House dust mites activate nociceptor-mast cell clusters to drive type 2 skin inflammation. Nature immunology Allergic skin diseases, such as atopic dermatitis, are clinically characterized by severe itching and type 2 immunity-associated hypersensitivity to widely distributed allergens, including those derived from house dust mites (HDMs). Here we found that HDMs with cysteine protease activity directly activated peptidergic nociceptors, which are neuropeptide-producing nociceptive sensory neurons that express the ion channel TRPV1 and Tac1, the gene encoding the precursor for the neuropeptide substance P. Intravital imaging and genetic approaches indicated that HDM-activated nociceptors drive the development of allergic skin inflammation by inducing the degranulation of mast cells contiguous to such nociceptors, through the release of substance P and the activation of the cationic molecule receptor MRGPRB2 on mast cells. These data indicate that, after exposure to HDM allergens, activation of TRPV1Tac1 nociceptor-MRGPRB2 mast cell sensory clusters represents a key early event in the development of allergic skin reactions. 10.1038/s41590-019-0493-z

Skin barrier damage after exposure to paraphenylenediamine. Meisser Sanne S,Altunbulakli Can,Bandier Josefine,Opstrup Morten S,Castro-Giner Francesc,Akdis Mübeccel,Bonefeld Charlotte M,Johansen Jeanne D,Akdis Cezmi A The Journal of allergy and clinical immunology BACKGROUND:p-Phenylenediamine (PPD) is a strong contact allergen used in hair dye that is known to cause allergic contact dermatitis (ACD). Both private and occupational exposure to PPD is frequent, but the effect of PPD exposure in nonallergic occupationally exposed subjects is unknown. OBJECTIVE:We sought to investigate the effects of PPD exposure on the skin of occupationally exposed subjects with and without clinical symptoms. METHODS:Skin biopsy specimens were collected from 4 patients with mild and 5 patients with severe PPD-related ACD and 7 hairdressers without contact dermatitis on day 4 after patch testing with 1% PPD in petrolatum. RNA sequencing and transcriptomics analyses were performed and confirmed by using quantitative RT-PCR. Protein expression was analyzed in skin from 4 hairdressers and 1 patient with ACD by using immunofluorescence staining. Reconstructed human epidermis was used to test the effects of PPD in vitro. RESULTS:RNA sequencing demonstrated downregulation of tight junction and stratum corneum proteins in the skin of patients with severe ACD after PPD exposure. Claudin-1 (CLDN-1), CLDN8, CLDN11, CXADR-like membrane protein (CLMP), occludin (OCLN), membrane-associated guanylate kinase inverted 1 (MAGI1), and MAGI2 mRNA expression was downregulated in patients with severe ACD. CLDN1 and CLMP expression were downregulated in nonresponding hairdressers and patients with mild ACD. Filaggrin 1 (FLG1), FLG2, and loricrin (LOR) expression were downregulated in patients with ACD. Confocal microscopic images showed downregulation of CLDN-1, FLG-1, and FLG-2 expression. In contrast, 3-dimensional skin cultures showed upregulation of FLG-1 in response to PPD but downregulation of FLG-2. CONCLUSION:PPD-exposed skin is associated with extensive transcriptomic changes, including downregulation of tight junction and stratum corneum proteins, even in the absence of clinical symptoms. 10.1016/j.jaci.2019.11.023

The nonlesional skin surface distinguishes atopic dermatitis with food allergy as a unique endotype. Leung Donald Y M,Calatroni Agustin,Zaramela Livia S,LeBeau Petra K,Dyjack Nathan,Brar Kanwaljit,David Gloria,Johnson Keli,Leung Susan,Ramirez-Gama Marco,Liang Bo,Rios Cydney,Montgomery Michael T,Richers Brittany N,Hall Clifton F,Norquest Kathryn A,Jung John,Bronova Irina,Kreimer Simion,Talbot C Conover,Crumrine Debra,Cole Robert N,Elias Peter,Zengler Karsten,Seibold Max A,Berdyshev Evgeny,Goleva Elena Science translational medicine Skin barrier dysfunction has been reported in both atopic dermatitis (AD) and food allergy (FA). However, only one-third of patients with AD have FA. The purpose of this study was to use a minimally invasive skin tape strip sampling method and a multiomics approach to determine whether children with AD and FA (AD +) have stratum corneum (SC) abnormalities that distinguish them from AD without FA (AD -) and nonatopic (NA) controls. Transepidermal water loss was found to be increased in AD +. Filaggrin and the proportion of ω-hydroxy fatty acid sphingosine ceramide content in nonlesional skin of children with AD + were substantially lower than in AD - and NA skin. These abnormalities correlated with morphologic changes in epidermal lamellar bilayer architecture responsible for barrier homeostasis. Shotgun metagenomic studies revealed that the nonlesional skin of AD + had increased abundance of compared to NA. Increased expression of keratins 5, 14, and 16 indicative of hyperproliferative keratinocytes was observed in the SC of AD +. The skin transcriptome of AD + had increased gene expression for dendritic cells and type 2 immune pathways. A network analysis revealed keratins 5, 14, and 16 were positively correlated with AD +, whereas filaggrin breakdown products were negatively correlated with AD +. These data suggest that the most superficial compartment of nonlesional skin in AD + has unique properties associated with an immature skin barrier and type 2 immune activation. 10.1126/scitranslmed.aav2685

The skin as an immune organ: Tolerance versus effector responses and applications to food allergy and hypersensitivity reactions. Guttman-Yassky Emma,Zhou Lisa,Krueger James G The Journal of allergy and clinical immunology Skin is replete with immunocompetent cells that modulate signaling pathways to maintain a salubrious immunogenic/tolerogenic balance. This fertile immune environment plays a significant role in the development of allergic responses and sensitivities, but the mechanisms underlying these pathways have been underappreciated and underused with respect to developing therapeutics. Among the complex repertoire of cells that promote tolerogenic pathways in the periphery, 2 key classes include dendritic cells and regulatory T (Treg) cells. Immature dendritic cells are the first line of defense, patrolling the periphery, sampling antigens, and secreting cytokines that suppress immune cells and promote the survival of Treg cells. Skin-homing Treg cells also play a critical role in mitigating the reactivity of immune cells, secreting high levels of cytokines that promote tolerance. Therapeutic approaches that capitalize on our knowledge of the rich cellular and molecular environment are emerging and show great promise. We will discuss the advantages and challenges of 5 such strategies and how these therapies might mitigate the atopic march by facilitating tolerance. We conclude that skin is a multifaceted structure that provides a fertile ground for therapeutic discovery. Accordingly, ongoing work in this domain will no doubt continue to deliver exciting progress for improved health outcomes. 10.1016/j.jaci.2019.03.021