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bioRxiv · 10.1101/2024.06.28.601141

Single cell transcriptome profiling reveals pathogenesis of Bullous Pemphigoid

Wang, Y.·Liang, G.·Zhao, C.·Wei, Q.·Feng, S.
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Abstract

Bullous pemphigoid (BP) triggers profound functional changes in both non-immune and immune cells in the skin and circulation, yet the underlying mechanisms remain elusive. In this study, we conducted single-cell transcriptome analysis on donor-matched lesional and non-lesional skin, as well as blood samples from BP patients. Lesional skin non-immune cells coordinately upregulated metabolism, wound healing, immune activation, and cell migration associated pathways. Skin LAMP3+ DCs derived from cDC2 exhibited higher pro-inflammatory signatures than those from cDC1, and VEGFA+ mast cells driving BP progression, were predominantly from lesional skin. As BP patients transition from active to remission stages, blood B cell function shifts from differentiation and memory formation to heightened type 1 interferon signaling and reduced IL-4 response. Blood CX3CR1+ZNF683+ and LAG3+ exhausted T cells exhibited the highest TCR expansion among clones shared with skin CD8+T cells, suggesting they likely represent BP-reactive cells fueling skin CD8+T cell clonal expansion. Clinical parameters for BP severity correlated positively with blood NK cell IFN-{gamma} production, whereas correlated negatively with NK cell AREG production. In lesional skin, NK cell-keratinocyte interactions exhibited reduced AREG-EGFR and enhanced IFNG-IFNGR1/2 signaling. NK cell-derived AREG mitigates IFN-{gamma}-induced keratinocyte apoptosis, highlighting a crucial balance between AREG and IFN-{gamma} in BP progression. These results reveal significant functional shifts in BP pathology within skin and blood cells and suggest new therapeutic targets for disease management. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=193 SRC="FIGDIR/small/601141v2_ufig1.gif" ALT="Figure 1"> View larger version (77K): org.highwire.dtl.DTLVardef@18517f2org.highwire.dtl.DTLVardef@e743e9org.highwire.dtl.DTLVardef@11b9228org.highwire.dtl.DTLVardef@11884c3_HPS_FORMAT_FIGEXP M_FIG C_FIG

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Wang, Y., Liang, G., Zhao, C., Wei, Q., Feng, S.. 2024-07-02. Single cell transcriptome profiling reveals pathogenesis of Bullous Pemphigoid. https://doi.org/10.1101/2024.06.28.601141

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