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Spatial and single cell mapping of castleman disease reveals key stromal cell types and cytokine pathways
David Smith1, Anna Eichinger2,3, Éanna Fennell4
1Center for Single Cell Biology, Children's Hospital of Philadelphia Research Institute, Philadelphia, PA, USA.
Insights
Castleman Disease (CD) involves increased stromal cells forming unique microenvironments. These stromal cells drive B cell activation, neovascularization, and tissue remodeling, underlying the disease pathology.
Area of Science:
- Immunology
- Oncology
- Cell Biology
Background:
- Castleman Disease (CD) is a rare lymphoproliferative disorder with poorly understood cellular and molecular underpinnings.
- Distinguishing between Unicentric CD (UCD) and Multicentric CD (MCD), including HHV8-associated MCD, is crucial for understanding disease heterogeneity.
Purpose of the Study:
- To elucidate the cellular and molecular basis of Castleman Disease (CD) by analyzing spatial proteomic and transcriptomic data.
- To identify key cellular players and signaling pathways involved in CD pathogenesis.
Main Methods:
- Spatial proteomic and transcriptomic analysis of lymph node samples from discovery and validation cohorts.
- Analysis included UCD, idiopathic MCD, HHV8-associated MCD, and reactive lymph nodes.
Main Results:
- CD exhibits increased stromal cells creating unique microenvironments, with specific cell types like follicular dendritic cells (FDCs), T-zone reticular cells (TRCs), and perivascular reticular cells (PRCs) being prominent.
- Activated FDCs interact with B cells, promoting B cell activation and differentiation. These stromal cells are key sources of VEGF and IL-6, driving neovascularization and signaling pathways (JAK-STAT, TGFβ, MAPK).
- MCD is characterized by increased TRCs, while UCD shows increased B-reticular cells (BRCs).
Conclusions:
- Stromal cell activation, B cell activation and differentiation, neovascularization, and stromal remodeling are fundamental to Castleman Disease pathogenesis.
- Specific stromal cell populations and their interactions with immune cells drive disease progression.
- Targeting these stromal-cell-mediated pathways may offer therapeutic strategies for CD.
Abstract:
To determine the cellular and molecular basis of Castleman Disease (CD), we analyze the spatial proteome and transcriptome from a discovery (n = 9 cases) and validation (n = 13 cases) cohort of Unicentric CD, idiopathic Multicentric CD, HHV8-associated MCD, and reactive lymph nodes. CD shows increased stromal cells that form unique microenvironments. Interaction of activated follicular dendritic cell (FDC) cytoplasmic meshworks with mantle-zone B cells is associated with B-cell activation and differentiation. CXCL13+ FDCs, PDGFRA + T-zone reticular cells (TRC), and ACTA2-positive perivascular reticular cells (PRC) were the predominant source of increased VEGF expression and IL-6 signaling. MCD is characterized by increased TRC while UCD shows increased B-reticular cells (BRC). VEGF expression by FDCs is associated with peri-follicular neovascularization. FDC, TRC and PRC of CD activates JAK-STAT, TGFβ, and MAPK pathways via specific ligand-receptor interactions. Here, we show that stromal-cell activation and associated B cell activation and differentiation, neovascularization and stromal remodeling underlie CD.
