Distinct monocyte subpopulations dominate peripheral blood in iMCD-affected and -unaffected sisters. (A) UMAP of the PBMCs from all 3 sisters (Twin-CS and Twin-CM at asymptomatic “baseline” state), showing heterogeneity within monocytes and other cell types. (B) The monocyte population formed the largest proportion of cell type within the PBMCs of affected twins, in contrast to their unaffected sister. (C) Further analysis of monocytes showed different subpopulations enriched within both affected twins (group 1) and their unaffected sister (group 3). The asymptomatic affected Twin-CM carried a relatively higher proportion of group 2 monocytes. (D) Group 1 monocytes were enriched for the expression of acute and chronic inflammatory genes including several S100A family genes (eg, S100A8, S100A12, S100A9, and S100A6). Group 2 monocytes expressed a cytotoxic gene signature including PRF1, GNLY, CTSW, GZMA, and GZMH. Group 3 monocytes enriched for expression of major histocompatibility complex (MHC) class II genes (eg, HLA-DRA, HLA-DPB1, HLA-DRB1, HLA-DPA1, CD74, HLA-DMA, HLA-DQB1, and HLA-DQA1). Minor subgroups identified include FCGR2B-expressing monocytes (group 4), FCGR3B-expressing nonclassical monocytes (group 5), and others (groups 6 and 7). (E) Gene ontology (GO) pathway analysis demonstrated enrichment of neutrophil degranulation and activation pathways in group 1 monocytes. Group 2 monocytes harbored signatures of T-cell activation and cytokine signaling. Group 3 monocytes were enriched for signatures of antigen processing. (F) Both the affected twins, particularly in Twin-CS, were predominantly carrying group 1 monocytes enriched for the expression of acute and chronic inflammatory gene signatures. Twin-CM carried a higher proportion of group 2 monocytes harboring signatures of cytotoxic T-cell activation. PBMCs from the twins were obtained at their asymptomatic “baseline” state (for Twin-CS, after rituximab therapy). In the unaffected sister, group 3 monocytes enriched for signatures of antigen processing were dominant.

Distinct monocyte subpopulations dominate peripheral blood in iMCD-affected and -unaffected sisters. (A) UMAP of the PBMCs from all 3 sisters (Twin-CS and Twin-CM at asymptomatic “baseline” state), showing heterogeneity within monocytes and other cell types. (B) The monocyte population formed the largest proportion of cell type within the PBMCs of affected twins, in contrast to their unaffected sister. (C) Further analysis of monocytes showed different subpopulations enriched within both affected twins (group 1) and their unaffected sister (group 3). The asymptomatic affected Twin-CM carried a relatively higher proportion of group 2 monocytes. (D) Group 1 monocytes were enriched for the expression of acute and chronic inflammatory genes including several S100A family genes (eg, S100A8, S100A12, S100A9, and S100A6). Group 2 monocytes expressed a cytotoxic gene signature including PRF1, GNLY, CTSW, GZMA, and GZMH. Group 3 monocytes enriched for expression of major histocompatibility complex (MHC) class II genes (eg, HLA-DRA, HLA-DPB1, HLA-DRB1, HLA-DPA1, CD74, HLA-DMA, HLA-DQB1, and HLA-DQA1). Minor subgroups identified include FCGR2B-expressing monocytes (group 4), FCGR3B-expressing nonclassical monocytes (group 5), and others (groups 6 and 7). (E) Gene ontology (GO) pathway analysis demonstrated enrichment of neutrophil degranulation and activation pathways in group 1 monocytes. Group 2 monocytes harbored signatures of T-cell activation and cytokine signaling. Group 3 monocytes were enriched for signatures of antigen processing. (F) Both the affected twins, particularly in Twin-CS, were predominantly carrying group 1 monocytes enriched for the expression of acute and chronic inflammatory gene signatures. Twin-CM carried a higher proportion of group 2 monocytes harboring signatures of cytotoxic T-cell activation. PBMCs from the twins were obtained at their asymptomatic “baseline” state (for Twin-CS, after rituximab therapy). In the unaffected sister, group 3 monocytes enriched for signatures of antigen processing were dominant.

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