Cellular Basis of Secondary Infections and Impaired Desquamation in Certain Inherited Ichthyoses

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.

Patients with congenital ichthyosis and TGM1 mutations overexpress other ARCI genes in the skin: Part of a barrier repair response?

“…Typically, neither of these conditions is prone to skin infections despite the barrier abnormalities. However, other subtypes of ichthyoses, that is, harlequin ichthyosis caused by ABCA12 mutations, Netherton syndrome caused by SPINK5 mutations and epidermolytic ichthyosis caused by KRT1 or KRT10 mutations show increased prevalences of secondary skin infections, which can be attributed both to a more severe barrier failure and to distinctive abnormalities in the lamellar bodies secretory system that collectively decrease the bioavailability of AMPs …”

“…However, other subtypes of ichthyoses, that is, harlequin ichthyosis caused by ABCA12 mutations, Netherton syndrome caused by SPINK5 mutations and epidermolytic ichthyosis caused by KRT1 or KRT10 mutations show increased prevalences of secondary skin infections, which can be attributed both to a more severe barrier failure and to distinctive abnormalities in the lamellar bodies secretory system that collectively decrease the bioavailability of AMPs. [26] Speculatively, a stimulation of innate immune responses in patient skin might be a consequence of the observed reduction of IL37, which is a known suppressor of innate immunity. [27] Furthermore, an enhanced adaptive immunity, reflected in increased IL36G transcription in the array and qPCR analyses, may in turn induce various chemokines and psoriasin (S100-A7), [28][29][30] which was also observed in our study.…”

Epidermal barrier in hereditary ichthyoses, atopic dermatitis, and psoriasis

“…Superinfections are common. There is insufficient secretion of antimicrobial peptides by Odland bodies, possibly in connection with the cytoskeletal keratin defect [25].…”

“…In the majority of patients, these are secondary effects resulting from loss of epidermal integrity (e.g. due to filaggrin deficiency) or immune dysregulation (Th2 inflammation inhibits the expression of antimicrobial peptides, see above) [19,25,26].…”

Gaucher Disease Type 2 Presenting with Collodion Membrane and Blueberry Muffin Lesions

“…According to our literature search, only 22 cases of collodion membrane or ichthyosis in association with GD have been reported . To our knowledge, this is the first case of GD presenting with skin findings that include collodion membrane and blueberry muffin lesions.…”