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

Aegean Chan, Elena Godoy-Gijon, Almudena Nuno-Gonzalez, Debra Crumrine, Melanie Hupe, Eung Ho Choi, Robert Gruber, Mary L. Williams, Keith Choate, Philip H. Fleckman, Peter M. Elias

Research output: Contribution to journalArticle

13 Citations (Scopus)

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. MAINOUTCOMEAND 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.

Original languageEnglish
Pages (from-to)285-292
Number of pages8
JournalJAMA Dermatology
Volume151
Issue number3
DOIs
Publication statusPublished - 2015 Mar 1

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Ichthyosis
Coinfection
Netherton Syndrome
Epidermolytic Hyperkeratosis
Lamellar Ichthyosis
Kallikreins
Cornea
Exocytosis
Library Materials
Proteins
X-Linked Ichthyosis
Defensins
Gaucher Disease
Enzymes
Epidermis
Cytosol
Proteolysis
Electron Microscopy
Peptide Hydrolases
Peptides

All Science Journal Classification (ASJC) codes

  • Dermatology

Cite this

Chan, A., Godoy-Gijon, E., Nuno-Gonzalez, A., Crumrine, D., Hupe, M., Choi, E. H., ... Elias, P. M. (2015). Cellular basis of secondary infections and impaired desquamation in certain inherited ichthyoses. JAMA Dermatology, 151(3), 285-292. https://doi.org/10.1001/jamadermatol.2014.3369
Chan, Aegean ; Godoy-Gijon, Elena ; Nuno-Gonzalez, Almudena ; Crumrine, Debra ; Hupe, Melanie ; Choi, Eung Ho ; Gruber, Robert ; Williams, Mary L. ; Choate, Keith ; Fleckman, Philip H. ; Elias, Peter M. / Cellular basis of secondary infections and impaired desquamation in certain inherited ichthyoses. In: JAMA Dermatology. 2015 ; Vol. 151, No. 3. pp. 285-292.
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Chan, A, Godoy-Gijon, E, Nuno-Gonzalez, A, Crumrine, D, Hupe, M, Choi, EH, Gruber, R, Williams, ML, Choate, K, Fleckman, PH & Elias, PM 2015, 'Cellular basis of secondary infections and impaired desquamation in certain inherited ichthyoses', JAMA Dermatology, vol. 151, no. 3, pp. 285-292. https://doi.org/10.1001/jamadermatol.2014.3369

Cellular basis of secondary infections and impaired desquamation in certain inherited ichthyoses. / Chan, Aegean; Godoy-Gijon, Elena; Nuno-Gonzalez, Almudena; Crumrine, Debra; Hupe, Melanie; Choi, Eung Ho; Gruber, Robert; Williams, Mary L.; Choate, Keith; Fleckman, Philip H.; Elias, Peter M.

In: JAMA Dermatology, Vol. 151, No. 3, 01.03.2015, p. 285-292.

Research output: Contribution to journalArticle

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AU - Chan, Aegean

AU - Godoy-Gijon, Elena

AU - Nuno-Gonzalez, Almudena

AU - Crumrine, Debra

AU - Hupe, Melanie

AU - Choi, Eung Ho

AU - Gruber, Robert

AU - Williams, Mary L.

AU - Choate, Keith

AU - Fleckman, Philip H.

AU - Elias, Peter M.

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Y1 - 2015/3/1

N2 - 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. MAINOUTCOMEAND 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.

AB - 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. MAINOUTCOMEAND 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.

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