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pubmed: 0091-6749



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Enhancement of cutaneous immunity during ageing by blocking p38 MAPkinase induced inflammation.

Enhancement of cutaneous immunity during ageing by blocking p38 MAPkinase induced inflammation.

J Allergy Clin Immunol. 2017 Nov 16;:

Authors: Vukmanovic-Stejic M, Chambers ES, Farinas MS, Sandhu D, Fuentes-Duculan J, Patel N, Agius E, Lacy KE, Turner CT, Larbi A, Birault V, Noursadeghi M, Mabbott NA, Rustin MHA, Krueger J, Akbar AN

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

PMID: 29155150 [PubMed - as supplied by publisher]




Drug hypersensitivity: we need to do more.

Drug hypersensitivity: we need to do more.

J Allergy Clin Immunol. 2017 Nov 16;:

Authors: Pichler WJ, Yerly D

PMID: 29155149 [PubMed - as supplied by publisher]




RASGRP1 mutation in autoimmune lymphoproliferative syndrome-like disease.

RASGRP1 mutation in autoimmune lymphoproliferative syndrome-like disease.

J Allergy Clin Immunol. 2017 Nov 15;:

Authors: Mao H, Yang W, Latour S, Yang J, Winter S, Zheng J, Ni K, Lv M, Liu C, Huang H, Chan KW, Pui-Wah Lee P, Tu W, Fischer A, Lau YL

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

PMID: 29155103 [PubMed - as supplied by publisher]




Targeting of Rac1 prevents bronchoconstriction and airway hyperresponsiveness.

Targeting of Rac1 prevents bronchoconstriction and airway hyperresponsiveness.

J Allergy Clin Immunol. 2017 Nov 15;:

Authors: André-Grégoire G, Dilasser F, Chesné J, Braza F, Magnan A, Loirand G, Sauzeau V

Abstract
BACKGROUND: The molecular mechanisms responsible for airway smooth muscle cells (aSMC) contraction and proliferation in airway hyperresponsiveness (AHR) associated with asthma are still largely unknown. The small GTPases of the Rho family (RhoA, Rac1 and Cdc42) play a central role in SMC functions including migration, proliferation and contraction.
OBJECTIVE: The objective of this study is to identify the role of Rac1 in aSMC contraction and to investigate its involvement in AHR associated with allergic asthma.
METHODS: To define the role of Rac1 in aSMC, ex- and in vitro analyses of bronchial reactivity were performed on bronchi from smooth muscle (SM)-specific Rac1 knockout mice (SM-Rac1-KO) and human individuals. In addition, this murine model was exposed to allergens (ovalbumin or house dust mite extract) to decipher in vivo the implication of Rac1 in AHR.
RESULTS: The specific SMC deletion or pharmacological inhibition of Rac1 in mice prevented the bronchoconstrictor response to methacholine. In human bronchi a similar role of Rac1 was observed during bronchoconstriction. We further demonstrated that Rac1 activation is responsible for bronchoconstrictor-induced increase in intracellular Ca(2+) concentration and contraction both in murine and human bronchial aSMC, through its association with phospholipase C β2 and the stimulation of inositol 1,4,5-trisphosphate production. In vivo, Rac1 deletion in SMC or pharmacological Rac1 inhibition by nebulization of NSC23766 prevented AHR in murine models of allergic asthma. Moreover, nebulization of NSC23766 decreased eosinophil and neutrophil populations in bronchoalveolar lavages from asthmatic mice.
CONCLUSION: Our data reveal an unexpected and essential role of Rac1 in the regulation of intracellular Ca(2+) and contraction of aSMC, and the development of AHR. Rac1 thus appears as an attractive therapeutic target in asthma, with a combined beneficial action on both bronchoconstriction and pulmonary inflammation.

PMID: 29155102 [PubMed - as supplied by publisher]




Type I IFN related NETosis in Ataxia Telangiectasia and Artemis deficiency.

Type I IFN related NETosis in Ataxia Telangiectasia and Artemis deficiency.

J Allergy Clin Immunol. 2017 Nov 15;:

Authors: Gul E, Sayar EH, Gungor B, Eroglu FK, Surucu N, Keles S, Guner SN, Fındık S, Alpdündar E, Ayanoglu IC, Kayaoglu B, Geçkin BN, Sanli HA, Kahraman T, Yakicier C, Muftuoglu M, Oguz B, Cagdas Ayvaz DN, Gursel I, Ozen S, Reisli I, Gursel M

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

PMID: 29155101 [PubMed - as supplied by publisher]




Defects in plasma cell differentiation is associated with primary immunodeficiency in humans.

Defects in plasma cell differentiation is associated with primary immunodeficiency in humans.

J Allergy Clin Immunol. 2017 Nov 15;:

Authors: Pan-Hammarström Q, Abolhassani H, Hammarström L

PMID: 29155100 [PubMed - as supplied by publisher]




Novel Therapies For Alopecia Areata: The Era Of Rational Drug Development.

Novel Therapies For Alopecia Areata: The Era Of Rational Drug Development.

J Allergy Clin Immunol. 2017 Nov 15;:

Authors: Wang ECE, Dai Z, Christiano AM

Abstract
The treatments for Alopecia Areata (AA) have evolved over the decades from broad and non-specific therapies, to those that are now more targeted and rationally selected. This was achieved by close co-operation and communication between clinicians and basic scientists, which resulted in the elucidation and understanding of the unique pathophysiology of AA. In this review, we discuss this evolution, and how novel therapies for AA has changed over the decades, what we have in our current arsenal of drugs for this potentially devastating disease, and what the future holds.

PMID: 29155099 [PubMed - as supplied by publisher]




ORAI1 mutations abolishing store-operated Ca(2+) entry cause anhidrotic ectodermal dysplasia with immunodeficiency (EDA-ID).

ORAI1 mutations abolishing store-operated Ca(2+) entry cause anhidrotic ectodermal dysplasia with immunodeficiency (EDA-ID).

