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JAMA Dermatol. 2015 Mar;151(3):285-92. doi: 10.1001/jamadermatol.2014.3369.

Cellular basis of secondary infections and impaired desquamation in certain inherited ichthyoses.

Author information

1
Dermatology Service, Department of Veterans Affairs Medical Center, University of California, San Francisco2Department of Dermatology, University of California, San Francisco.
2
Department of Dermatology, Yonsei University, Wonju College of Medicine, Wonju, South Korea.
3
Department of Dermatology and Venereology, Medical University of Innsbruck, Innsbruck, Austria.
4
Department of Dermatology, University of California, San Francisco5Department of Pediatrics, University of California, San Francisco.
5
Department of Dermatology, Yale University, New Haven, Connecticut7Department of Pathology, Yale University, New Haven, Connecticut.
6
Division of Dermatology, University of Washington, Seattle.

Abstract

IMPORTANCE:

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]).

DESIGN, SETTING, AND PARTICIPANTS:

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.

MAIN OUTCOME AND MEASURES:

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 AND RELEVANCE:

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.

PMID:
25565224
PMCID:
PMC4498571
DOI:
10.1001/jamadermatol.2014.3369
[Indexed for MEDLINE]
Free PMC Article

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