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Th1 Signatures Are Present in the Lower Airways of Children with Severe Asthma, Regardless of Allergic Status.

Th1 Signatures Are Present in the Lower Airways of Children with Severe Asthma, Regardless of Allergic Status.

J Allergy Clin Immunol. 2017 Sep 19;:

Authors: Wisniewski JA, Muehling LM, Eccles JD, Capaldo BJ, Agrawal R, Shirley DA, Patrie JT, Workman LJ, Schuyler AJ, Lawrence MG, Teague WG, Woodfolk JA

Abstract
BACKGROUND: The pathogenesis of severe asthma in childhood remains poorly understood.
OBJECTIVE: To construct the immunological landscape in the airways of children with severe asthma.
METHODS: Comprehensive analysis of multiple cell types and mediators was performed by flow cytometry and multiplex assay using bronchoalveolar lavage (BAL) specimens (n=68) from 52 highly characterized allergic and non-allergic children (0.5-17 years) with severe treatment-refractory asthma. Multiple relationships were tested by linear mixed-effects modeling.
RESULTS: Memory CCR5(+) Th1 cells were enriched in BAL fluid versus blood, and pathogenic respiratory viruses and bacteria were readily detected. IFN-γ(+)IL-17(+) and IFN-γ(-)IL-17(+) subsets constituted secondary Th types, and BAL CD8(+) T cells were almost exclusively IFN-γ(+). The Th17-associated mediators, IL-23 and MIP-3α/CCL20 were highly expressed. Despite low Th2 numbers, Th2 cytokines were detected and Th2-skewing correlated with total IgE levels. ILC2s and basophils were scarce in BAL fluid. Levels of IL-5, IL-33 and IL-28A/IFN-λ2, were increased in multi-sensitized children and correlated with IgE to dust mite, ryegrass and fungi, but not cat, ragweed or food sources. Additionally, levels of IL-5, but no other cytokine, increased with age and correlated with eosinophil numbers in BAL fluid and blood. Both plasmacytoid and IgE(+)FcεRI(+) myeloid dendritic cells were present in BAL fluid.
CONCLUSIONS: The lower airways of children with severe asthma display a dominant Th1 signature, and atypical cytokine profiles that link to allergic status. Our findings deviate from established paradigms, and warrant further assessment of the pathogenicity of Th1 cells in severe asthma.

PMID: 28939412 [PubMed - as supplied by publisher]




High prevalence of severe asthma in a large random population study.

High prevalence of severe asthma in a large random population study.

J Allergy Clin Immunol. 2017 Sep 19;:

Authors: Mincheva R, Ekerljung L, Bossios A, Lundbäck B, Lötvall J

Abstract
BACKGROUND: The prevalence of asthma severity is not well described at a population level.
OBJECTIVE: To determine the prevalence of phenotypic signs of asthma severity among individuals with asthma in a general population, and to describe risk factors for asthma severity.
METHODS: Epidemiological study conducted between 2008 and 2012 (West Sweden Asthma Study). A postal questionnaire was sent to random population (N = 30,000) in West Sweden, with 18,087 responses. A total of 2,006 individuals were carefully phenotyped. Only individuals with "active asthma" (symptoms or medication in the last year, N = 744) were analyzed in this study, to determine degree of severity of the disease within an asthma cohort. Phenotypes of severity were calculated based on: 1) multiple symptoms during the day despite the ongoing use of asthma medications, 2) FEV1 below 70% of predicted value, 3) daily or almost daily use of rescue medications, 4) nighttime symptoms once a week or more, and 5) oral corticosteroid use/emergency room visits. Asthmatics were grouped as non-severe, one sign of severity or two or more signs of severity.
RESULTS: A total of 36.2% of asthmatics expressed at least one sign of asthma severity, and 13.2% had two or more signs. The group with two or more signs was older in age, had higher BMI, a higher rate of tobacco smoking and lower lung function. Bronchial hyperreactivity, airway inflammation and sensitization were significantly different among the three groups. At a population level, the prevalence of asthma severity was 3.1% for one sign, and 1.3% for at least two signs.
CONCLUSION: More than one in three asthmatics show at least one sign of asthma severity. The phenotypes of asthma severity are highly diverse, which is important to consider when implementing personalized medicine in asthma.
CLINICAL IMPLICATIONS: Our data is based on a random population, which results in minimal bias vs patient selection, and argues that asthma severity is present in 13% to 36% of asthmatics.

PMID: 28939411 [PubMed - as supplied by publisher]




Human CD40L-expressing type 3 innate lymphoid cells induce IL-10-producing immature transitional regulatory B cells.

Human CD40L-expressing type 3 innate lymphoid cells induce IL-10-producing immature transitional regulatory B cells.

J Allergy Clin Immunol. 2017 Sep 19;:

Authors: Komlósi ZI, Kovács N, van de Veen W, Kirsch A, Fahrner HB, Wawrzyniak M, Rebane A, Stanic B, Palomares O, Rückert B, Menz G, Akdis M, Losonczy G, Akdis CA

Abstract
BACKGROUND: Type 3 innate lymphoid cells (ILC3s) are involved in the maintenance of mucosal homeostasis; however, their role in immunoregulation has been unknown. Immature transitional regulatory B (itBreg) cells are innate-like B cells with immunosuppressive properties, and the in vivo mechanisms by which they are induced have not been fully clarified.
OBJECTIVE: We aimed to investigate the ILC3-B cell interaction that probably takes place in human tonsils.
METHODS: ILC3s were isolated from peripheral blood and palatine tonsils, expanded and cocultured with naïve B cells. Tonsillar ILC3s and Breg cells were visualized with immunofluorescence histology. The frequencies of ILC3s were measured in tonsil tissue of allergic and non-allergic patients; and in peripheral blood of allergic asthmatics and healthy controls.
RESULTS: A mutually beneficial relationship was revealed between ILC3s and B cells: ILC3s induced IL-15 production in B cells via BAFF-receptor, while IL-15, a potent growth factor for ILC3s, induced the expression of CD40L on circulating and tonsillar ILC3s. IL-15-activated CD40L(+)ILC3s helped B cell survival, proliferation and the differentiation of IL-10-secreting, functional itBreg cells in a CD40L- and BAFF-receptor-dependent manner. ILC3s and Breg cells were in close connection with each other in palatine tonsils. The frequency of ILC3s was reduced in tonsil tissue of allergic patients and in peripheral blood of allergic asthmatics.
CONCLUSION: Human CD40L(+)ILC3s provide innate B cell help, and are involved in an innate immunoregulatory mechanism by the induction of itBreg cell differentiation, which takes place in palatine tonsils in vivo. This mechanism may contribute to the maintenance of the immune tolerance and become insufficient in allergic diseases.

PMID: 28939410 [PubMed - as supplied by publisher]




Early-life home environment and risk of asthma among inner-city children.

Early-life home environment and risk of asthma among inner-city children.

