christoph Hudemann, Mikhail Matrosovich, Christian Möbs, Sinu Paul, Andreas Wachtendorf, Bilal Alashkar Alhamwe, Daniel P. Potaczek, Stefanie Hagner, Diethard Gemsa, Holger Garn, Alessandro Sette, Harald Renz

    Background The hygiene hypothesis is the leading concept to explain the current asthma epidemic, which is built on the observation that a lack of bacterial contact early in life induces allergic Th2 immune responses. Objective Since little is known about the contribution of respiratory viruses in this context, we evaluated the effect of prior influenza-infection on the development of allergic asthma. Methods Mice were infected with influenza and once recovered, subjected to an ovalbumin or house dust mite-induced experimental asthma protocol. Influenza-polarized T effector memory cells (Tem) were adoptively transferred to allergen sensitized animals prior to allergen challenge. A comprehensive in silico analysis assessed homologies between virus- and allergen- derived proteins. Influenza-polarized Tem cells were stimulated ex vivo with candidate peptides. Mice were immunized with a pool of virus-derived T-cell epitopes. Results We found in two murine models a long-lasting preventive effect against experimental asthma features. Protection could be attributed about equally to CD4+ and CD8+ T-effector memory (Tem) cells from influenza-infected mice. An in silico bioinformatic analysis identified four influenza and three allergen-derived MHC-class I and –class II candidate T-cell epitopes with potential antigen-specific cross-reactivity between influenza and allergens. Lymphocytes from influenza-infected mice produced IFNγ and IL-2 but not IL-5 upon stimulation with the aforementioned peptides. Immunization with a mixture of the influenza-peptides conferred asthma protection, and peptide immunized mice transferred protection via CD4+ and CD8+ Tem cells. Conclusion Our results illustrate for the first time heterologous immunity of virus-infected animals towards allergens. This finding extends the original hygiene hypothesis.

    更新日期:2017-11-11
  • Title: Experimental Asthma Persists in IL33 Receptor Knockout Mice Due to the Emergence of a TSLP-driven IL9+ and IL13+ ILC2 subpopulations
    J. Allergy Clin. Immunol. (IF 13.081) Pub Date : 2017-11-10
    Mukesh Verma, Sucai Liu, Lidia Michalec, Anand Sripada, Magdalena M. Gorska, Rafeul Alam

    Background IL33 plays an important role in development of experimental asthma. Objective To study the role of the IL33 receptor (ST2) in persistence of asthma in a mouse model. Methods We studied allergen-induced experimental asthma in ST2 knockout (KO) and wild-type control mice. We measured airway hyperresponsiveness (AHR) by flexivent, inflammatory indices by ELISA, histology and real-time PCR, and ILC2s in lung single cell preparations by flow cytometry. Results The AHR level was elevated in allergen-treated ST2 KO mice and was comparable to that from allergen-treated WT controls. Peribronchial and perivascular inflammation and mucus production were largely similar in both groups. Persistence of experimental asthma in ST2 KO mice was associated with an increase in the level of TSLP, IL9 and IL13 but not IL5 in bronchoalveolar lavage (BAL). ST2 deletion expectedly caused a reduction in IL13+ CD4 T cells, Foxp3+ Tregs and IL5+ ILC2s. Unexpectedly, ST2 deletion led to an overall increase in ILCs (CD45+lin-CD25+ cells), IL13+ ILC2s, the emergence of a TSLP-R+ IL9+ ILC2 population and an increase in intraepithelial mast cells in the lung. An anti-TSLP antibody abrogated AHR, inflammation and mucus production in allergen-treated ST2 KO mice. It also caused a reduction in ILCs, ILC2s, and IL9+ and IL13+ ILC2s in the lung. Conclusions Genetic deletion of the IL33 receptor paradoxically increases TSLP production, which stimulates the emergence of IL9+ and IL13+ ILC2s and mast cells, and leads to the development of chronic experimental asthma. An anti-TSLP antibody abrogates all pathologic features of asthma in this model.

    更新日期:2017-11-11
  • Ventilation Defect Percent in Helium-3 MRI as a Biomarker of Severe Outcomes in Asthma
    J. Allergy Clin. Immunol. (IF 13.081) Pub Date : 2017-11-10
    David G. Mummy, Stanley J. Kruger, Wei Zha, Ronald L. Sorkness, Nizar N. Jarjour, Mark L. Schiebler, Loren C. Denlinger, Michael D. Evans, Sean B. Fain

    Ventilation defect percent (VDP) measured in asthmatics with hyperpolarized helium-3 MRI was more strongly associated with ED visits and hospitalizations due to asthma exacerbation than were conventional biomarkers of lung function and inflammation.

    更新日期:2017-11-10
  • The β and α2δ auxiliary subunits of Cav1 channels are required for Th2-lymphocyte function and acute allergic airway inflammation
    J. Allergy Clin. Immunol. (IF 13.081) Pub Date : 2017-11-10
    Nicolas Rosa, Emily Triffaux, Virginie Robert, Marion Mars, Martin Klein, Gregory Bouchaud, Astrid Canivet, Antoine Magnan, Jean-Charles Guéry, Lucette Pelletier, Magali Savignac

    BackgroundT-lymphocytes express not only the cell membrane calcium ORAI1 but also voltage-dependent Cav1 channels. In excitable cells, these channels are composed of the ion forming pore α1 and auxiliary subunits (β and α2δ) needed for proper trafficking and activation of the channel. We previously disclosed the role of Cav1.2 α1 in mouse and human Th2- but not Th1-cell functions and showed that knocking-down Cav1 α1 prevents experimental asthmaObjectiveWe investigated the role of β and α2δ auxiliary subunits on Cav1 α1 function in Th2 lymphocytes and on the development of acute allergic airway inflammation.MethodsWe used antisense oligonucleotides (CavβAS) to knockdown Cavβ and gabapentin, a drug that binds to and inhibits α2δ1 and α2δ2, to test their effects on Th2 functions and their capacity to reduce allergic airway inflammation.ResultsMouse and human Th2-cells express mainly Cavβ1, β3 and α2δ2 subunits. CavβAS reduces TCR-driven calcium responses and cytokine production by mouse and human Th2, with no effect on Th1-cells. Cavβ is mainly involved in restraining Cav1.2 α1 degradation through the proteasome as a proteasome inhibitor partially restores the α1 protein level. Gabapentin impairs TCR-driven calcium response and cytokine production associated with the loss of α2δ2 protein in Th2-cells.ConclusionsThese results stress the role of Cavβ and α2δ2 auxiliary subunits in the stability and activation of Cav1.2 channels in Th2 lymphocytes both in vitro and in vivo as demonstrated by the beneficial effect of CavβAS and gabapentin in allergic airway inflammation.Clinical implicationsThe demonstration that auxiliary subunits are involved in calcium signaling through Cav1 channels and function of mouse and human Th2-lymphocytes supports their potential beneficial effect on allergic asthma.

    更新日期:2017-11-10
  • EoE genetic susceptibility is mediated by synergistic interactions between EoE-specific and general atopic disease loci
    J. Allergy Clin. Immunol. (IF 13.081) Pub Date : 2017-11-10
    L.J. Martin, H. He, M.H. Collins, J.P. Abonia, J.M. Biagini Myers, M. Eby, H.E. Johansson, L.C. Kottyan, G.K. Khurana Hershey, M.E. Rothenberg

    BackgroundEosinophilic esophagitis (EoE) is an esophageal inflammatory disease associated with atopic diseases. TSLP and CAPN14 genetic variation contribute to EoE, but how this relates to atopy is unclear. The purpose of this study was to explore the relationship between EoE, atopy and genetic risk.MethodsEoE-atopy enrichment was tested using 700 EoE cases and 801 community controls. Probing 372 SNPs in 63 atopy-genes, we evaluated EoE associations using 412 non-atopic and 868 atopic disease controls. Interaction and stratified analyses of EoE-specific and atopy SNPs were performed.ResultsAtopic disease was enriched in EoE (p < 0.0001). Comparing EoE and non-atopic controls, EoE associated strongly with IL4/KIF3A (p = 2.8×10-6; odds ratio (OR) = 1.85), moderately with TSLP (p = 1.5×10-4; OR = 1.43), and nominally with CAPN14 (p = 0.029; OR = 1.35). Comparing EoE to atopic disease controls, EoE associated strongly with ST2 (p = 3.5×10-6; OR = 1.79) and nominally with IL4/KIF3A (p = 0.019, OR = 1.25); TSLP’s association persisted (p = 4.7×10-5; OR = 1.37), and CAPN14’s association strengthened (p = 0.0001; OR = 1.71). Notably, there was gene-gene interaction between TSLP and IL4 SNPs (p = 0.0074). Children with risk alleles for both genes were at higher risk for EoE (p = 2.0×10-10; OR = 3.67).ConclusionsEoE genetic susceptibility is mediated by EoE-specific and general atopic disease loci which may have synergistic effects. These results may aid in identifying potential therapeutics and predicting EoE susceptibility.Clinical Implications.EoE susceptibility is mediated by multiple genes, which have synergistic effects. These genes include both EoE-specific and general atopic disease loci. Identifying these effects may help customize treatments.