J Allergy Clin Immunol. 2017 Nov 15;:

Authors: Lian J, Cuk M, Kahlfuss S, Kozhaya L, Vaeth M, Rieux-Laucat F, Picard C, Benson MJ, Jakovcevic A, Bilic K, Martinac I, Stathopulos P, Kacskovics I, Vraetz T, Speckmann C, Ehl S, Issekutz T, Unutmaz D, Feske S

Abstract
BACKGROUND: Store-operated Ca(2+) entry (SOCE) through Ca(2+) release-activated Ca(2+) (CRAC) channels is an essential signaling pathway in many cell types. CRAC channels are formed by ORAI1, ORAI2 and ORAI3 proteins and activated by stromal interaction molecule 1 (STIM1) and STIM2. Mutations in ORAI1 and STIM1 genes that abolish SOCE cause a combined immunodeficiency (CID) syndrome that is accompanied by autoimmunity and non-immunological symptoms.
OBJECTIVE: Molecular and immunological analysis of patients with CID, anhidrosis and ectodermal dysplasia of unknown etiology.
METHODS: DNA sequencing of ORAI1 gene, modeling of mutations on ORAI1 crystal structure, analysis of ORAI1 mRNA and protein expression, measurements of SOCE, immunological analysis of peripheral blood lymphocyte populations by flow cytometry, histological and ultrastructural analysis of patient tissues.
RESULTS: We identified 3 novel autosomal recessive mutations in ORAI1 in unrelated kindreds with CID, autoimmunity, ectodermal dysplasia with anhidrosis (EDA) and muscular dysplasia. The patients were homozygous for p.V181SfsX8, p.L194P and p.G98R mutations in the ORAI1 gene that suppressed ORAI1 protein expression and SOCE in the patients' lymphocytes and fibroblasts. Besides impaired T cell cytokine production, ORAI1 mutations were associated with strongly reduced numbers of invariant natural killer (iNKT) and regulatory T (Treg) cells, and altered composition of γδ T cell and NK cell subsets.
CONCLUSION: ORAI1 null mutations are associated with reduced numbers of iNKT and Treg cells that likely contribute to the patients' immunodeficiency and autoimmunity. ORAI1 deficient patients suffer from dental enamel defects and anhidrosis representing a new form of anhidrotic ectodermal dysplasia with immunodeficiency (EDA-ID) that is distinct from previously reported patients with EDA-ID due to mutations in the NF-kB signaling pathway (IKBKG and NFKBIA).

PMID: 29155098 [PubMed - as supplied by publisher]




14-3-3z sequesters cytosolic T-bet, up-regulating IL-13 in Tc2 and scleroderma CD8+ lymphocytes.

14-3-3z sequesters cytosolic T-bet, up-regulating IL-13 in Tc2 and scleroderma CD8+ lymphocytes.

J Allergy Clin Immunol. 2017 Nov 15;:

Authors: Cascio S, Medsger TA, Hawse WF, Watkins SC, Milcarek C, Moreland LW, Lafyatis RA, Fuschiotti P

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

PMID: 29155097 [PubMed - as supplied by publisher]




Patients with atopic dermatitis and history of eczema herpeticum elicit HSV-specific type 2 immune responses.

Patients with atopic dermatitis and history of eczema herpeticum elicit HSV-specific type 2 immune responses.

J Allergy Clin Immunol. 2017 Nov 15;:

Authors: Traidl S, Kienlin P, Begemann G, Jing L, Koelle DM, Werfel T, Roesner LM

Abstract
An increased type 2 and in parallel decreased type 1 T cell immune response to herpes simplex virus 1 may lead to the clinical phenotype of eczema herpeticum.

PMID: 29155096 [PubMed - as supplied by publisher]




Early life innate immune signatures of persistent food allergy.

Early life innate immune signatures of persistent food allergy.

J Allergy Clin Immunol. 2017 Nov 14;:

Authors: Neeland MR, Koplin JJ, Dang TD, Dharmage SC, Tang ML, Prescott SL, Saffery R, Martino DJ, Allen KJ

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

PMID: 29154959 [PubMed - as supplied by publisher]




Pathogenic Th17 inflammation is sustained in the lungs by conventional dendritic cells and TLR4 signaling.

Pathogenic Th17 inflammation is sustained in the lungs by conventional dendritic cells and TLR4 signaling.

J Allergy Clin Immunol. 2017 Nov 14;:

Authors: Shalaby KH, Lyons-Cohen MR, Whitehead GS, Thomas SY, Prinz I, Nakano H, Cook DN

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

PMID: 29154958 [PubMed - as supplied by publisher]




Predicting the atopic march: Results from the Canadian Healthy Infant Longitudinal Development Study.

Predicting the atopic march: Results from the Canadian Healthy Infant Longitudinal Development Study.

J Allergy Clin Immunol. 2017 Nov 01;:

Authors: Tran MM, Lefebvre DL, Dharma C, Dai D, Lou WYW, Subbarao P, Becker AB, Mandhane PJ, Turvey SE, Sears MR, Canadian Healthy Infant Longitudinal Development Study investigators

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

PMID: 29153857 [PubMed - as supplied by publisher]




Could Substance P be an antiviral mediator and potential therapeutic target in the nose?
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Could Substance P be an antiviral mediator and potential therapeutic target in the nose?

J Allergy Clin Immunol. 2017 Nov 13;:

Authors: Kulka M

PMID: 29146273 [PubMed - as supplied by publisher]




Obstruction phenotype as a predictor of asthma severity and instability in children.
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Obstruction phenotype as a predictor of asthma severity and instability in children.

J Allergy Clin Immunol. 2017 Nov 13;:

Authors: Sorkness RL, Zoratti EM, Kattan M, Gergen PJ, Evans MD, Visness CM, Gill M, Khurana Hershey GK, Kercsmar CM, Liu AH, O'Connor GT, Pongracic JA, Pillai D, Sorkness CA, Togias A, Wood RA, Busse WW

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

PMID: 29146272 [PubMed - as supplied by publisher]




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J Allergy Clin Immunol. 2017 Nov 14;:

Authors: Palmer DJ, Prescott SL, Makrides M

PMID: 29146011 [PubMed - as supplied by publisher]




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J Allergy Clin Immunol. 2017 Nov 14;:

Authors: Bellach J, Beyer K

PMID: 29146010 [PubMed - as supplied by publisher]




Timing of regular egg intake for prevention of egg allergy.
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Timing of regular egg intake for prevention of egg allergy.

J Allergy Clin Immunol. 2017 Nov 14;:

Authors: Jiang WH, Deng L, Ye QJ, Cai JR, Cai XR, Li X

PMID: 29146009 [PubMed - as supplied by publisher]




Autoinflammatory phenotypes in Aicardi-Goutières syndrome with interferon upregulation and serological autoimmune features.
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Autoinflammatory phenotypes in Aicardi-Goutières syndrome with interferon upregulation and serological autoimmune features.

J Allergy Clin Immunol. 2017 Nov 10;:

Authors: Sugawara Y, Imai K, Kashimada A, Moriyama K, Baba S, Nishikomori R, Motegi M, Takeuchi Y, Morio T

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

PMID: 29132962 [PubMed - as supplied by publisher]




Title: Experimental Asthma Persists in IL33 Receptor Knockout Mice Due to the Emergence of a TSLP-driven IL9+ and IL13+ ILC2 subpopulations.
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Title: Experimental Asthma Persists in IL33 Receptor Knockout Mice Due to the Emergence of a TSLP-driven IL9+ and IL13+ ILC2 subpopulations.

J Allergy Clin Immunol. 2017 Nov 10;:

Authors: Verma M, Liu S, Michalec L, Sripada A, Gorska MM, Alam R

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

PMID: 29132961 [PubMed - as supplied by publisher]




Influenza-derived peptides cross-react with allergens and provide asthma protection.
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Influenza-derived peptides cross-react with allergens and provide asthma protection.

