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Translational implications of Th17-skewed inflammation due to genetic deficiency of a cadherin stress sensor
Lisa M. Godsel, … , Johann E. Gudjonsson, Kathleen J. Green
Lisa M. Godsel, … , Johann E. Gudjonsson, Kathleen J. Green
Published December 14, 2021
Citation Information: J Clin Invest. 2022;132(3):e144363. https://doi.org/10.1172/JCI144363.
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Research Article Dermatology Immunology Article has an altmetric score of 34

Translational implications of Th17-skewed inflammation due to genetic deficiency of a cadherin stress sensor

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Abstract

Desmoglein 1 (Dsg1) is a cadherin restricted to stratified tissues of terrestrial vertebrates, which serve as essential physical and immune barriers. Dsg1 loss-of-function mutations in humans result in skin lesions and multiple allergies, and isolated patient keratinocytes exhibit increased proallergic cytokine expression. However, the mechanism by which genetic deficiency of Dsg1 causes chronic inflammation is unknown. To determine the systemic response to Dsg1 loss, we deleted the 3 tandem Dsg1 genes in mice. Whole transcriptome analysis of embryonic Dsg1–/– skin showed a delay in expression of adhesion/differentiation/keratinization genes at E17.5, a subset of which recovered or increased by E18.5. Comparing epidermal transcriptomes from Dsg1-deficient mice and humans revealed a shared IL-17–skewed inflammatory signature. Although the impaired intercellular adhesion observed in Dsg1–/– mice resembles that resulting from anti-Dsg1 pemphigus foliaceus antibodies, pemphigus skin lesions exhibit a weaker IL-17 signature. Consistent with the clinical importance of these findings, treatment of 2 Dsg1-deficient patients with an IL-12/IL-23 antagonist originally developed for psoriasis resulted in improvement of skin lesions. Thus, beyond impairing the physical barrier, loss of Dsg1 function through gene mutation results in a psoriatic-like inflammatory signature before birth, and treatment with a targeted therapy significantly improved skin lesions in patients.

Authors

Lisa M. Godsel, Quinn R. Roth-Carter, Jennifer L. Koetsier, Lam C. Tsoi, Amber L. Huffine, Joshua A. Broussard, Gillian N. Fitz, Sarah M. Lloyd, Junghun Kweon, Hope E. Burks, Marihan Hegazy, Saki Amagai, Paul W. Harms, Xianying Xing, Joseph Kirma, Jodi L. Johnson, Gloria Urciuoli, Lynn T. Doglio, William R. Swindell, Rajeshwar Awatramani, Eli Sprecher, Xiaomin Bao, Eran Cohen-Barak, Caterina Missero, Johann E. Gudjonsson, Kathleen J. Green

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Figure 7

Differentially expressed genes in Dsg1–/– mice and patients with SAM syndrome overlap with patients with PSO and to a lesser extent those with AD.

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Differentially expressed genes in Dsg1–/– mice and patients with SAM syn...
(A) The gene fold change signature (Dsg1–/–/Dsg1+/+) from E18.5 data set #2 was compared with those obtained from 36 comparisons yielding PSO/control (n = 21) or AD/control (n = 15) gene fold change signatures (ADa = acute atopic dermatitis; ADc = chronic atopic dermatitis). The 36 comparisons are ranked based upon the Spearman correlation coefficient estimate. (B) GSEA analysis of PSO/AD-increased genes. (C) GSEA analysis of PSO/AD-decreased genes. In B and C, the top 100 genes most strongly increased or decreased in each disease were analyzed. The figure shows cumulative overlap of these genes (vertical axis) with genes ranked based on Dsg1–/–/Dsg1+/+ FC estimates (horizontal axis). The area between each curve and the diagonal is shown with corresponding P values (Wilcoxon rank sum test). (D) Gene fold change signatures (Dsg1–/–/Dsg1+/+) from E18.5 data set #1 were compared with the PSO and AD gene fold change signatures and the Spearman correlation was graphed to demonstrate correlation. (E) Overlap between genes upregulated or downregulated in the Dsg1–/– mouse skin and patients with SAM syndrome or PSO. (F) Percentage overlap of genes upregulated in E18.5 Dsg1–/– mouse skin and patients with SAM syndrome or PSO. (G) Overlap between genes upregulated or downregulated in the E18.5 Dsg1–/– mouse skin and patients with SAM syndrome or AD. (H) Percentage overlap of genes upregulated in E18.5 Dsg1–/– mouse skin and patients with SAM syndrome or AD.

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