    更新日期:2017-11-10
  • Identification of atopic dermatitis subgroups in children from two longitudinal birth cohorts
    J. Allergy Clin. Immunol. (IF 13.081) Pub Date : 2017-11-10
    Lavinia Paternoster, Olga E.M. Savenije, Jon Heron, David M. Evans, Judith M. Vonk, Bert Brunekreef, Alet H. Wijga, A. John Henderson, Gerard H. Koppelman, Sara J. Brown

    BackgroundAtopic dermatitis (AD) is a prevalent disease with variable natural history. Longitudinal birth cohort studies provide an opportunity to define subgroups based on disease trajectories, which may represent different genetic and environmental pathomechanisms.ObjectiveTo investigate the existence of distinct longitudinal phenotypes of AD and test whether these findings are reproducible in two independent cohorts.MethodsThe presence of AD was examined in two birth cohort studies including 9,894 children from the UK (ALSPAC) and 3,652 from the Netherlands (PIAMA). AD was defined by parental report of a typical itchy and/or flexural rash. Longitudinal latent class analysis was used to investigate patterns of AD from birth to the age of 11 to 16 years. We investigated associations with known AD risk factors, including FLG null mutations, 23 other established AD-genetic risk variants and atopic comorbidity.ResultsSix latent classes were identified, representing subphenotypes of AD, with remarkable consistency between the two cohorts. The most prevalent class was early-onset-early-resolving AD, which was associated with male gender. Two classes of persistent disease were identified (early-onset-persistent and early-onset-late-resolving); these were most strongly associated with the AD-genetic risk score as well as personal and parental history of atopic disease. A yet unrecognised class of mid-onset-resolving AD, not associated with FLG mutations, but strongly associated with asthma, was identified.ConclusionSix classes based on temporal trajectories of rash were consistently identified in two population-based cohorts. The differing risk factor profiles and diverse prognoses demonstrate the potential importance of a stratified medicine approach for AD.Clinical ImplicationsAtopic dermatitis ranges from a transient condition to lifelong morbidity. This study has identified distinct subphenotypes of atopic dermatitis in children, which could indicate the importance of a stratified approach to management of this complex disease.

    更新日期:2017-11-10
  • Staged development of long lived TCRαβ Th17 resident memory T cell population to Candida albicans after skin infection
    J. Allergy Clin. Immunol. (IF 13.081) Pub Date : 2017-11-09
    Chang Ook Park, Xiujun Fu, Xiaodong Jiang, Youdong Pan, Jessica E. Teague, Nicholas Collins, Tian Tian, John T. O’Malley, Ryan O. Emerson, Ji Hye Kim, Yookyung Jung, Rei Watanabe, Robert C. Fuhlbrigge, Francis R. Carbone, Thomas Gebhardt, Rachael A. Clark, Charles P. Lin, Thomas S. Kupper

    BackgroundCandida albicans is a dimorphic fungus to which humans are exposed early in life and by adulthood it is part of the mycobiome of skin and other tissues. Neonatal skin lacks resident memory T (TRM) cells, but in adults the C. albicans skin test is a surrogate for immunocompetence. Young adult mice raised under SPF conditions are naive to C. albicans, and have recently been shown to have an immune system resembling that of neonatal humans.ObjectiveWe studied the evolution of the adaptive cutaneous immune response to Candida.MethodsWe examined both human skin T cells and the de novo and memory immune responses in a mouse model of C. albicans skin infection.ResultsIn mice, the initial IL-17 producing cells after C. albicans infection were dermal γδ T cells, but by day 7 αβ Th17 T effector cells were predominant. By day 30, the majority of C. albicans reactive IL-17 producing T cells were CD4 TRM cells. Intravital microscopy showed that CD4 effector T cells were recruited to the site of primary infection and were highly motile 10 days post infection. Between 30-90 days post infection, these CD4 T cells became increasingly sessile, acquired expression of CD69 and CD103, and localized to the papillary dermis. These established TRM produced IL-17 upon challenge, while motile migratory memory T (TMM) cells did not. TRM rapidly clear an infectious challenge with C. albicans more effectively than re-circulating T cells, though both populations participate. We found that in normal human skin, IL-17 producing CD4+ TRM that responded to C. albicans in an MHC Class II restricted fashion could be readily identified.ConclusionsThese studies demonstrate that C. albicans infection of skin preferentially generates CD4+ IL-17 producing TRM, which mediate durable protective immunity.

    更新日期:2017-11-10
  • Synchronous Immune Alterations Mirror Clinical Response During Allergen Immunotherapy
    J. Allergy Clin. Immunol. (IF 13.081) Pub Date : 2017-11-09
    Amedee Renand, Mohamed H. Shamji, Kristina M. Harris, Tielin Qin, Erik Wambre, Guy W. Scadding, Peter A. Wurtzen, Stephen J. Till, Alkis Togias, Gerald T. Nepom, William W. Kwok, Stephen R. Durham

    BackgroundThree years treatment with either sublingual or subcutaneous allergen immunotherapy has been shown to be effective and to induce long-term tolerance. The GRASS∗ trial demonstrated that two years treatment via either route was effective in suppressing the response to nasal allergen challenge, although was insufficient for inhibition one year after discontinuation.ObjectiveTo examine in the GRASS trial the time-course of immunologic changes during two years sublingual and subcutaneous immunotherapy and for one year after treatment discontinuation.MethodsWe performed multi-modal immunomonitoring to assess allergen-specific CD4 T cell properties, in parallel with analysis of local mucosal cytokine responses induced by nasal allergen exposure and humoral immune responses that included IgE-dependent basophil activation and measurement of serum inhibitory activity for allergen-IgE binding to B cells (IgE-Facilitated Allergen Binding).ResultsAll three of these distinct arms of the immune response displayed significant and coordinate alterations during 2 years allergen desensitization, followed by reversal at 3 years, reflecting a lack of a durable immunological effect. Whereas frequencies of antigen-specific Th2 cells in peripheral blood determined by HLA class II tetramer analysis most closely paralleled clinical outcomes, IgE-antibody dependent functional assays remained partially inhibited one year following discontinuation.ConclusionTwo years of allergen immunotherapy were effective but insufficient for long-term tolerance. Allergen-specific Th2 cells most closely paralleled the transient clinical outcome and it is likely that recurrence of the T cell ‘drivers’ of allergic immunity abrogated the potential for durable tolerance. On the other hand, persistence of IgE-blocking antibody one year after discontinuation may be an early indicator of a pro-tolerogenic mechanism.

    更新日期:2017-11-10
  • Bi-allelic IRF8 mutation: a complex immunodeficiency syndrome with dendritic cell deficiency, monocytopenia and immune dysregulation
    J. Allergy Clin. Immunol. (IF 13.081) Pub Date : 2017-11-08
    Venetia Bigley, Sheetal Maisuria, Urszula Cytlak, Laura Jardine, Matthew A. Care, Kile Green, Merry Gunawan, Paul Milne, Rachel Dickinson, Sarah Wiscombe, David Parry, Rainer Doffinger, Arian Laurence, Claudia Fonseca Lic, Oda Stoevesandt, Andrew Gennery, Andrew Cant, Reuben Tooze, A John Simpson, Sophie Hambleton, Sinisa Savic, Gina Doody, Matthew Collin

    BackgroundHomozygous K108E mutation of interferon regulatory factor 8 (IRF8) is reported to cause dendritic cell and monocyte deficiency. However, more widespread immune dysfunction is predicted from the multiple roles ascribed to IRF8 in immune cell development and function.ObjectiveWe sought to describe the effect on hematopoiesis and immunity of compound heterozygous R83C/ R291Q mutation of IRF8, present in a patient with recurrent viral infection, granulo-proliferation and intracerebral calcification.MethodsVariant IRF8 alleles were identified by exome sequencing and their function tested by reporter assays. The cellular phenotype was studied in detail using flow cytometry, functional immunologic assays transcriptional profiling and antigen receptor profiling.ResultsBoth mutations affected conserved residues and R291Q is orthologous to R294, mutated in the BXH2 IRF8-deficient mouse. R83C showed reduced nuclear translocation and neither mutant was able to regulate the Ets/IRF composite element or interferon-stimulated response element, while R291Q retained BATF/JUN interactions. Dendritic cell deficiency and monocytopenia were observed in blood, dermis and lung lavage fluid. Granulocytes were consistently elevated, dysplastic and hypofunctional. NK development maturation was arrested. Th1, Th17 and CD8+ memory T cell differentiation was significantly reduced, and T cells failed to express CXCR3. B cell development was impaired with fewer memory cells, reduced class-switching and lower frequency and complexity of somatic hypermutation. Cell-specific gene expression was widely disturbed in interferon and IRF8-regulated transcripts.ConclusionsThis analysis defines the clinical features of human bi-allelic IRF8 deficiency, revealing a complex immunodeficiency syndrome caused by dendritic cell and monocyte deficiency combined with widespread immune dysregulation.