J Allergy Clin Immunol. 2017 Nov 10;:

Authors: Skevaki C, Hudemann C, Matrosovich M, Möbs C, Paul S, Wachtendorf A, Alhamwe BA, Potaczek DP, Hagner S, Gemsa D, Garn H, Sette A, Renz H

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

PMID: 29132960 [PubMed - as supplied by publisher]




Breastfeeding and risk of asthma, hay fever and eczema.
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Breastfeeding and risk of asthma, hay fever and eczema.

J Allergy Clin Immunol. 2017 Nov 10;:

Authors: Weronica E E, Torgny K, Carlos AH, Mathias RA, Åsa J

PMID: 29132959 [PubMed - as supplied by publisher]




Transforming growth factor-β1 decreases epithelial tight junction integrity in chronic rhinosinusitis with nasal polyps.
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Transforming growth factor-β1 decreases epithelial tight junction integrity in chronic rhinosinusitis with nasal polyps.

J Allergy Clin Immunol. 2017 Nov 10;:

Authors: Jiao J, Wang M, Duan S, Meng Y, Meng N, Li Y, Fan E, Akdis C, Zhang L

PMID: 29132958 [PubMed - as supplied by publisher]




Allergy terminology: towards a common language and shared understanding.
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Allergy terminology: towards a common language and shared understanding.

J Allergy Clin Immunol. 2017 Nov 10;:

Authors: Levin M

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

PMID: 29132957 [PubMed - as supplied by publisher]




The XTEND-CIU study: long term use of Omalizumab in Chronic Idiopathic Urticaria.
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The XTEND-CIU study: long term use of Omalizumab in Chronic Idiopathic Urticaria.

J Allergy Clin Immunol. 2017 Nov 10;:

Authors: Maurer M, Kaplan A, Rosén K, Holden M, Iqbal A, Trzaskoma BL, Yang M, Casale TB

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

PMID: 29132956 [PubMed - as supplied by publisher]




Identification of atopic dermatitis subgroups in children from two longitudinal birth cohorts.
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Identification of atopic dermatitis subgroups in children from two longitudinal birth cohorts.

J Allergy Clin Immunol. 2017 Nov 09;:

Authors: Paternoster L, Savenije OEM, Heron J, Evans DM, Vonk JM, Brunekreef B, Wijga AH, Henderson AJ, Koppelman GH, Brown SJ

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

PMID: 29129583 [PubMed - as supplied by publisher]




Ventilation Defect Percent in Helium-3 MRI as a Biomarker of Severe Outcomes in Asthma.
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Ventilation Defect Percent in Helium-3 MRI as a Biomarker of Severe Outcomes in Asthma.

J Allergy Clin Immunol. 2017 Nov 09;:

Authors: Mummy DG, Kruger SJ, Zha W, Sorkness RL, Jarjour NN, Schiebler ML, Denlinger LC, Evans MD, Fain SB

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

PMID: 29129582 [PubMed - as supplied by publisher]




EoE genetic susceptibility is mediated by synergistic interactions between EoE-specific and general atopic disease loci.
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EoE genetic susceptibility is mediated by synergistic interactions between EoE-specific and general atopic disease loci.

J Allergy Clin Immunol. 2017 Nov 09;:

Authors: Martin LJ, He H, Collins MH, Abonia JP, Biagini Myers JM, Eby M, Johansson HE, Kottyan LC, Khurana Hershey GK, Rothenberg ME

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

PMID: 29129581 [PubMed - as supplied by publisher]




The β and α2δ auxiliary subunits of Cav1 channels are required for Th2-lymphocyte function and acute allergic airway inflammation.
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The β and α2δ auxiliary subunits of Cav1 channels are required for Th2-lymphocyte function and acute allergic airway inflammation.

J Allergy Clin Immunol. 2017 Nov 09;:

Authors: Rosa N, Triffaux E, Robert V, Mars M, Klein M, Bouchaud G, Canivet A, Magnan A, Guéry JC, Pelletier L, Savignac M

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

PMID: 29129580 [PubMed - as supplied by publisher]




Staged development of long lived TCRαβ Th17 resident memory T cell population to Candida albicans after skin infection.
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Staged development of long lived TCRαβ Th17 resident memory T cell population to Candida albicans after skin infection.

J Allergy Clin Immunol. 2017 Nov 08;:

Authors: Park CO, Fu X, Jiang X, Pan Y, Teague JE, Collins N, Tian T, O'Malley JT, Emerson RO, Kim JH, Jung Y, Watanabe R, Fuhlbrigge RC, Carbone FR, Gebhardt T, Clark RA, Lin CP, Kupper TS

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

PMID: 29128674 [PubMed - as supplied by publisher]




Bi-allelic IRF8 mutation: a complex immunodeficiency syndrome with dendritic cell deficiency, monocytopenia and immune dysregulation.
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Bi-allelic IRF8 mutation: a complex immunodeficiency syndrome with dendritic cell deficiency, monocytopenia and immune dysregulation.

J Allergy Clin Immunol. 2017 Nov 08;:

Authors: Bigley V, Maisuria S, Cytlak U, Jardine L, Care MA, Green K, Gunawan M, Milne P, Dickinson R, Wiscombe S, Parry D, Doffinger R, Laurence A, Lic CF, Stoevesandt O, Gennery A, Cant A, Tooze R, Simpson AJ, Hambleton S, Savic S, Doody G, Collin M

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

PMID: 29128673 [PubMed - as supplied by publisher]




Long term immune reconstitution after matched unrelated hematopoietic stem cell transplantation for immunodeficiency.
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Long term immune reconstitution after matched unrelated hematopoietic stem cell transplantation for immunodeficiency.

J Allergy Clin Immunol. 2017 Nov 08;:

Authors: Kim VH, Reid B, Atkinson A, Upton J, Grunebaum E, Roifman CM

PMID: 29128672 [PubMed - as supplied by publisher]




Identification of dominant anti-glycan IgE responses in school-children by glycan microarray.
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Identification of dominant anti-glycan IgE responses in school-children by glycan microarray.

J Allergy Clin Immunol. 2017 Nov 08;:

Authors: Amoah AS, Asuming-Brempong EK, Obeng BB, Versteeg SA, Larbi IA, Aryeetey Y, Platts-Mills TAE, Mari A, Brzezicka K, Gyan BA, Mutocheluh M, Boakye DA, Reichardt NC, van Ree R, Hokke CH, van Diepen A, Yazdanbakhsh M

PMID: 29128671 [PubMed - as supplied by publisher]




Synchronous Immune Alterations Mirror Clinical Response During Allergen Immunotherapy.
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Synchronous Immune Alterations Mirror Clinical Response During Allergen Immunotherapy.

J Allergy Clin Immunol. 2017 Nov 08;:

Authors: Renand A, Shamji MH, Harris KM, Qin T, Wambre E, Scadding GW, Wurtzen PA, Till SJ, Togias A, Nepom GT, Kwok WW, Durham SR

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

PMID: 29128670 [PubMed - as supplied by publisher]




Corticosteroid treatment is associated with increased filamentous fungal burden in allergic fungal disease.
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Corticosteroid treatment is associated with increased filamentous fungal burden in allergic fungal disease.

