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

• Published in: The Journal of clinical investigation Vol. 132; no. 3; pp. 1 - 17
• Main Authors: Godsel, Lisa M, Roth-Carter, Quinn R, Koetsier, Jennifer L, Tsoi, Lam C, Huffine, Amber L, Broussard, Joshua A, Fitz, Gillian N, Lloyd, Sarah M, Kweon, Junghun, Burks, Hope E, Hegazy, Marihan, Amagai, Saki, Harms, Paul W, Xing, Xianying, Kirma, Joseph, Johnson, Jodi L, Urciuoli, Gloria, Doglio, Lynn T, Swindell, William R, Awatramani, Rajeshwar, Sprecher, Eli, Bao, Xiaomin, Cohen-Barak, Eran, Missero, Caterina, Gudjonsson, Johann E, Green, Kathleen J
• Format: Journal Article
• Language: English
• Published: United States American Society for Clinical Investigation 01.02.2022
• Subjects: Animals; Biomedical research; Cadherins; CD4 lymphocytes; Cell adhesion; Cell adhesion & migration; CRISPR; Cytokines; Dermatitis; Dermatology; Desmoglein 1; Desmoglein 1 - genetics; Desmoglein 1 - immunology; Desmosomes - genetics; Desmosomes - immunology; Embryos; Gene expression; Genetic aspects; Genetic translation; Health aspects; Helper cells; Immunology; Inflammation; Interleukin 12; Interleukin 17; Interleukin 23; Keratinization; Keratinocytes; Keratinocytes - immunology; Lymphocytes T; Mice; Mutation; Patients; Pemphigus; Pemphigus - genetics; Pemphigus - immunology; Physiological aspects; Point mutation; Proteins; Psoriasis; Skin diseases; Skin lesions; Th17 Cells - immunology; Transcriptomes; Tumor necrosis factor-TNF; United States; Skin; Immunology; Genetic diseases; Dermatology; Bioinformatics
• ISSN: 1558-8238; 0021-9738; 1558-8238
• DOI: 10.1172/jci144363

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.