Sustained Successful Peanut Oral Immunotherapy Associated with Low Basophil Activation and Peanut-Specific IgE Publication date: Available online 2 December 2019 Source: Journal of Allergy and Clinical Immunology Author(s): Mindy Tsai, Kaori Mukai, R. Sharon Chinthrajah, Kari C. Nadeau, Stephen J. Galli Abstract Background Oral immunotherapy (OIT) can successfully desensitize many peanut allergic subjects, but clinical tolerance diminishes over time upon discontinuation, or low dose maintenance, of peanut. Therefore, in order to improve the efficacy and sustainability of such therapy, we sought to identify biomarkers and clinical tools that can predict therapeutic outcomes and monitor treatment responses. Objective We evaluated whether basophil activation in whole blood, and plasma levels of peanut-specific immunoglobulins, are useful biomarkers for peanut OIT. Methods We longitudinally measured, before, during and after OIT, basophil activation in whole blood ex vivo in response to peanut stimulation, and peanut-specific IgE and IgG4, in a large, single-site, double-blind, randomized, placebo-controlled, phase 2 peanut OIT study. We compared basophil responsiveness and peanut specific immunoglobulins between those who were clinically reactive vs. tolerant to peanut oral challenges. Results Peanut OIT significantly decreased basophil activation, peanut-specific, Ara h 1, Ara h 2 and Ara h 3 IgEs, and sIgE/total IgE, but increased sIgG4/sIgE. Participants who became reactive to 4 g of peanut 13 weeks off active OIT exhibited higher peanut-induced basophil activation ex vivo and higher peanut-specific IgEs and sIgE/total IgE, but lower sIgG4/sIgE. Notably, participants entering the study with low basophil responsiveness were more likely to achieve treatment success. Substantial suppression of basophil activation was required to maintain long-term clinical tolerance after peanut OIT. Conclusion Assessments of peanut-specific basophil activation and peanut-specific immunoglobulins can help to predict treatment outcomes, and to differentiate transient desensitization vs. sustained unresponsiveness after OIT.

Germline gain-of-function mutation of STAT1 rescued by somatic mosaicism in immune dysregulation-polyendocrinopathy-enteropathy-X-linked-like disorder Publication date: Available online 2 December 2019 Source: Journal of Allergy and Clinical Immunology Author(s): Jeong Seok Lee, Yohan An, Christopher J. Yoon, Jeong Yeon Kim, Kyung Hwan Kim, Alexandra F. Freeman, Jae-Joon Yim, Eui-Cheol Shin, Steven M. Holland, Eun Young Lee, Young Seok Ju

IL-13 and IL-4, but not IL-5 nor IL-17A, induce hyperresponsiveness in isolated human small airways Publication date: Available online 2 December 2019 Source: Journal of Allergy and Clinical Immunology Author(s): Martijn L. Manson, Jesper Säfholm, Anna James, Anna-Karin Johnsson, Per Bergman, Mamdoh Al-Ameri, Ann-Charlotte Orre, Carina Kärrman Mårdh, Sven-Erik Dahlén, Mikael Adner Abstract Background Specific inflammatory pathways are indicated to contribute to severe asthma but their individual involvement in the development of airway hyperresponsiveness remains unexplored. Objective This experimental study in human small bronchi aimed to provide insight into which of the Type-2 and Type-17 cytokines cause hyperresponsiveness of airway smooth muscle. Methods Explanted small bronchi isolated from human lung tissue and human airway smooth muscle cells (HASMC) were treated for 2 and 1 day(s) respectively with 100ng/mL of IL-4, IL-5, IL-13 or IL-17A, and contractile responses, Ca2+-mobilization, and receptor expression were assessed. Results Treatment with IL-13 increased the potency of histamine, carbachol and leukotriene D4 as contractile agonists. IL-4, but not IL-5 or IL-17A, also increased the potency of histamine. In HASMC, IL-13 and IL-4, but not IL-5 and IL-17A, enhanced the histamine-induced Ca2+-mobilisation that was accompanied with increased mRNA expression of histamine H1 and CysLT1 receptors. RNA sequencing of isolated bronchi confirmed the IL-13-mediated up-regulation of H1 and CysLT1 receptors, without showing an alteration of muscarinic M3 receptors. Dexamethasone had no effects on IL-13-induced hyperresponsiveness in human bronchi, the increased Ca2+-mobilisation or the enhanced receptor expression. In contrast, antagonism of the common receptor for IL-13 and IL-4 by the biologic dupilumab, prevented the effects of both IL-13 and IL-4 in human bronchi and HASMC. Conclusion The glucocorticoid-insensitive hyperrresponsiveness in isolated human airways induced by IL-13 and IL-4 provides further evidence that the IL-4Rα pathway should be targeted as a new strategy for treatment of airway hyperresponsiveness in asthma. Graphical abstract

