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pubmed: 0091-6749



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Early-onset pediatric atopic dermatitis is TH2 but also TH17 polarized in skin.
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Early-onset pediatric atopic dermatitis is TH2 but also TH17 polarized in skin.

J Allergy Clin Immunol. 2016 Sep 15;

Authors: Esaki H, Brunner PM, Renert-Yuval Y, Czarnowicki T, Huynh T, Tran G, Lyon S, Rodriguez G, Immaneni S, Johnson DB, Bauer B, Fuentes-Duculan J, Zheng X, Peng X, Estrada YD, Xu H, de Guzman Strong C, Suárez-Fariñas M, Krueger JG, Paller AS, Guttman-Yassky E

Abstract
BACKGROUND: Atopic dermatitis (AD) affects 15% to 25% of children and 4% to 7% of adults. Paradigm-shifting discoveries about AD have been based on adult biomarkers, reflecting decades of disease activity, although 85% of cases begin by 5 years. Blood phenotyping shows only TH2 skewing in patients with early-onset pediatric AD, but alterations in early pediatric skin lesions are unknown, limiting advancement of targeted therapies.
OBJECTIVE: We sought to characterize the early pediatric AD skin phenotype and its differences from pediatric control subjects and adults with AD.
METHODS: Using immunohistochemistry and quantitative real-time PCR, we assessed biopsy specimens from 19 children with AD younger than 5 years within 6 months of disease onset in comparison with adults with AD or psoriasis and pediatric and adult control subjects.
RESULTS: In lesional skin children showed comparable or greater epidermal hyperplasia (thickness and keratin 16) and cellular infiltration (CD3(+), CD11c(+), and FcεRI(+)) than adults with AD. Similar to adults, strong activation of the TH2 (IL-13, IL-31, and CCL17) and TH22 (IL-22 and S100As) axes and some TH1 skewing (IFN-γ and CXCL10) were present. Children showed significantly higher induction of TH17-related cytokines and antimicrobials (IL-17A, IL-19, CCL20, LL37, and peptidase inhibitor 3/elafin), TH9/IL-9, IL-33, and innate markers (IL-8) than adults (P < .02). Despite the characteristic downregulation in adult patients with AD, filaggrin expression was similar in children with AD and healthy children. Nonlesional skin in pediatric patients with AD showed higher levels of inflammation (particularly IL-17A and the related molecules IL-19 and LL37) and epidermal proliferation (keratin 16 and S100As) markers (P < .001).
CONCLUSION: The skin phenotype of new-onset pediatric AD is substantially different from that of adult AD. Although excess TH2 activation characterizes both, TH9 and TH17 are highly activated at disease initiation. Increases in IL-19 levels might link TH2 and TH17 activation.

PMID: 27671162 [PubMed - as supplied by publisher]




T-bet inhibits innate lymphoid cell-mediated eosinophilic airway inflammation by suppressing IL-9 production.
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T-bet inhibits innate lymphoid cell-mediated eosinophilic airway inflammation by suppressing IL-9 production.

J Allergy Clin Immunol. 2016 Sep 23;

Authors: Matsuki A, Takatori H, Makita S, Yokota M, Tamachi T, Suto A, Suzuki K, Hirose K, Nakajima H

Abstract
BACKGROUND: Innate lymphoid cells (ILCs) are emerging subsets of immune cells that produce large amounts of cytokines upon cytokine and/or alarmin stimulation. Recent studies have shown that T-bet plays pivotal roles in the development of ILC3s and ILC1s; however, the roles of T-bet in lung ILC2s remain unknown.
OBJECTIVE: To determine the role of T-bet in ILC2-mediated airway inflammation.
METHODS: The expression of T-bet in lung ILCs (defined as Thy1.2(+) Lin(-) cells) was examined. The roles of T-bet in the development of lung ILC2s and airway inflammation induced by IL-33 administration were examined by using T-bet-deficient (T-bet(-/-)) mice. Gene expression profiles of T-bet(-/-) lung ILCs were analyzed by RNA sequencing.
RESULTS: T-bet was expressed in lung ILC2s (defined as Thy1.2(+) Lin(-) cells expressing ST2 or CD25) and IFN-γ enhanced its expression. While the development of lung ILC2s at steady-state conditions was normal in T-bet(-/-) mice, IL-33-induced accumulation of lung ILC2s and eosinophilic airway inflammation were exacerbated in T-bet(-/-) mice. The exacerbated accumulation of ILC2s and eosinophilic airway inflammation by the absence of T-bet was evident even in a RAG2(-/-) background, suggesting that T-bet expressed in non-T/non-B population is involved in the suppression of IL-33-induced eosinophilic airway inflammation. Transcriptome analysis revealed that IL-9 expression in IL-33-stimulated lung ILCs was up-regulated in T-bet(-/-) mice compared with that in wild-type mice. Importantly, neutralization of IL-9 markedly attenuated IL-33-induced accumulation of lung ILC2s and eosinophilic inflammation in T-bet(-/-) mice.
CONCLUSION: T-bet suppresses IL-9 production from lung ILC2s and thereby inhibits IL-33-induced eosinophilic airway inflammation.

PMID: 27670243 [PubMed - as supplied by publisher]




Dogs, Cats and Asthma: Will We Ever Really Know the True Risks and Benefits?
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Dogs, Cats and Asthma: Will We Ever Really Know the True Risks and Benefits?