    更新日期:2017-11-10
  • Corticosteroid treatment is associated with increased filamentous fungal burden in allergic fungal disease
    J. Allergy Clin. Immunol. (IF 13.081) Pub Date : 2017-11-06
    Marcin G. Fraczek, Livingstone Chishimba, Rob M. Niven, Mike Bromley, Angela Simpson, Lucy Smyth, David W. Denning, Paul Bowyer

    BackgroundAllergic diseases caused by fungi are common. The best understood conditions are allergic bronchopulmonaryaspergillosis (ABPA) and severe asthma with fungal sensitisation (SAFS). Our knowledge of the fungal microbiome (mycobiome) is limited to a few studies involving healthy individuals, asthmatics and smokers. No study has yet examined the mycobiome in fungal lung disease.ObjectivesThe main aim of this study was to determine the mycobiome in lungs of individuals with well characterised fungal disease. A secondary objective was to determine possible effects of treatment on the mycobiome.MethodsAfter bronchoscopy, ITS1 DNA was amplified and sequenced and fungal load determined by RT-PCR. Clinical and treatment variables were correlated with the main species identified. ABPA (n=16), SAFS (n=16), severe asthma not sensitised to fungi, (n=9), mild asthma patients(n=7) and 10 healthy controls were studied.ResultsThe mycobiome was highly varied with severe asthmatics carrying higher loads of fungus. Healthy individuals had low fungal loads, mostly poorly characterised Malasezziales.The most common fungus in asthmatics was Aspergillus fumigatus complex and this taxon accounted for the increased burden of fungus in the high level samples. Corticosteroid treatment was significantly associated with increased fungal load (p<0.01).ConclusionsThe mycobiome is highly variable. Highest loads of fungus are observed in severe asthmatics and the most common fungus is Aspergillusfumigatus complex. Individuals receiving steroid therapy had significantly higher levels of Aspergillus and total fungus in their BAL.

    更新日期:2017-11-10
  • TRIM21 negatively regulates intestinal mucosal inflammation through inhibiting Th1/Th17 cell differentiation in inflammatory bowel diseases
    J. Allergy Clin. Immunol. (IF 13.081) Pub Date : 2017-11-04
    Guangxi Zhou, Wei Wu, Lin Yu, Tianming Yu, Wenjing Yang, Ping Wang, Xiaoping Zhang, Yingzi Cong, Zhanju Liu

    BackgroundTripartite motif-containing (TRIM)21 has been implicated in pathogenesis of several types of autoimmune diseases.ObjectiveWe sought to elucidate expression of TRIM21 in patients with inflammatory bowel disease (IBD) and its role in regulating intestinal mucosal inflammation.MethodsTRIM21 expression was analyzed in inflamed mucosa of IBD patients by qRT-PCR and immunohistochemistry. Peripheral blood CD4+ T cells were transfected with lentivirus-expressing-TRIM21 (LV-TRIM21) or LV-sh-TRIM21, and cytokine expression was determined by qRT-PCR and ELISA. TRIM21−/− mice were generated, and trinitrobenzene sulphonic acid (TNBS)- and CD45RBhighCD4+ T cell-induced colitis models were established to determine its role in the induction of intestinal inflammation.ResultsTRIM21 was predominantly expressed in CD4+ T cells and markedly decreased in inflamed mucosa of IBD patients compared with healthy controls. Ectopic expression of TRIM21 inhibited IBD CD4+ T cells to differentiate into T helper (Th)1 and Th17 cells, whereas downregulation of TRIM21 had opposite effects. TRIM21−/− mice developed more severe colitis following administration of TNBS compared with wild-type mice, characterized by increased expression of IFN-γ, TNF-α, and IL-17A in the colon. TRIM21−/− CD45RBhighCD4+ T cells reconstituted into Rag-1−/− mice induced more severe colitis than wild-type controls. Mechanistically, IRF3 was identified as a functional downstream target of TRIM21, in that silencing of IRF3 suppressed TRIM21−/−CD4+ T cell differentiation into Th1 and Th17 cells.ConclusionsTRIM21 plays a protective role in mucosal inflammation through inhibiting Th1 and Th17 cell differentiation. Thus, TRIM21 may serve as a potential therapeutic target for treatment of IBD.

    更新日期:2017-11-10
  • Interleukin-1/inhibitory kappa B kinase epsilon-induced glycolysis augment epithelial effector function and promote allergic airways disease
    J. Allergy Clin. Immunol. (IF 13.081) Pub Date : 2017-11-03
    Xi Qian, Reem Aboushousha, Cheryl van de Wetering, Shi B. Chia, Eyal Amiel, Robert W. Schneider, Jos LJ. van der Velden, Karolyn G. Lahue, Daisy A. Hoagland, Dylan T. Casey, Nirav Daphtary, Jennifer L. Ather, Matthew J. Randall, Minara Aliyeva, Kendall E. Black, David G. Chapman, Lennart K.A. Lundblad, David H. McMillan, Anne E. Dixon, Vikas Anathy, Charles G. Irvin, Matthew E. Poynter, Emiel. F.M. Wouters, Pamela M. Vacek, Monique Henket, Florence Schleich, Renaud Louis, Albert van der Vliet, Yvonne M.W. Janssen-Heininger

    BackgroundEmerging studies suggest that enhanced glycolysis accompanies inflammatory responses. Virtually nothing is known about the relevance of glycolysis in allergic asthma.ObjectivesHere we sought to determine if glycolysis is altered in allergic asthma and to address its importance in the pathogenesis of allergic asthma.MethodsWe examined alterations in glycolysis in sputum samples from asthmatics and primary human nasal cells, and used murine models of allergic asthma as well as primary mouse tracheal epithelial cells to evaluate the relevance of glycolysis.ResultsIn a murine model of allergic asthma, glycolysis was induced in the lungs in an IL-1-dependent manner. Furthermore, administration of IL-1β into airways stimulated lactate production and expression of glycolytic enzymes, with notable expression of lactate dehydrogenase A occurring in the airway epithelium. Indeed, exposure of mouse tracheal epithelial cells to IL-1β or IL-1α resulted in increased glycolytic flux, glucose usage, expression of glycolysis genes, and lactate production. Enhanced glycolysis was required for IL-1β- or IL-1α-mediated pro-inflammatory responses and the stimulatory effects of IL-1β on HDM-induced release of TSLP, and GM-CSF from tracheal epithelial cells. Inhibitor of κB kinase ε was downstream of house dust mite (HDM) or IL-1β, and was required for HDM-induced glycolysis and the pathogenesis of allergic airways disease. SiRNA-ablation of lactate dehydrogenase A attenuated HDM-induced increases in lactate and attenuated HDM-induced disease. Primary nasal epithelial cells from asthmatics intrinsically produced more lactate as compared to cells from healthy subjects. Lactate content was significantly higher in sputum supernatants from asthmatics, notably those patients with >61% neutrophils. A positively correlation was observed between sputum lactate and IL-1β, and lactate content negatively correlated with lung function.ConclusionsCollectively, these findings demonstrate that IL-1β/IKKε signaling plays an important role in HDM-induced glycolysis and the pathogenesis of allergic airways disease.

