Mechanisms of abnormal lamellar body secretion and the dysfunctional skin barrier in patients with atopic dermatitis

Abstract

We review here how diverse inherited and acquired abnormalities in epidermal structural and enzymatic proteins converge to produce defective permeability barrier function and antimicrobial defense in AD. Although best known are mutations in filaggrin (FLG), mutations in other member of the fused S-100 family of proteins (i.e., hornerin [hrn] and filaggrin 2 [flg-2]); the cornified envelope precursor (e.g., SPRR3); mattrin, encoded by Tmem79, which regulates the assembly of lamellar bodies; SPINK5, which encodes the serine protease inhibitor, LEKTI1; and the fatty acid transporter, FATP4, have all been linked to AD. Yet, these abnormalities often only predispose to AD; additional acquired stressors that further compromise barrier function; e.g., psychological stress, a low ambient humidity, or high pH surfactants, often are required to trigger disease. Th2 cytokines can also compromise barrier function by downregulating expression of multiple epidermal structural proteins, lipid synthetic enzymes and antimicrobial peptides. All of these inherited and acquired abnormalities converge on the lamellar body secretory system, producing abnormalities in lipid composition, secretion and/or extracellular lamellar membrane organization, as well as in antimicrobial defense. Finally, we briefly review therapeutic options that address this new pathogenic paradigm.

Dose-dependent role of claudin-1 in vivo in orchestrating features of atopic dermatitis

“…Around 70% of AD cases start in children under 5 y of age, and the disease tends to show spontaneous remission with aging (16,17). Although immunological imbalances were previously proposed to explain the features of AD, such as increased immunoglobulin E (IgE) levels and the acquired immune response, recent studies showed that epidermal barrier functions critically influence the pathological features of AD (18,19). However, the cause and development of AD with respect to epidermal barrier functions have not been systematically studied.…”

Atopik Dermatit ve Genetik

“…Bu artışın da AD'deki inflamasyonun ilk sitokin kaskadını başlattığı kabul edilir. Bu durum AD FLG hastaların sağlam derilerinde proinflamatuvar bir durumun varlığını gösterir (18).…”

Prevalence and determinants of eczema among females aged 21 to 32 years in Jeddah city – Saudi Arabia

“…A multiplicity of factors, including skin barrier abnormalities, defects in innate immunity response, Th2-skewed adaptive immune response, and altered skin resident microbial flora are involved in the pathogenesis of atopic dermatitis [15,16]. Whether skin inflammation is initiated by skin barrier dysfunction ("outside-in" hypothesis) or by immune dysregulation ("inside-out" hypothesis) is still in debate.…”