J Allergy Clin Immunol. 2016 Sep 23;

Authors: Ownby DR, Johnson CC

PMID: 27670242 [PubMed - as supplied by publisher]




Human Lung NK Cells are Predominantly Comprised of Highly Differentiated Hypofunctional CD69(-)CD56(dim) Cells.
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Human Lung NK Cells are Predominantly Comprised of Highly Differentiated Hypofunctional CD69(-)CD56(dim) Cells.

J Allergy Clin Immunol. 2016 Sep 23;

Authors: Marquardt N, Kekäläinen E, Chen P, Kvedaraite E, Wilson JN, Ivarsson MA, Mjösberg J, Berglin L, Säfholm J, Manson ML, Adner M, Al-Ameri M, Bergman P, Orre AC, Svensson M, Dahlén B, Dahlén SE, Ljunggren HG, Michaëlsson J

Abstract
BACKGROUND: In contrast to the extensive knowledge about human NK cells in peripheral blood, relatively little is known about NK cells in human lung. Knowledge about the composition, differentiation, and function of human lung NK cells is critical to better understand their role in diseases affecting the lung, including asthma, COPD, infections, and cancer.
OBJECTIVE: We sought to analyze and compare the phenotypic as well as functional characteristics of NK cells in the human lung and peripheral blood at the single cell level.
METHODS: NK cells in human lung tissue and matched peripheral blood from 132 subjects were analyzed by 16-color flow cytometry and confocal microscopy.
RESULTS: CD56(dim)CD16(+) NK cells made up the vast majority of NK cells in human lung, had a more differentiated phenotype and more frequently expressed educating KIRs compared to NK cells in peripheral blood. Despite this, human lung NK cells were hyporesponsive towards target cell stimulation, even after priming with IFN-α. Furthermore, we detected a small subset of NK cells expressing CD69, a marker of tissue-residency. These CD69(+) NK cells in the lung consisted predominantly of immature CD56(bright)CD16(-) NK cells and less differentiated CD56(dim)CD16(+) NK cells.
CONCLUSION: We here characterize the major NK cell populations in the human lung. Our data suggest a model where the majority of NK cells in the human lung dynamically moves between blood and the lung, rather than residing in the lung as bona fide tissue-resident CD69(+) NK cells.

PMID: 27670241 [PubMed - as supplied by publisher]




IFNγ orchestrates mesenchymal stem cells plasticity through STAT1, STAT3 and mTOR pathways.
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IFNγ orchestrates mesenchymal stem cells plasticity through STAT1, STAT3 and mTOR pathways.

J Allergy Clin Immunol. 2016 Sep 23;

Authors: Vigo T, Procaccini C, Ferrara G, Baranzini S, Oksenberg JR, Matarese G, Diaspro A, Kerlero de Rosbo N, Uccelli A

Abstract
BACKGROUND: Mesenchymal stem cells (MSC) display a therapeutic plasticity, due to their ability to modulate immunity, foster tissue repair and differentiate into mesodermal cells. IFNγ has been described to differently affect human and mouse MSC immunomodulation and differentiation, depending on the inflammatory milieu.
OBJECTIVE: We aimed at dissecting the relevant intracellular pathways through which IFNγ affects MSC plasticity and the consequence of their manipulation on MSC functions.
METHODS: Modification of relevant IFNγ-dependent pathways in mouse MSC was carried out in vitro through gene silencing or chemical inhibition of key components. Functional outcomes were assessed by western blotting, real-time PCR, differentiation and proliferation assays on MSC. The impact on T cells was addressed by T-cell proliferation assays; the effect of mTOR manipulation in MSC was studied in vivo in a mouse model of delayed-type hypersensitivity assay (DTH). To address whether similar mechanisms are involved also in human MSC upon IFNγ stimulation, the effect of chemical inhibition on the same intracellular pathways was assessed by western blotting and the final outcome on immunomodulatory properties evaluated by real-time PCR and on T-cell proliferation.
RESULTS: We revealed that, in mouse MSC, IFNγ-induced immunoregulation is mediated by an early phosphorylation of STAT1 and STAT3, significantly enhanced by an ERK1/2-dependent mTOR inhibition, thereby promoting pSTAT1 nuclear translocation. Accordingly, following intracellular mTOR inhibition, MSC augmented their ability to inhibit T cell proliferation and control DTH in vivo. Similarly, upon mTOR blockade, human MSC also enhanced their immunoregulatory features. A sustained exposure to IFNγ lead to inhibition of STAT3 activity, which, in mouse MSC resulted in an impaired proliferation and differentiation.
CONCLUSION: These results provide new insights about MSC intracellular pathways affected by IFNγ, demonstrating that pharmacological or genetic manipulation of MSC may enhance their immunomodulatory functions, which could be translated into novel therapeutic approaches.

PMID: 27670240 [PubMed - as supplied by publisher]




D-Tryptophan from probiotic bacteria influences the gut microbiome and allergic airway disease.
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D-Tryptophan from probiotic bacteria influences the gut microbiome and allergic airway disease.