J Allergy Clin Immunol. 2017 Sep 12;:

Authors: O'Connor GT, Lynch SV, Bloomberg GR, Kattan M, Wood RA, Gergen PJ, Jaffee KF, Calatroni A, Bacharier LB, Beigelman A, Sandel MT, Johnson CC, Faruqi A, Santee C, Fujimura KE, Fadrosh D, Boushey H, Visness CM, Gern JE

Abstract
BACKGROUND: Environmental exposures in early life appear to play an important role in the pathogenesis of childhood asthma, but the potentially modifiable exposures that lead to asthma remain uncertain.
OBJECTIVE: We sought to identify early-life environmental risk factors for childhood asthma in a birth cohort of high-risk inner-city children.
METHODS: We examined the relationship of prenatal and early-life environmental factors to the occurrence of asthma at 7 years of age among 442 children.
RESULTS: Higher house dust concentrations of cockroach, mouse, and cat allergens in the first 3 years of life were associated with lower risk of asthma (for cockroach allergen: odds ratio per interquartile range increase in concentration, 0.55; 95% CI, 0.36-0.86; P < .01). House dust microbiome analysis using 16S ribosomal RNA sequencing identified 202 and 171 bacterial taxa that were significantly (false discovery rate < 0.05) more or less abundant, respectively, in the homes of children with asthma. A majority of these bacteria were significantly correlated with 1 of more allergen concentrations. Other factors associated significantly positively with asthma included umbilical cord plasma cotinine concentration (odds ratio per geometric SD increase in concentration, 1.76; 95% CI, 1.00-3.09; P = .048) and maternal stress and depression scores.
CONCLUSION: Among high-risk inner-city children, higher indoor levels of pet or pest allergens in infancy were associated with lower risk of asthma. The abundance of a number of bacterial taxa in house dust was associated with increased or decreased asthma risk. Prenatal tobacco smoke exposure and higher maternal stress and depression scores in early life were associated with increased asthma risk.

PMID: 28939248 [PubMed - as supplied by publisher]




TLR7/8 agonists stimulate plasmacytoid dendritic cells to initiate a Th17-deviated acute contact dermatitis in humans.
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TLR7/8 agonists stimulate plasmacytoid dendritic cells to initiate a Th17-deviated acute contact dermatitis in humans.

J Allergy Clin Immunol. 2017 Sep 18;:

Authors: Garzorz-Stark N, Lauffer F, Krause L, Thomas J, Atenhan A, Franz R, Roenneberg S, Boehner A, Jargosch M, Batra R, Mueller NS, Haak S, Groß C, Groß O, Traidl-Hoffmann C, Theis FJ, Schmidt-Weber CB, Biedermann T, Eyerich S, Eyerich K

Abstract
BACKGROUND: A standardized human model to study early pathogenic events in psoriasis is missing. Activation of Toll-like receptor 7/8 by topical application of imiquimod is the most commonly used mouse model of psoriasis.
OBJECTIVE: To investigate the potential of a human imiquimod patch test model to resemble human psoriasis.
METHODS: Imiquimod (Aldara® 5% cream) was applied twice a week onto the back of volunteers (n=18) and the development of skin lesions was monitored over a time period of four weeks. Consecutive biopsies were taken for whole genome expression analysis, histology and T cell isolation. pDC were isolated from whole blood, stimulated with TLR7 agonist and analysed by extracellular flux analysis and real time PCR.
RESULTS: We demonstrate imiquimod induces a monomorphic and self-limited inflammatory response in healthy individuals as well as psoriasis or eczema patients, respectively. The clinical and histologic phenotype as well as transcriptome of imiquimod-induced inflammation in human skin resembles an acute contact dermatitis rather than psoriasis. Nevertheless, the imiquimod model mimics hallmarks of psoriasis. Namely, plasmacytoid dendritic cells (pDC) are primary sensors of imiquimod, responding with production of pro-inflammatory and Th17-skewing cytokines. This results in a Th17 immune response with IL-23 as a key driver. In a proof-of-concept setting, systemic treatment with ustekinumab diminished the imiquimod-induced inflammation.
CONCLUSION: In humans, imiquimod induces contact dermatitis with the distinctive feature that pDC are the primary sensors, leading to an IL-23/Th17 deviation. Despite these shortcomings, the human imiquimod model might be useful to investigate early pathogenic events and prove molecular concepts in psoriasis.

PMID: 28935206 [PubMed - as supplied by publisher]




CD4-T cell-restricted IL-2 signaling defect in a patient with a novel IFNGR1-deficiency.
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CD4-T cell-restricted IL-2 signaling defect in a patient with a novel IFNGR1-deficiency.

J Allergy Clin Immunol. 2017 Sep 16;:

Authors: Khanolkar A, Kirschmann DA, Caparelli EA, Wilks JD, Cerullo JM, Bergerson JRE, Jennings LJ, Fuleihan RL

Abstract
In depth analysis of immune function in a patient with a defined defect in IFNγR1 expression additionally identified an IL-2 associated signaling deficiency that was restricted primarily to the circulating CD4 T cell subset.

PMID: 28927822 [PubMed - as supplied by publisher]




A novel IKAROS haploinsufficiency kindred with unexpectedly late and variable B cell maturation defects.
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A novel IKAROS haploinsufficiency kindred with unexpectedly late and variable B cell maturation defects.

J Allergy Clin Immunol. 2017 Sep 16;:

Authors: Bogaert DJ, Kuehn HS, Bonroy C, Calvo KR, Dehoorne J, Vanlander AV, De Bruyne M, Cytlak U, Bigley V, De Baets F, De Baere E, Rosenzweig SD, Haerynck F, Dullaers M

Abstract
We report on the first truncating IKZF1 mutation associated with IKAROS haploinsufficiency and illustrate an unexpectedly late and variable block in central and peripheral B cell development in two patients and their asymptomatic mother.

PMID: 28927821 [PubMed - as supplied by publisher]




A novel role for cilia function in atopy: ADGRV1 and DNAH5 interactions.
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A novel role for cilia function in atopy: ADGRV1 and DNAH5 interactions.

J Allergy Clin Immunol. 2017 Sep 16;:

Authors: Sugier PE, Brossard M, Sarnowski C, Vaysse A, Morin A, Pain L, Margaritte-Jeannin P, Dizier MH, Cookson WOCM, Lathrop M, Moffatt MF, Laprise C, Demenais F, Bouzigon E

Abstract
BACKGROUND: Atopy, an endotype underlying allergic diseases, has a substantial genetic component.
OBJECTIVE: Our goal was to identify novel genes associated with atopy in asthma-ascertained families.
METHODS: We implemented a three-step analysis strategy in three datasets: The Epidemiological study on the Genetics and Environment of Asthma (EGEA) dataset: 1,660 subjects; The Saguenay-Lac-Saint-Jean (SLSJ) dataset: 1,138 subjects; and The Medical Research Council (MRC) dataset: 446 subjects). This strategy included a single-SNP genome-wide association study (GWAS), the selection of related gene pairs based on statistical filtering of GWAS results and text-mining filtering using GRAIL and SNP-SNP interaction analysis of selected gene pairs.
RESULTS: We identified the 5q14 locus, harboring the adhesion G protein-coupled receptor V1 (ADGRV1) gene, that showed genome-wide significant association with atopy (rs4916831; Pmeta=6.8x10(-9)). Statistical filtering of GWAS results followed by text-mining filtering revealed relationships between ADGRV1 and three genes showing suggestive association with atopy (P≤10(-4)). SNP-SNP interaction analysis between ADGRV1 and these three genes showed significant interaction between ADGRV1 rs17554723 and two correlated SNPs (rs2134256 and rs1354187) within dynein axonemal heavy chain 5 (DNAH5) gene (Pmeta-int=3.6x10(-5) and 6.1x10(-5), that met the multiple-testing corrected threshold of 7.3x10(-5)). Further conditional analysis indicated that rs2134256 alone accounted for the interaction signal with rs17554723.
CONCLUSION: As both DNAH5 and ADGRV1 contribute to function of cilia, this study suggests that cilia dysfunction may represent a novel mechanism underlying atopy. Combining GWAS and epistasis analysis driven by statistical and knowledge-based evidence represents a promising approach for identifying new genes involved in complex traits.

PMID: 28927820 [PubMed - as supplied by publisher]




Effect of endotoxin and alum adjuvant vaccine on peanut allergy.
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Effect of endotoxin and alum adjuvant vaccine on peanut allergy.

