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Single-cell landscape of idiopathic multicentric Castleman disease in identical twins
•Candidate pathogenic germ line variants in TRAF3 and NCOA4 were identified for iMCD occurring in identical twins.•Using scRNAseq and Stereo-seq, IL-6 pathway signals were dominant in nodal fibroblastic reticular cells and endothelial cells. [Display omitted] Idiopathic multicentric Castleman diseas...
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Published in: | Blood 2024-05, Vol.143 (18), p.1837-1844 |
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Main Authors: | , , , , , , , , , , , , , , , , , , , , |
Format: | Article |
Language: | English |
Subjects: | |
Citations: | Items that this one cites Items that cite this one |
Online Access: | Get full text |
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Summary: | •Candidate pathogenic germ line variants in TRAF3 and NCOA4 were identified for iMCD occurring in identical twins.•Using scRNAseq and Stereo-seq, IL-6 pathway signals were dominant in nodal fibroblastic reticular cells and endothelial cells.
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Idiopathic multicentric Castleman disease (iMCD) is a rare cytokine-driven disorder characterized by systemic inflammation, generalized lymphadenopathy, and organ dysfunction. Here, we present an unusual occurrence of iMCD in identical twins and examined the immune milieu within the affected lymphoid organs and the host circulation using multiomic high-dimensional profiling. Using spatial enhanced resolution omics sequencing (Stereo-seq) transcriptomic profiling, we performed unsupervised spatially constrained clustering to identify different anatomic structures, mapping the follicles and interfollicular regions. After a cell segmentation approach, interleukin 6 (IL-6) pathway genes significantly colocalized with endothelial cells and fibroblastic reticular cells, confirming observations using a single-cell sequencing approach (10× Chromium). Furthermore, single-cell sequencing of peripheral blood mononuclear cells revealed an “inflammatory” peripheral monocytosis enriched for the expression of S100A family genes in both twins. In summary, we provided evidence of the putative cell-of-origin of IL-6 signals in iMCD and described a distinct monocytic host immune response phenotype through a unique identical twin model.
Idiopathic multicentric Castleman disease (iMCD) encompasses several disorders with similar distinctive lymph node histological features. Half of the cases are associated with either human herpesvirus 8 infection or POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, skin changes) syndrome, while causation is unknown in the remaining cases. Chan et al investigated iMCD in identical twins, finding 2 potentially causative germ line mutations. Through advanced single-cell omics, the authors pinpointed nodal fibroblastic reticular cells and endothelial cells as the cells that overproduce interleukin-6, which drives the disease. |
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ISSN: | 0006-4971 1528-0020 1528-0020 |
DOI: | 10.1182/blood.2023021992 |