IFN-γ promotes the progression of iMCD by activating inflammatory monocytes Available to Purchase

• IL-6 is primarily expressed by B cells in lymph nodes, and the IL-6 pathway is strongly activated in monocytes, driving inflammatory storms.

• Specific NK/NKT cells amplify monocyte proinflammatory activity via IFN-γ secretion, linked to disease severity and treatment resistance.

A deeper understanding of the immune landscape in patients with idiopathic multicentric Castleman disease (iMCD) is essential to establish early prognostic stratification and uncover novel therapeutic targets. We used single-cell RNA sequencing of peripheral blood mononuclear cells (PBMCs) from a cohort of 15 patients with iMCD and 4 healthy controls. To explore the sources of interleukin-6 (IL-6), we included lymph node and bone marrow samples for comparison with PBMCs. Our results indicate that IL-6 primarily originates from the lymph nodes, particularly from activated B cells. Similarly, in peripheral blood, activated B cells are also the main source of IL-6. IL-6 receptor is primarily expressed in monocytes in PBMCs, with CCL monocytes showing the strongest activation of the IL-6 signaling pathway. This suggests that CCL monocytes in iMCD may play an important role in driving peripheral inflammatory storms. CellChat analysis reveals that during disease flares, CCL monocytes interact with specific natural killer (NK)/NKT cells through enhanced type II interferon (IFN-II) signaling, whereas this interaction significantly diminishes during remission, indicating a significant role for IFN-II in the pathogenesis of iMCD. Notably, serum IFN-γ levels positively correlate with both disease severity and treatment resistance, a finding validated by a large independent iMCD cohort. Our findings confirm that the IL-6 pathway remains central to iMCD pathogenesis and highlight a significant role for IFN-II pathway activation in amplifying inflammatory storms. Our findings provide valuable biomarkers for assessing disease severity and identify new therapeutic targets for iMCD.