Updated model of iMCD pathogenesis. Three hypothesized mechanisms may be responsible for the iMCD cytokine and chemokine storm: first, the autoimmune/autoinflammatory hypothesis involves (1a) auto-antibodies triggering proinflammatory cytokine release by antigen-presenting cells that induce the as-yet-unknown hypercytokine-secreting cell to release IL-6 or other pathologic cytokines; (1b/c) dysregulated signaling in an antigen presenting cell or other as-yet-unknown hypercytokine-secreting cell releasing IL-6 or other pathologic cytokines, or (1d) a defect in the regulation of activated inflammatory cells. The cytokine and chemokine storm is perpetuated by positive feedback of IL-6, other pathologic cytokines, and/or possibly further auto-antibody stimulation. Second, the paraneoplastic syndrome hypothesis involves a somatic mutation in benign or malignant cells inside or outside of the lymph node that causes constitutive cytokine release. Preliminary data suggest these may be lymph node stromal cells. Third, the pathogen hypothesis involves either infection with HHV-8 that is clinically undetectable, a novel virus, or another pathogen signaling proinflammatory cytokines. An active infection by a single virus is less likely based on preliminary data generated from pathogen discovery studies. Regardless of the etiology, the cytokine and chemokine storm is the common pathway that results in the subsequent clinical and histopathological features of iMCD. AAB, autoantibodies; AIHA, autoimmune hemolytic anemia; AIT, autoimmune thrombocytopenia; LAD, lymphadenopathy; PMN, polymorphic neutrophil. Adapted from Fajgenbaum et al.¹