J Allergy Clin Immunol. 2016 Sep 23;

Authors: Kepert I, Fonseca J, Müller C, Milger K, Hochwind K, Kostric M, Fedoseeva M, Ohnmacht C, Dehmel S, Nathan P, Bartel S, Eickelberg O, Schloter M, Hartmann A, Schmitt-Kopplin P, Krauss-Etschmann S

Abstract
BACKGROUND: Chronic immune diseases (CIDs), such as asthma, are highly prevalent. Currently available pharmaceuticals improve symptoms, but cannot cure the disease. This prompted demands for alternatives to pharmaceuticals such as probiotics for prevention of allergic disease. However, clinical trials have given inconsistent results. This is at least partly explained by the highly complex crosstalk among probiotic bacteria, the host´s microbiota, and immune cells. The identification of a bioactive substance from probiotic bacteria could circumvent this difficulty.
OBJECTIVE: To identify and characterize a bioactive, probiotic metabolite for potential prevention of allergic airway disease.
METHODS: Probiotic supernatants were screened for their ability to concordantly lower the constitutive CCL17 secretion of a human Hodgkin lymphoma cell line and prevent upregulation of costimulatory molecules of LPS-stimulated human dendritic cells.
RESULTS: Supernatants from 13 of 37 tested probiotic strains showed immunoactivity. Bioassay-guided chromatographic fractionation of two supernatants according to polarity, followed by total ion chromatograms and mass spectrometry, yielded C11H12N2O2 as molecular formula of a bioactive substance. Proton nuclear magnetic resonance and enantiomeric separation identified D-Tryptophan. In contrast, L-Tryptophan and eleven other D-amino acids were inactive. Feeding D-Tryptophan to mice prior to experimental asthma induction, increased numbers of lung and gut regulatory T cells, lowered lung Th2 responses, and ameliorated allergic airway inflammation and hyperresponsiveness. Allergic airway inflammation reduced the gut microbial diversity, which was increased by D-Tryptophan.
CONCLUSIONS: D-Tryptophan is a newly identified product from probiotic bacteria. Our findings support the concept that defined bacterial products might be exploited in novel preventative strategies for CIDs.

PMID: 27670239 [PubMed - as supplied by publisher]




Killer cell immunoglobulin-like receptors are associated with common variable immune deficiency pathogenesis.
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Killer cell immunoglobulin-like receptors are associated with common variable immune deficiency pathogenesis.

J Allergy Clin Immunol. 2016 Sep 21;

Authors: Wang Y, Hwangpo T, Martin MP, Vince N, Qi Y, Reynolds RJ, Absher D, Gao X, Ballinger CA, Burrows PD, Atkinson TP, Brown EE, Elgavish A, Liu C, Carrington M, Schroeder HW

PMID: 27665490 [PubMed - as supplied by publisher]




Exercise-induced bronchoconstriction update-2016.
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Exercise-induced bronchoconstriction update-2016.

J Allergy Clin Immunol. 2016 Sep 15;

Authors: Weiler JM, Brannan JD, Randolph CC, Hallstrand TS, Parsons J, Silvers W, Storms W, Zeiger J, Bernstein DI, Blessing-Moore J, Greenhawt M, Khan D, Lang D, Nicklas RA, Oppenheimer J, Portnoy JM, Schuller DE, Tilles SA, Wallace D

Abstract
The first practice parameter on exercise-induced bronchoconstriction (EIB) was published in 2010. This updated practice parameter was prepared 5 years later. In the ensuing years, there has been increased understanding of the pathogenesis of EIB and improved diagnosis of this disorder by using objective testing. At the time of this publication, observations included the following: dry powder mannitol for inhalation as a bronchial provocation test is FDA approved however not currently available in the United States; if baseline pulmonary function test results are normal to near normal (before and after bronchodilator) in a person with suspected EIB, then further testing should be performed by using standardized exercise challenge or eucapnic voluntary hyperpnea (EVH); and the efficacy of nonpharmaceutical interventions (omega-3 fatty acids) has been challenged. The workgroup preparing this practice parameter updated contemporary practice guidelines based on a current systematic literature review. The group obtained supplementary literature and consensus expert opinions when the published literature was insufficient. A search of the medical literature on PubMed was conducted, and search terms included pathogenesis, diagnosis, differential diagnosis, and therapy (both pharmaceutical and nonpharmaceutical) of exercise-induced bronchoconstriction or exercise-induced asthma (which is no longer a preferred term); asthma; and exercise and asthma. References assessed as relevant to the topic were evaluated to search for additional relevant references. Published clinical studies were appraised by category of evidence and used to document the strength of the recommendation. The parameter was then evaluated by Joint Task Force reviewers and then by reviewers assigned by the parent organizations, as well as the general membership. Based on this process, the parameter can be characterized as an evidence- and consensus-based document.

PMID: 27665489 [PubMed - as supplied by publisher]




Interleukin-33: Linking impaired skin barrier function to esophageal allergic inflammation.
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Interleukin-33: Linking impaired skin barrier function to esophageal allergic inflammation.

J Allergy Clin Immunol. 2016 Sep 21;

Authors: Travers J, Rochman M, Miracle CE, Cohen JP, Rothenberg ME

PMID: 27664378 [PubMed - as supplied by publisher]




Current Application of Exhaled Nitric Oxide in Clinical Practice.
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Current Application of Exhaled Nitric Oxide in Clinical Practice.

J Allergy Clin Immunol. 2016 Sep 21;

Authors: Spahn JD, Malka J, Szefler SJ, Journal of Allergy and Clinical Immunology, Paradigms and Perspectives Series

PMID: 27664377 [PubMed - as supplied by publisher]




Preservation of epithelial cell barrier function and muted inflammation in resistance to allergic rhinoconjunctivitis from house dust mite challenge.
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Preservation of epithelial cell barrier function and muted inflammation in resistance to allergic rhinoconjunctivitis from house dust mite challenge.

