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Transcriptome Response to Autoantibodies in Human Primary Epidermis Keratinocyte Model for Pemphgus Vulgaris

ABSTRACT: Pemphigus vulgaris (PV) is an autoimmune disease caused by autoantibodies (AAbs) targeting Desmoglein 1 (DSG1) or Desmoglein 3 (DSG3) on keratinocytes, leading to disrupted cell-cell adhesion and epidermal blistering. To investigate the early signaling events triggered by AAb binding, we examined transcriptomic responses in a human primary epidermis keratinocyte (HPEK) model for PV. After incubating the single-chain variable fragment (scFv) PX43, which targets DSG1 and DSG3, and human IgG as control for 5h, 10h and 24h, differentially expressed genes (DEGs) and regulated pathways was analyzed using DESeq2 and pathway enrichment analysis. Few significantly differentially expressed DEGs (under 10) were identified of PX43 compared to hIgG at all three time points (5h, 10h and 24h) with adjusted pvalue below 0.05 and |log2FC| >1. Upregulated inflammatory related pathways including TNFα signaling were identified only at 24h. Correlation analysis of the log2 transformed transcripts per million (TPM) shows the very high positive correlation of PX43 and hIgG at all time points (spearman correlation above 0.9) These findings indicate that AAbs targeting DSG1 and DSG3 do not drive broad transcriptomic or proteomic changes at the HPEK model.

ORGANISM(S): Homo sapiens

PROVIDER: GSE288492 | GEO | 2025/02/10

REPOSITORIES: GEO

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Transcriptome Response and Protein Abundance are Correlated with Split Formation and Cell Detachment as Secondary Effects to Autoantibodies in Human Skin Organ Culture Models for Pemphgus Vulgaris

Project description:Pemphigus vulgaris (PV) is an autoimmune disease caused by autoantibodies (AAbs) targeting Desmoglein 1 (DSG1) or Desmoglein 3 (DSG3) on keratinocytes, leading to disrupted cell-cell adhesion and epidermal blistering. To investigate the early signaling events triggered by AAb binding, we examined transcriptomic and proteomic responses in a human skin organ culture (HSOC) model for PV. After injecting the single-chain variable fragment (scFv) PX43, which targets DSG1 and DSG3, or the mouse-derived DSG3 AAb AK23, we quantified transcriptome changes at 0, 5, 10, and 24 hours and proteome responses at 0 and 24 hours, using human or murine IgG as controls. Differential pathway regulation was analyzed over time using gene set variation and enrichment analysis, with pathway responses compared to in vitro and in situ responses of normal human epithelial keratinocytes (NHEKs) under conditions such as stretching, differentiation, migration, detachment, and acute wounding. Only PX43 induced split formation in the HSOC model, which was associated with significant transcriptomic and proteomic changes, while AK23 did not alter gene expression or protein levels. Enriched pathways in response to split formation included TNFα, Interferon α/γ, IL2-STAT5, and IL5-STAT3 signaling across all time points. The transcriptomic response closely resembled that of acute skin wounding and keratinocyte detachment, with an inverse correlation to cell stretching and differentiation and no correlation to keratinocyte migration. These findings indicate that AAbs targeting DSG1 and/or DSG3 alone do not drive broad transcriptomic or proteomic changes; rather, observed changes result from split formation, resembling the response to wounding and inflammation.

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