    更新日期:2017-11-10
  • CD8+CD28CD127loCD39+ regulatory T-cell expansion: A new possible pathogenic mechanism for HIV infection?
    J. Allergy Clin. Immunol. (IF 13.081) Pub Date : 2017-11-02
    Daniela Fenoglio, Chiara Dentone, Alessio Signori, Antonio Di Biagio, Alessia Parodi, Francesca Kalli, Giorgia Nasi, Monica Curto, Giovanni Cenderello, Pasqualina De Leo, Valentina Bartolacci, Giancarlo Orofino, Laura Ambra Nicolini, Lucia Taramasso, Edoardo Fiorillo, Valeria Orrù, Paolo Traverso, Bianca Bruzzone, Federico Ivaldi, Eugenio Mantia, Michele Guerra, Simone Negrini, Mauro Giacomini, Sanjay Bhagani, Gilberto Filaci

    BackgroundHIV-associated immunodeficiency is related to loss of CD4+ T cells. This mechanism does not explain certain manifestations of HIV disease, such as immunodeficiency events in patients with greater than 500 CD4+ T cells/μL. CD8+CD28−CD127loCD39+ T cells are regulatory T (Treg) lymphocytes that are highly concentrated within the tumor microenvironment and never analyzed in the circulation of HIV-infected patients.ObjectivesWe sought to analyze the frequency of CD8+CD28−CD127loCD39+ Treg cells in the circulation of HIV-infected patients.MethodsThe frequency of circulating CD8+CD28−CD127loCD39+ Treg cells was analyzed and correlated with viral load and CD4+ T-cell counts/percentages in 93 HIV-1–infected patients subdivided as follows: naive (n = 63), elite controllers (n = 19), long-term nonprogressors (n = 7), and HIV-infected patients affected by tumor (n = 4). The same analyses were performed in HIV-negative patients with cancer (n = 53), hepatitis C virus–infected patients (n = 17), and healthy donors (n = 173).ResultsHIV-infected patients had increased circulating levels of functional CD8+CD28−CD127loCD39+ Treg cells. These cells showed antigen specificity against HIV proteins. Their frequency after antiretroviral therapy (ART) correlated with HIV viremia, CD4+ T-cell counts, and immune activation markers, suggesting their pathogenic involvement in AIDS- or non–AIDS-related complications. Their increase after initiation of ART heralded a lack of virologic or clinical response, and hence their monitoring is clinically relevant.ConclusionHIV infection induces remarkable expansion of CD8+CD28−CD127loCD39+ Treg cells, the frequency of which correlates with both clinical disease and signs of chronic immune cell activation. Monitoring their frequency in the circulation is a new marker of response to ART when effects on viremia and clinical response are not met.

    更新日期:2017-11-10
  • The allergen-specificity of early peanut consumption and the impact on the development of allergic disease in the LEAP Study Cohort
    J. Allergy Clin. Immunol. (IF 13.081) Pub Date : 2017-10-31
    George du Toit, Peter H. Sayre, Graham Roberts, Kaitie Lawson, Michelle L. Sever, Henry T. Bahnson, Helen R. Fisher, Mary Feeney, Suzana Radulovic, Monica Basting, Marshall Plaut, Gideon Lack

    BackgroundEarly introduction of dietary peanut in high-risk infants with severe eczema and/or egg allergy prevented peanut allergy at 5 years of age in the LEAP Study; the protective effect persisted after 12 months of avoiding peanuts in the LEAP-On Study. It is unclear whether this benefit is allergen and allergic-disease specific.ObjectiveTo assess the impact of early introduction of peanut on the development of allergic disease, food sensitization and aeroallergen sensitization.MethodsAsthma, eczema and rhinoconjunctivitis were diagnosed by clinical assessment. Reported allergic reactions and consumption of tree nuts and sesame were recorded by questionnaire. Sensitization to food and aeroallergens was determined by skin prick testing and specific IgE measurement.ResultsA high and increasing burden of food and aeroallergen sensitization and allergic disease was noted across study time points; 76% of LEAP participants had at least one allergic disease at 60 months of age. There were no differences in allergic disease between LEAP groups. There were small differences in sensitization and reported allergic reactions for select tree nuts; levels were higher in the LEAP consumption group. Significant resolution of eczema and sensitization to egg and milk occurred in LEAP participants; this was not affected by peanut consumption.ConclusionEarly consumption of peanut in infants at high risk of peanut allergy is allergen-specific and does not prevent the development of other allergic disease, sensitization to other foods and aeroallergens, or reported allergic reactions to tree nuts and sesame. Furthermore, peanut consumption does not hasten the resolution of eczema or egg allergy.

    更新日期:2017-11-01
  • Cat ownership, cat allergen exposure, and trajectories of sensitization and asthma throughout childhood
    J. Allergy Clin. Immunol. (IF 13.081) Pub Date : 2017-10-28
    Healson Ihuoma, Danielle C. Belgrave, Clare S. Murray, Philip Foden, Angela Simpson, Adnan Custovic

    Exposure to cat and/or cat allergens can confer either an increase in risk, or protection, or will have no effect, depending on the age of the assessment, study design and the choice of study population.

    更新日期:2017-10-28
  • Prenatal and Early Life Triclosan and Parabens Exposure and Allergic Outcomes
    J. Allergy Clin. Immunol. (IF 13.081) Pub Date : 2017-10-27
    Kathleen Lee-Sarwar, Russ Hauser, Antonia M. Calafat, Xiaoyun Ye, George T. O’Connor, Megan Sandel, Leonard B. Bacharier, Robert S. Zeiger, Nancy Laranjo, Diane R. Gold, Scott T. Weiss, Augusto A. Litonjua, Jessica H. Savage

    Background In cross-sectional studies, triclosan and parabens, ubiquitous ingredients in personal care and other products, are associated with allergic disease. Objectives We investigated the association between prenatal and early life triclosan and parabens exposure and childhood allergic disease in a prospective, longitudinal study. Methods Subjects were enrollees in VDAART, the Vitamin D Antenatal Asthma Reduction Trial. Triclosan, methyl paraben and propyl paraben concentrations were quantified in maternal plasma samples pooled from first and third trimesters and urine samples from children at age 3 or 4 years. Outcomes were parental report of physician-diagnosed asthma or recurrent wheezing, and allergic sensitization to food or environmental antigens based on serum specific IgE levels at age 3 in high-risk children. Results Analysis included 467 mother-child pairs. Overall, there were no statistically significant associations of maternal plasma or child urine triclosan or parabens concentrations with asthma or recurrent wheeze, food or environmental sensitization at age 3. A trend toward an inverse association between triclosan and parabens exposure and allergic sensitization was observed. There was evidence of effect measure modification by sex, with higher odds of environmental sensitization associated with increasing concentrations of parabens in males compared to females. Conclusions We did not identify a consistent association between prenatal and early life triclosan or parabens concentrations and childhood asthma, recurrent wheeze or allergic sensitization in the overall study population. The differential effects of triclosan or parabens exposure on allergic sensitization by sex observed in this study warrants further exploration.

    更新日期:2017-10-28
  • The Notch Pathway Inhibitor SAHM1 Abrogates the Hallmarks of Allergic Asthma
    J. Allergy Clin. Immunol. (IF 13.081) Pub Date : 2017-10-27
    Alex KleinJan, Irma Tindemans, Jeffrey E. Montgomery, Melanie Lukkes, Marjolein J.W. de Bruijn, Menno van Nimwegen, Ingrid Bergen, Raymond E. Moellering, Henk C. Hoogsteden, Louis Boon, Derk Amsen, R.W. Hendriks

    Background The Notch signaling pathway has been implicated in the pathogenesis of allergic airway inflammation. Targeting the active Notch transactivation complex by the cell-permeable, hydrocarbon-stapled synthetic peptide SAHM1 was results in genome-wide suppression of Notch-activated genes in leukemic cells and other models. However, efficacy of SAHM1 in allergic asthma models has remained unexplored. Objective We aimed to investigate therapeutic efficacy of SAHM1 in a house dust mite (HDM)-driven asthma model. Methods Topical therapeutic intervention with SAHM1 or a control peptide was performed during sensitization and/or challenge with HDM in mice. Airway inflammation was assessed by multi-color flow cytometry and bronchial hyperreactivity (BHR) was studied. Additionally, SAHM1 therapy was investigated in established asthma and in a model in which we neutralized IFNγ during HDM challenge to support the Th2 response and exacerbate asthma. Results SAHM1 treatment during the challenge phase led to a marked reduction of eosinophils and T-cells in bronchoalveolar lavage (BAL), compared with diluent-treated or control peptide-treated mice. Likewise, T-cell cytokine content and BHR were reduced. SAHM1 treatment dampened Th2-inflammation during ongoing HDM challenge and enhanced recovery following established asthma. Additionally, in the presence of anti-IFNγ antibodies, SAHM1 downregulated expression of the key Th2 transcription factor (TF) GATA3 and intracellular IL-4 in BAL T-cells, but expression of the Th17 TF RORγt or intracellular IL-17 was not affected. SAHM1 therapy also reduced serum IgE levels. Conclusions Therapeutic intervention of Notch signaling by SAHM1 inhibits allergic airway inflammation in mice and is therefore an interesting new topical treatment opportunity in asthma.

