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

• 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 monocytes pro-inflammatory 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 employed single-cell RNA sequencing (scRNA-seq) of peripheral blood mononuclear cells (PBMCs) from a cohort of 15 patients with iMCD and four 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 (IL-6R) 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 NK/NKT cells through enhanced type II interferon (IFN-II) signaling, while 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 was 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 of IFN-II pathway activation in amplifying inflammatory storms. Our findings provide valuable biomarkers for assessing disease severity and identify new therapeutic targets for iMCD.