J Allergy Clin Immunol. 2017 Nov 06;:

Authors: Fraczek MG, Chishimba L, Niven RM, Bromley M, Simpson A, Smyth L, Denning DW, Bowyer P

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

PMID: 29122659 [PubMed - as supplied by publisher]




Human plasma C3 is essential for the development of memory B, but not T, lymphocytes.
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Human plasma C3 is essential for the development of memory B, but not T, lymphocytes.

J Allergy Clin Immunol. 2017 Nov 04;:

Authors: Jiménez-Reinoso A, Marin AV, Subias M, López-Lera A, Román-Ortiz E, Payne K, Ma CS, Arbore G, Kolev M, Freeley SJ, Kemper C, Tangye SG, Fernández-Malavé E, Rodríguez de Córdoba S, López-Trascasa M, Regueiro JR

Abstract
Primary or secondary plasma C3 deficiency due to mutations in C3 or in complement Factor I impairs memory B, but not T, cell differentiation, but does not preclude intracellular C3 fragment expression in lymphocytes.

PMID: 29113906 [PubMed - as supplied by publisher]




TRIM21 negatively regulates intestinal mucosal inflammation through inhibiting Th1/Th17 cell differentiation in inflammatory bowel diseases.
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TRIM21 negatively regulates intestinal mucosal inflammation through inhibiting Th1/Th17 cell differentiation in inflammatory bowel diseases.

J Allergy Clin Immunol. 2017 Nov 04;:

Authors: Zhou G, Wu W, Yu L, Yu T, Yang W, Wang P, Zhang X, Cong Y, Liu Z

Abstract
BACKGROUND: Tripartite motif-containing (TRIM)21 has been implicated in pathogenesis of several types of autoimmune diseases.
OBJECTIVE: We sought to elucidate expression of TRIM21 in patients with inflammatory bowel disease (IBD) and its role in regulating intestinal mucosal inflammation.
METHODS: TRIM21 expression was analyzed in inflamed mucosa of IBD patients by qRT-PCR and immunohistochemistry. Peripheral blood CD4(+) T cells were transfected with lentivirus-expressing-TRIM21 (LV-TRIM21) or LV-sh-TRIM21, and cytokine expression was determined by qRT-PCR and ELISA. TRIM21(-/-) mice were generated, and trinitrobenzene sulphonic acid (TNBS)- and CD45RB(high)CD4(+) T cell-induced colitis models were established to determine its role in the induction of intestinal inflammation.
RESULTS: TRIM21 was predominantly expressed in CD4(+) T cells and markedly decreased in inflamed mucosa of IBD patients compared with healthy controls. Ectopic expression of TRIM21 inhibited IBD CD4(+) T cells to differentiate into T helper (Th)1 and Th17 cells, whereas downregulation of TRIM21 had opposite effects. TRIM21(-/-) mice developed more severe colitis following administration of TNBS compared with wild-type mice, characterized by increased expression of IFN-γ, TNF-α, and IL-17A in the colon. TRIM21(-/-) CD45RB(high)CD4(+) T cells reconstituted into Rag-1(-/-) mice induced more severe colitis than wild-type controls. Mechanistically, IRF3 was identified as a functional downstream target of TRIM21, in that silencing of IRF3 suppressed TRIM21(-/-)CD4(+) T cell differentiation into Th1 and Th17 cells.
CONCLUSIONS: TRIM21 plays a protective role in mucosal inflammation through inhibiting Th1 and Th17 cell differentiation. Thus, TRIM21 may serve as a potential therapeutic target for treatment of IBD.

PMID: 29113905 [PubMed - as supplied by publisher]




Home freezers kill house dust mites.
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Home freezers kill house dust mites.

J Allergy Clin Immunol. 2017 Oct 27;:

Authors: Feichtner CR, Arlian LG, Morgan MS, Vyszenski-Moher DL

PMID: 29111219 [PubMed - as supplied by publisher]




The Notch Pathway Inhibitor SAHM1 Abrogates the Hallmarks of Allergic Asthma.
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The Notch Pathway Inhibitor SAHM1 Abrogates the Hallmarks of Allergic Asthma.

J Allergy Clin Immunol. 2017 Oct 27;:

Authors: KleinJan A, Tindemans I, Montgomery JE, Lukkes M, de Bruijn MJW, van Nimwegen M, Bergen I, Moellering RE, Hoogsteden HC, Boon L, Amsen D, Hendriks RW

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

PMID: 29111218 [PubMed - as supplied by publisher]




Ruxolitinib partially reverses functional NK cell deficiency in patients with STAT1 gain-of-function mutations.
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Ruxolitinib partially reverses functional NK cell deficiency in patients with STAT1 gain-of-function mutations.

J Allergy Clin Immunol. 2017 Oct 27;:

Authors: Vargas-Hernandez A, Mace EM, Zimmerman O, Zerbe CS, Freeman AF, Rosenzweig S, Leiding JW, Torgerson T, Altman MC, Schussler E, Cunningham-Rundles C, Chinn IK, Carisey AF, Hanson IC, Rider NL, Holland SM, Orange JS, Forbes LR

Abstract
BACKGROUND: Natural Killer (NK) cells are critical innate effector cells whose development is dependent on the JAK-STAT pathway. NK deficiency can result in severe or refractory viral infections. Patients with Signal Transducer and Activator of Transcription (STAT)1 gain of function (GOF) mutations have increased viral susceptibility.
OBJECTIVE: We sought to investigate NK cell function in STAT1 GOF patients.
METHODS: NK cell phenotype and function were determined in 16 STAT1 GOF patients. NK cell lines expressing patient mutations were generated with CRISPR-Cas9 mediated gene editing. STAT1 GOF NK cells were treated in vitro with ruxolitinib.
RESULTS: Peripheral blood NK cells from of STAT1 GOF patients had impaired terminal maturation. Specifically, patients with STAT1 GOF mutations have immature CD56(dim) NK cells with decreased expression of CD16, perforin, CD57 and impaired cytolytic function. STAT1 phosphorylation was elevated but STAT5 was aberrantly phosphorylated in response to IL-2 stimulation. Upstream inhibition of STAT signaling with the small molecule JAK1/2 inhibitor ruxolitinib in vitro and in vivo restored perforin expression in CD56(dim) NK cells and partially restored NK cell cytotoxic function.
CONCLUSIONS: Properly regulated STAT1 signaling is critical for NK cell maturation and function. Modulation of elevated STAT1 phosphorylation with ruxolitinib is an important option for therapeutic intervention in patients with STAT1 GOF mutations.

PMID: 29111217 [PubMed - as supplied by publisher]




Cat ownership, cat allergen exposure, and trajectories of sensitization and asthma throughout childhood.
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Cat ownership, cat allergen exposure, and trajectories of sensitization and asthma throughout childhood.

