Targeting soluble immunoglobulins ameliorates idiopathic multicentric Castleman disease in a mouse model

Idiopathic multicentric Castleman disease (iMCD) is a rare lymphoproliferative disorder that affects lymph nodes at multiple sites and can progress to life-threatening organ dysfunction. While curative therapies remain unavailable, largely due to a critical gap in understanding the disease’s underlying etiology, the cytokine interleukin-6 (IL-6) is recognized as a major pathogenic driver, particularly in iMCD patients with plasmacytic lymphadenopathy. Here, we demonstrate the presence of Foxp3-expressing cells alongside plasma cells within germinal centers of lymph nodes from such iMCD patients. Based on this observation, we directed IL-6 overexpression specifically to Foxp3 ⁺ Treg cells and established a novel preclinical mouse model of iMCD. This targeted approach successfully recapitulated the key characteristics of iMCD in mice, including multifocal lymphadenopathy, splenomegaly, anemia, thrombocytopenia, marked plasmacytosis, and mortality in young adults. Advanced disease was characterized by renal pathology, including proteinuria and elevated creatinine levels. In this model, IL-6 directly promoted plasmacytosis, resulting in profound IgG1 hyperimmunoglobulinemia. Genetic ablation of soluble immunoglobulin production ameliorated iMCD symptoms, prevented renal dysfunction, and significantly extended survival. Our findings identify IL-6-driven IgG1 plasmacytosis as a critical pathogenic factor in iMCD, shedding light on the mechanisms underlying its development.