title: Cellular basis of secondary infections and impaired desquamation in certain inherited ichthyoses.
abstract: OBJECTIVE
  Secondary infections and impaired desquamation complicate certain inherited ichthyoses, but their cellular basis remains unknown. In healthy human epidermis, the antimicrobial peptides cathelicidin (LL-37) and human β-defensin 2 (HBD2), as well as the desquamatory protease kallikrein-related peptidase 7 (KLK7), are delivered to the stratum corneum (SC) interstices by lamellar body (LB) exocytosis.
  
  
  OBJECTIVE
  To assess whether abnormalities in the LB secretory system could account for increased risk of infections and impaired desquamation in inherited ichthyoses with known abnormalities in LB assembly (Harlequin ichthyosis [HI]), secretion (epidermolytic ichthyosis [EI]), or postsecretory proteolysis (Netherton syndrome [NS]).
  
  
  METHODS
  Samples from library material were taken from patients with HI, EI, NS, and other ichthyoses, but with a normal LB secretory system, and in healthy controls and were evaluated by electron microscopy and immunohistochemical analysis from July 1, 2010, through March 31, 2013.
  
  
  METHODS
  Changes in LB secretion and in the fate of LB-derived enzymes and antimicrobial peptides in ichthyotic patients vs healthy controls.
  
  
  RESULTS
  In healthy controls and patients with X-linked ichthyosis, neutral lipid storage disease with ichthyosis, and Gaucher disease, LB secretion is normal, and delivery of LB-derived proteins and LL-37 immunostaining persists high into the SC. In contrast, proteins loaded into nascent LBs and their delivery to the SC interstices decrease markedly in patients with HI, paralleled by reduced immunostaining for LL-37, HBD2, and KLK7 in the SC. In patients with EI, the cytoskeletal abnormality impairs the exocytosis of LB contents and thus results in decreased LL-37, HBD2, and KLK7 secretion, causing substantial entombment of these proteins within the corneocyte cytosol. Finally, in patients with NS, although abundant enzyme proteins loaded in parallel with accelerated LB production, LL-37 disappears, whereas KLK7 levels increase markedly in the SC.
  
  
  CONCLUSIONS
  Together, these results suggest that diverse abnormalities in the LB secretory system account for the increased risk of secondary infections and impaired desquamation in patients with HI, EI, and NS.
authors.affiliation: Dermatology Service, Department of Veterans Affairs Medical Center, University of California, San Francisco2Department of Dermatology, University of California, San Francisco.
authors.forename: Aegean
authors.initials: A
authors.lastname: Chan
authors.affiliation: Dermatology Service, Department of Veterans Affairs Medical Center, University of California, San Francisco2Department of Dermatology, University of California, San Francisco.
authors.forename: Elena
authors.initials: E
authors.lastname: Godoy-Gijon
authors.affiliation: Dermatology Service, Department of Veterans Affairs Medical Center, University of California, San Francisco2Department of Dermatology, University of California, San Francisco.
authors.forename: Almudena
authors.initials: A
authors.lastname: Nuno-Gonzalez
authors.affiliation: Dermatology Service, Department of Veterans Affairs Medical Center, University of California, San Francisco2Department of Dermatology, University of California, San Francisco.
authors.forename: Debra
authors.initials: D
authors.lastname: Crumrine
authors.affiliation: Dermatology Service, Department of Veterans Affairs Medical Center, University of California, San Francisco2Department of Dermatology, University of California, San Francisco.
authors.forename: Melanie
authors.initials: M
authors.lastname: Hupe
authors.affiliation: Department of Dermatology, Yonsei University, Wonju College of Medicine, Wonju, South Korea.
authors.forename: Eung-Ho
authors.initials: EH
authors.lastname: Choi
authors.affiliation: Department of Dermatology and Venereology, Medical University of Innsbruck, Innsbruck, Austria.
authors.forename: Robert
authors.initials: R
authors.lastname: Gruber
authors.affiliation: Department of Dermatology, University of California, San Francisco5Department of Pediatrics, University of California, San Francisco.
authors.forename: Mary L
authors.initials: ML
authors.lastname: Williams
authors.affiliation: Department of Dermatology, Yale University, New Haven, Connecticut7Department of Pathology, Yale University, New Haven, Connecticut.
authors.forename: Keith
authors.initials: K
authors.lastname: Choate
authors.affiliation: Division of Dermatology, University of Washington, Seattle.
authors.forename: Philip H
authors.initials: PH
authors.lastname: Fleckman
authors.affiliation: Dermatology Service, Department of Veterans Affairs Medical Center, University of California, San Francisco2Department of Dermatology, University of California, San Francisco.
authors.forename: Peter M
authors.initials: PM
authors.lastname: Elias
mesh_terms: D023181:Antimicrobial Cationic Peptides / Q000378:metabolism; D016022:Case-Control Studies; D005089:Exocytosis; D006801:Humans; D007057:Ichthyosis / Q000150:complications* / Q000235:genetics / Q000473:pathology; D007150:Immunohistochemistry; D007610:Kallikreins / Q000378:metabolism; D008854:Microscopy, Electron; D012867:Skin / Q000473:pathology*; D012874:Skin Diseases, Infectious / Q000209:etiology* / Q000473:pathology; D023083:beta-Defensins / Q000378:metabolism; D054804:Cathelicidins
chemical_list: D023181:Antimicrobial Cationic Peptides; C106641:DEFB4A protein, human; D023083:beta-Defensins; C082472:KLK7 protein, human; D007610:Kallikreins; D054804:Cathelicidins