    更新日期:2017-10-28
  • MCPIP1 controls allergic airway inflammation by suppressing IL-5-producing Th2 cells through Notch/Gata3 pathway
    J. Allergy Clin. Immunol. (IF 13.081) Pub Date : 2017-10-27
    Hui Peng, Huan Ning, Qinghong Wang, Wenbao Lu, Yingzi Chang, Tony T. Wang, Jinping Lai, Pappachan E. Kolattukudy, Rong Hou, Daniel F. Hoft, Mark S. Dykewicz, Jianguo Liu
    更新日期:2017-10-28
  • Ruxolitinib partially reverses functional NK cell deficiency in patients with STAT1 gain-of-function mutations
    J. Allergy Clin. Immunol. (IF 13.081) Pub Date : 2017-10-27
    Alexander Vargas-Hernandez, Emily M. Mace, Ofer Zimmerman, Christa S. Zerbe, Alexandra F. Freeman, Sergio Rosenzweig, Jennifer W. Leiding, Troy Torgerson, Matthew C. Altman, Edith Schussler, Charlotte Cunningham-Rundles, Ivan K. Chinn, Alexandre F. Carisey, Imelda C. Hanson, Nicholas L. Rider, Steven M. Holland, Jordan S. Orange, Lisa R. Forbes

    Background Natural Killer (NK) cells are critical innate effector cells whose development is dependent on the JAK-STAT pathway. NK deficiency can result in severe or refractory viral infections. Patients with Signal Transducer and Activator of Transcription (STAT)1 gain of function (GOF) mutations have increased viral susceptibility. Objective We sought to investigate NK cell function in STAT1 GOF patients. Methods NK cell phenotype and function were determined in 16 STAT1 GOF patients. NK cell lines expressing patient mutations were generated with CRISPR-Cas9 mediated gene editing. STAT1 GOF NK cells were treated in vitro with ruxolitinib. Results Peripheral blood NK cells from of STAT1 GOF patients had impaired terminal maturation. Specifically, patients with STAT1 GOF mutations have immature CD56dim NK cells with decreased expression of CD16, perforin, CD57 and impaired cytolytic function. STAT1 phosphorylation was elevated but STAT5 was aberrantly phosphorylated in response to IL-2 stimulation. Upstream inhibition of STAT signaling with the small molecule JAK1/2 inhibitor ruxolitinib in vitro and in vivo restored perforin expression in CD56dim NK cells and partially restored NK cell cytotoxic function. Conclusions Properly regulated STAT1 signaling is critical for NK cell maturation and function. Modulation of elevated STAT1 phosphorylation with ruxolitinib is an important option for therapeutic intervention in patients with STAT1 GOF mutations.

    更新日期:2017-10-28
  • Chronic Rhinosinusitis: Endotypes, Biomarkers and Treatment Response
    J. Allergy Clin. Immunol. (IF 13.081) Pub Date : 2017-10-26
    Jose Gurrola II, Larry Borish

    It is increasingly recognized that chronic rhinosinusitis (CRS) comprises a spectrum of different diseases with distinct clinical presentations and pathogenic mechanisms. Defining the distinct phenotypes and endotypes of CRS impacts prognosis and most importantly is necessary as the basis for making therapeutic decisions. The need for individualized defining of pathogenic mechanisms prior to initiating therapy extends to virtually all therapeutic considerations. This is clearly crucial with antibiotics where, barring an influence from their off-target anti-inflammatory pharmacological effects, an understanding of the role of individual biome predicts likelihood of therapeutic benefit. But this need for identifying individual phenotypes and endotypes also extends to the agent that is currently considered the mainstay of treatment of CRS, specifically glucocorticoids (GCS). As with asthma, it is recognized that a large minority of CRS patients have a steroid-resistant phenotype, identification of which will preclude use of these agents with their potential side effects. Identification of endotypes is also becoming increasingly imperative as targeted biotherapeutic agents, such as anti-IgE and anti-cytokine antibodies are becoming available. These agents are likely to benefit patients in whom the targeted mediator is not only expressed but demonstrably driving a central mechanism in that individual. In summary, the treatment of CRS is at an exciting crossroad. On the positive side, numerous therapeutics are in development that seem likely to positively impact our patients who suffer from this condition. The challenge is that these therapies will require targeted individualized treatments based upon identifying subjects with the relevant endotype.

    更新日期:2017-10-27
  • Interferon response to RSV by bronchial epithelium from children with asthma is inversely correlated with pulmonary function
    J. Allergy Clin. Immunol. (IF 13.081) Pub Date : 2017-10-26
    M.C. Altman, S.R. Reeves, A.R. Parker, E. Whalen, K.M.S. Misura, K.A. Barrow, R.G. James, T.S. Hallstrand, S.F. Ziegler, J.S. Debley

    Background Respiratory viral infection in early childhood, including that from respiratory syncytial virus (RSV), has been previously associated with the development of asthma. Objective We aimed to determine whether ex vivo RSV infection of bronchial epithelial cells (BECs) from children with asthma would induce specific gene expression patterns, and whether such patterns associate with lung function among BEC donors. Methods Primary BECs from carefully characterized children with asthma (n=18) and matched healthy children without asthma (n=8) were differentiated at an air-liquid interface (ALI) for 21 days. ALI cultures were infected with RSV for 96 hours and RNA was subsequently isolated from BECs. In each case, we analyzed gene expression using RNA sequencing and assessed differences between conditions by linear modeling of the data. BEC donors completed spirometry to measure lung function. Results RSV infection of BECs from subjects with asthma led to a significant increase in expression of 6927 genes compared to uninfected BECs. There was a significantly increased expression of 195 genes in BECs from children with asthma and airway obstruction (FEV1/FVC<0.85 and FEV1<100% predicted) compared to children with asthma without obstruction, as well as compared to healthy children. These specific genes were found to be highly enriched for viral response genes induced in parallel with type I and III IFNs. Conclusion BECs from children with asthma and with obstructive physiology exhibit greater expression of type I and type III IFN and IFN-stimulated genes than cells from children with normal lung function, and expression of IFN-associated genes correlates with the degree of airway obstruction. These findings suggest that an exaggerated IFN response to viral infection by airway epithelial cells may be a mechanism leading to lung function decline in a subset of children with asthma.

    更新日期:2017-10-27
  • Anti-apoptotic Serine Protease Inhibitors contribute towards the survival of allergenic Th2 cells
    J. Allergy Clin. Immunol. (IF 13.081) Pub Date : 2017-10-26
    Mohamed H. Shamji, Jeff N. Temblay, Wei Cheng, Susan M. Byrne, Ellen Macfarlane, Amy R. Switzer, Natalia D.C. Francisco, Fedina Olexandra, Fabian Jacubczik, Stephen R. Durham, Philip G. Ashton-Rickardt

    Background The mechanisms regulating the maintenance of persistent Th2 cells that potentiate allergic inflammation are not well understood. Objective The function of Serine Protease Inhibitor 2A (Spi2A) was studied in mouse Th2 cells and Serine Protease Inhibitor (SERPIN) B3 and B4 genes were studied in Th2 cells from grass pollen allergic individuals. Methods Spi2A deficient Th2 cells were studied in vitro culture or in vivo after challenge of Spi2A Knock-Out (KO) mice with ovalbumin in alum. The expression of SERPIN B3 and B4 mRNA was measured in vitro cultured Th2 cell and in ex vivo CD27-CD4+ and ICL2 cells from grass pollen allergic individuals using quantitative PCR. SERPIN B3 and B4 mRNA levels were knocked down in cultured CD27-CD4+ cells with shRNA. Results There were lower levels of in vitro polarized Th2 cells from Spi2A KO mice (P<0.005) and in vivo after OVA challenge (P<0.05), higher levels of apoptosis (annexin V positivity P<0.005) and less lung allergic inflammation (number of lung eosinophils P<0.005). In vitro polarized Th2 cells from grass pollen allergic individuals expressed higher levels of both SERPIN B3 and B4 (both P<0.05) mRNA compared to un- polarized CD4 T cells. CD27-CD4+ from grass pollen allergic individuals expressed higher levels of both SERPIN B3 and B4 (both P<0.0005) mRNA compared to CD27+CD4+ cells. ICL2 cells expressed higher levels of both SERPIN B3 and B4 (both P<0.0005) mRNA compared to ICL1 cells. Knock-down of either SERPIN B3 or B4 (both P <0.005) mRNA levels resulted in decreased viability of CD27-CD4+ compared to control transduced cells. Conclusion The serpins Spi2A in mice and Serpin B3 and B4 in allergic individuals, control viability of Th2 cells. This provides proof-of-principle for a therapeutic approach for allergic disease through the ablation of allergic memory Th2 cells through mRNA SERPIN B3 and B4 down-regulation.