J Allergy Clin Immunol. 2017 Oct 27;:

Authors: Ihuoma H, Belgrave DC, Murray CS, Foden P, Simpson A, Custovic A

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

PMID: 29111216 [PubMed - as supplied by publisher]




Methotrexate versus azathioprine in patients with atopic dermatitis: two years follow-up data.
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Methotrexate versus azathioprine in patients with atopic dermatitis: two years follow-up data.

J Allergy Clin Immunol. 2017 Oct 27;:

Authors: Roekevisch E, Schram ME, Geertruida Leeflang MM, Dorothée Brouwer MW, Andrea Gerbens LA, Bos JD, Spuls PI

PMID: 29111215 [PubMed - as supplied by publisher]




Association of Rhinovirus Species with Common Cold and Asthma Symptoms and Bacterial Pathogens.
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Association of Rhinovirus Species with Common Cold and Asthma Symptoms and Bacterial Pathogens.

J Allergy Clin Immunol. 2017 Oct 27;:

Authors: Bashir H, Grindle K, Vrtis R, Vang F, Kang T, Salazar L, Anderson E, Pappas T, Gangnon R, Evans MD, Jackson DJ, Lemanske RF, Bochkov YA, Gern JE

PMID: 29111214 [PubMed - as supplied by publisher]




Prenatal and Early Life Triclosan and Parabens Exposure and Allergic Outcomes.
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Prenatal and Early Life Triclosan and Parabens Exposure and Allergic Outcomes.

J Allergy Clin Immunol. 2017 Oct 27;:

Authors: Lee-Sarwar K, Hauser R, Calafat AM, Ye X, O'Connor GT, Sandel M, Bacharier LB, Zeiger RS, Laranjo N, Gold DR, Weiss ST, Litonjua AA, Savage JH

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

PMID: 29111213 [PubMed - as supplied by publisher]




MCPIP1 controls allergic airway inflammation by suppressing IL-5-producing Th2 cells through Notch/Gata3 pathway.
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MCPIP1 controls allergic airway inflammation by suppressing IL-5-producing Th2 cells through Notch/Gata3 pathway.

J Allergy Clin Immunol. 2017 Oct 27;:

Authors: Peng H, Ning H, Wang Q, Lu W, Chang Y, Wang TT, Lai J, Kolattukudy PE, Hou R, Hoft DF, Dykewicz MS, Liu J

Abstract
BACKGROUND: Asthmatic and allergic inflammation is mediated by Th2 cytokines (IL-4, IL-5 and IL-13). Though we have learned much about how Th2 cells are differentiated, the Th2 checkpoint mechanisms remain elusive.
OBJECTIVES: In this study, we investigate how monocyte chemotactic protein induced protein-1 (MCPIP1, encoded by zc3h12a gene) regulates IL-5-producing Th2 cell differentiation and Th2-mediated inflammation.
METHODS: The functions of zc3h12a(-/-) CD4 T cells were evaluated by checking the expression of Th2 cytokines and transcription factors in vivo and in vitro. Allergic airway inflammation of zc3h12a(-/-) mice was examined with murine asthma models. In addition, antigen-specific CD4 T cells deficient in MCPIP1 were transferred to WT recipient mice, challenged with OVA or HDM, and accessed for Th2 inflammation.
RESULTS: Zc3h12a(-/-) mice spontaneously develop severe lung inflammation, with an increase mainly in IL-5- and IL-13-producing but not IL-4-producing Th2 cells in the lung. Mechanistically, the differentiation of IL-5-producing zc3h12a(-/-) Th2 cells is mediated through Notch signaling and Gata3 independent of IL-4. Gata3 mRNA is stabilized in zc3h12a(-/-) Th2 cells. MCPIP1 promotes Gata3 mRNA decay via the RNase domain. Furthermore, deletion of MCPIP1 in OVA- or HDM-specific T cells leads to significantly increased Th2-mediated airway inflammation in OVA or HDM murine models of asthma.
CONCLUSIONS: Our study reveals that MCPIP1 regulates the development and functions of IL-5-producing Th2 cells through Notch/Gata3 pathway. MCPIP1 represents a new promising target for the treatments of asthma and other Th2-mediated diseases.

PMID: 29111212 [PubMed - as supplied by publisher]




Interleukin-1/inhibitory kappa B kinase epsilon-induced glycolysis augment epithelial effector function and promote allergic airways disease.
Related Articles Interleukin-1/inhibitory kappa B kinase epsilon-induced glycolysis augment epithelial effector function and promote allergic airways disease. J Allergy Clin Immunol. 2017 Nov 03;: Authors: Qian X, Aboushousha R, van de Wetering C, Chia SB, Amiel E, Schneider RW, van der Velden JL, Lahue KG, Hoagland DA, Casey DT, Daphtary N, Ather JL, Randall MJ, Aliyeva M, Black KE, Chapman DG, Lundblad LKA, McMillan DH, Dixon AE, Anathy V, Irvin CG, Poynter ME, Wouters EFM, Vacek PM, Henket M, Schleich F, Louis R, van der Vliet A, Janssen-Heininger YMW Abstract BACKGROUND: Emerging studies suggest that enhanced glycolysis accompanies inflammatory responses. Virtually nothing is known about the relevance of glycolysis in allergic asthma. OBJECTIVES: Here we sought to determine if glycolysis is altered in allergic asthma and to address its importance in the pathogenesis of allergic asthma. METHODS: We examined alterations in glycolysis in sputum samples from asthmatics and primary human nasal cells, and used murine models of allergic asthma as well as primary mouse tracheal epithelial cells to evaluate the relevance of glycolysis. RESULTS: In a murine model of allergic asthma, glycolysis was induced in the lungs in an IL-1-dependent manner. Furthermore, administration of IL-1β into airways stimulated lactate production and expression of glycolytic enzymes, with notable expression of lactate dehydrogenase A occurring in the airway epithelium. Indeed, exposure of mouse tracheal epithelial cells to IL-1β or IL-1α resulted in increased glycolytic flux, glucose usage, expression of glycolysis genes, and lactate production. Enhanced glycolysis was required for IL-1β- or IL-1α-mediated pro-inflammatory responses and the stimulatory effects of IL-1β on HDM-induced release of TSLP, and GM-CSF from tracheal epithelial cells. Inhibitor of κB kinase ε was downstream of house dust mite (HDM) or IL-1β, and was required for HDM-induced glycolysis and the pathogenesis of allergic airways disease. SiRNA-ablation of lactate dehydrogenase A attenuated HDM-induced increases in lactate and attenuated HDM-induced disease. Primary nasal epithelial cells from asthmatics intrinsically produced more lactate as compared to cells from healthy subjects. Lactate content was significantly higher in sputum supernatants from asthmatics, notably those patients with >61% neutrophils. A positively correlation was observed between sputum lactate and IL-1β, and lactate content negatively correlated with lung function. CONCLUSIONS: Collectively, these findings demonstrate that IL-1β/IKKε signaling plays an important role in HDM-induced glycolysis and the pathogenesis of allergic airways disease. PMID: 29108965 [PubMed - as supplied by publisher] [...]



