Report from the National Institute of Allergy and Infectious Diseases workshop on "Atopic dermatitis and the atopic march: Mechanisms and interventions"

Abstract

Atopic dermatitis (AD) affects up to 20% of children worldwide and is an increasing public health problem, particularly in developed countries. Although AD in infants and young children can resolve, there is a well-recognized increased risk of sequential progression from AD to other atopic diseases, including food allergy (FA), allergic rhinitis, allergic asthma, and allergic rhinoconjunctivitis, a process referred to as the atopic march. The mechanisms underlying the development of AD and subsequent progression to other atopic comorbidities, particularly FA, are incompletely understood and the subject of intense investigation. Other major research objectives are the development of effective strategies to prevent AD and FA, as well as therapeutic interventions to inhibit the atopic march. In 2017, the Division of Allergy, Immunology, and Transplantation of the National Institute of Allergy and Infectious Diseases sponsored a workshop to discuss current understanding and important advances in these research areas and to identify gaps in knowledge and future research directions. International and national experts in the field were joined by representatives from several National Institutes of Health institutes. Summaries of workshop presentations, key conclusions, and recommendations are presented herein.

Keywords: Atopic march; asthma; atopic dermatitis; biomarkers; food allergy; interventions; skin barrier; skin microbiome.

FIG 1.

A proposed model of the atopic march. AD prevalence peaks early in infancy, potentially increasing the risk for consequent development of the atopic march. Development of FA, asthma, and allergic rhinitis correlates with AD severity in infancy.

FIG 2.

Allergic multimorbidity of asthma, rhinitis, and eczema over 20 years in the German birth cohort Multicenter Allergy Study. A, Percentages of all participants with allergic parents. B, Percentages of all participants with nonallergic parents. Multimorbidity of asthma, eczema, and allergic rhinitis up to 20 years of age (n = 941) by parental allergy and age is shown.

FIG 3.

Bayesian machine learning methods identified 8 distinct latent disease classes based on individual profiles of eczema, wheeze, and rhinitis across 2 population-based birth cohorts: Avon Longitudinal Study of Parents and Children (ALSPAC) and Manchester Asthma and Allergy Study (MAAS). The number of children and proportion of the study population are indicated for each class. Plots indicate longitudinal trajectories of wheeze, eczema, and rhinitis within each class.

FIG 4.

Overlap between AD, allergic sensitization, and wheezing in urban children. Although the individual conditions are relatively common, at age 3 years, only 3% of children experienced all 3 conditions. Figure courtesy of Dr James Gern.

FIG 5.

Skin structure and abnormalities associated with AD. Impaired skin barrier promotes foreign antigen (eg, dust mites and food allergens) penetration and activation of innate immune and pattern recognition receptors. Pathogen-associated molecular patterns and damage-associated molecular patterns are secreted secondary to tissue damage and/or an altered microbial profile to initiate and perpetuate tissue inflammation. Concurrently, antigen stimulation leads to T_H2-promoting cytokine secretion (IL-25, IL-33, and TSLP), consequent IgE- and FcεRI-bearing Langerhans cell and dermal dendritic cell (DC) activation, and migration to regional draining lymph nodes to initiate T_H2 differentiation and B-cell IgE skewing. In turn, T cells circulate back to infiltrate the skin (cutaneous lymphocyte–associated antigen [CLA]⁺ effector memory T [T_EM]/central memory T [T_CM] cells) or are distributed peripherally (CLA⁻ T_EM/T_CM cells) to other end organs to initiate diverse atopic disorders. APC, Antigen-presenting cell; DAMP, damage-associated molecular pattern; PAMP, pathogen-associated molecular pattern; PRR, pattern recognition receptor; TSLPR, TSLP receptor. Figure adapted from Czarnowicki et al, with permission.

FIG 6.

In the Il4raF709 model IL-33–induced IL-4 production by ILC2s plays a crucial role in enabling sensitization to food allergens by promoting production of T_H2 cell–like Treg cells that have impaired Treg cell function.

FIG 7.

Commensals can have essential functions in oral tolerance. Dysbiotic commensals can promote pathogenic T_H2 cell–like reprogramming of gut Treg cells and MC dysregulation leading to FA. DCs, Dendritic cells; IRF, interferon regulatory factor; iTreg, induced Treg cell; OX40L, OX40 ligand; ROR-γT, retinoic acid–related orphan receptor γT; STAT6, signal transducer and activator of transcription 6. Figure courtesy of Dr Talal Chatila.

FIG 8.

A model of barrier disruption and skin sensitization. Allergens, infections, and tissue damage can stimulate release of TSLP, IL-33, and IL-25 from the epithelium. These epithelial cell–derived cytokines license dendritic cells (DCs) to drive type 2 responses but also act on a variety of cell types, including basophils, eosinophils, MCs, and innate lymphoid cells, to initiate and maintain allergic inflammation.

FIG 9.

Immune communication between the skin and gut and tolerance induction determined by using EPIT. Epicutaneous exposure to peanut results in generation of latency-associated peptide (LAP)⁺ Treg cells with gut- and skin-homing receptors that suppress MCs in the gut and skin through a TGF-β–dependent mechanism.