
==== Front
bioRxiv
BIORXIV
bioRxiv
2692-8205
Cold Spring Harbor Laboratory

10.1101/2024.09.09.609717
preprint
1
Article
Spatial and Single Cell Mapping of Castleman Disease Reveals Key Stromal Cell Types and Cytokine Pathways
Smith David
Eichinger Anna
Rech Andrew
Wang Julia
Esteva Eduardo
Seyedian Arta
Yang Xiaoxu
Zhang Mei
Martinez Dan
Tan Kai http://orcid.org/0000-0002-9104-5567

Luo Minjie
Park Christopher http://orcid.org/0000-0003-2018-3476

Reizis Boris http://orcid.org/0000-0003-1140-7853

Pillai Vinodh http://orcid.org/0000-0001-7126-6226

09 9 2024
2024.09.09.609717https://creativecommons.org/licenses/by-nc-nd/4.0/ This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which allows reusers to copy and distribute the material in any medium or format in unadapted form only, for noncommercial purposes only, and only so long as attribution is given to the creator.
http://biorxiv.org/lookup/doi/10.1101/2024.09.09.609717
nihpp-2024.09.09.609717.pdf
Abstract

Castleman disease (CD) is inflammatory lymphoproliferative disorder of unclear etiology. To determine the cellular and molecular basis of CD, we analyzed the spatial proteome of 4,485,009 single cells, transcriptome of 50,117 single nuclei, immune repertoire of 8187 single nuclei, and pathogenic mutations in Unicentric CD, idiopathic Multicentric CD, HHV8-associated MCD, and reactive lymph nodes. CD was characterized by increased non-lymphoid and stromal cells that formed unique microenvironments where they interacted with lymphoid cells. Interaction of activated follicular dendritic cell (FDC) cytoplasmic meshworks with mantle zone B cells was associated with B cell activation and differentiation. VEGF, IL-6, MAPK, and extracellular matrix pathways were elevated in stromal cells of CD. CXCL13+ FDCs, PDGFRA+ T-zone reticular cells (TRC), and ACTA2-positive perivascular reticular cells (PRC) were identified as the predominant source of increased VEGF expression and IL-6 signaling in CD. VEGF expression by FDCs was associated with peri-follicular neovascularization. FDC, TRC and PRC of CD activated JAK-STAT, TGFβ, and MAPK pathways via ligand-receptor interactions involving collagen, integrins, complement components, and VEGF receptors. T, B and plasma cells were polyclonal but showed class-switched and somatically hypermutated IgG1+ plasma cells consistent with stromal cell-driven germinal center activation. In conclusion, our findings show that stromal cell activation and associated B-cell activation and differentiation, neovascularization and stromal remodeling underlie CD and suggest new targets for treatment.

Key points

Castleman Disease is characterized by activation and proliferation of CXCL13+ FDCs, PDGFRA+ reticular cells, and ACTA2-positive PRCs.

VEGF and IL-6 from lymph node stromal cells are associated with B-cell activation and differentiation, endothelial proliferation, and inflammation in CD
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pmc
