Transcriptome and unique cytokine microenvironment of Castleman disease

Area of Science:

• Hematology
• Immunology
• Oncology

Background:

• Castleman disease (CD) is a rare, heterogeneous group of disorders with poorly understood cellular underpinnings.
• Unicentric CD (UCD) affects a single lymph node, while multicentric CD (MCD) involves multiple lymph node regions.

Purpose of the Study:

• To elucidate the cellular and molecular basis of UCD and MCD.
• To identify distinct molecular signatures differentiating UCD, MCD, and non-CD controls.
• To uncover potential therapeutic targets for Castleman disease.

Main Methods:

• Multi-platform analysis including targeted RNA sequencing, RNA in-situ hybridization (ISH), and adaptive immune receptor rearrangements (AIRR) profiling.
• Archived tissue samples from 26 UCD, 14 MCD, and 31 non-CD reactive controls were analyzed.

Main Results:

• UCD exhibited differential expression of follicular dendritic cell markers, angiogenesis factors, extracellular matrix remodeling factors, complement components, and germinal center activation markers.
• MCD showed upregulation of IL-6 pathway genes, IL-2, plasma cell differentiation markers, FDC markers, CCL21, VEGF, and mTORC1 pathway genes compared to UCD and controls.
• ISH confirmed increased VEGF in MCD follicles and macrophages, and higher IL-6 expression in MCD vasculature-associated cells. Oligoclonal T-cell expansions were observed in some MCD and UCD cases.

Conclusions:

• The study highlights unique genes, pathways, and cell types involved in the pathogenesis of UCD and MCD.
• Distinct molecular profiles differentiate UCD and MCD, suggesting different underlying mechanisms.
• Identified molecular pathways and cell types represent potential novel therapeutic targets for Castleman disease.