J Allergy Clin Immunol. 2016 Sep 19;

Authors: Ahuja SK, Manoharan MS, Harper NL, Jimenez F, Hobson BD, Martinez H, Ingale P, Liu YG, Carrillo A, Lou Z, Kellog DL, Ahuja SS, Rather CG, Esch RE, Ramirez DA, Clark RA, Nadeau K, Andrews CP, Jacobs RL, He W

Abstract
BACKGROUND: An emerging paradigm holds that resistance to the development of allergic diseases, including allergic rhinoconjunctivitis (AR), relates to an intact epithelial/epidermal barrier during early childhood. Conceivably, the immunologic and genomic footprint of this resistance is preserved in nonatopic, nonallergic adults and is unmasked during exposure to an aeroallergen.
OBJECTIVE: To obtain direct support of the epithelial/epidermal barrier model for AR.
METHODS: Twenty-three adults allergic to house dust mites (HDM; M+) and 15 nonsensitive, nonallergic (M-) participants completed 3-hour exposures to aerosolized HDM (Dermatophagoides pteronyssinus) powder on 4 consecutive days in an allergen challenge chamber (ACC). We analyzed (1) peripheral blood leukocyte levels and immune responses and (2) RNA-seq-derived expression profiles of nasal cells, before and after HDM exposure.
RESULTS: During HDM challenge (1) only M+ persons developed AR symptoms and (2) peripheral blood leukocyte levels/responses and gene expression patterns in nasal cells were largely concordant between M+ and M- participants; gross differences in these parameters were not observed at baseline (pre-exposure). Two key differences were observed. First, peripheral blood CD4+ and CD8+ T-cell activation levels initially decreased in M- vs increased in M+ participants. Second, in M- compared with M+ participants, genes that promoted epidermal/epithelial barrier function (e.g., filaggrin) vs. inflammation (e.g., chemokines) and innate immunity (interferon) were upregulated vs. muted, respectively.
CONCLUSION: An imprint of resistance to HDM challenge in nonatopic, nonallergic adults was muted T-cell activation and inflammatory responses in the peripheral blood and nasal compartment, respectively, coupled with upregulation of genes that promote epidermal/epithelial cell barrier function.

PMID: 27658763 [PubMed - as supplied by publisher]




Efficacy and safety of canakinumab in Schnitzler's syndrome: a multi-center randomized placebo-controlled study.
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Efficacy and safety of canakinumab in Schnitzler's syndrome: a multi-center randomized placebo-controlled study.

J Allergy Clin Immunol. 2016 Sep 19;

Authors: Krause K, Tsianakas A, Wagner N, Fischer J, Weller K, Metz M, Church MK, Maurer M

Abstract
BACKGROUND: Schnitzler's syndrome is an adult-onset autoinflammatory disease characterized by urticarial exanthema and monoclonal gammopathy accompanied by systemic symptoms such as fever, bone and muscle pain. Up to now, approved treatment options are not available.
OBJECTIVE: We here assessed the effects of the anti-IL-1ß monoclonal antibody canakinumab on the clinical signs and symptoms of Schnitzler's syndrome.
METHODS: In this phase II, randomized placebo-controlled multi-center study, 20 patients with active disease enrolled in four German study centers. Patients were randomly assigned to receive single subcutaneous canakinumab 150 mg or placebo injections for 7 days, followed by a 16-week open-label phase with canakinumab injections upon confirmed relapse of symptoms. The primary endpoint was the proportion of patients with complete clinical response evaluated by physician global assessment at day 7. Key secondary endpoints included changes in patient-reported disease activity (Schnitzler activity score), inflammation markers (C-reactive protein [CRP], serum amyloid A [SAA]) and quality of life assessments (DLQI, SF-36).
RESULTS: The proportion of patients with complete clinical response at day 7 was significantly higher (P = 0.001) in the canakinumab-treated group (n = 5/7) than the placebo group (n = 0/13). Levels of inflammation markers CRP and SAA and quality of life scores significantly reduced in canakinumab-treated but not in placebo-treated individuals. Positive effects continued up to 16 weeks. Adverse events were manageable and included respiratory tract infections, gastrointestinal symptoms and hypertension.
CONCLUSION: In this first placebo-controlled study, canakinumab was effective in patients with Schnitzler's syndrome, and thus canakinumab may be further evaluated as a therapeutic option for this rare disease.

PMID: 27658762 [PubMed - as supplied by publisher]




A prospective study on the natural history of patients with profound combined immunodeficiency (P-CID): an interim analysis.
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A prospective study on the natural history of patients with profound combined immunodeficiency (P-CID): an interim analysis.