J Allergy Clin Immunol. 2017 Sep 16;:

Authors: Johnson-Weaver BT, McRitchie S, Mercier KA, Pathmasiri W, Sumner SJ, Chan C, Germolec D, Kulis M, Burks AW, Staats HF

Abstract
Environmental endotoxin and alum-adjuvanted vaccines did not influence peanut-allergy development in mice. Exposure to alum and CpG-adjuvanted vaccines indirectly reduced allergic disease severity. Fecal metabolites differentiated mice based on disease severity.

PMID: 28927819 [PubMed - as supplied by publisher]




Specific Allergy & Asthma Prevention Coming to an Age: A Milestone in Children.
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Specific Allergy & Asthma Prevention Coming to an Age: A Milestone in Children.

J Allergy Clin Immunol. 2017 Sep 16;:

Authors: Bachert C, Akdis C

PMID: 28927818 [PubMed - as supplied by publisher]




Psoriasis pathogenesis and the development of novel targeted immune therapies.
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Psoriasis pathogenesis and the development of novel targeted immune therapies.

J Allergy Clin Immunol. 2017 Sep;140(3):645-653

Authors: Hawkes JE, Chan TC, Krueger JG

Abstract
Psoriasis is caused by a complex interplay between the immune system, psoriasis-associated susceptibility loci, autoantigens, and multiple environmental factors. Over the last 2 decades, research has unequivocally shown that psoriasis represents a bona fide T cell-mediated disease primarily driven by pathogenic T cells that produce high levels of IL-17 in response to IL-23. The discovery of the central role for the IL-23/type 17 T-cell axis in the development of psoriasis has led to a major paradigm shift in the pathogenic model for this condition. The activation and upregulation of IL-17 in prepsoriatic skin produces a "feed forward" inflammatory response in keratinocytes that is self-amplifying and drives the development of mature psoriatic plaques by inducing epidermal hyperplasia, epidermal cell proliferation, and recruitment of leukocyte subsets into the skin. Clinical trial data for mAbs against IL-17 signaling (secukinumab, ixekizumab, and brodalumab) and newer IL-23p19 antagonists (tildrakizumab, guselkumab, and risankizumab) underscore the central role of these cytokines as predominant drivers of psoriatic disease. Currently, we are witnessing a translational revolution in the treatment and management of psoriasis. Emerging bispecific antibodies offer the potential for even better disease control, whereas small-molecule drugs offer future alternatives to the use of biologics and less costly long-term disease management.

PMID: 28887948 [PubMed - indexed for MEDLINE]




Therapeutic pipeline for atopic dermatitis: End of the drought?
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Therapeutic pipeline for atopic dermatitis: End of the drought?

J Allergy Clin Immunol. 2017 Sep;140(3):633-643

Authors: Paller AS, Kabashima K, Bieber T

Abstract
Until the past year, our therapeutic armamentarium for treating atopic dermatitis (AD) was still primarily topical corticosteroids and, for more severe disease, systemic immunosuppressants. The pipeline of more targeted topical and systemic therapies is expanding based on our growing understanding of the mechanism for AD and is particularly focused on suppressing the skewed immune activation. Most agents are in phase 2 clinical trials. Crisaborole, a topical phosphodiesterase 4 (PDE4) inhibitor, became available in late 2016 in the United States for mild-to-moderate AD, with other PDE4 inhibitors, an agonist of the aryl hydrocarbon receptor, Janus kinase inhibitors, and commensal organisms also in trials for topical application. The first highly effective mAb for AD, dupilumab, targets the IL-4/IL-13 receptor and was approved in early 2017 in the United States for moderate-to-severe adult AD. Other biologics similarly inhibit TH2 cytokines (thymic stromal lymphopoietin, IL-4, IL-5, IL-13, and the itch-specific cytokine IL-31 and their receptors) or TH22/TH17 cytokines, levels of which are increased in lesional skin. Orally administered small-molecule inhibitors that suppress inflammation (targeting chemoattractant receptor-homologous molecules expressed on TH2 lymphocytes, PDE4, the histamine 4 receptor, and Janus kinase) or specifically itching (eg, NK1R inhibitors) are also being studied. Comparing biomarkers with individual responses to experimental agents will help to determine subphenotypes within AD that predict prognosis and treatment responses.

PMID: 28887947 [PubMed - indexed for MEDLINE]




Vitiligo: Mechanistic insights lead to novel treatments.
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Vitiligo: Mechanistic insights lead to novel treatments.

J Allergy Clin Immunol. 2017 Sep;140(3):654-662

Authors: Frisoli ML, Harris JE

Abstract
Vitiligo is an autoimmune disease of the skin characterized by patchy depigmentation. Current treatments are moderately effective at reversing disease by suppressing autoimmune inflammation in the skin and promoting melanocyte regeneration. Recent basic and translational research studies have significantly improved our understanding of disease pathogenesis, which is now leading to emerging treatment strategies based on targeted therapy. Here we discuss important clinical characteristics of vitiligo, current therapies and their limitations, advances in understanding disease pathogenesis, emerging targeted treatments, and strategies to optimize clinical trials to efficiently and effectively test these new treatments.

PMID: 28778794 [PubMed - indexed for MEDLINE]




Advances in asthma in 2016: Designing individualized approaches to management.
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Advances in asthma in 2016: Designing individualized approaches to management.

J Allergy Clin Immunol. 2017 Sep;140(3):671-680

Authors: Anderson WC, Apter AJ, Dutmer CM, Searing DA, Szefler SJ

Abstract
In this year's Advances in Asthma review, we discuss viral infections in asthmatic patients and potential therapeutic agents, the microbiome, novel genetic associations with asthma, air quality and climate effects on asthma, exposures during development and long-term sequelae of childhood asthma, patient-centered outcomes research, and precision medicine. In addition, we discuss application of biomarkers to precision medicine and new information on asthma medications. New evidence indicates that rhinovirus-triggered asthma exacerbations become more severe as the degree of sensitization to dust mite and mouse increase. The 2 biggest drivers of asthma severity are an allergy pathway starting with allergic sensitization and an environmental tobacco smoke pathway. In addition, allergic sensitization and blood eosinophils can be used to select medications for management of early asthma in young children. These current findings, among others covered in this review, represent significant steps toward addressing rapidly advancing areas of knowledge that have implications for asthma management.

PMID: 28709967 [PubMed - indexed for MEDLINE]




Moving toward endotypes in atopic dermatitis: Identification of patient clusters based on serum biomarker analysis.
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Moving toward endotypes in atopic dermatitis: Identification of patient clusters based on serum biomarker analysis.

J Allergy Clin Immunol. 2017 Sep;140(3):730-737

Authors: Thijs JL, Strickland I, Bruijnzeel-Koomen CAFM, Nierkens S, Giovannone B, Csomor E, Sellman BR, Mustelin T, Sleeman MA, de Bruin-Weller MS, Herath A, Drylewicz J, May RD, Hijnen D

Abstract
BACKGROUND: Atopic dermatitis (AD) is a complex, chronic, inflammatory skin disease with a diverse clinical presentation. However, it is unclear whether this diversity exists at a biological level.
OBJECTIVE: We sought to test the hypothesis that AD is heterogeneous at the biological level of individual inflammatory mediators.
METHODS: Sera from 193 adult patients with moderate-to-severe AD (six area, six sign atopic dermatitis [SASSAD] score: geometric mean, 22.3 [95% CI, 21.3-23.3] and 39.1 [95% CI, 37.5-40.9], respectively) and 30 healthy control subjects without AD were analyzed for 147 serum mediators, total IgE levels, and 130 allergen-specific IgE levels. Population heterogeneity was assessed by using principal component analysis, followed by unsupervised k-means cluster analysis of the principal components.
RESULTS: Patients with AD showed pronounced evidence of inflammation compared with healthy control subjects. Principal component analysis of data on sera from patients with AD revealed the presence of 4 potential clusters. Fifty-seven principal components described approximately 90% of the variance. Unsupervised k-means cluster analysis of the 57 largest principal components delivered 4 distinct clusters of patients with AD. Cluster 1 had high SASSAD scores and body surface areas with the highest levels of pulmonary and activation-regulated chemokine, tissue inhibitor of metalloproteinases 1, and soluble CD14. Cluster 2 had low SASSAD scores with the lowest levels of IFN-α, tissue inhibitor of metalloproteinases 1, and vascular endothelial growth factor. Cluster 3 had high SASSAD scores with the lowest levels of IFN-β, IL-1, and epithelial cytokines. Cluster 4 had low SASSAD scores but the highest levels of the inflammatory markers IL-1, IL-4, IL-13, and thymic stromal lymphopoietin.
CONCLUSION: AD is a heterogeneous disease both clinically and biologically. Four distinct clusters of patients with AD have been identified that could represent endotypes with unique biological mechanisms. Elucidation of these endotypes warrants further investigation and will require future intervention trials with specific agents, such as biologics.

