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Atopic dermatitis (AD) is a frequent chronic inflammatory skin disease which is often complicated by recurrent microbial superinfections. Genetically based modifications which might have an impact on the innate immune system, such as impairment of the skin barrier, modifications of pattern recognition receptors, deficiency of antimicrobial peptides, antiviral natural killer cells and plasmacytoid dendritic cells, facilitate the entry of allergens and infectious microbes into the skin, where they encounter immunocompetent cells. The micromilieu in the skin of AD patients further potentiates dysfunctions of the innate immune system, leading to a vicious circle promoting the disease. This article provides an overview of modifications of the innate immune system in AD.

Atopic dermatitis (AD) affects up to 20% of children and is considered the starting point of the atopic march with the development of food allergy, asthma, and allergic rhinitis. The heterogeneous phenotype reflects distinct and/or overlapping pathogenetic mechanisms with varying degrees of epidermal barrier disruption, activation of different T cell subsets and dysbiosis of the skin microbiome. Here, we review current evidence suggesting a systemic impact of the cutaneous inflammation in AD together with a higher risk of asthma and other comorbidities, especially in severe and persistent AD. Thus, early therapy of AD to restore the impaired skin barrier, modified microbiome, and target type 2 inflammation, depending on the (endo)phenotype, in a tailored approach is crucial. We discuss what we can learn from the comorbidities and the implications for preventive and therapeutic interventions from precision dermocosmetics to precision medicine. The stratification of AD patients into biomarker-based endotypes for a precision medicine approach offers opportunities for better long-term control of AD with the potential to reduce the systemic impact of a chronic skin inflammation and even prevent or modify the course, not only of AD, but possibly also the comorbidities, depending on the patient’s age and disease stage.

Andre Franke and colleagues perform an association study of atopic dermatitis based on high-density genotyping using the Immunochip array. They identify four new susceptibility loci for this common inflammatory skin disease. Atopic dermatitis is a common inflammatory skin disease with a strong heritable component. Pathogenetic models consider keratinocyte differentiation defects and immune alterations as scaffolds 1 , and recent data indicate a role for autoreactivity in at least a subgroup of patients 2 . FLG (encoding filaggrin) has been identified as a major locus causing skin barrier deficiency 3 . To better define risk variants and identify additional susceptibility loci, we densely genotyped 2,425 German individuals with atopic dermatitis (cases) and 5,449 controls using the Immunochip array followed by replication in 7,196 cases and 15,480 controls from Germany, Ireland, Japan and China. We identified four new susceptibility loci for atopic dermatitis and replicated previous associations. This brings the number of atopic dermatitis risk loci reported in individuals of European ancestry to 11. We estimate that these susceptibility loci together account for 14.4% of the heritability for atopic dermatitis.