Single-cell landscape of idiopathic Multicentric Castleman Disease in identical twins

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 affected lymphoid organs and the host circulation using multi-omic high-dimensional profiling. Using Stereo-seq spatial transcriptomic profiling, we performed unsupervised spatially-constrained clustering to identify different anatomic structures, mapping the follicles and interfollicular regions. Following a cell segmentation approach, IL-6 pathway genes significantly colocalized with endothelial cells and fibroblastic reticular cells, confirming observations using a single-cell sequencing approach (10X 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.