Elsevier

Journal of Investigative Dermatology

Volume 142, Issue 9, September 2022, Pages 2363-2374.e18
Journal of Investigative Dermatology

Original Article
Clinical Research
Transcriptomic Analysis of the Major Orphan Ichthyosis Subtypes Reveals Shared Immune and Barrier Signatures

https://doi.org/10.1016/j.jid.2022.03.022Get rights and content
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Preliminary work suggested upregulation of inflammatory pathways in patients with common forms of ichthyosis. However, a comprehensive characterization of skin from various ichthyosis subtypes is unavailable, precluding the development of targeted treatments. Thus, we sought to characterize the immune and barrier profiles of common and subtype-specific skin transcriptomes in a large group of patients with ichthyosis. We performed a global RNA-sequencing analysis in 54 patients with ichthyosis (7 with Netherton syndrome, 13 with epidermolytic ichthyosis, 16 with lamellar ichthyosis, and 18 with congenital ichthyosiform erythroderma) and 40 healthy controls. Differentially expressed genes were defined on the basis of fold changes > 2 and false discovery rate < 0.05 criteria. We found robust and significant T helper (Th) 22/Th17 skewing in all subtypes (e.g., IL-17A/C/F, S100A7/8/9/12; P < 0.001) with modest changes in Th2 pathway, primarily in Netherton syndrome, and Th1 skewing in congenital ichthyosiform erythroderma. Across all subtypes (less evident in epidermolytic ichthyosis), lipid metabolism and barrier junction markers were downregulated (e.g., FA2H, CDH10/11/12/2; P < 0.05), whereas epidermal cornification and proliferation measures were upregulated (e.g., SPRR1A/1B/2C/2G, EREG; P < 0.05). Our findings suggest that the common ichthyosis variants share aberrations in Th17/Th22 and barrier function, with minimal Th2 modulation. This may help to elucidate the pathogeneses of these subtypes and inform the development of subtype-specific treatments.

Abbreviations

CE
cornified envelope
CIE
congenital ichthyosiform erythroderma
CLA
cutaneous lymphocyte-associated antigen
DEG
differentially expressed gene
EDC
epidermal differentiation complex
EI
epidermolytic ichthyosis
FCH
fold change
FDR
false discovery rate
GSVA
gene set variation analysis
HI
harlequin ichthyosis
IASI
Ichthyosis Area and Severity Index
IASI-E
Ichthyosis Area and Severity Index-erythema
LI
lamellar ichthyosis
NS
Netherton syndrome
RNA-seq
RNA-sequencing
TEWL
transepidermal water loss
Th
T helper

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See related commentary on pg 2303

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These authors contributed equally to this work.