PMID: 28412391 [PubMed - indexed for MEDLINE]




Basophils, high-affinity IgE receptors, and CCL2 in human anaphylaxis.
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Basophils, high-affinity IgE receptors, and CCL2 in human anaphylaxis.

J Allergy Clin Immunol. 2017 Sep;140(3):750-758.e15

Authors: Korosec P, Turner PJ, Silar M, Kopac P, Kosnik M, Gibbs BF, Shamji MH, Custovic A, Rijavec M

Abstract
BACKGROUND: The role of basophils in anaphylaxis is unclear.
OBJECTIVE: We sought to investigate whether basophils have an important role in human anaphylaxis.
METHODS: In an emergency department study we recruited 31 patients with acute anaphylaxis, predominantly to Hymenoptera venom. We measured expression of basophil activation markers (CD63 and CD203c); the absolute number of circulating basophils; whole-blood FCER1A, carboxypeptidase A3 (CPA3), and L-histidine decarboxylase (HDC) gene expression; and serum markers (CCL2, CCL5, CCL11, IL-3, and thymic stromal lymphopoietin) at 3 time points (ie, during the anaphylactic episode and in convalescent samples 7 and 30 days later). We recruited 134 patients with Hymenoptera allergy and 76 healthy control subjects for comparison. We then investigated whether the changes observed during venom-related anaphylaxis also occur during allergic reactions to food in 22 patients with peanut allergy undergoing double-blind, placebo-controlled food challenge to peanut.
RESULTS: The number of circulating basophils was significantly lower during anaphylaxis (median, 3.5 cells/μL) than 7 and 30 days later (17.5 and 24.7 cells/μL, P < .0001) and compared with those in patients with venom allergy and healthy control subjects (21 and 23.4 cells/μL, P < .0001). FCER1A expression during anaphylaxis was also significantly lower than in convalescent samples (P ≤ .002) and control subjects with venom allergy (P < .0001). CCL2 levels (but not those of other serum markers) were significantly higher during anaphylaxis (median, 658 pg/mL) than in convalescent samples (314 and 311 pg/mL at 7 and 30 days, P < .001). Peanut-induced allergic reactions resulted in a significant decrease in circulating basophil counts compared with those in prechallenge samples (P = .016), a decrease in FCER1A expression (P = .007), and an increase in CCL2 levels (P = .003).
CONCLUSIONS: Our findings imply an important and specific role for basophils in the pathophysiology of human anaphylaxis.

PMID: 28342911 [PubMed - indexed for MEDLINE]




Urban residence, neighborhood poverty, race/ethnicity, and asthma morbidity among children on Medicaid.
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Urban residence, neighborhood poverty, race/ethnicity, and asthma morbidity among children on Medicaid.

J Allergy Clin Immunol. 2017 Sep;140(3):822-827

Authors: Keet CA, Matsui EC, McCormack MC, Peng RD

Abstract
BACKGROUND: Although poor-urban (inner-city) areas are thought to have high asthma prevalence and morbidity, we recently found that inner cities do not have higher prevalent pediatric asthma. Whether asthma morbidity is higher in inner-city areas across the United States is not known.
OBJECTIVE: This study sought to examine relationships between residence in poor and urban areas, race/ethnicity, and asthma morbidity among children with asthma who are enrolled in Medicaid.
METHODS: Children aged 5 to 19 enrolled in Medicaid in 2009 to 2010 were included. Asthma was defined by at least 1 outpatient or emergency department (ED) visit with a primary diagnosis code of asthma over the 2-year period. Urbanization status was defined at the county level and neighborhood poverty at the zip-code level. Among children with asthma, logistic models were created to examine the effects of urbanization, neighborhood poverty, and race/ethnicity on rates of asthma outpatient visits, ED visits, and hospitalizations.
RESULTS: This study included 16,860,716 children (1,534,820 with asthma). Among children enrolled in Medicaid, residence in inner-city areas did not confer increased risk of prevalent asthma in either crude or adjusted analyses, but it was associated with significantly more asthma-related ED visits and hospitalizations among those with asthma in crude analyses (risk ratio, 1.48; 95% CI, 1.24-1.36; and 1.97; 95% CI, 1.50-1.72, respectively) and when adjusted for race/ethnicity, age, and sex (adjusted risk ratio, 1.23; 95% CI, 1.08-1.15; and 1.62; 95% CI, 1.26-1.43). Residence in urban or poor areas and non-Hispanic black race/ethnicity were all independently associated with increased risk of asthma-related ED visits and hospitalizations.
CONCLUSIONS: Residence in poor and urban areas is an important risk factor for asthma morbidity, but not for prevalence, among low-income US children.

PMID: 28283418 [PubMed - indexed for MEDLINE]




Effects of structured patient education in adults with atopic dermatitis: Multicenter randomized controlled trial.
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Effects of structured patient education in adults with atopic dermatitis: Multicenter randomized controlled trial.

J Allergy Clin Immunol. 2017 Sep;140(3):845-853.e3

Authors: Heratizadeh A, Werfel T, Wollenberg A, Abraham S, Plank-Habibi S, Schnopp C, Sticherling M, Apfelbacher C, Biedermann T, Breuer K, Fell I, Fölster-Holst R, Heine G, Grimm J, Hennighausen L, Kugler C, Reese I, Ring J, Schäkel K, Schmitt J, Seikowski K, von Stebut E, Wagner N, Waßmann-Otto A, Wienke-Graul U, Weisshaar E, Worm M, Gieler U, Kupfer J, Arbeitsgemeinschaft Neurodermitisschulung für Erwachsene (ARNE) Study Group

Abstract
BACKGROUND: Atopic dermatitis (AD) is a chronic relapsing skin disease prevalent in 1% to 3% of adults in Western industrialized countries.
OBJECTIVE: We sought to investigate the effectiveness of educational training in an outpatient setting on coping with the disease, quality of life, symptoms, and severity in adults with AD.
METHODS: In this German prospective, randomized controlled multicenter study, adult patients with moderate-to-severe AD were educated by referring to a comprehensive 12-hour training manual consented by a multiprofessional study group from different centers (Arbeitsgemeinschaft Neurodermitisschulung für Erwachsene [ARNE]). Patients were randomly allocated to the intervention or waiting control groups. Study visits were performed at baseline and after 1 year (1 year of follow-up). Primary outcomes were defined as a decrease in (1) "catastrophizing cognitions" with respect to itching (Juckreiz-Kognitions-Fragebogen questionnaire), (2) "social anxiety" (Marburger Hautfragebogen questionnaire), (3) subjective burden by symptoms of the disease (Skindex-29 questionnaire), and (4) improvement of disease signs and symptoms assessed by using the SCORAD index at 1 year of follow-up. Data were analyzed on an intention-to-treat basis.
RESULTS: At 1 year of follow-up, patients from the intervention group (n = 168) showed a significantly better improvement compared with the waiting group (n = 147) in the following defined primary study outcomes: coping behavior with respect to itching (P < .001), quality of life assessed by using the Skindex-29 questionnaire (P < .001), and the SCORAD index (P < .001).
CONCLUSIONS: This is the first randomized, controlled multicenter study on patient education in adult AD. The ARNE training program shows significant beneficial effects on a variety of psychosocial parameters, as well as AD severity.