Global issues in allergy and immunology: Parasitic infections and allergy.
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Global issues in allergy and immunology: Parasitic infections and allergy.

J Allergy Clin Immunol. 2017 Nov;140(5):1217-1228

Authors: Cruz AA, Cooper PJ, Figueiredo CA, Alcantara-Neves NM, Rodrigues LC, Barreto ML

Abstract
Allergic diseases are on the increase globally in parallel with a decrease in parasitic infection. The inverse association between parasitic infections and allergy at an ecological level suggests a causal association. Studies in human subjects have generated a large knowledge base on the complexity of the interrelationship between parasitic infection and allergy. There is evidence for causal links, but the data from animal models are the most compelling: despite the strong type 2 immune responses they induce, helminth infections can suppress allergy through regulatory pathways. Conversely, many helminths can cause allergic-type inflammation, including symptoms of "classical" allergic disease. From an evolutionary perspective, subjects with an effective immune response against helminths can be more susceptible to allergy. This narrative review aims to inform readers of the most relevant up-to-date evidence on the relationship between parasites and allergy. Experiments in animal models have demonstrated the potential benefits of helminth infection or administration of helminth-derived molecules on chronic inflammatory diseases, but thus far, clinical trials in human subjects have not demonstrated unequivocal clinical benefits. Nevertheless, there is sufficiently strong evidence to support continued investigation of the potential benefits of helminth-derived therapies for the prevention or treatment of allergic and other inflammatory diseases.

PMID: 29108604 [PubMed - in process]




Anti-apoptotic Serine Protease Inhibitors contribute towards the survival of allergenic Th2 cells.
Related Articles Anti-apoptotic Serine Protease Inhibitors contribute towards the survival of allergenic Th2 cells. J Allergy Clin Immunol. 2017 Oct 26;: Authors: Shamji MH, Temblay JN, Cheng W, Byrne SM, Macfarlane E, Switzer AR, Francisco NDC, Olexandra F, Jacubczik F, Durham SR, Ashton-Rickardt PG Abstract BACKGROUND: The mechanisms regulating the maintenance of persistent Th2 cells that potentiate allergic inflammation are not well understood. OBJECTIVE: The function of Serine Protease Inhibitor 2A (Spi2A) was studied in mouse Th2 cells and Serine Protease Inhibitor (SERPIN) B3 and B4 genes were studied in Th2 cells from grass pollen allergic individuals. METHODS: Spi2A deficient Th2 cells were studied in vitro culture or in vivo after challenge of Spi2A Knock-Out (KO) mice with ovalbumin in alum. The expression of SERPIN B3 and B4 mRNA was measured in vitro cultured Th2 cell and in ex vivo CD27(-)CD4(+) and ICL2 cells from grass pollen allergic individuals using quantitative PCR. SERPIN B3 and B4 mRNA levels were knocked down in cultured CD27(-)CD4(+) cells with shRNA. RESULTS: There were lower levels of in vitro polarized Th2 cells from Spi2A KO mice (P<0.005) and in vivo after OVA challenge (P<0.05), higher levels of apoptosis (annexin V positivity P<0.005) and less lung allergic inflammation (number of lung eosinophils P<0.005). In vitro polarized Th2 cells from grass pollen allergic individuals expressed higher levels of both SERPIN B3 and B4 (both P<0.05) mRNA compared to un- polarized CD4 T cells. CD27(-)CD4(+) from grass pollen allergic individuals expressed higher levels of both SERPIN B3 and B4 (both P<0.0005) mRNA compared to CD27(+)CD4(+) cells. ICL2 cells expressed higher levels of both SERPIN B3 and B4 (both P<0.0005) mRNA compared to ICL1 cells. Knock-down of either SERPIN B3 or B4 (both P <0.005) mRNA levels resulted in decreased viability of CD27(-)CD4(+) compared to control transduced cells. CONCLUSION: The serpins Spi2A in mice and Serpin B3 and B4 in allergic individuals, control viability of Th2 cells. This provides proof-of-principle for a therapeutic approach for allergic disease through the ablation of allergic memory Th2 cells through mRNA SERPIN B3 and B4 down-regulation. PMID: 29106998 [PubMed - as supplied by publisher] [...]



Interferon response to RSV by bronchial epithelium from children with asthma is inversely correlated with pulmonary function.
Related Articles Interferon response to RSV by bronchial epithelium from children with asthma is inversely correlated with pulmonary function. J Allergy Clin Immunol. 2017 Oct 26;: Authors: Altman MC, Reeves SR, Parker AR, Whalen E, Misura KMS, Barrow KA, James RG, Hallstrand TS, Ziegler SF, Debley JS Abstract BACKGROUND: Respiratory viral infection in early childhood, including that from respiratory syncytial virus (RSV), has been previously associated with the development of asthma. OBJECTIVE: We aimed to determine whether ex vivo RSV infection of bronchial epithelial cells (BECs) from children with asthma would induce specific gene expression patterns, and whether such patterns associate with lung function among BEC donors. METHODS: Primary BECs from carefully characterized children with asthma (n=18) and matched healthy children without asthma (n=8) were differentiated at an air-liquid interface (ALI) for 21 days. ALI cultures were infected with RSV for 96 hours and RNA was subsequently isolated from BECs. In each case, we analyzed gene expression using RNA sequencing and assessed differences between conditions by linear modeling of the data. BEC donors completed spirometry to measure lung function. RESULTS: RSV infection of BECs from subjects with asthma led to a significant increase in expression of 6927 genes compared to uninfected BECs. There was a significantly increased expression of 195 genes in BECs from children with asthma and airway obstruction (FEV1/FVC<0.85 and FEV1<100% predicted) compared to children with asthma without obstruction, as well as compared to healthy children. These specific genes were found to be highly enriched for viral response genes induced in parallel with type I and III IFNs. CONCLUSION: BECs from children with asthma and with obstructive physiology exhibit greater expression of type I and type III IFN and IFN-stimulated genes than cells from children with normal lung function, and expression of IFN-associated genes correlates with the degree of airway obstruction. These findings suggest that an exaggerated IFN response to viral infection by airway epithelial cells may be a mechanism leading to lung function decline in a subset of children with asthma. PMID: 29106997 [PubMed - as supplied by publisher] [...]



Chronic Rhinosinusitis: Endotypes, Biomarkers and Treatment Response.
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Chronic Rhinosinusitis: Endotypes, Biomarkers and Treatment Response.

J Allergy Clin Immunol. 2017 Oct 26;:

Authors: Gurrola J, Borish L

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

PMID: 29106996 [PubMed - as supplied by publisher]




Inhibition of ABCC4 potentiates combination beta agonist and glucocorticoid responses in human airway epithelial cells.
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Inhibition of ABCC4 potentiates combination beta agonist and glucocorticoid responses in human airway epithelial cells.

