Abnormal lamellar body exocytosis accounted for abnormalities in inherited ichthyoses

1. Three inherited ichthyoses, harlequin ichthyosis (HI), epidermolytic ichthyosis (EI), and Netherton syndrome (NS), shared a common decrease in an anti-microbial protein, cathelicidin (LL-37), in the stratum corneum.

2. Decreased protein loading in lamellar bodies (LB), increased proteolysis with inadequate compensation of increased protein loading and secretion in LB, and decreased exocytosis of LB were the demonstrated cellular abnormalities implicated in HI, NS, and EI, respectively.

Evidence Rating Level: 3 (Average)           

Study Rundown: Ichthyoses are a family of skin diseases that are associated with dry, thickened and scaly skin. In healthy skin, antimicrobial proteins that protect the skin from infection and proteins that cause desquamation or shedding of the skin are delivered to the outer layer of skin by organelles known as lamellar bodies. HI, EI, and NS are three ichthyoses that are characterized by (1) varying degrees of desquamation impairment and with (2) increased rates of infection. Abnormal secretion of LBs is thought to play a role; however, the cellular mechanisms are not well understood. These authors used electron microscopy and immunohistochemical analysis to assess LB secretion in HI, EI, and NS. Though cathelicidin was uniformly decreased in all three diseases, distinct abnormalities in the LB secretory system were found. A limitation of this study was that investigators were not able to quantify key anti-microbial and desquamatory peptides, which limited a comprehensive understanding of these aberrant pathways.

Click to read the study in JAMA Dermatology 

Relevant Reading: Incidence of Moderate to Severe Ichthyosis in the United States 

In-Depth [cross-sectional study]: Immunostaining and electron microscopy were used to visualize the delivery of antimicrobial peptides cathelicidin (LL-37), human B-defensin 2 (HBD2), and desquamatory protease kallikrein-related peptidase 7 (KLK7) to the stratum corneum (SC) by lamellar bodies. The LB secretory pathways in HI, EI and NS were compared to healthy controls and to other diseases associated with normal LB secretion (X-linked icthyosis and Gaucher’s disease). In patients with Gaucher’s, X-linked icthyosis and healthy controls, LB secretion was normal, and LL-37 was high in the SC. Patients with HI, divergently had decreased LB secretion to the SC as well as reduced immunostaining for LL-37, HBD2 and KLK7. Patients with EI had impaired exocytosis of LB contents and therefore also had similar decreases in LL-37, HBD2 and KLK7 in the SC. Because NS is associated with proteolysis of LL-37, in NS there was an observed compensatory, albeit inadequate, increase in protein loading in LBs and secretion of LBs that resulted in a net decrease in levels of LL-37 in the SC with increased levels of KLK7.

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Image: PD

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