Genetic deficiency in TIPE2 resulted in significant immunopathological changes, including splenomegaly, leukocytosis, hypersensitivity to Toll-like receptor (TLR) and T-cell receptor (TCR) actuation, and cytokine overproduction, due to the proapoptotic effect of TIPE2 via the negative regulation of the activating protein (AP)-1 and nuclear factor (NF)-κB pathways, as well as the interaction with Caspase-8 and FasL [22]. The gene discussed is CASP8; the disease is Splenomegaly.