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Papers of the Week

Papers: 23 Sep 2023 - 29 Sep 2023

Psychology, Review

Human Studies, Molecular/Cellular, Neurobiology

Inflammation/Inflammatory, Itch, Psychological/Comorbidities

2023 Sep 25

Ann Allergy Asthma Immunol


Filaggrin and Beyond: New Insights into the Skin Barrier in Atopic Dermatitis and Allergic Diseases, From Genetics to Therapeutic Perspectives.


Stefanovic N, Irvine AD


Atopic dermatitis is the most common inflammatory skin disease worldwide, affecting 20% of children and 5% of adults. One critical component in the pathophysiology of atopic dermatitis is the epidermal skin barrier, with its outermost layer- the stratum corneum (SC) being conferring biochemical properties that enable resilience against environmental threats and maintain homeostasis. The skin barrier may be conceptualized as a key facilitator of complex interactions between genetics, host immunity, the cutaneous microbiome, and environmental exposures. The key genetic risk factor for AD development and persistence is a loss of function mutation in filaggrin (FLG), with recent advances in genomics focusing on rare variant discovery, establishment of pathogenic mechanisms and exploration of the role of other epidermal differentiation complex gene variants in AD. Aberrant type 2 inflammatory responses downregulate the transcription of key epidermal barrier genes, alter the composition of SC lipids and induce further injury via a neuro-cutaneous feedback loop and the itch-scratch cycle. The dysbiotic epidermis exhibits reduced bacterial diversity and enhanced colonization with Staphylococcus and Malassezia species, which contribute to both direct barrier injury via the action of bacterial toxins and to perpetuation of the inflammatory cascades. Enhanced understanding of each of the pathogenic mechanisms underpinning barrier disruption has led to the development of novel topical and systemic molecules, including IL-4Ra, IL-13, PDE4 and JAK inhibitors, whose clinical effectiveness exceeds conventional treatment modalities. In this narrative review, we aim to summarise the current understanding of the above pathophysiologic and therapeutic mechanisms, with a focus on the genetic, cellular and molecular mechanisms underpinning AD development.