Upadacitinib in Adults With Moderate-to-Severe Atopic Dermatitis: 16-Week Results From a Randomized, Placebo-Controlled Trial Publication date: Available online 29 November 2019 Source: Journal of Allergy and Clinical Immunology Author(s): Emma Guttman-Yassky, Diamant Thaçi, Aileen L. Pangan, H. Chih-ho Hong, Kim A. Papp, Kristian Reich, Lisa A. Beck, Mohamed-Eslam F. Mohamed, Ahmed A. Othman, Jaclyn K. Anderson, Yihua Gu, Henrique D. Teixeira, Jonathan I. Silverberg Abstract Background Atopic dermatitis is a chronic inflammatory skin disease characterized by pruritic skin lesions. Objective This study evaluated the safety and efficacy of multiple doses of the selective Janus kinase 1 inhibitor upadacitinib in patients with moderate-to-severe atopic dermatitis. Methods In the 16-week, double-blind, placebo-controlled, parallel-group, dose-ranging portion of this 88-week trial in 8 countries (ClinicalTrials.gov, NCT02925117; ongoing, not recruiting), adults with moderate-to-severe disease and inadequate control by topical treatment were randomized 1:1:1:1, using an interactive response system and stratified geographically, to once-daily upadacitinib oral monotherapy 7.5, 15, or 30 mg or placebo. The primary endpoint was percentage improvement in Eczema Area and Severity Index from baseline at week 16. Efficacy was analyzed by intention-to-treat in all randomized patients. Safety was analyzed in all randomized patients who received study medication, based on actual treatment. Results Patients (N=167) enrolled from November 21, 2016, to April 20, 2017. All were randomized and analyzed for efficacy (each upadacitinib group, n=42; placebo, n=41); 166 were analyzed for safety (each upadacitinib group, n=42; placebo, n=40). The mean (standard error) primary efficacy endpoint was 39% (6.2%), 62% (6.1%), and 74% (6.1%) for the upadacitinib 7.5-, 15-, and 30-mg groups, respectively, versus 23% (6.4%) for placebo (P=0.03, <0.001, and <0.001). Serious adverse events occurred in 4.8% [2/42], 2.4% [1/42], 0% [0/42] of upadacitinib groups (vs 2.5% [1/40] for placebo). Conclusion A dose-response relationship was observed for upadacitinib efficacy; the 30-mg once-daily dose showed the greatest clinical benefit. Dose-limiting toxicity was not observed.

Sensitization of spinal itch transmission neurons in a mouse model of chronic itch requires an astrocytic factor Publication date: Available online 28 November 2019 Source: Journal of Allergy and Clinical Immunology Author(s): Keisuke Koga, Ryo Yamagata, Keita Kohno, Takuya Yamane, Miho Shiratori-Hayashi, Yuta Kohro, Hidetoshi Tozaki-Saitoh, Makoto Tsuda Background Chronic itch is a highly debilitating symptom among patients with inflammatory skin diseases. Recent studies have revealed that gastrin-releasing peptide (GRP) and its receptor (gastrin-releasing peptide receptor [GRPR]) in the spinal dorsal horn (SDH) play a central role in itch transmission. Objective We aimed to investigate whether GRP-GRPR signaling is altered in SDH neurons in a mouse model of chronic itch and to determine the potential mechanisms underlying these alterations. Methods Patch-clamp recordings from enhanced green fluorescent protein (EGFP)–expressing (GRPR+) SDH neurons were used to examine GRP-GRPR signaling in spinal cord slices obtained from Grpr-EGFP mice. Immunohistochemical, genetic (gene expression and editing through adeno-associated virus vectors), and behavioral approaches were also used for in vivo experiments. Results We observed potentiation of GRP-evoked excitation in the GRPR+ SDH neurons of mice with contact dermatitis, without concomitant changes in GRPR expression. Interestingly, increases in excitation were attenuated by suppressing the reactive state of SDH astrocytes, which are known to be reactive in patients with chronic itch conditions. Furthermore, CRISPR-Cas9–mediated astrocyte-selective in vivo editing of a gene encoding lipocalin-2 (LCN2), an astrocytic factor implicated in chronic itch, suppressed increases in GRP-induced excitation of GRPR+ neurons, repetitive scratching, and skin damage in mice with contact dermatitis. Moreover, LCN2 potentiated GRP-induced excitation of GRPR+ neurons in normal mice. Conclusion Our findings indicate that, under chronic itch conditions, the GRP-induced excitability of GRPR+ SDH neurons is enhanced through a non–cell-autonomous mechanism involving LCN2 derived from reactive astrocytes. Graphical abstract

