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Spatial transcriptomic data of a lymph node from an individual with Multicentric Castleman Disease

ABSTRACT: Spatial transcriptomic data of a lymph node from an individual with Multicentric Castleman Disease

PROVIDER: PRJNA1005401 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR25636000_1.fastq.gz	Fastqsanger.gz
	SRR25636000_2.fastq.gz	Fastqsanger.gz
	SRR25636001_1.fastq.gz	Fastqsanger.gz
	SRR25636001_2.fastq.gz	Fastqsanger.gz
	SRR25636002_1.fastq.gz	Fastqsanger.gz

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The lymph node transcriptome of unicentric and idiopathic multicentric Castleman disease

Project description:Castleman disease is polyclonal lymphoproliferative disorder characterized by unicentric or multicentric lymphadenopathy with characteristic histomorphologic features, in addition to variable inflammatory symptomatology. The molecular mechanisms and etiologies of unicentric Castleman disease (UCD) and idiopathic multicentric Castleman disease (iMCD) are poorly understood, and identification of targetable disease mediators remains an unmet clinical need. We performed whole exome sequencing on lymph node biopsies from patients with UCD and iMCD; and compared the transcriptomic profile to that of benign control lymph nodes. We identified significantly upregulated genes in UCD (443), iMCD (316) or both disease subtypes (51); in addition to downregulated genes in UCD (321), iMCD (105) or both (10). The transcriptomes of UCD and iMCD showed enrichment and upregulation of elements of the complement cascade. By immunohistochemistry, C4d deposits indicative of complement activation were present in UCD and iMCD mostly within abnormally regressed germinal centers, but also in association with plasma cell clusters, endothelial cells and stroma cells proliferations. Other enriched gene sets included collagen organization, S1P3 pathway and VEGFR pathway in UCD; and humoral response, oxidative phosphorylation and proteosome in iMCD. Analysis of cytokine transcripts showed upregulation of CXCL13 but not IL-6 in UCD and iMCD. Among angiogenic mediators, the VEGFR1 ligand placental growth factor (PGF) was upregulated in both disease subtypes. We hereby report for the first time the whole lymph node transcriptome of UCD and iMCD, underscoring findings that could aid in the discovery of targetable disease mediators.

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Spatial transcriptomic data of a lymph node from an individual with Multicentric Castleman Disease

Project description:Idiopathic Multicentric Castleman Disease (iMCD) is a rare IL-6-driven hematological disorder characterized by systemic lymphadenopathy, elevated immunoglobulin levels, and prominent plasmacytosis in the bone marrow and lymph nodes. Here, we present an unusual occurrence of iMCD in identical twins. Using single cell sequencing, we identified nodal endothelial cells and fibroblastic reticular cells as the source of IL-6 signals. An “inflammatory” peripheral monocytosis enriched for the expression of S100A family genes was evident in both twins, as well as a group of monocytes expressing cytotoxic gene signatures in the affected twin with milder clinical manifestations.

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Project description:The lymph node transcriptome of unicentric and idiopathic multicentric Castleman disease

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Project description:Idiopathic multicentric Castleman disease (iMCD) is a rare and poorly-understood cytokine storm-driven inflammatory disorder. Interleukin-6 (IL-6) is a known disease driver in some patients, but anti-IL-6 therapy with siltuximab is not effective in all patients, and biomarkers indicating success at an early time point following treatment initiation are lacking. Here we show, by comparison of levels of 1,178 proteins in sera of healthy participants (N=42), patients with iMCD (N=88), and with related diseases (N=60), a comprehensive landscape of candidate disease mediators and predictors of siltuximab response. C-X-C Motif Chemokine Ligand-13 (CXCL13) is identified and validated as the protein most prominently up-regulated in iMCD. Early and significant decrease in CXCL13 levels clearly distinguishes siltuximab responders from non-responders; a 17% reduction by day 8 following siltuximab therapy initiation is predictive of response at later time points. Our study thus suggests that CXCL13 is a predictive biomarker of response to siltuximab in iMCD.

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CXCL13 is a predictive biomarker in idiopathic multicentric Castleman disease

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