Cutaneous barrier dysfunction in allergic diseases

Abstract

The fundamental defect(s) that drives atopic dermatitis (AD) remains controversial. ''Outside in'' proponents point to the important association of filaggrin gene mutations and other skin barrier defects with AD. The ''inside out'' proponents derive support from evidence that AD occurs in genetic animal models with overexpression of type 2 immune pathways in their skin, and humans with gain-of-function mutations in their type 2 response develop severe AD. The observation that therapeutic biologics, targeting type 2 immune responses, can reverse AD provides compelling support for the importance of ''inside out'' mechanisms of AD. In this review, we propose a central role for epithelial cell dysfunction that accounts for the dual role of skin barrier defects and immune pathway activation in AD. The complexity of AD has its roots in the dysfunction of the epithelial barrier that allows the penetration of allergens, irritants, and microbes into a cutaneous milieu that facilitates the induction of type 2 immune responses. The AD phenotypes and endotypes that result in chronic skin inflammation and barrier dysfunction are modified by genes, innate/adaptive immune responses, and different environmental factors that cause skin barrier dysfunction. There is also compelling evidence that skin barrier dysfunction can alter the course of childhood asthma, food allergy, and allergic rhinosinusitis. Effective management of AD requires a multipronged approach, not only restoring cutaneous barrier function, microbial flora, and immune homeostasis but also enhancing INFORMATION FOR CATEGORY 1 CME CREDIT Credit can now be obtained, free for a limited time, by reading the review articles in this issue. Please note the following instructions.

Whole Goat Milk as a Source of Fat and Milk Fat Globule Membrane in Infant Formula

“…Alteration to this lipid structure results in compromised epidermal functions and skin diseases such as atopic dermatitis. A strong skin barrier is required to prevent the penetration of microbes, allergens and irritants, and the subsequent activation of type-2 immune and inflammatory responses [ 105 ]. Clinical observations have concluded that skin lipid metabolism is critical in atopic dermatitis independent of the filaggrin genotype [ 105 ].…”

“…A strong skin barrier is required to prevent the penetration of microbes, allergens and irritants, and the subsequent activation of type-2 immune and inflammatory responses [ 105 ]. Clinical observations have concluded that skin lipid metabolism is critical in atopic dermatitis independent of the filaggrin genotype [ 105 ]. Skin lipids are critical for skin barrier integrity but also as antimicrobial and anti-inflammatory agents.…”

“…Skin lipids are critical for skin barrier integrity but also as antimicrobial and anti-inflammatory agents. Skin lipids in atopic dermatitis subjects tend to have disorganized lamellar membrane structures, different classes of ceramides as well as reduced fatty acid chain length in ceramides, and polar lipids [ 105 ]. Such disruption in the skin lipid structure leads to transepidermal water loss and xerosis in atopic dermatitis skin.…”

“…Of note, human milk had more SM with ultra-long chain-fatty acids (ULCFAs) than cow milk but less than goat milk. Ceramides with ULCFAs are prevalent in healthy skin [ 105 ]. Milk glucosylceramides, galactosylceramides and lactosylceramides are hydrolysed to ceramides in the gut.…”

Topical doxycycline monohydrate hydrogel 1% targeting proteases/PAR2 pathway is a novel therapeutic for atopic dermatitis

“…[2][3][4] The pathogenesis of AD is complex and multifactorial explained by two complementary hypotheses: (a) inside out, the immune system defect drives the skin damage, and (b) outside in, in which the skin barrier defect drives the aberrant immune response. [1,5] In either case, there is an active cross talk between skin barrier and immune system; thus feeding a vicious cycle that supports the chronicity of the disease and the need to target both the skin barrier and the immune system to ensure optimal treatment of the disease.…”