PMID: 28242304 [PubMed - indexed for MEDLINE]




Microparticles in nasal lavage fluids in chronic rhinosinusitis: Potential biomarkers for diagnosis of aspirin-exacerbated respiratory disease.
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Microparticles in nasal lavage fluids in chronic rhinosinusitis: Potential biomarkers for diagnosis of aspirin-exacerbated respiratory disease.

J Allergy Clin Immunol. 2017 Sep;140(3):720-729

Authors: Takahashi T, Kato A, Berdnikovs S, Stevens WW, Suh LA, Norton JE, Carter RG, Harris KE, Peters AT, Hulse KE, Grammer LC, Welch KC, Shintani-Smith S, Tan BK, Conley DB, Kern RC, Bochner BS, Schleimer RP

Abstract
BACKGROUND: Microparticles (MPs) are submicron-sized shed membrane vesicles released from activated or injured cells and are detectable by flow cytometry. MP levels have been used as biomarkers to evaluate cell injury or activation in patients with pathological conditions.
OBJECTIVE: We sought to compare MP types and levels in nasal lavage fluids (NLFs) from controls and patients with chronic rhinosinusitis without nasal polyps (CRSsNP), chronic rhinosinusitis with nasal polyps (CRSwNP), and aspirin-exacerbated respiratory disease (AERD).
METHODS: We collected NLFs from patients with CRSsNP (n = 33), CRSwNP (n = 45), and AERD (n = 31) and control (n = 24) subjects. Standardized flow cytometry methods were used to characterize the following MP types: endothelial MPs, epithelial MPs (epithelial cell adhesion molecule [EpCAM](+)MPs, E-cadherin(+)MPs), platelet MPs (CD31(+)CD41(+)MPs), eosinophil MPs (EGF-like module-containing mucin-like hormone receptor-like 1[EMR1](+)MPs), mast cell MPs (high-affinity IgE receptor [FcεRI](+)c-kit(+)MPs), and basophil MPs (CD203c(+)c-kit(-)MPs). Basophil activation was evaluated by the mean fluorescence intensity of CD203c on basophil MPs.
RESULTS: Activated mast cell MPs (CD137(+) FcεRI(+)c-kit(+)MPs) were significantly increased in NLFs of controls compared with NLFs of patients with CRSsNP (2.3-fold; P < .02), CRSwNP (2.3-fold; P < .03), and AERD (7.4-fold; P < .0001). Platelet MPs (3.5-fold; P < .01) and basophil MPs (2.5-fold; P < .05) were increased only in patients with AERD. Mean fluorescence intensity of CD203c on MPs was increased in patients with CRSwNP (P < .002) and AERD (P < .0001), but not in patients with CRSsNP. EpCAM(+)MPs in patients with CRSwNP were no different from control (P = .91) and lower than those in patients with CRSsNP (P < .02) and AERD (P < .002).
CONCLUSIONS: Based on released MPs, mast cells, platelets, and basophils were more highly activated in patients with AERD than in patients with CRS. Epithelial injury was lower in patients with CRSwNP than in patients with CRSsNP and AERD. MP analysis may help identify phenotypes of CRS, and in distinguishing AERD from CRSwNP.

PMID: 28238741 [PubMed - indexed for MEDLINE]




Recognition of viral and self-antigens by TH1 and TH1/TH17 central memory cells in patients with multiple sclerosis reveals distinct roles in immune surveillance and relapses.
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Recognition of viral and self-antigens by TH1 and TH1/TH17 central memory cells in patients with multiple sclerosis reveals distinct roles in immune surveillance and relapses.

J Allergy Clin Immunol. 2017 Sep;140(3):797-808

Authors: Paroni M, Maltese V, De Simone M, Ranzani V, Larghi P, Fenoglio C, Pietroboni AM, De Riz MA, Crosti MC, Maglie S, Moro M, Caprioli F, Rossi R, Rossetti G, Galimberti D, Pagani M, Scarpini E, Abrignani S, Geginat J

Abstract
BACKGROUND: Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS) that is caused by autoreactive T cells and associated with viral infections. However, the phenotype of pathogenic T cells in peripheral blood remains to be defined, and how viruses promote MS is debated.
OBJECTIVE: We aimed to identify and characterize potentially pathogenic autoreactive T cells, as well as protective antiviral T cells, in patients with MS.
METHODS: We analyzed CD4(+) helper T-cell subsets from peripheral blood or cerebrospinal fluid for cytokine production, gene expression, plasticity, homing potentials, and their reactivity to self-antigens and viral antigens in healthy subjects and patients with MS. Moreover, we monitored their frequencies in untreated and fingolimod- or natalizumab-treated patients with MS.
RESULTS: TH1/TH17 central memory (TH1/TH17CM) cells were selectively increased in peripheral blood of patients with relapsing-remitting MS with a high disease score. TH1/TH17CM cells were closely related to conventional TH17 cells but had more pathogenic features. In particular, they could shuttle between lymph nodes and the CNS and produced encephalitogenic cytokines. The cerebrospinal fluid of patients with active MS was enriched for CXCL10 and contained mainly CXCR3-expressing TH1 and TH1/TH17 subsets. However, while TH1 cells responded consistently to viruses, TH1/TH17CM cells reacted strongly with John Cunningham virus in healthy subjects but responded instead to myelin-derived self-antigens in patients with MS. Fingolimod and natalizumab therapies efficiently targeted autoreactive TH1/TH17CM cells but also blocked virus-specific TH1 cells.
CONCLUSIONS: We propose that autoreactive TH1/TH17CM cells expand in patients with MS and promote relapses after bystander recruitment to the CNS, whereas TH1 cells perform immune surveillance. Thus the selective targeting of TH1/TH17 cells could inhibit relapses without causing John Cunningham virus-dependent progressive multifocal encephalomyelitis.

PMID: 28237728 [PubMed - indexed for MEDLINE]




Shared genetic variants suggest common pathways in allergy and autoimmune diseases.
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Shared genetic variants suggest common pathways in allergy and autoimmune diseases.

J Allergy Clin Immunol. 2017 Sep;140(3):771-781

Authors: Kreiner E, Waage J, Standl M, Brix S, Pers TH, Couto Alves A, Warrington NM, Tiesler CMT, Fuertes E, Franke L, Hirschhorn JN, James A, Simpson A, Tung JY, Koppelman GH, Postma DS, Pennell CE, Jarvelin MR, Custovic A, Timpson N, Ferreira MA, Strachan DP, Henderson J, Hinds D, Bisgaard H, Bønnelykke K

Abstract
BACKGROUND: The relationship between allergy and autoimmune disorders is complex and poorly understood.
OBJECTIVE: We sought to investigate commonalities in genetic loci and pathways between allergy and autoimmune diseases to elucidate shared disease mechanisms.
METHODS: We meta-analyzed 2 genome-wide association studies on self-reported allergy and sensitization comprising a total of 62,330 subjects. These results were used to calculate enrichment for single nucleotide polymorphisms (SNPs) previously associated with autoimmune diseases. Furthermore, we probed for enrichment within genetic pathways and of transcription factor binding sites and characterized commonalities in variant burden on tissue-specific regulatory sites by calculating the enrichment of allergy SNPs falling in gene regulatory regions in various cells using Encode Roadmap DNase-hypersensitive site data. Finally, we compared the allergy data with those of all known diseases.
RESULTS: Among 290 loci previously associated with 16 autoimmune diseases, we found a significant enrichment of loci also associated with allergy (P = 1.4e-17) encompassing 29 loci at a false discovery rate of less than 0.05. Such enrichment seemed to be a general characteristic for autoimmune diseases. Among the common loci, 48% had the same direction of effect for allergy and autoimmune diseases. Additionally, we observed an enrichment of allergy SNPs falling within immune pathways and regions of chromatin accessible in immune cells that was also represented in patients with autoimmune diseases but not those with other diseases.
CONCLUSION: We identified shared susceptibility loci and commonalities in pathways between allergy and autoimmune diseases, suggesting shared disease mechanisms. Further studies of these shared genetic mechanisms might help in understanding the complex relationship between these diseases, including the parallel increase in disease prevalence.