J Allergy Clin Immunol. 2016 Sep 19;

Authors: Speckmann C, Doerken S, Aiuti A, Albert MH, Al-Herz W, Allende LM, Scarselli A, Avcin T, Perez-Becker R, Cancrini C, Cant A, Di Cesare S, Finocchi A, Fischer A, Gaspar HB, Ghosh S, Gennery A, Gilmour K, González-Granado LI, Martinez-Gallo M, Hambleton S, Hauck F, Hoenig M, Moshous D, Neven B, Niehues T, Notarangelo L, Picard C, Rieber N, Schulz A, Schwarz K, Seidel MG, Soler-Palacin P, Stepensky P, Strahm B, Vraetz T, Warnatz K, Winterhalter C, Worth A, Fuchs S, Uhlmann A, Ehl S, PCID-study of the Inborn Errors Working Party of the EBMT

Abstract
BACKGROUND: Absent T cell immunity resulting in life-threatening infections provides a clear rationale for hematopoetic stem cell transplantation (HSCT) in patients with severe combined immunodeficiency (SCID). Combined immunodeficiencies (CID) and "atypical" SCID show reduced, not absent T-cell immunity. If associated with infections or autoimmunity, they represent profound CID (P-CID), for which outcome data are insufficient for unambiguous early transplant decisions.
OBJECTIVES: We recruit non-transplanted P-CID patients aged 1-16 years to compare natural histories of severity-matched patients with/without subsequent transplantation and to determine whether immunological and/or clinical parameters may be predictive for outcome.
METHODS: Prospective and retrospective observational study.
RESULTS: 51 patients have been recruited (median age 9.6 years). 13/51 have a genetic diagnosis of "atypical" SCID and 14/51 of CID. About half of the patients had <10% naïve T-cells, reduced/absent T-cell proliferation and at least one significant clinical event/year, demonstrating their profound immunodeficiency. Nineteen patients (37%) were transplanted within 1 year after enrolment, 5/51 patients died. Analysis of the HSCT decisions revealed the anticipated heterogeneity, favoring an ongoing prospective matched-pair analysis of patients with similar disease severity with or without transplantation. Importantly, so far neither the genetic diagnosis nor basic measurements of T-cell immunity were good predictors of disease evolution.
CONCLUSION: The P-CID study for the first time characterizes a group of patients with non-typical SCID T-cell deficiencies from a therapeutic perspective. Since genetic and basic T-cell parameters provide limited guidance, prospective data from this study will be a helpful resource for guiding the difficult HSCT decisions in P-CID patients.

PMID: 27658761 [PubMed - as supplied by publisher]




High resolution metabolomics to identify urine biomarkers in corticosteroid resistant asthmatic children.
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High resolution metabolomics to identify urine biomarkers in corticosteroid resistant asthmatic children.

J Allergy Clin Immunol. 2016 Sep 19;

Authors: Park YH, Fitzpatrick AM, Medriano CA, Jones DP

Abstract
BACKGROUND: Corticosteroid (CS) treatment has been established as the first anti-inflammatory treatment for adults and children with asthma. However, a subset of patients fails to respond to combined systemic and inhaled CS treatment.
OBJECTIVE: This study is aimed at further understanding CS resistance among severe asthmatic children.
METHODS: High resolution metabolomics (HRM) was performed on urine samples from CS-respondent (n=15) and CS-nonrespondent (n=15) children to determine possible urine biomarkers related to CS resistance. The metabolic phenotypes of CS-responders and CS-nonresponders were analyzed using bioinformatics including Manhattan plot with false discovery rate (FDR), hierarchical cluster analysis (HCA), Kyoto Encyclopedia Genes and Genomes (KEGG) and Mummichog pathway analysis.
RESULTS: The two-way HCA study determined 30 metabolites showing significantly different levels between CS-responders and CS-nonresponders. The important metabolites annotated were 3,6-dihydronicotinic acid (126.05 m/z, RT: 106, [M+H](+)), 3-methoxy-4-hydroxyphenyl(ethylene)glycol (185.05 m/z, RT: 155, [M+H](+)), 3, 4-dihydroxy-phenylalanine (198.07 m/z, RT: 446, [M+H](+)), γ-glutamylcysteine (236.06 m/z, RT: 528, [M+S(34)+H] (+)), Cys-Gly, (253.06 m/z, RT: 528, [M-NH3+H](+)), reduced FMN (517.0794 m/z, RT: 533, [M+NaCl](+)). Tyrosine metabolism, degradation of aromatic compounds and glutathione metabolism are suggested to be significant pathways relating to CS resistance.
CONCLUSION: High resolution metabolomics (HRM) is a promising approach in asthma research. Five candidate markers were identified to be related to CS resistant severe asthmatic children. These compounds, upon validation, may contribute further in the understanding of CS resistance among severe asthmatics through the use of urine.

PMID: 27658760 [PubMed - as supplied by publisher]




Childhood obesity and asthma -to BMI or not to BMI?
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Childhood obesity and asthma -to BMI or not to BMI?

J Allergy Clin Immunol. 2016 Sep 19;

Authors: Forno E

PMID: 27658759 [PubMed - as supplied by publisher]




Antibodies and Superantibodies in Chronic Rhinosinusitis with Nasal Polyps.
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Antibodies and Superantibodies in Chronic Rhinosinusitis with Nasal Polyps.