J Allergy Clin Immunol. 2017 Nov 02;:

Authors: Huff RD, Rider CF, Yan D, Newton R, Giembycz MA, Carlsten C, Hirota JA

Abstract
ABCC4 inhibition potentiates cAMP signaling and the effect of glucocorticoids at the genomic and functional level, with implications for future asthma management.

PMID: 29103996 [PubMed - as supplied by publisher]




Ectopic Lymphoid Tissues Support Local Immunoglobulin Production in Chronic Rhinosinusitis with Nasal Polyps.
Related Articles Ectopic Lymphoid Tissues Support Local Immunoglobulin Production in Chronic Rhinosinusitis with Nasal Polyps. J Allergy Clin Immunol. 2017 Nov 02;: Authors: Song J, Wang H, Zhang YN, Cao PP, Liao B, Wang ZZ, Shi LL, Yao Y, Zhai GT, Wang ZC, Liu LM, Zeng M, Lu X, Wang H, Yang XP, Yu D, Bachert C, Liu Z Abstract BACKGROUND: The contribution of ectopic lymphoid tissues (eLTs) to local immunoglobulin (Ig) hyperproduction in chronic rhinosinusitis with nasal polyps (CRSwNP) is unclear. OBJECTIVE: We sought to explore the cellular basis, formation mechanisms, and function of eLTs in CRSwNP. METHODS: We graded lymphoid aggregations in sinonasal mucosa and histologically studied their structures. The expression of lymphorganogenic factors and molecules required for Ig production was measured using real-time PCR and their localization was analyzed by immunohistochemistry and immunofluorescence. The phenotype of T follicular helper (TFH) cells was analyzed by performing flow cytometry. Ig levels were quantified by using Bio-Plex assay or ImmunoCAP system. Nasal tissue explants were challenged ex vivo with Dermatophagoides pteronyssinus group 1 (Der p1), and the expression of Iε-Cμ and Iε-Cγ circle transcripts was detected using semi-nested PCR. RESULTS: Increased formation of eLTs with germinal center-like structures was discovered in eosinophilic (20.69%) and non-eosinophilic CRSwNP (17.31%) compared to chronic rhinosinusitis without nasal polyps (5.66%) and controls (3.70%). The presence of eLTs was associated with increased expression of lymphorganogenic and inflammatory chemokines and cytokines, as well as their receptors. The expression of molecules required for Ig production, the generation of TFH cells, and the production of IgE in eosinophilic polyps and IgG and IgA in both eosinophilic and non-eosinophilic polyps were predominantly up-regulated in cases with eLTs. After the challenge of Der p1 ex vivo, Iε-Cμ transcript was only detected in eosinophilic polyps with eLTs but not in those without eLTs and non-eosinophilic polyps. CONCLUSION: eLTs may support local Ig production and therefore significantly contribute to the development of CRSwNP. PMID: 29103995 [PubMed - as supplied by publisher] [...]



Sputum cell interleukin-1 receptor expression level is a marker of airway neutrophilia and airflow obstruction in asthma.
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Sputum cell interleukin-1 receptor expression level is a marker of airway neutrophilia and airflow obstruction in asthma.

J Allergy Clin Immunol. 2017 Nov 02;:

Authors: Evans MD, Esnault S, Denlinger LC, Jarjour NN

Abstract
BACKGROUND: Various clinical, biologic or physiologic markers of asthma have been used to identify patient clusters and potential targets for therapy. However, these identifiers frequently overlap among the different asthma groups. For instance, both eosinophils and neutrophils are often increased in the airway of asthma patients despite their typical association with type-2 and type-17 immune response, respectively.
OBJECTIVES: To determine whether inflammatory gene expressions are related to patterns of airway inflammation and lung function, and identify molecular markers for neutrophilic asthma.
METHODS: Expression levels of 17 genes characterizing type-1, type-2 and type-17 lymphocytes were measured in sputum samples from 48 participants with asthma. The relationships between gene expression levels and sputum cell differentials or measures of pulmonary function were examined using partial least squares regression.
RESULTS: Gene expression levels were strongly associated with cell differentials, explaining 71% of variation in eosinophil counts and 64% of variation in neutrophil counts. The three genes with the strongest relationships to sputum neutrophils were IL1R1 (standardized regression coefficient β=+0.27, p=0.005), IL1RAP (β=+0.32, p=0.0004), and IL4R (β=+0.29, p=0.002). Higher expression levels of IL1R1, IL1RAP, and IL4R were associated with reduced FEV1/FVC (β=-0.11, -0.08, -0.10; p=0.005, 0.07, 0.05).
CONCLUSION: IL-1 receptor appears to be a marker of neutrophilic inflammation and airflow obstruction in patients with asthma that have a wide range of disease severity. The IL-1 pathway may contribute to airway neutrophilia, and is a potential therapeutic target in neutrophilic asthma.

PMID: 29103994 [PubMed - as supplied by publisher]




Role of TWIK-related potassium channel-1 (TREK-1) in chronic rhinosinusitis.
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Role of TWIK-related potassium channel-1 (TREK-1) in chronic rhinosinusitis.

J Allergy Clin Immunol. 2017 Nov 02;:

Authors: Kim HK, Kim JH, Kim HJ, Kim TH, Lee SH

Abstract
TREK-1 constitutively expressed in normal sinus mucosa is down-regulated in inflammatory sinus mucosa where it may be involved in defective epithelial and endothelial barrier integrity. These results suggest that TREK-1 activating compounds may be used therapeutically to maintain the epithelial and endothelial barrier integrity in chronic rhinosinusitis.

PMID: 29103993 [PubMed - as supplied by publisher]