PMID: 28188724 [PubMed - indexed for MEDLINE]




Quantitative computed tomographic imaging-based clustering differentiates asthmatic subgroups with distinctive clinical phenotypes.
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Quantitative computed tomographic imaging-based clustering differentiates asthmatic subgroups with distinctive clinical phenotypes.

J Allergy Clin Immunol. 2017 Sep;140(3):690-700.e8

Authors: Choi S, Hoffman EA, Wenzel SE, Castro M, Fain S, Jarjour N, Schiebler ML, Chen K, Lin CL, National Heart, Lung and Blood Institute's Severe Asthma Research Program

Abstract
BACKGROUND: Imaging variables, including airway diameter, wall thickness, and air trapping, have been found to be important metrics when differentiating patients with severe asthma from those with nonsevere asthma and healthy subjects.
OBJECTIVE: The objective of this study was to identify imaging-based clusters and to explore the association of the clusters with existing clinical metrics.
METHODS: We performed an imaging-based cluster analysis using quantitative computed tomography-based structural and functional variables extracted from the respective inspiration and expiration scans of 248 asthmatic patients. The imaging-based metrics included a broader set of multiscale variables, such as inspiratory airway dimension, expiratory air trapping, and registration-based lung deformation (inspiration vs expiration). Asthma subgroups derived from a clustering method were associated with subject demographics, questionnaire results, medication history, and biomarker variables.
RESULTS: Cluster 1 was composed of younger patients with early-onset nonsevere asthma and reversible airflow obstruction and normal airway structure. Cluster 2 was composed of patients with a mix of patients with nonsevere and severe asthma with marginal inflammation who exhibited airway luminal narrowing without wall thickening. Clusters 3 and 4 were dominated by patients with severe asthma. Cluster 3 patients were obese female patients with reversible airflow obstruction who exhibited airway wall thickening without airway narrowing. Cluster 4 patients were late-onset older male subjects with persistent airflow obstruction who exhibited significant air trapping and reduced regional deformation. Cluster 3 and 4 patients also showed decreased lymphocyte and increased neutrophil counts, respectively.
CONCLUSIONS: Four image-based clusters were identified and shown to be correlated with clinical characteristics. Such clustering serves to differentiate asthma subgroups that can be used as a basis for the development of new therapies.

PMID: 28143694 [PubMed - indexed for MEDLINE]




Damaging heterozygous mutations in NFKB1 lead to diverse immunologic phenotypes.
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Damaging heterozygous mutations in NFKB1 lead to diverse immunologic phenotypes.

J Allergy Clin Immunol. 2017 Sep;140(3):782-796

Authors: Kaustio M, Haapaniemi E, Göös H, Hautala T, Park G, Syrjänen J, Einarsdottir E, Sahu B, Kilpinen S, Rounioja S, Fogarty CL, Glumoff V, Kulmala P, Katayama S, Tamene F, Trotta L, Morgunova E, Krjutškov K, Nurmi K, Eklund K, Lagerstedt A, Helminen M, Martelius T, Mustjoki S, Taipale J, Saarela J, Kere J, Varjosalo M, Seppänen M

Abstract
BACKGROUND: The nuclear factor κ light-chain enhancer of activated B cells (NF-κB) signaling pathway is a key regulator of immune responses. Accordingly, mutations in several NF-κB pathway genes cause immunodeficiency.
OBJECTIVE: We sought to identify the cause of disease in 3 unrelated Finnish kindreds with variable symptoms of immunodeficiency and autoinflammation.
METHODS: We applied genetic linkage analysis and next-generation sequencing and functional analyses of NFKB1 and its mutated alleles.
RESULTS: In all affected subjects we detected novel heterozygous variants in NFKB1, encoding for p50/p105. Symptoms in variant carriers differed depending on the mutation. Patients harboring a p.I553M variant presented with antibody deficiency, infection susceptibility, and multiorgan autoimmunity. Patients with a p.H67R substitution had antibody deficiency and experienced autoinflammatory episodes, including aphthae, gastrointestinal disease, febrile attacks, and small-vessel vasculitis characteristic of Behçet disease. Patients with a p.R157X stop-gain experienced hyperinflammatory responses to surgery and showed enhanced inflammasome activation. In functional analyses the p.R157X variant caused proteasome-dependent degradation of both the truncated and wild-type proteins, leading to a dramatic loss of p50/p105. The p.H67R variant reduced nuclear entry of p50 and showed decreased transcriptional activity in luciferase reporter assays. The p.I553M mutation in turn showed no change in p50 function but exhibited reduced p105 phosphorylation and stability. Affinity purification mass spectrometry also demonstrated that both missense variants led to altered protein-protein interactions.
CONCLUSION: Our findings broaden the scope of phenotypes caused by mutations in NFKB1 and suggest that a subset of autoinflammatory diseases, such as Behçet disease, can be caused by rare monogenic variants in genes of the NF-κB pathway.

PMID: 28115215 [PubMed - indexed for MEDLINE]




Profound loss of esophageal tissue differentiation in patients with eosinophilic esophagitis.
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Profound loss of esophageal tissue differentiation in patients with eosinophilic esophagitis.

J Allergy Clin Immunol. 2017 Sep;140(3):738-749.e3

Authors: Rochman M, Travers J, Miracle CE, Bedard MC, Wen T, Azouz NP, Caldwell JM, Kc K, Sherrill JD, Davis BP, Rymer JK, Kaufman KM, Aronow BJ, Rothenberg ME

Abstract
BACKGROUND: A key question in the allergy field is to understand how tissue-specific disease is manifested. Eosinophilic esophagitis (EoE) is an emerging tissue-specific allergic disease with an unclear pathogenesis.
OBJECTIVE: Herein we tested the hypothesis that a defect in tissue-specific esophageal genes is an integral part of EoE pathogenesis.
METHODS: We interrogated the pattern of expression of esophagus-specific signature genes derived from the Human Protein Atlas in the EoE transcriptome and in EPC2 esophageal epithelial cells. Western blotting and immunofluorescence were used for evaluating expression of esophageal proteins in biopsy specimens from control subjects and patients with active EoE. Whole-exome sequencing was performed to identify mutations in esophagus-specific genes.
RESULTS: We found that approximately 39% of the esophagus-specific transcripts were altered in patients with EoE, with approximately 90% being downregulated. The majority of transcriptional changes observed in esophagus-specific genes were reproduced in vitro in esophageal epithelial cells differentiated in the presence of IL-13. Functional enrichment analysis revealed keratinization and differentiation as the most affected biological processes and identified IL-1 cytokines and serine peptidase inhibitors as the most dysregulated esophagus-specific protein families in patients with EoE. Accordingly, biopsy specimens from patients with EoE evidenced a profound loss of tissue differentiation, decreased expression of keratin 4 (KRT4) and cornulin (CRNN), and increased expression of KRT5 and KRT14. Whole-exome sequencing of 33 unrelated patients with EoE revealed 39 rare mutations in 18 esophagus-specific differentially expressed genes.
CONCLUSIONS: A tissue-centered analysis has revealed a profound loss of esophageal tissue differentiation (identity) as an integral and specific part of the pathophysiology of EoE and implicated protease- and IL-1-related activities as putative central pathways in disease pathogenesis.

