Proposed model of iMCD pathogenesis. Three hypothesized mechanisms may be responsible for iMCD proinflammatory hypercytokinemia. (1) The systemic inflammatory disease hypothesis involves (1a) autoantibodies triggering proinflammatory cytokine release by antigen-presenting cells that induce the hypercytokine-secreting cell to release IL-6; (1b/c) an error in kinase or inhibitory signaling in an antigen presenting cell or other hypercytokine-secreting cell causing IL-6 secretion, or (1d) a defect in the regulation of activated inflammatory cells. Systemic inflammation is perpetuated by positive feedback of IL-6 and possibly further autoantibody stimulation. (2) The paraneoplastic syndrome hypothesis involves a somatic mutation in benign or malignant cells inside or outside of the lymph node that causes constitutive proinflammatory cytokine release. (3) The virally driven hypothesis involves a non-HHV-8 virus (ex: EBV, HHV-6) signaling proinflammatory cytokines. Regardless of the etiology, the proinflammatory hypercytokinemia 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.