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

J Allergy Clin Immunol. 2014 Oct;134(4):781-791.e1. doi: 10.1016/j.jaci.2014.05.048. Epub 2014 Aug 15.


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.

Keywords: Antimicrobial peptides; T(H)2 cells; atopic dermatitis; barrier function; ceramides; cytokines; filaggrin; kallikreins; lamellar bodies; lipid composition; pH; serine protease inhibitors.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Review

MeSH terms

  • Animals
  • Bodily Secretions / physiology
  • Dermatitis, Atopic / etiology
  • Dermatitis, Atopic / physiopathology*
  • Fatty Acid Transport Proteins / genetics
  • Fatty Acid Transport Proteins / metabolism*
  • Filaggrin Proteins
  • Gene-Environment Interaction
  • Humans
  • Immunity, Innate
  • Inclusion Bodies / genetics
  • Inclusion Bodies / immunology
  • Intermediate Filament Proteins / genetics
  • Intermediate Filament Proteins / metabolism*
  • Lipid Metabolism / genetics
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism*
  • Proteinase Inhibitory Proteins, Secretory / genetics
  • Proteinase Inhibitory Proteins, Secretory / metabolism*
  • Proteolysis
  • Serine Peptidase Inhibitor Kazal-Type 5
  • Skin / pathology*


  • FLG protein, human
  • FLG2 protein, human
  • Fatty Acid Transport Proteins
  • Filaggrin Proteins
  • Intermediate Filament Proteins
  • Membrane Proteins
  • Proteinase Inhibitory Proteins, Secretory
  • SPINK5 protein, human
  • Serine Peptidase Inhibitor Kazal-Type 5
  • Tmem79 protein, human