    更新日期:2017-10-27
  • Cat exposure in early life decreases asthma risk from the 17q21 high-risk variant
    J. Allergy Clin. Immunol. (IF 13.081) Pub Date : 2017-10-25
    Jakob Stokholm, Bo L. Chawes, Nadja Vissing, Klaus Bønnelykke, Hans Bisgaard
    更新日期:2017-10-25
  • Histamine and T helper cytokine driven epithelial barrier dysfunction in allergic rhinitis
    J. Allergy Clin. Immunol. (IF 13.081) Pub Date : 2017-10-23
    Brecht Steelant, Sven F. Seys, Laura Van Gerven, Matthias Van Woensel, Ricard Farré, Paulina Wawrzyniak, Inge Kortekaas Krohn, Dominique M. Bullens, Karel Talavera, Ulrike Raap, Louis Boon, Cezmi A. Akdis, Guy Boeckxstaens, Jan L. Ceuppens, Peter W. Hellings
    更新日期:2017-10-24
  • A novel recycling mechanism of native IgE-antigen complexes in human B cells facilitates transfer of antigen to dendritic cells for antigen presentation
    J. Allergy Clin. Immunol. (IF 13.081) Pub Date : 2017-10-23
    P. Engeroff, M. Fellmann, D. Yerly, M.F. Bachmann, M. Vogel

    Background IgE-immune complexes have been shown to enhance antibody and T cell responses in mice by targeting CD23 (FcεRII), the low-affinity receptor for IgE on B cells. In humans, the mechanism by which CD23-expressing cells take up IgE-immune complexes (IgE-IC) and process them is not well understood. Objective To investigate this question, we compared the fate of IgE-IC in human B cells and in CD23 expressing monocyte-derived dendritic cells (moDCs) that represent classical APCs and we aimed at studying IgE-dependent antigen presentation in both cell types. Methods B cells and monocytes were isolated from peripheral blood and monocytes were differentiated into moDCs. Both cell types were stimulated with IgE-immune complexes consisting of NIP-specific IgE JW8 and NIP-BSA to assess binding, uptake and degradation dynamics. To assess CD23-dependent T cell proliferation, B cells and moDCs were pulsed with IgE-NIP-Tetanus Toxoid (TT) complexes and cocultured with autologous T cells. Results IgE-IC binding was CD23-dependent in B cells and moDCs and CD23 aggregation, as well as IgE-IC internalization, occurred in both cell types. While IgE-IC was degraded in moDCs, B cells did not degrade the complexes but recycled them in native form to the cell surface enabling IgE-IC uptake by moDCs in cocultures. The resulting proliferation of specific T cells was dependent on cell-cell contact between B cells and moDC which was explained by increased upregulation of co-stimulatory molecules CD86 and MHC class II on moDCs induced by B cells. Conclusion Our findings argue for a novel model in which human B cells promote specific T cell proliferation upon IgE-IC encounter. On one hand, B cells act as carriers transferring antigen to more efficient APCs such as dendritic cells, on the other hand, B cells can directly promote DC maturation and thereby enhance T cell stimulation.

    更新日期:2017-10-24
  • Step-up empiric elimination diet for pediatric and adult eosinophilic esophagitis: the 2-4-6 Study
    J. Allergy Clin. Immunol. (IF 13.081) Pub Date : 2017-10-23
    Javier Molina-Infante, Ángel Arias, Javier Alcedo, Ruth Garcia-Romero, Sergio Casabona-Frances, Alicia Prieto-Garcia, Ines Modolell, Pedro L. Gonzalez-Cordero, Isabel Perez-Martinez, Jose Luis Martin-Lorente, Carlos Guarner-Argente, Maria L. Masiques, Victor Vila-Miravet, Roger Garcia-Puig, Edoardo Savarino, Carlos Teruel Sanchez-Vegazo, Cecilio Santander, Alfredo J. Lucendo

    Background Numerous dietary restrictions and endoscopies limit the implementation of empiric elimination diets in eosinophilic esophagitis (EoE). Milk and wheat/gluten are the most common food triggers. Objective To assess the effectiveness of a step-up dietary strategy for EoE. Methods Prospective study conducted in 14 centers. Patients underwent a 6-week two-food group elimination diet (TFGED) (milk and gluten-containing cereals). Remission was defined by symptom improvement and <15 eos/HPF. Non-responders were gradually offered a four-food group elimination diet (FFGED: TFGED + egg and legumes) and a six-food group elimination diet (SFGED: FFGED + nuts and fish/seafood). In responders, eliminated food groups were individually reintroduced, followed by endoscopy. Results 130 patients (25 pediatric) were enrolled with 97 completing all phases of the study. A TFGED achieved EoE remission in 56 patients (43%), with no differences between ages. Food triggers in TFGED responders were milk (52%), gluten-containing grains (16%) and both (28%). EoE induced only by milk was present in 18% and 33% of adults and children, respectively. Remission rates with FFGED and SFGED were 60% and 79%, with increasing food triggers, especially after SFGED. Overall, 55/60 (91.6%) of responders to TFGED/FFGED had one or two food triggers. Compared to initial SFGED, a step-up strategy reduced endoscopic procedures and diagnostic process time by 20%. Conclusions A TFGED diet achieves EoE remission in 43% of children and adults. A step-up approach identifies early a majority of responders to empiric diet with few food triggers, avoiding unnecessary dietary restrictions, saving endoscopies and shortening the diagnostic process.

    更新日期:2017-10-24
  • MicroRNA
    J. Allergy Clin. Immunol. (IF 13.081) Pub Date : 2017-10-23
    Thomas X. Lu, Marc E. Rothenberg

    MicroRNAs (miRNAs) are small endogenous RNAs that regulate gene-expression post-transcriptionally. MiRNA research in allergy is expanding because miRNAs are crucial regulators of gene expression and promising candidates for biomarker development. MiRNA mimics and miRNA inhibitors currently in preclinical development have shown promise as novel therapeutic agents. Multiple technological platforms have been developed for miRNA isolation, miRNA quantitation, miRNA profiling, miRNA target detection and for modulating miRNA levels in vitro and in vivo. Here we will review the major technological platforms with consideration given for the advantages and disadvantages of each platform.

    更新日期:2017-10-24
  • Plasmacytoid dendritic cells drive acute exacerbations of asthma
    J. Allergy Clin. Immunol. (IF 13.081) Pub Date : 2017-10-17
    Aikaterini-Dimitra Chairakaki, Maria-Ioanna Saridaki, Katerina Pyrillou, Marios-Angelos Mouratis, Ourania Koltsida, Ross P. Walton, Nathan W. Bartlett, Athanasios Stavropoulos, Louis Boon, Nikoletta Rovina, Nikolaos G. Papadopoulos, Sebastian L. Johnston, Evangelos Andreakos
    更新日期:2017-10-17
  • Eosinophils and Eosinophil-Associated Diseases: an Update
    J. Allergy Clin. Immunol. (IF 13.081) Pub Date : 2017-10-16
    Jeremy A. O’Sullivan, Bruce S. Bochner

    The goal of this series is to offer a survey of the latest literature for clinicians and scientists alike, providing a list of important recent advances relevant to the broad field of allergy and immunology. This particular assignment was to cover the topic of eosinophils. In an attempt to highlight major ideas, themes, trends and advances relevant to basic and clinical aspects of eosinophil biology, a search of papers published since 2015 in JACI and other high impact journals was performed. Manuscripts were then reviewed and organized, and then key findings were summarized. Given space limitations, many outstanding papers could not be included, but the hope is that what follows provides a succinct overview of recently published work that has significantly added to our knowledge of eosinophils and eosinophil-associated diseases.

    更新日期:2017-10-16
  • Fibrinogen-cleavage products and TLR4 promote the generation of programmed cell death 1 ligand 2(PD-L2)+ dendritic cells in allergic asthma
    J. Allergy Clin. Immunol. (IF 13.081) Pub Date : 2017-10-14
    Minkyoung Cho, Jeong-Eun Lee, Hoyong Lim, Hyun-Woo Shin, Roza Khalmuratova, Garam Choi, Hyuk Soon Kim, Wahn Soo Choi, Young-Jun Park, Inbo Shim, Byung-Seok Kim, Chang-Yuil Kang, Jae-Ouk Kim, Shinya Tanaka, Masato Kubo, Yeonseok Chung
    更新日期:2017-10-14
  • Interaction of DJ-1 with Lyn is essential for IgE-mediated stimulation of human mast cells
    J. Allergy Clin. Immunol. (IF 13.081) Pub Date : 2017-10-13
    Do-Kyun Kim, Michael A. Beaven, Dean D. Metcalfe, Ana Olivera
    更新日期:2017-10-14
  • Advances in mechanisms of allergic disease in 2016
    J. Allergy Clin. Immunol. (IF 13.081) Pub Date : 2017-10-13
    Marc E. Rothenberg, Hirohisa Saito, R. Stokes Peebles Jr.

    This review highlights advances in mechanisms of allergic disease, particularly type 2 innate lymphoid cells; TH2 lymphocytes; eicosanoid regulation of inflammation; extracellular vesicles in allergic responses; IL-33; microbiome properties, especially as they relate to mucosal barrier function; and a series of findings concerning the allergic inflammatory cells eosinophils, basophils, and mast cells. During the last year, mechanistic advances occurred in understanding type 2 innate lymphoid cells, particularly related to their response to ozone, involvement with experimental food allergy responses, and regulation by IL-33. Novel ways of regulating TH2 cells through epigenetic regulation of GATA-3 through sirtuin-1, a class III histone deacetylase, were published. The understanding of eicosanoid regulation of inflammation increased and focused on additional properties of phospholipase A2 and the role of prostaglandin D2 and its receptors and inhibitory prostaglandin E2 pathways. Mechanisms through which extracellular vesicles are released and contribute to allergic responses were reported. There was a deeper appreciation of mucosal barrier function, the epithelial alarmin IL-33, and the microbiome. Finally, there were advances concerning allergic inflammatory cells (mast cells, basophils, and eosinophils) that will undoubtedly have an effect on disease understanding and new therapeutic strategies.