J Allergy Clin Immunol. 2016 Sep 19;

Authors: Chen JB, James LK, Davies AM, Wu YC, Rimmer J, Lund VJ, Chen JH, McDonnell JM, Chan YC, Hutchins GH, Chang TW, Sutton BJ, Kariyawasam HH, Gould HJ

Abstract
BACKGROUND: Chronic rhinosinusitis with nasal polyps (CRSwNP) is associated with local immunoglobulin hyperproduction and the presence of IgE antibodies against Staphylococcus aureus enterotoxins (SAEs). Aspirin-exacerbated respiratory disease (AERD) is a severe form of CRSwNP in which nearly all patients express anti-SAEs.
OBJECTIVES: We aimed to understand antibodies reactive to SAEs and determine whether they recognize SAEs through their complementarity-determining regions (CDRs) or framework regions (FRs).
METHODS: Labeled Staphylococcal enterotoxin A (SEA), SED and SEE were used to isolate single SAE-specific B cells from the nasal polyps of three AERD patients by FACS. Recombinant antibodies with "matched" heavy- and light-chains were cloned as IgG1, and those of high-affinity for specific SAEs, assayed by ELISA and surface plasmon resonance (SPR), were re-cloned as IgE and Fab. The activities of the IgEs were tested in basophil degranulation assays.
RESULTS: Thirty-seven SAE-specific, IgG or IgA-expressing B cells were isolated and yielded six anti-SAE clones, two each for SEA, SED and SEE. Competition binding assays revealed that the anti-SEE antibodies recognize non-overlapping epitopes in SEE. Unexpectedly, each anti-SEE mediated SEE-induced basophil degranulation and IgG1 or Fab of each anti-SEE enhanced degranulation by the other anti-SEE.
CONCLUSIONS: SEE may activate basophils by simultaneously binding as antigens in the conventional manner to CDRs and as superantigens to FRs of anti-SEE IgE in anti-SEE IgE-FcεRI complexes. Anti-SEE IgG1s may enhance the activity of anti-SEE IgEs as conventional antibodies via CDRs or simultaneously as conventional antibodies and as "superantibodies" via CDRs and FRs to SEEs in SEE-anti-SEE IgE-FcεRI complexes (Figure 7).

PMID: 27658758 [PubMed - as supplied by publisher]




The impact of a history of asthma on long-term outcomes of people with newly diagnosed chronic obstructive pulmonary disease: A population study.
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The impact of a history of asthma on long-term outcomes of people with newly diagnosed chronic obstructive pulmonary disease: A population study.

J Allergy Clin Immunol. 2016 Aug 28;

Authors: Kendzerska T, To TM, Aaron SD, Lougheed MD, Sadatsafavi M, FitzGerald JM, Gershon AS, Canadian Respiratory Research Network

Abstract
BACKGROUND: Little is known about the natural history of chronic obstructive pulmonary disease (COPD) that has developed from airway remodeling due to asthma, as compared with other COPD phenotypes.
OBJECTIVE: We compared long-term health outcomes of individuals with COPD with and without a history of asthma in a population-based cohort study.
METHODS: All individuals with physician-diagnosed COPD between the ages 40 and 55 years from 2009 and 2011 were identified and followed until March 2013 through provincial health administrative data (Ontario, Canada). The exposure was a history of asthma at least 2 years before the diagnosis of COPD to ensure it preceded COPD. The hazards of COPD-, respiratory-, and cardiovascular (CV)-related hospitalizations and all-cause mortality were compared between groups using a Cox regression model controlling for demographic characteristics, comorbidities, and level of health care.
RESULTS: Among 9053 patients with COPD, 2717 (30%) had a history of asthma. Over a median of 2.9 years, 712 (8%) individuals had a first COPD hospitalization, 964 (11%) a first respiratory-related and 342 (4%) a first CV-related hospitalization, and 556 (6%) died. Controlling for confounding, a history of asthma was significantly associated with COPD and respiratory-related hospitalizations (hazard ratio, 1.53 [95% CI, 1.29-1.82] and hazard ratio, 1.63 [95% CI, 1.14-1.88], respectively), but not with CV-related hospitalizations or all-cause mortality. Additional analyses confirmed that these findings were not likely a result of unmeasured confounding or misclassification.
CONCLUSIONS: Middle-aged individuals with physician-diagnosed COPD and a history of asthma had a higher hazard of hospitalizations due to COPD and other respiratory diseases than did those without.

PMID: 27641119 [PubMed - as supplied by publisher]




Rethinking Chronic Rhinosinusitis Phenotypes.
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Rethinking Chronic Rhinosinusitis Phenotypes.

J Allergy Clin Immunol. 2016 Sep 14;

Authors: Borish L

PMID: 27639940 [PubMed - as supplied by publisher]




Heterogenous inflammatory patterns in chronic rhinosinusitis without nasal polyps in Chicago, Illinois.
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Heterogenous inflammatory patterns in chronic rhinosinusitis without nasal polyps in Chicago, Illinois.

J Allergy Clin Immunol. 2016 Sep 14;

Authors: Tan BK, Klingler AI, Stevens WW, Poposki JA, Peters AT, Suh LA, Norton J, Carter RG, Hulse KE, Harris KE, Grammer LC, Schleimer RP, Welch KC, Smith SS, Conley DB, Kern RC, Kato A

Abstract
CRSsNP is a heterogenous disease but type 2 inflammation in CRSsNP was more common than type 1 inflammation among patients in Chicago, Illinois. Distinct therapeutic strategies may be needed depending on the type of inflammation found in CRSsNP.

PMID: 27639939 [PubMed - as supplied by publisher]




In utero exposure to 25(OH) D and risk of childhood asthma, wheeze and respiratory tract infections: a meta-analysis of birth cohort studies.
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In utero exposure to 25(OH) D and risk of childhood asthma, wheeze and respiratory tract infections: a meta-analysis of birth cohort studies.

