title: Mechanisms of abnormal lamellar body secretion and the dysfunctional skin barrier in patients with atopic dermatitis.
abstract: I review how diverse inherited and acquired abnormalities in epidermal structural and enzymatic proteins converge to produce defective permeability barrier function and antimicrobial defense in patients with atopic dermatitis (AD). Although best known are mutations in filaggrin (FLG), mutations in other member of the fused S-100 family of proteins (ie, hornerin [hrn] and filaggrin 2 [flg-2]); the cornified envelope precursor (ie, SPRR3); mattrin, which is encoded by TMEM79 and regulates the assembly of lamellar bodies; SPINK5, which encodes the serine protease inhibitor lymphoepithelial Kazal-type trypsin inhibitor type 1; and the fatty acid transporter fatty acid transport protein 4 have all been linked to AD. Yet these abnormalities often only predispose to AD; additional acquired stressors that further compromise barrier function, such as psychological stress, low ambient humidity, or high-pH surfactants, often are required to trigger disease. T(H)2 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 antimicrobial defense. Finally, I briefly review therapeutic options that address this new pathogenic paradigm.
authors.affiliation: Dermatology Service, Veterans Affairs Medical Center, and the Department of Dermatology, University of California, San Francisco, Calif. Electronic address: eliasp@derm.ucsf.edu.
authors.forename: Peter M
authors.initials: PM
authors.lastname: Elias
authors.affiliation: Dermatology Service, Veterans Affairs Medical Center, and the Department of Dermatology, University of California, San Francisco, Calif.
authors.forename: Joan S
authors.initials: JS
authors.lastname: Wakefield
mesh_terms: D000818:Animals; D012634:Bodily Secretions / Q000502:physiology; D003876:Dermatitis, Atopic / Q000209:etiology / Q000503:physiopathology*; D050612:Fatty Acid Transport Proteins / Q000235:genetics / Q000378:metabolism*; D000091344:Filaggrin Proteins; D059647:Gene-Environment Interaction; D006801:Humans; D007113:Immunity, Innate; D002479:Inclusion Bodies / Q000235:genetics / Q000276:immunology; D007381:Intermediate Filament Proteins / Q000235:genetics / Q000378:metabolism*; D050356:Lipid Metabolism / Q000235:genetics; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D053491:Proteinase Inhibitory Proteins, Secretory / Q000235:genetics / Q000378:metabolism*; D059748:Proteolysis; D000074163:Serine Peptidase Inhibitor Kazal-Type 5; D012867:Skin / Q000473:pathology*
chemical_list: C000717249:FLG protein, human; C000717250:FLG2 protein, human; D050612:Fatty Acid Transport Proteins; D000091344:Filaggrin Proteins; D007381:Intermediate Filament Proteins; D008565:Membrane Proteins; D053491:Proteinase Inhibitory Proteins, Secretory; C120650:SPINK5 protein, human; D000074163:Serine Peptidase Inhibitor Kazal-Type 5; C585426:Tmem79 protein, human
keywords: Antimicrobial peptides; T(H)2 cells; atopic dermatitis; barrier function; ceramides; cytokines; filaggrin; kallikreins; lamellar bodies; lipid composition; pH; serine protease inhibitors