    更新日期:2017-10-14
  • Early-life environmental exposures interact with genetic susceptibility variants in pediatric patients with eosinophilic esophagitis
    J. Allergy Clin. Immunol. (IF 13.081) Pub Date : 2017-10-10
    Elizabeth T. Jensen, Jonathan T. Kuhl, Lisa J. Martin, Carl D. Langefeld, Evan S. Dellon, Marc E. Rothenberg

    Background Although eosinophilic esophagitis (EoE) is associated with certain gene variants, the rapidly increasing incidence of EoE suggests that environmental factors contribute to disease development. Objective We tested for gene-environment interaction between EoE-predisposing polymorphisms (within TSLP, LOC283710/KLF13, CAPN14, CCL26, and TGFB) and implicated early-life factors (antibiotic use in infancy, cesarean delivery, breast-feeding, neonatal intensive care unit [NICU] admission, and absence of pets in the home). Methods We conducted a case-control study using hospital-based cases (n = 127) and control subjects representative of the hospital catchment area (n = 121). We computed case-only interaction tests and in secondary analyses evaluated the combined and independent effects of genotype and environmental factors on the risk of EoE. Results Case-only analyses identified interactions between rs6736278 (CAPN14) and breast-feeding (P = .02) and rs17815905 (LOC283710/KLF13) and NICU admission (P = .02) but not with any of the factors examined. Case-control analyses suggested that disease risk might be modifiable in subjects with certain gene variants. In particular, breast-feeding in those with the susceptibility gene variant at rs6736278 (CAPN14) reduced the risk of EoE (adjusted odds ratio, 0.08; 95% CI, 0.01-0.59). Admission to the NICU in those without the susceptibility gene variant at rs17815905 (LOC283710/KLF13) significantly increased the risk of having disease (adjusted odds ratio, 4.83; 95% CI, 1.49-15.66). Conclusions The interplay of gene (CAPN14 and LOC283710/KLF13) and early-life environment factors (breast-feeding and NICU admission) might contribute to EoE susceptibility.

    更新日期:2017-10-10
  • Genome-wide association study and meta-analysis in multiple populations identifies new loci for peanut allergy and establishes c11orf30/EMSY as a genetic risk factor for food allergy
    J. Allergy Clin. Immunol. (IF 13.081) Pub Date : 2017-10-10
    Yuka Asai, Aida Eslami, C. Dorien van Ginkel, Loubna Akhabir, Ming Wan, George Ellis, Moshe Ben-Shoshan, David Martino, Manuel A. Ferreira, Katrina Allen, Bruce Mazer, Hans de Groot, Nicolette W. de Jong, Roy N. Gerth van Wijk, Anthony E.J. Dubois, Rick Chin, Steven Cheuk, Joshua Hoffman, Eric Jorgensen, John S. Witte, Ronald B. Melles, Xiumei Hong, Xiaobin Wang, Jennie Hui, Arthur W. (Bill) Musk, Michael Hunter, Alan L. James, Gerard H. Koppelman, Andrew J. Sandford, Ann E. Clarke

    Background Peanut allergy (PA) is a complex disease with both environmental and genetic risk factors. Previously PA loci were identified in FLG and HLA in candidate gene studies, and loci in HLA in a genome-wide association study and meta-analysis. Objective To investigate genetic susceptibility to PA. Methods Eight hundred and fifty cases and 926 hyper-controls and >7.8 million genotyped and imputed single nucleotide polymorphisms (SNPs) were analyzed in a genome-wide association study to identify susceptibility variants for PA in the Canadian population. Meta-analysis of two phenotypes (PA and food allergy) was conducted using 7 studies from the Canadian, American (2), Australian, German and Dutch (2) populations. Results A SNP near ITGA6 reached genome-wide significance with PA (p=1.80×10-8), while SNPs associated with SKAP1, MMP12/MMP13, CTNNA3, ARHGAP24, ANGPT4, c11orf30 (EMSY), and EXOC4 reached a threshold suggestive of association (p≤1.49×10-6). In the meta-analysis of PA, loci in or near ITGA6, ANGPT4, MMP12/MMP13, c11orf30 and EXOC4 were significant (p≤1.49×10-6). When a phenotype of any food allergy was used for meta-analysis, the c11orf30 locus reached genome-wide significance (p=7.50×10-11), while SNPs associated with ITGA6, ANGPT4, MMP12/MMP13, EXOC4 and additional c11orf30 SNPs were suggestive (p≤1.49×10-6). Functional annotation indicated SKAP1 regulates expression of CBX1, which co-localizes with the EMSY protein coded by c11orf30. Conclusion This study identifies multiple novel loci as risk factors for PA and food allergy and establishes c11orf30 as a risk locus for both peanut and food allergy. Multiple genes (c11orf30/EMSY, SKAP1 and CTNNA3) identified by this study are involved in epigenetic regulation of gene expression.

    更新日期:2017-10-10
  • Chronic rhinosinusitis in Asia
    J. Allergy Clin. Immunol. (IF 13.081) Pub Date : 2017-10-05
    Yuan Zhang, Elien Gevaert, Hongfei Lou, Xiangdong Wang, Luo Zhang, Claus Bachert, Nan Zhang

    Chronic rhinosinusitis (CRS), although possibly overdiagnosed, is associated with a high burden of disease and is often difficult to treat in those truly affected. Recent research has demonstrated that inflammatory signatures of CRS vary around the world, with less eosinophilic and more neutrophilic inflammation found in Asia compared with Europe and North America. Although in the Western world about 80% of nasal polyps carry a type 2 signature, this might be between 20% and 60% in China and Korea or Thailand, respectively. These differences are associated with a lower asthma comorbidity and risk of disease recurrence after surgery in the Asian population. As a hallmark of severe type 2 inflammation, eosinophils attacking Staphylococcus aureus at the epithelial barrier have been described recently; they also can be found in a subgroup of Asian patients with nasal polyps. Furthermore, the percentage of type 2 signature disease in patients with CRS is dramatically increasing (“eosinophilic shift”) in several Asian countries over the last 20 years. Establishing an accurate diagnosis along with considering the current and shifting patterns of inflammation seen in Asia will enable more effective selection of appropriate pharmacotherapy, surgical therapy, and eventually biotherapy. Determining the causes and pathophysiology for this eosinophilic shift will require additional research.

    更新日期:2017-10-05
  • Nitrogen Dioxide Exposure in School Classrooms of Inner-City Children with Asthma
    J. Allergy Clin. Immunol. (IF 13.081) Pub Date : 2017-10-05
    Jonathan M. Gaffin, Marissa Hauptman, Carter R. Petty, William J. Sheehan, Peggy S. Lai, Jack M. Wolfson, Diane R. Gold, Brent A. Coull, Petros Koutrakis, Wanda Phipatanakul

    Background Ambient and home exposure to nitrogen dioxide (NO2) causes asthma symptoms and decreased lung function in children with asthma. Little is known about the health effects of school classroom pollution exposure. Objective We aimed to determine the effect of indoor classroom NO2 on lung function and symptoms of inner-city schoolchildren with asthma. Methods Children enrolled in the School Inner City Asthma Study were followed for one academic year. Subjects performed spirometry and fractional exhaled nitric oxide (FeNO) twice during the school year, at school. Classroom NO2 was collected by passive sampling for 1 week periods, twice per year coinciding with lung function testing. Generalized estimating equation models assessed lung function and symptom relationships with the temporally nearest classroom NO2 level. Results NO2 mean values were 11.1ppb (range 4.3 – 29.7ppb). In total, exposure data was available for 296 subjects; 188 with complete spirometry data. Above a threshold of 8ppb NO2, and after adjusting for race and season (spirometry standardized by age, height, and gender), NO2 was highly associated with airflow obstruction such that each 10ppb rise in NO2 was associated with a 5% decline in FEV1/FVC (β: -0.05, 95% confidence interval (CI) [-0.08, -0.02], p=0.01). FEF25-75% predicted was also inversely associated with higher NO2 exposure (β: -22.8, 95%CI [-36.0, -9.7], p=0.01). There was no significant association of NO2 with FEV1% predicted, FeNO or asthma symptoms. Additionally, there was no effect modification of atopy on lung function or symptom outcomes. Conclusion In children with asthma, indoor classroom NO2 may be associated with increased airflow obstruction.