J Allergy Clin Immunol. 2016 Sep 14;

Authors: Feng H, Xun P, Pike K, Wills AK, Chawes BL, Bisgaard H, Cai W, Wan Y, He K

Abstract
BACKGROUND: Studies of the associations between in utero 25-hydroxyvitamin D [25(OH) D] exposure and childhood asthma risk, wheeze and respiratory tract infections are inconsistent and inconclusive.
OBJECTIVES: To assess the associations between 25(OH) D levels in cord blood or maternal venous blood and risk of offspring's asthma, wheeze and respiratory tract infections.
METHODS: Data were derived from PubMed, EMBASE, Google Scholar, references from relevant articles, and de novo results from published studies until December, 2015. Random-effects meta-analysis was conducted among 16 birth cohort studies.
RESULTS: Comparing the highest to the lowest category of 25 (OH) D levels, the pooled ORs were 0.84 (95% CI, 0.70 to 1.01; P = 0.064) for asthma, 0.77 (0.58 to 1.03; P = 0.083) for wheeze, and 0.85 (0.66 to 1.09; P = 0.187) for respiratory tract infections. The observed inverse association for wheeze was more pronounced and became statistically significant in the studies that measured 25 (OH) D levels in cord blood (0.43, 0.29 to 0.62; P < 0.001).
CONCLUSIONS: Accumulated evidence generated from this meta-analysis suggests that increased in utero exposure to 25 (OH) D is inversely associated with the risk of asthma and wheeze during childhood. These findings are in keeping with the results of two recently published randomized clinical trials of vitamin D supplementation during pregnancy.

PMID: 27639938 [PubMed - as supplied by publisher]




MUC4 impairs the anti-inflammatory effects of corticosteroids in chronic rhinosinusitis with nasal polyps.
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MUC4 impairs the anti-inflammatory effects of corticosteroids in chronic rhinosinusitis with nasal polyps.

J Allergy Clin Immunol. 2016 Sep 14;

Authors: Milara J, Morell A, Ballester B, Armengot M, Morcillo EJ, Cortijo J

Abstract
BACKGROUND: Current evidence suggests that membrane tethered mucins could mediate corticosteroid efficacy interacting with glucocorticoid receptor (GR) in patients with chronic rhinosinusitis with nasal polyps (CRSwNP). MUC4 tethered mucin is expressed in nasal polyp epithelial cells and up-regulated under inflammatory conditions. Moreover MUC4β has the capacity to interact with other intracellular proteins. We hypothesized that MUC4 modulates corticosteroid efficacy of patients with CRSwNP.
OBJECTIVE: To analyze the role of MUC4 in corticosteroid effectiveness in different cohorts of patients with CRSwNP and elucidate the possible mechanisms involved.
METHODS: Eighty-one patients with CRSwNP took oral corticosteroid for 15 days. Corticosteroid resistance was evaluated by nasal endoscopy. The expression of MUC4 and MUC4β was evaluated by real-time PCR, western blotting, and immunohistochemistry. Beas2b knockdown with RNA interference for MUC4 (siRNA-MUC4) were used to analyze the role of MUC4 in the anti-inflammatory effects of dexamethasone.
RESULTS: Twenty two patients had nasal polyps that were resistant to oral corticosteroids (NP-CR). MUC4 expression was upregulated in these patients. In siRNA-MUC4 Beas2B airway epithelial cells, dexamethasone showed higher anti-inflammatory effects, increased inhibition of phopho-ERK1/2, elevated MKP1 expression and increased glucocorticoid response element (GRE) activation. Immunoprecipitation and immunofluorescence experiments revealed that MUC4β form a complex with GRα in the nucleus of nasal polyp epithelial cells from corticosteroid resistant patients.
CONCLUSION: MUC4β participates in the corticosteroid resistance process inhibiting the correct GRα nuclear function. The high expression of MUC4 in patients with CRSwNP may participate in corticosteroid resistance.

PMID: 27639937 [PubMed - as supplied by publisher]




Increased Immune Reactivity to Central Nervous System Derived Naturally Presented Peptides in Patients with Active Multiple Sclerosis.
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Increased Immune Reactivity to Central Nervous System Derived Naturally Presented Peptides in Patients with Active Multiple Sclerosis.

J Allergy Clin Immunol. 2016 Sep 14;

Authors: Riedhammer C, Halbritter D, Weissert R

PMID: 27639936 [PubMed - as supplied by publisher]




IL-17 enhances the migration of B cells during asthma by inducing CXCL13 chemokine production in structural lung cells.
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IL-17 enhances the migration of B cells during asthma by inducing CXCL13 chemokine production in structural lung cells.

J Allergy Clin Immunol. 2016 Sep 14;

Authors: Al-Kufaidy R, Vazquez-Tello A, BaHammam AS, Hamid Q, Al-Muhsen S, Halwani R

Abstract
Here, we report a positive correlation between expression of IL-17 cytokines with CXCL13(+) cells and B cells numbers in asthmatic airways. IL-17A/F stimulated CXCL13 release from fibroblast and endothelial cells which induced B cells chemotaxis.

PMID: 27639935 [PubMed - as supplied by publisher]




Cardiovascular and cerebrovascular events among patients receiving omalizumab: Results from EXCELS, a prospective cohort study of moderate-to-severe asthma.
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Cardiovascular and cerebrovascular events among patients receiving omalizumab: Results from EXCELS, a prospective cohort study of moderate-to-severe asthma.

