Profound B cell dysregulation in idiopathic multicentric Castleman disease

Idiopathic multicentric Castleman disease (iMCD) is a rare and life-threatening hematologic illness characterized by lymphadenopathy at multiple sites by unknown causes. Patients with iMCD experience periods of systemic inflammation, or disease flares, due to cytokine release that includes interleukin-6 (IL-6). Treatment with IL-6 inhibition is effective in one-third of patients suggesting that other key mechanisms contribute to disease pathogenesis. To reveal other pathogenic mediators of iMCD, we performed serum proteomic analysis and high dimensional immunophenotyping on the blood of iMCD patients during disease flare. Compared to healthy donors, we discovered that the chemokine, CXCL13, was among the top most upregulated serum analytes in iMCD confirming our previously published data, and correlated with disease severity. In the same group of patients with a severe, life-threatening clinical phenotype, the expression of chemokine receptor, CXCR5, which binds CXCL13, was decreased across lymphocyte populations including all B cell subsets. In addition, we observed evidence of B cell activation in iMCD as determined by increased soluble B-cell activation factor (BAFF) and Ki-67 expression. Together, our data suggest that flare episodes in iMCD involves mobilization and subsequent activation of B cells and that these mechanisms may play an important role in disease pathogenesis.