Transcriptomic profile reveals cellular composition contribute to hyaline-vascular variant in unicentric Castleman disease-associated paraneoplastic pemphigus.

Summary

Integrated bulk and single-cell transcriptomics of UCD-PNP lymph nodes identify endothelial cell expansion and ECM gene upregulation as central drivers of hyaline-vascular pathology. Endothelial-derived COL4A1 engages B-cell CD44 and promotes basement membrane accumulation (HSPG2) and CCL4 release in co-cultures, revealing a targetable endothelial–stromal–immune axis.

Key Findings

• Bulk RNA-seq showed ECM dysregulation with significant collagen gene upregulation in UCD-PNP.
• scRNA-seq (58,811 cells) revealed expansion of endothelial cells, pericytes, and fibroblasts, with reduced follicular dendritic cells.
• Ligand–receptor analysis implicated endothelial COL4A1–ITGA1/ITGB1 and LAMB1–ITGA6/ITGB1 signaling in perivascular hyalinization.
• Endothelial-derived COL4A1 interacted with B-cell CD44; co-cultures showed increased HSPG2 (Perlecan) deposition and CCL4 release.

Clinical Implications

Although focused on pathophysiology, the findings nominate potential targets (e.g., COL4A1–integrin/CD44 signaling, basement membrane assembly) for future therapies and suggest biomarker development for endothelial dysregulation.

Limitations

• Rare-disease cohort with modest sample size; generalizability requires external validation
• Primarily cross-sectional human tissue analyses; limited in vivo functional testing

Future Directions

Test therapeutic modulation of the endothelial–ECM axis (e.g., targeting COL4A1/CD44 or integrin signaling) in preclinical models and develop biomarkers of endothelial dysregulation for stratified clinical trials.