    更新日期:2017-10-05
  • 更新日期:2017-09-29
  • Allergy and immunology in Africa: Challenges and unmet needs
    J. Allergy Clin. Immunol. (IF 13.081) Pub Date : 2017-09-27
    Yehia M. El-Gamal, Elham M. Hossny, Zeinab A. El-Sayed, Shereen M. Reda

    The tremendous increase in allergy in the African continent cannot simply be explained by the change in public hygiene. There are many “prehygiene” communities with sewage-contaminated water supplies, helminth infestations, bare footedness, and poor housing, and still there is a high prevalence of allergic disease. Africans can be exposed to many risk factors facilitating severe asthma and wheezing, including airborne viruses, smoke, indoor dampness, cockroaches, and poor access to health care. Although the reporting on food allergy is inadequate to perform systematic reviews or meta-analyses, the available data suggest that food allergy is underdiagnosed. The rate of new HIV infections in high-prevalence settings in Africa remains unacceptably high. Although the annual number of new HIV infections in Sub-Saharan Africa has decreased lately, new HIV infections in the Middle East and North Africa region have increased; however, the current prevalence of 0.1% is still among the lowest globally. Africa is densely populated, and consanguineous mating is high in some areas of North and Sub-Saharan Africa. This allows for emergence of many autosomal recessive primary immunodeficiency diseases. There is urgent need for the establishment of primary immunodeficiency disease registries, stem cell transplantation facilities, and neonatal screening programs. To address these expanding problems and perform local cutting-edge research, Africans need to be empowered by motivated governments, dedicated funds, and compassionate scientific partnership.

    更新日期:2017-09-29
  • Chronic IL-33 expression predisposes to viral-induced exacerbations of asthma by increasing type-2 inflammation and dampening antiviral immunity
    J. Allergy Clin. Immunol. (IF 13.081) Pub Date : 2017-09-22
    Rhiannon B. Werder, B Biomed Sci, Vivian Zhang, Jason P. Lynch, Natale Snape, John W. Upham, Kirsten Spann, Simon Phipps

    Background Rhinovirus infection triggers acute exacerbations of asthma. IL-33 is an instructive cytokine of type-2 inflammation whose expression is associated with viral load during experimental rhinovirus infection of asthmatic subjects. Objective To determine whether anti-IL-33 therapy is effective during disease progression, established disease, or viral exacerbation using a preclinical model of chronic asthma and in vivo human primary airway epithelial cells (AECs). Methods To model disease onset, progression, and chronicity, mice were exposed to pneumonia virus of mouse and cockroach extract in early-life and later-life, then challenged with rhinovirus. Interventions included anti-IL-33 or dexamethasone at various stages of disease. AECs were obtained from asthmatic and healthy patients, and treated with anti-IL-33 following RV infection. Results Anti-IL-33 decreased type-2 inflammation in all phases of disease; however, the ability to prevent airway smooth muscle growth was lost after the progression phase. After the chronic phase, IL-33 levels were persistently high and rhinovirus challenge exacerbated the type-2 inflammatory response. Treatment with anti-IL-33 or dexamethasone diminished exacerbation severity and anti-IL-33, but not dexamethasone, promoted antiviral IFN expression and decreased viral load. RV replication was higher and IFN-lambda lower in asthmatic compared to healthy AECs. Anti-IL-33 lowered RV replication and increased IFN-λ at the gene and protein level. Conclusion Anti-IL-33 or dexamethasone suppressed the magnitude of type-2 inflammation during a rhinovirus-induced acute exacerbation, however only anti-IL-33 boosted antiviral immunity and lowered viral replication. The latter phenotype was replicated in RV infected human AECs, suggesting that anti-IL-33 therapy has the additional benefit of enhancing host defence.

    更新日期:2017-09-29
  • Concomitant suppression of Th2 and Th17 cell responses in allergic asthma by targeting RORγt
    J. Allergy Clin. Immunol. (IF 13.081) Pub Date : 2017-09-22
    Hyeongjin Na, Hoyong Lim, Garam Choi, Byung Keun Kim, Sae-Hoon Kim, Yoon-Seok Chang, Roza Nurieva, Chen Dong, Seon Hee Chang, Yeonseok Chung

    Background Allergic asthma is a heterogeneous chronic inflammatory disease in the airway with a massive infiltration of eosinophils or neutrophils mediated by allergen-specific Th2 cells and Th17 cells, respectively. Successful treatment of allergic asthma will therefore require suppression of both Th2 and Th17 cells. Objective We sought to investigate the role of Th17 cell pathway in regulating Th2 cell responses in allergic asthma. Methods Allergic asthma was induced by intranasal challenges with proteinase allergens in C57BL/6, Il17a−/−Il17f− /−and RORγtgfp/gfp mice. Pharmacological RORγt inhibitor was used to evaluate its preventive and therapeutic effects in allergic asthma. Characteristics of allergic airway inflammation were analyzed by flow cytometry, histology, qRT-PCR and ELISA. Mixed bone marrow chimeric mice, fate mapping analysis, shRNA transduction and in vitro T cell differentiation were employed for mechanistic studies. Results Mice deficient in IL-17A and IL-17F as well as in RORγt exhibited a significant reduction not only in Th17 cell responses, but also in Th2 cell responses in an animal model of allergic asthma. Similarly, mice treated with an RORγt inhibitor showed significantly diminished Th17 as well as Th2 cell responses, leading to reduced numbers of neutrophils and eosinophils in the airway. RORγt-deficient T cells were intrinsically defective in differentiating into Th2 cells and expressed increased level of Bcl6. Knock-down of Bcl6 resulted in a remarkable restoration of Th2 cell differentiation in RORγt-deficient T cells. Blockade of RORγt also significantly hampered the differentiation of human Th2 cells and Th17 cells from naïve CD4+ T cells. Conclusion RORγt in T cells is required for optimal Th2 cell differentiation by suppressing Bcl6 expression; this finding suggests that targeting RORγt might be a promising approach for the treatment of allergic asthma by concomitantly suppressing Th17 and Th2 cell responses in the airway.

    更新日期:2017-09-29
  • Eosinophils release extracellular DNA traps in response to Aspergillus fumigatus
    J. Allergy Clin. Immunol. (IF 13.081) Pub Date : 2017-09-21
    Valdirene S. Muniz, Juliana C. Silva, Yasmim A.V. Braga, Rossana C.N. Melo, Shigeharu Ueki, Masahide Takeda, Akira Hebisawa, Koichiro Asano, Rodrigo T. Figueiredo, Josiane S. Neves
    更新日期:2017-09-29
  • Inhibition of IL-17–committed T cells in a murine psoriasis model by a vitamin D analogue
    J. Allergy Clin. Immunol. (IF 13.081) Pub Date : 2017-09-21
    Nobuhiro Kusuba, Akihiko Kitoh, Teruki Dainichi, Tetsuya Honda, Atsushi Otsuka, Gyohei Egawa, Saeko Nakajima, Yoshiki Miyachi, Kenji Kabashima

    Background A better understanding of the means by which topical vitamin D analogues exert their therapeutic effect on psoriasis is of theoretical and practical importance. Objective We sought to clarify whether and how the topical vitamin D analogue calcipotriol (CAL) controls the IL-17A–mediated pathogenesis of murine psoriasis-like dermatitis in vivo. Methods Psoriasis-like dermatitis was induced by the topical application of an imiquimod (IMQ)–containing cream on the murine ear for 4 to 6 consecutive days. For topical CAL treatment, mice were treated daily with CAL solution on the ear before IMQ application. Results Mice treated topically with CAL exhibited much milder IMQ-induced psoriasis-like dermatitis compared with vehicle-treated mice, with impaired accumulation of IL-17A–committed T (T17) cells in the lesional skin. The IMQ-induced upregulation of Il12b and Il23a was marked in the epidermis and was abrogated by CAL application, suggesting CAL-mediated suppression of IL-23 expression. CAL inhibited Il12b and Il23a expression by Langerhans cells ex vivo stimulated with IMQ and CD40 cross-linking. Topical CAL also inhibited T17 cell expansion in the draining lymph nodes of IMQ-treated skin, implying a possible effect on T17 cell–mediated dermatitis at distant sites. In fact, topical CAL application on the IMQ-treated left ear resulted in amelioration of T17 cell accumulation and psoriasis-like dermatitis in the right ear subsequently treated with IMQ. Conclusion Topical CAL can exert its antipsoriatic effect on CAL-treated lesions and, concomitantly, distant lesions by attenuating the T17 cell accumulation in both CAL-treated lesions and draining lymph nodes.

    更新日期:2017-09-29
  • 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.

    更新日期:2017-09-21
Some contents have been Reproduced with permission of the American Chemical Society.
Some contents have been Reproduced by permission of The Royal Society of Chemistry.
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