卡斯特曼病的空间和单细胞图谱揭示了关键的基质细胞类型和细胞因子途径。

Spatial and single cell mapping of castleman disease reveals key stromal cell types and cytokine pathways.

作者信息

Smith David, Eichinger Anna, Fennell Éanna, Xu-Monette Zijun Y, Rech Andrew, Wang Julia, Esteva Eduardo, Seyedian Arta, Yang Xiaoxu, Zhang Mei, Martinez Dan, Tan Kai, Luo Minjie, Young Katherine J, Murray Paul G, Park Christopher, Reizis Boris, Pillai Vinodh

机构信息

Center for Single Cell Biology, Children's Hospital of Philadelphia Research Institute, Philadelphia, PA, USA.

Department of Pathology, New York University Grossman School of Medicine, New York City, NY, USA.

出版信息

Nat Commun. 2025 Jul 1;16(1):6009. doi: 10.1038/s41467-025-61214-1.

DOI:10.1038/s41467-025-61214-1

PMID:40593805

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.

摘要

为了确定卡斯特曼病（CD）的细胞和分子基础，我们分析了来自单中心CD、特发性多中心CD、HHV8相关MCD和反应性淋巴结的发现队列（n = 9例）和验证队列（n = 13例）的空间蛋白质组和转录组。CD显示形成独特微环境的基质细胞增加。活化的滤泡树突状细胞（FDC）细胞质网络与套区B细胞的相互作用与B细胞活化和分化相关。CXCL13 + FDC、PDGFRA + T区网状细胞（TRC）和ACTA2阳性血管周围网状细胞（PRC）是VEGF表达增加和IL-6信号传导的主要来源。MCD的特征是TRC增加，而UCD显示B网状细胞（BRC）增加。FDC的VEGF表达与滤泡周围新血管形成相关。CD的FDC、TRC和PRC通过特定的配体-受体相互作用激活JAK-STAT、TGFβ和MAPK途径。在这里，我们表明基质细胞活化以及相关的B细胞活化和分化、新血管形成和基质重塑是CD的基础。