CD8(+)CD28(-)CD127(lo)CD39(+) regulatory T-cell expansion: A new possible pathogenic mechanism for HIV infection?
Related Articles CD8(+)CD28(-)CD127(lo)CD39(+) regulatory T-cell expansion: A new possible pathogenic mechanism for HIV infection? J Allergy Clin Immunol. 2017 Oct 28;: Authors: Fenoglio D, Dentone C, Signori A, Di Biagio A, Parodi A, Kalli F, Nasi G, Curto M, Cenderello G, De Leo P, Bartolacci V, Orofino G, Nicolini LA, Taramasso L, Fiorillo E, Orrù V, Traverso P, Bruzzone B, Ivaldi F, Mantia E, Guerra M, Negrini S, Giacomini M, Bhagani S, Filaci G Abstract BACKGROUND: HIV-associated immunodeficiency is related to loss of CD4(+) T cells. This mechanism does not explain certain manifestations of HIV disease, such as immunodeficiency events in patients with greater than 500 CD4(+) T cells/μL. CD8(+)CD28(-)CD127(lo)CD39(+) T cells are regulatory T (Treg) lymphocytes that are highly concentrated within the tumor microenvironment and never analyzed in the circulation of HIV-infected patients. OBJECTIVES: We sought to analyze the frequency of CD8(+)CD28(-)CD127(lo)CD39(+) Treg cells in the circulation of HIV-infected patients. METHODS: The frequency of circulating CD8(+)CD28(-)CD127(lo)CD39(+) Treg cells was analyzed and correlated with viral load and CD4(+) T-cell counts/percentages in 93 HIV-1-infected patients subdivided as follows: naive (n = 63), elite controllers (n = 19), long-term nonprogressors (n = 7), and HIV-infected patients affected by tumor (n = 4). The same analyses were performed in HIV-negative patients with cancer (n = 53), hepatitis C virus-infected patients (n = 17), and healthy donors (n = 173). RESULTS: HIV-infected patients had increased circulating levels of functional CD8(+)CD28(-)CD127(lo)CD39(+) Treg cells. These cells showed antigen specificity against HIV proteins. Their frequency after antiretroviral therapy (ART) correlated with HIV viremia, CD4(+) T-cell counts, and immune activation markers, suggesting their pathogenic involvement in AIDS- or non-AIDS-related complications. Their increase after initiation of ART heralded a lack of virologic or clinical response, and hence their monitoring is clinically relevant. CONCLUSION: HIV infection induces remarkable expansion of CD8(+)CD28(-)CD127(lo)CD39(+) Treg cells, the frequency of which correlates with both clinical disease and signs of chronic immune cell activation. Monitoring their frequency in the circulation is a new marker of response to ART when effects on viremia and clinical response are not met. PMID: 29103633 [PubMed - as supplied by publisher] [...]



Reply.
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Reply.

J Allergy Clin Immunol. 2017 Oct 25;:

Authors: Kolkhir P, Church MK, Weller K, Metz M, Schmetzer O, Maurer M

PMID: 29102069 [PubMed - as supplied by publisher]




Autoimmune chronic spontaneous urticaria.
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Autoimmune chronic spontaneous urticaria.

J Allergy Clin Immunol. 2017 Oct 25;:

Authors: Grattan C

PMID: 29102068 [PubMed - as supplied by publisher]




Cat exposure in early life decreases asthma risk from the 17q21 high-risk variant.
Related Articles Cat exposure in early life decreases asthma risk from the 17q21 high-risk variant. J Allergy Clin Immunol. 2017 Oct 14;: Authors: Stokholm J, Chawes BL, Vissing N, Bønnelykke K, Bisgaard H Abstract BACKGROUND: Early-life exposure to cats and dogs has shown diverging associations with childhood asthma risk, and gene-environment interaction is one possible explanation. OBJECTIVES: We investigated interactions between cat and dog exposure and single nucleotide polymorphism rs7216389 variants in the chromosome 17q21 locus, the strongest known genetic risk factor for childhood asthma. METHODS: Genotyping was performed in 377 children from the at-risk Copenhagen Prospective Studies on Asthma in Childhood2000. The primary end point was the development of asthma until age 12 years. The secondary end point was the number of episodes with pneumonia and bronchiolitis from 0 to 3 years of age. Exposures included cat and dog ownership from birth and cat and dog allergen levels in bedding at age 1 year. Replication was performed in the unselected COPSAC2010 cohort with follow-up until 5 years of age. RESULTS: Cat and/or dog exposure from birth was associated with a lower prevalence of asthma among children with the rs7216389 high-risk TT genotype (adjusted hazard ratio, 0.16; 95% CI, 0.04-0.71; P = .015), with no effect in those with the CC/CT genotype (adjusted P = .283), demonstrating interaction between cat and dog exposure and the rs7216389 genotype (adjusted P = .044). Cat allergen levels were inversely associated with asthma development in children with the TT genotype (adjusted hazard ratio, 0.83; 95% CI, 0.71-0.97; P = .022), supporting the cat-rs7216389 genotype interaction (adjusted P = .008). Dog allergen exposure did not show such interaction. Furthermore, the TT genotype was associated with higher risk of pneumonia and bronchiolitis, and this increased risk was likewise decreased in children exposed to cat. Replication showed similar effects on asthma risk. CONCLUSION: The observed gene-environment interaction suggests a role of early-life exposure, especially to cat, for attenuating the risk of childhood asthma, pneumonia, and bronchiolitis in genetically susceptible subjects. PMID: 29102067 [PubMed - as supplied by publisher] [...]



The allergen-specificity of early peanut consumption and the impact on the development of allergic disease in the LEAP Study Cohort.
Related Articles The allergen-specificity of early peanut consumption and the impact on the development of allergic disease in the LEAP Study Cohort. J Allergy Clin Immunol. 2017 Oct 30;: Authors: du Toit G, Sayre PH, Roberts G, Lawson K, Sever ML, Bahnson HT, Fisher HR, Feeney M, Radulovic S, Basting M, Plaut M, Lack G, Immune Tolerance Network LEAP Study Team Abstract BACKGROUND: Early introduction of dietary peanut in high-risk infants with severe eczema and/or egg allergy prevented peanut allergy at 5 years of age in the LEAP Study; the protective effect persisted after 12 months of avoiding peanuts in the LEAP-On Study. It is unclear whether this benefit is allergen and allergic-disease specific. OBJECTIVE: To assess the impact of early introduction of peanut on the development of allergic disease, food sensitization and aeroallergen sensitization. METHODS: Asthma, eczema and rhinoconjunctivitis were diagnosed by clinical assessment. Reported allergic reactions and consumption of tree nuts and sesame were recorded by questionnaire. Sensitization to food and aeroallergens was determined by skin prick testing and specific IgE measurement. RESULTS: A high and increasing burden of food and aeroallergen sensitization and allergic disease was noted across study time points; 76% of LEAP participants had at least one allergic disease at 60 months of age. There were no differences in allergic disease between LEAP groups. There were small differences in sensitization and reported allergic reactions for select tree nuts; levels were higher in the LEAP consumption group. Significant resolution of eczema and sensitization to egg and milk occurred in LEAP participants; this was not affected by peanut consumption. CONCLUSION: Early consumption of peanut in infants at high risk of peanut allergy is allergen-specific and does not prevent the development of other allergic disease, sensitization to other foods and aeroallergens, or reported allergic reactions to tree nuts and sesame. Furthermore, peanut consumption does not hasten the resolution of eczema or egg allergy. PMID: 29097103 [PubMed - as supplied by publisher] [...]



Advances in Environmental and Occupational Disorders 2016.
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Advances in Environmental and Occupational Disorders 2016.

J Allergy Clin Immunol. 2017 Oct 25;:

Authors: Sheehan WJ, Gaffin JM, Peden DB, Bush RK, Phipatanakul W

Abstract
In this review, we highlight recent studies that advance the knowledge and understanding of the effects of various environmental factors and the associated immune responses in patients with allergic diseases. This review will focus on new literature regarding allergic and immune responses to a variety of environmental factors including aeroallergens, stinging insects, fungi, pollutants, viral respiratory infections, climate change, and microbial exposures.

PMID: 29080787 [PubMed - as supplied by publisher]