Delivery of Allergen Powder for Safe and Effective Epicutaneous Immunotherapy Publication date: Available online 27 November 2019 Source: Journal of Allergy and Clinical Immunology Author(s): Yang Yu, Mudnakudu Nagaraju Kiran Kumar, Mei X. Wu Abstract Background More effective and safer immunotherapies to manage peanut allergy are in great demand despite extensive investigation of sublingual/oral (SLIT/OIT) and epicutaneous (EPIT) immunotherapies currently in the clinics. Objective To develop a powder-laden, dissolvable microneedle array (PLD-MNA) for epidermic delivery of powdered allergens and to evaluate efficacy of this novel EPIT in peanut-sensitized mice. Methods PLD-MNA was packaged with a mixture of powdered peanut allergen (PNA), vitamin-D3 (VD3), and CpG. Its epidermic delivery and therapeutic efficacy were evaluated, alongside PNA-specific Foxp3+T regulatory (Treg) cells and IL-10+ and TGF-β1+ skin-resident macrophages. Results PLD-MNA was successfully laden with PNA/VD3/CpG powder and capable to epidermically deliver most of its content one hour after applied onto intact mouse skin, concomitant with no significant leakage into the circulation or skin irritation. PLD-MNA-mediated EPIT substantially reduced clinical allergy scores to 1, from 3.5 in sham controls (p<0.001) after six treatments, accompanied with lower levels of PNA-specific IgE and intestinal mucosal mast cells and eosinophils over sham treatments. Moreover, in comparison with allergens intradermally administered, powdered allergens delivered by PLD-MNA preferentially attracted immunoregulatory macrophages and stimulated the cells to produce IL-10 and/or TGF-β at the immunization site, which may account for increased numbers of Treg-like cells in lymph tissues in association with systemic tolerance. PNA/VD3/CpG-laden PLD-MNA was safe and required only six treatments and one fifth of the PNA-adjuvant dose with improved outcomes, when compared to twelve conventional intradermal immunotherapies. Conclusions PLD-MNA holds great promise as a novel, safe, effective, and self-applicable modality to manage IgE-mediated allergies. Graphical abstract

Skin barrier damage after exposure to para-phenylenediamine Publication date: Available online 26 November 2019 Source: Journal of Allergy and Clinical Immunology Author(s): Sanne S. Meisser, Can Altunbulakli, Josefine Bandier, Morten S. Opstrup, Francesc Castro-Giner, Mübeccel Akdis, Charlotte M. Bonefeld, Jeanne D. Johansen, Cezmi A. Akdis Abstract Background p-Phenylenediamine (PPD) is a strong contact allergen used in hair dye known to cause allergic contact dermatitis (ACD). Both private and occupational exposure to PPD is frequent, but the effect of PPD exposure in non-allergic occupational exposed individuals is unknown. Objective To investigate effects of PPD exposure on the skin of occupationally exposed individuals with and without clinical symptoms. Methods Skin biopsies were collected from 4 mild and 5 severe PPD ACD patients and 7 hairdressers without contact dermatitis on day 4 after patch testing with 1% PPD in vaseline. RNA-sequencing and transcriptomics analyses were performed and confirmed by qRT-PCR. Protein expression was analyzed in skin from 4 hairdressers and 1 ACD patient with immunofluorescence staining. Reconstructed human epidermis was used to test the effects of PPD in vitro. Results RNA-sequencing demonstrated down-regulation of tight junction (TJ) and stratum corneum (SC) proteins in skin of severe ACD patients after PPD exposure. Claudin-1 (CLDN1), claudin-8 (CLDN8), claudin-11 (CLDN11), CLMP, occludin, MAGI1, and MAGI2 expression were downregulated in severe ACD patients. CLDN1 and CLMP expression were downregulated in non-responding hairdressers and mild ACD patients. Filaggrin-1(FLG1), filaggrin-2 (FLG2) and loricrin expression were downregulated in ACD individuals. Confocal microscopy images showed down regulation of claudin-1 and filaggrin 1 and 2. In contrast, 3D skin cultures showed up-regulation of filaggrin-1 in response to PPD but down-regulation of filaggrin-2. Conclusion PPD-exposed skin is associated with extensive transcriptomic changes including down-regulation of TJ and SC proteins even in the absence of clinical symptoms. Graphical abstract

PSMB10, the last immunoproteasome gene missing for PRAAS Publication date: Available online 26 November 2019 Source: Journal of Allergy and Clinical Immunology Author(s): Guillaume Sarrabay, Déborah Méchin, Aicha Salhi, Guilaine Boursier, Cécile Rittore, Yanick Crow, Gillian Rice, Tu-Anh Tran, Renaud Cezar, Darragh Duffy, Vincent Bondet, Lakhdar Boudhane, Chistophe Broca, Benjamin P. Kant, Mariëlle VanGijn, Sylvie Grandemange, Eric Richard, Florence Apparailly, Isabelle Touitou

Defining the biological responses of IL-6 by the study of a novel IL-6 receptor chain (IL6R) immunodeficiency Publication date: Available online 26 November 2019 Source: Journal of Allergy and Clinical Immunology Author(s): Amit Nahum, Nigel Sharfe, Arnon Broides, Harjit Dadi, Zahra Naghdi, Amarilla B. Mandola, Linda Vong, Adi Arbiv, Ilan Dalal, Jacov Levy, Ido Brami, Ohad Wormser, Chaim M. Roifman

Omalizumab safety in pregnancy Publication date: Available online 26 November 2019 Source: Journal of Allergy and Clinical Immunology Author(s): Francesca Levi-Schaffer, David Mankuta