Spatial and Single Cell Mapping of Castleman Disease Reveals Key Stromal Cell Types and Cytokine Pathways

Area of Science:

• Immunology
• Oncology
• Cell Biology

Background:

• Castleman disease (CD) is an inflammatory lymphoproliferative disorder with an unknown cause.
• The cellular and molecular mechanisms driving CD pathogenesis remain incompletely understood.

Purpose of the Study:

• To elucidate the cellular and molecular underpinnings of Castleman disease (CD).
• To identify the specific cell types and molecular pathways involved in CD pathogenesis.
• To explore potential therapeutic targets based on the identified mechanisms.

Main Methods:

• Spatial proteomic analysis of over 4.4 million single cells.
• Transcriptomic analysis of over 50,000 single nuclei.
• Immune repertoire profiling of over 8,000 single nuclei.
• Analysis of pathogenic mutations in various CD subtypes and reactive lymph nodes.

Main Results:

• CD is characterized by an increase in non-lymphoid and stromal cells forming unique microenvironments.
• Activated follicular dendritic cells (FDCs) interact with B cells, promoting B cell activation and differentiation.
• Elevated VEGF, IL-6, MAPK, and extracellular matrix pathways were observed in CD stromal cells.
• Specific stromal cell populations (FDCs, TRCs, PRCs) were identified as key sources of VEGF and IL-6.
• Stromal cells activate JAK-STAT, TGFβ, and MAPK pathways through ligand-receptor interactions.
• Polyclonal B cells exhibit class-switched and somatically hypermutated IgG1+ plasma cells, indicating stromal cell-driven germinal center activation.

Conclusions:

• Stromal cell activation is a central mechanism in Castleman disease (CD).
• Associated B-cell activation, differentiation, neovascularization, and stromal remodeling contribute to CD.
• These findings suggest novel therapeutic targets for Castleman disease.