Clusterin expression and germinal center morphometry help distinguish idiopathic multicentric castleman disease from...

Idiopathic multicentric Castleman disease (iMCD) is a heterogeneous cytokine storm disorder involving systemic inflammation, multicentric lymphadenopathy with characteristic histopathology, and life-threatening multiple organ dysfunction. Patients can present with symptoms ranging from thrombocytopenia, anasarca, fever/elevated C-reactive protein (CRP), reticulin myelofibrosis, renal dysfunction, and organomegaly (iMCD-TAFRO) to thrombocytosis, hypergammaglobulinemia, and plasmacytosis (iMCD-IPL), with patients not falling into either group (iMCD-NOS). The molecular mechanisms across the clinical subtypes have not been elucidated and new effective treatments are needed. Here, we performed bulk RNA sequencing and targeted gene expression quantification in lymph node tissue from multiple iMCD clinical subtypes, pathologically related disorders, and controls. We identified 249 upregulated and 42 downregulated genes in iMCD-TAFRO lymph node tissue, which were enriched in the following pathways: angiogenesis, cell proliferation, and various aspects of the humoral and innate immune response. The targeted gene expression analysis revealed shared differentially expressed genes (DEGs) across all three iMCD clinical subtypes, including SPP1, XBP1, PRDM1, and CLU. We identified unique DEGs in each iMCD clinical subtype, including PLA2G2A, MSR1, IL8 (iMCD-TAFRO), IL9, KIR3DL1, IL18RAP (iMCD-IPL), and IL7, TLR8, and CX3CR1 (iMCD-NOS). Since Clusterin (CLU) was significantly upregulated in iMCD but not in related conditions, we performed immunohistochemistry and observed that Clusterin is elevated in the germinal center and mantle zone regions of iMCD patient lymph nodes. A composite model incorporating CLU expression in these lymph node compartments with germinal center features demonstrated strong performance in differentiating iMCD from selected lymphadenopathies. Together, this work identified pathways dysregulated in iMCD lymph nodes and suggests that Clusterin, particularly when integrated with germinal center features, could be a novel biomarker.