J Allergy Clin Immunol. 2016 Sep 14;

Authors: Iribarren C, Rahmaoui A, Long AA, Szefler SJ, Bradley MS, Carrigan G, Eisner MD, Chen H, Omachi TA, Farkouh ME, Rothman KJ

Abstract
BACKGROUND: EXCELS was a postmarketing commitment to the US Food and Drug Administration to assess long-term safety of omalizumab in an observational setting, focusing predominantly on malignancies.
OBJECTIVE: To examine a potential association between omalizumab and cardiovascular (CV)/cerebrovascular (CBV) events in EXCELS.
METHODS: Cohort study of patients (≥12 years of age) with moderate-to-severe allergic asthma followed ≤5 years, treated with omalizumab (n = 5007) or not treated with omalizumab (n = 2829) at baseline. Analyses included overall CV/CBV events, but focused on the subset of arterial thromboembolic events (ATE), comprising CV death, myocardial infarction, ischemic stroke, transient ischemic attack, or unstable angina. A prespecified analysis for the endpoint of ATE was conducted to control for available potential confounders. A blinded independent expert panel adjudicated all events.
RESULTS: At baseline, cohorts had similar demographic characteristics, but severe asthma was more common in the omalizumab versus non-omalizumab cohorts (50% vs 23%). Omalizumab-treated patients had a higher rate of CV/CBV serious adverse events (13.4 per 1000 person-years [PY]) than non-omalizumab-treated patients (8.1 per 1000 PY). ATE rate per 1000 PY was 6.66 (101 patients/15,160 PY) for the omalizumab cohort and 4.64 (46 patients/9904 PY) for the non-omalizumab cohort. After controlling for available confounding factors, the hazard ratio was 1.32 (95% CI, 0.91-1.91).
CONCLUSION: Results from this observational study demonstrated a higher incidence rate of CV/CBV events in the omalizumab versus non-omalizumab cohorts. Differences in asthma severity between cohorts likely contributed to this imbalance, but some increase in risk cannot be excluded (NCT00252135).
CLINICAL IMPLICATIONS: Current asthma management guidelines should not be affected. However, health professionals should be aware of a possible association of omalizumab and serious cardiovascular/cerebrovascular events.

PMID: 27639934 [PubMed - as supplied by publisher]




Bullous pemphigoid outcome is associated with CXCL10-induced MMP-9 secretion from monocytes and neutrophils but not lymphocytes.
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Bullous pemphigoid outcome is associated with CXCL10-induced MMP-9 secretion from monocytes and neutrophils but not lymphocytes.

J Allergy Clin Immunol. 2016 Sep 13;

Authors: Riani M, Le Jan S, Plée J, Durlach A, Le Naour R, Haegeman G, Bernard P, Antonicelli F

Abstract
BACKGROUND: Outcome of bullous pemphigoid (BP), the most frequent autoimmune skin blistering disease, involves MMP-9, IL-17 and IL-23 release from infiltrated inflammatory cells. The chemokine CXCL10 has been associated with several autoimmune diseases but its participation to BP pathophysiology still needs to be clarified.
OBJECTIVE: We sought to assess whether BP outcome was associated with different CXCL10 levels, and to evaluate CXCL10 contribution to the described cytokine/protease inflammatory loop associated to disease outcome.
METHODS: BP skin biopsy specimens (n=16), sera (n=114), blister fluid (n=23) as well as primary inflammatory cells from BP patients were used to investigate CXCL10 expression and function.
RESULTS: At baseline, both resident such as keratinocytes and fibroblasts, and infiltrating immune cells expressed CXCL10 at lesional site in BP skin. CXCL10 levels were higher in BP patient blister fluids (p<0.0001) and sera (p<0.005) than in age- and sex-matched control sera (n=34). Furthermore, CXCL10 serum levels increased at day 60 only in patients who relapsed within the first year of treatment (n=33; p<0.005). Interestingly, cxcl10 expression could be upregulated by itself and IL-17 in inflammatory cells. Notably, neutrophils and monocytes from BP patients only, but not lymphocytes, responded to CXCL10 by increasing MMP-9 secretion through the activation of the ERK1/2, P38, PI3K signalling pathways. Finally, CXCL10-increased MMP-9 secretion was inhibited by methylprednisolone and also by compound A, a novel non-steroidal glucocorticoid receptor ligand.
CONCLUSION: We showed that increased level of inflammatory biomarkers in BP such as CXCL10 favours neutrophil- and monocyte-associated MMP-9 release and disease relapse, and opened new therapeutic horizons in this autoimmune disease.

PMID: 27637385 [PubMed - as supplied by publisher]




Wheezing disorders in children: Are girls and boys different?
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Wheezing disorders in children: Are girls and boys different?

J Allergy Clin Immunol. 2016 Sep 13;

Authors: Deshpande D, Morgan W

PMID: 27637384 [PubMed - as supplied by publisher]




Severe winter asthma exacerbations may be prevented by omalizumab but no carry over effect.
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Severe winter asthma exacerbations may be prevented by omalizumab but no carry over effect.

J Allergy Clin Immunol. 2016 Sep 13;

Authors: Sly PD, Varghese J, Noor F, Tang ML, Laing I, Oo S, Prastanti F, LeSouef PN, Holt PG

Abstract
Our proof-of-concept study shows that omalizumab given during the winter respiratory viral season can prevent severe exacerbations but only while the drug is being taken.

PMID: 27637383 [PubMed - as supplied by publisher]