PMID: 28104354 [PubMed - indexed for MEDLINE]




Abnormal CD161(+) immune cells and retinoic acid receptor-related orphan receptor γt-mediate enhanced IL-17F expression in the setting of genetic hypertension.
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Abnormal CD161(+) immune cells and retinoic acid receptor-related orphan receptor γt-mediate enhanced IL-17F expression in the setting of genetic hypertension.

J Allergy Clin Immunol. 2017 Sep;140(3):809-821.e3

Authors: Singh MV, Cicha MZ, Kumar S, Meyerholz DK, Irani K, Chapleau MW, Abboud FM

Abstract
BACKGROUND: Hypertension is considered an immunologic disorder. However, the role of the IL-17 family in genetic hypertension in the spontaneously hypertensive rat (SHR) has not been investigated.
OBJECTIVE: We tested the hypothesis that enhanced TH17 programming and IL-17 expression in abundant CD161(+) immune cells in SHRs represent an abnormal proinflammatory adaptive immune response. Furthermore, we propose that this response is driven by the master regulator retinoic acid receptor-related orphan receptor γt (RORγt) and a nicotinic proinflammatory innate immune response.
METHODS: We measured expression of the CD161 surface marker on splenocytes in SHRs and normotensive control Wistar-Kyoto (WKY) rats from birth to adulthood. We compared expression of IL-17A and IL-17F in splenic cells under different conditions. We then determined the functional effect of these cytokines on vascular reactivity. Finally, we tested whether pharmacologic inhibition of RORγt can attenuate hypertension in SHRs.
RESULTS: SHRs exhibited an abnormally large population of CD161(+) cells at birth that increased with age, reaching more than 30% of the splenocyte population at 38 weeks. The SHR splenocytes constitutively expressed more RORγt than those of WKY rats and produced more IL-17F on induction. Exposure of WKY rat aortas to IL-17F impaired endothelium-dependent vascular relaxation, whereas IL-17A did not. Moreover, in vivo inhibition of RORγt by digoxin decreased systolic blood pressure in SHRs.
CONCLUSIONS: SHRs have a markedly enhanced potential for RORγt-driven expression of proinflammatory and prohypertensive IL-17F in response to innate immune activation. Increased RORγt and IL-17F levels contribute to SHR hypertension and might be therapeutic targets.

PMID: 28093217 [PubMed - indexed for MEDLINE]




Patterns of immune development in urban preschoolers with recurrent wheeze and/or atopy.
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Patterns of immune development in urban preschoolers with recurrent wheeze and/or atopy.

J Allergy Clin Immunol. 2017 Sep;140(3):836-844.e7

Authors: Gern JE, Calatroni A, Jaffee KF, Lynn H, Dresen A, Cruikshank WW, Lederman HM, Sampson HA, Shreffler W, Bacharier LB, Gergen PJ, Gold DR, Kattan M, O'Connor GT, Sandel MT, Wood RA, Bloomberg GR

Abstract
BACKGROUND: Disadvantaged urban children have high rates of allergic diseases and wheezing, which are diseases associated with type 2-biased immunity.
OBJECTIVE: We sought to determine whether environmental exposures in early life influence cytokine responses that affect the development of recurrent wheezing illnesses and allergic sensitization.
METHODS: A birth cohort of 560 urban families was recruited from neighborhoods with high rates of poverty, and 467 (83%) children were followed until 3 years of age. Cytokine responses were measured in blood cell samples obtained at birth (cord blood) and ages 1 and 3 years. Cytokine responses were examined in relation to personal characteristics and environmental exposures to allergens and endotoxin and to the development of allergic sensitization and recurrent wheeze assessed at age 3 years.
RESULTS: Cytokine responses generally increased with age, but responses at birth were poorly predictive for those at ages 1 and 3 years. Exposure to certain allergens (cockroach, mouse, dust mite) was significantly associated with enhanced cytokine responses at age 3 years, including IFN-α and IL-10 responses to certain stimulants and responses to phytohemagglutinin. Regarding the clinical outcomes, reduced LPS-induced IL-10 responses at birth were associated with recurrent wheeze. In contrast, reduced respiratory syncytial virus-induced IL-8 responses and increased 5'-cytosine-phosphate-guanine-3' (CpG)-induced IL-12p40 and allergen-induced IL-4 responses were associated with atopy.
CONCLUSIONS: These findings suggest that diverse biologic exposures, including allergens and endotoxin, in urban homes stimulate the development of cytokine responses in early life, and that cytokine responses to specific microbial and viral stimuli are associated with the development of allergic sensitization and recurrent wheeze.

PMID: 28089873 [PubMed - indexed for MEDLINE]




Identification of airway mucosal type 2 inflammation by using clinical biomarkers in asthmatic patients.
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Identification of airway mucosal type 2 inflammation by using clinical biomarkers in asthmatic patients.

J Allergy Clin Immunol. 2017 Sep;140(3):710-719

Authors: Silkoff PE, Laviolette M, Singh D, FitzGerald JM, Kelsen S, Backer V, Porsbjerg CM, Girodet PO, Berger P, Kline JN, Chupp G, Susulic VS, Barnathan ES, Baribaud F, Loza MJ, Airways Disease Endotyping for Personalized Therapeutics (ADEPT) study investigators

Abstract
BACKGROUND: The Airways Disease Endotyping for Personalized Therapeutics (ADEPT) study profiled patients with mild, moderate, and severe asthma and nonatopic healthy control subjects.
OBJECTIVE: We explored this data set to define type 2 inflammation based on airway mucosal IL-13-driven gene expression and how this related to clinically accessible biomarkers.
METHODS: IL-13-driven gene expression was evaluated in several human cell lines. We then defined type 2 status in 25 healthy subjects, 28 patients with mild asthma, 29 patients with moderate asthma, and 26 patients with severe asthma based on airway mucosal expression of (1) CCL26 (the most differentially expressed gene), (2) periostin, or (3) a multigene IL-13 in vitro signature (IVS). Clinically accessible biomarkers included fraction of exhaled nitric oxide (Feno) values, blood eosinophil (bEOS) counts, serum CCL26 expression, and serum CCL17 expression.
RESULTS: Expression of airway mucosal CCL26, periostin, and IL-13-IVS all facilitated segregation of subjects into type 2-high and type 2-low asthmatic groups, but in the ADEPT study population CCL26 expression was optimal. All subjects with high airway mucosal CCL26 expression and moderate-to-severe asthma had Feno values (≥35 ppb) and/or high bEOS counts (≥300 cells/mm(3)) compared with a minority (36%) of subjects with low airway mucosal CCL26 expression. A combination of Feno values, bEOS counts, and serum CCL17 and CCL26 expression had 100% positive predictive value and 87% negative predictive value for airway mucosal CCL26-high status. Clinical variables did not differ between subjects with type 2-high and type 2-low status. Eosinophilic inflammation was associated with but not limited to airway mucosal type 2 gene expression.
CONCLUSION: A panel of clinical biomarkers accurately classified type 2 status based on airway mucosal CCL26, periostin, or IL-13-IVS gene expression. Use of Feno values, bEOS counts, and serum marker levels (eg, CCL26 and CCL17) in combination might allow patient selection for novel type 2 therapeutics.

