09/12/2025 Important insight for Castleman disease patients: Idiopathic multicentric Castleman disease (iMCD) is a rare lymphoproliferative disorder characterized by systemic inflammation and lymphadenopathy. Two major clinical subtypes, idiopathic plasmacytic lymphadenopathy (iMCD-IPL) and iMCD with thrombocytopenia, anasarca, fever, renal dysfunction/reticulin fibrosis, and organomegaly (iMCD-TAFRO), exhibit distinct pathophysiologic mechanisms. While interleukin-6 (IL-6) is known to be elevated in iMCD, the differences in IL-6 production sources between subtypes remain unclear. The authors examined the source of IL-6 production and its transcriptional regulation across iMCD subtypes using immunohistochemistry (IHC), in situ hybridization (ISH), and gene expression profiling. Their findings suggest that XBP1-mediated IL-6 production may contribute to iMCD-IPL pathogenesis, potentially explaining its favorable responses to IL-6 blockade therapy. In contrast, IL-6 production in iMCD-TAFRO may be predominantly from vascular endothelial cells, suggesting that elevated serum IL-6 is a secondary phenomenon of the cytokine storm in this subtype. Future studies should clarify how proteomics and gene expression profiling can inform subtype-specific therapeutic strategies in iMCD.