PMID: 28089872 [PubMed - indexed for MEDLINE]




Parents' childhood socioeconomic circumstances are associated with their children's asthma outcomes.
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Parents' childhood socioeconomic circumstances are associated with their children's asthma outcomes.

J Allergy Clin Immunol. 2017 Sep;140(3):828-835.e2

Authors: Chen E, Shalowitz MU, Story RE, Ehrlich KB, Manczak EM, Ham PJ, Le V, Miller GE

Abstract
BACKGROUND: Previous literature documents associations between low socioeconomic status (SES) and poor health outcomes, including asthma. However, this literature has largely focused on the effects of current family circumstances.
OBJECTIVE: We sought to test an intergenerational hypothesis, that the childhood SES that parents experience will be associated with asthma outcomes in their children, independent of effects of current family SES. Second, we aimed to test whether this association is in part due to difficulties in current parent-child relationships.
METHODS: This was an observational study, whereby 150 parents were interviewed about their childhood SES and their children (physician-diagnosed asthma, ages 9-17 years) were interviewed about current family stress. Asthma control was assessed by parent report and child report (primary outcome), and blood was collected from children to measure cytokine production relevant to asthma (secondary outcomes).
RESULTS: To the degree that parents had lower childhood SES, their offspring showed worse asthma outcomes across multiple indicators. This included lower asthma control scores (parent and child report, Ps < .05), and greater stimulated production of TH2 and TH1 cytokines by PBMCs (Ps < .05). These associations were independent of current family SES. Mediation analyses were consistent with a scenario wherein parents with low childhood SES had current family relationships that were more stressful, and these difficulties, in turn, related to worse asthma control and greater cytokine production in children.
CONCLUSIONS: These results suggest the potential "long reach" of low SES across generations, and the importance of expanding theories of how the social environment can affect childhood asthma to include characteristics of earlier generations.

PMID: 28089871 [PubMed - indexed for MEDLINE]




Diagnostic accuracy of fractional exhaled nitric oxide measurement in predicting cough-variant asthma and eosinophilic bronchitis in adults with chronic cough: A systematic review and meta-analysis.
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Diagnostic accuracy of fractional exhaled nitric oxide measurement in predicting cough-variant asthma and eosinophilic bronchitis in adults with chronic cough: A systematic review and meta-analysis.

J Allergy Clin Immunol. 2017 Sep;140(3):701-709

Authors: Song WJ, Kim HJ, Shim JS, Won HK, Kang SY, Sohn KH, Kim BK, Jo EJ, Kim MH, Kim SH, Park HW, Kim SS, Chang YS, Morice AH, Lee BJ, Cho SH

Abstract
BACKGROUND: Individual studies have suggested the utility of fractional exhaled nitric oxide (Feno) measurement in detecting cough-variant asthma (CVA) and eosinophilic bronchitis (EB) in patients with chronic cough.
OBJECTIVE: We sought to obtain summary estimates of diagnostic test accuracy of Feno measurement in predicting CVA, EB, or both in adults with chronic cough.
METHODS: Electronic databases were searched for studies published until January 2016, without language restriction. Cross-sectional studies that reported the diagnostic accuracy of Feno measurement for detecting CVA or EB were included. Risk of bias was assessed with Quality Assessment of Diagnostic Accuracy Studies 2. Random effects meta-analyses were performed to obtain summary estimates of the diagnostic accuracy of Feno measurement.
RESULTS: A total of 15 studies involving 2187 adults with chronic cough were identified. Feno measurement had a moderate diagnostic accuracy in predicting CVA in patients with chronic cough, showing the summary area under the curve to be 0.87 (95% CI, 0.83-0.89). Specificity was higher and more consistent than sensitivity (0.85 [95% CI, 0.81-0.88] and 0.72 [95% CI, 0.61-0.81], respectively). However, in the nonasthmatic population with chronic cough, the diagnostic accuracy to predict EB was found to be relatively lower (summary area under the curve, 0.81 [95% CI, 0.77-0.84]), and specificity was inconsistent.
CONCLUSIONS: The present meta-analyses indicated the diagnostic potential of Feno measurement as a rule-in test for detecting CVA in adult patients with chronic cough. However, Feno measurement may not be useful to predict EB in nonasthmatic subjects with chronic cough. These findings warrant further studies to validate the roles of Feno measurement in clinical practice of patients with chronic cough.

PMID: 28088474 [PubMed - indexed for MEDLINE]




Idiopathic systemic capillary leak syndrome (Clarkson disease).
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Idiopathic systemic capillary leak syndrome (Clarkson disease).

J Allergy Clin Immunol. 2017 Sep;140(3):663-670

Authors: Druey KM, Parikh SM

Abstract
In 1960, Dr Bayard Clarkson described a woman experiencing sporadic recurrent episodes of shock and anasarca. Plasma from an acute attack induced a shock-like syndrome when injected into rats. The enigmatic systemic capillary leak syndrome (SCLS) named for Dr Clarkson is characterized by transient and severe but reversible hemoconcentration and hypoalbuminemia caused by leakage of fluids and macromolecules into tissues. Although less than 500 cases of SCLS have been reported in the literature since 1960, the condition is probably underdiagnosed because of a lack of awareness and a high mortality without treatment. Allergists should be vigilant of this diagnosis because its presentation can resemble more common plasma leakage syndromes, including angioedema or systemic anaphylaxis. Although the precise molecular cause of SCLS remains unknown, substantial advances over the last 5 years have increased our understanding of SCLS pathogenesis.

PMID: 28012935 [PubMed - indexed for MEDLINE]




Sialylated Fetuin-A as a candidate predictive biomarker for successful grass pollen allergen immunotherapy.
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Sialylated Fetuin-A as a candidate predictive biomarker for successful grass pollen allergen immunotherapy.

J Allergy Clin Immunol. 2017 Sep;140(3):759-770.e13

Authors: Caillot N, Bouley J, Jain K, Mariano S, Luce S, Horiot S, Airouche S, Beuraud C, Beauvallet C, Devillier P, Chollet-Martin S, Kellenberger C, Mascarell L, Chabre H, Batard T, Nony E, Lombardi V, Baron-Bodo V, Moingeon P

Abstract
BACKGROUND: Eligibility to immunotherapy is based on the determination of IgE reactivity to a specific allergen by means of skin prick or in vitro testing. Biomarkers predicting the likelihood of clinical improvement during immunotherapy would significantly improve patient selection.
METHODS: Proteins were differentially assessed by using 2-dimensional differential gel electrophoresis and label-free mass spectrometry in pretreatment sera obtained from clinical responders and nonresponders within a cohort of 82 patients with grass pollen allergy receiving sublingual immunotherapy or placebo. Functional studies of Fetuin-A (FetA) were conducted by using gene silencing in a mouse asthma model, human dendritic cell in vitro stimulation assays, and surface plasmon resonance.
RESULTS: Analysis by using quantitative proteomics of pretreatment sera from patients with grass pollen allergy reveals that high levels of O-glycosylated sialylated FetA isoforms are found in patients exhibiting a strong decrease in rhinoconjunctivitis symptoms after sublingual immunotherapy. Although FetA is involved in numerous inflammatory conditions, its potential role in allergy is unknown. In vivo silencing of the FETUA gene in BALB/c mice results in a dramatic upregulation of airway hyperresponsiveness, lung resistance, and TH2 responses after allergic sensitization to ovalbumin. Both sialylated and nonsialytated FetA bind to LPS, but only the former synergizes with LPS and grass pollen or mite allergens to enhance the Toll-like receptor 4-mediated proallergic properties of human dendritic cells.
CONCLUSIONS: As a reflection of the patient's inflammatory status, pretreatment levels of sialylated FetA in the blood are indicative of the likelihood of clinical responses during grass pollen immunotherapy.

PMID: 27965111 [PubMed - indexed for MEDLINE]