A very rare genetic disorder of the immune system can also be caused by mutations in this gene. This disease, called CEDS, stands for “
Caspase eight deficiency state.” CEDS has features similar to
ALPS, another genetic disease of
apoptosis, with the addition of an
immunodeficient phenotype. Thus, the clinical manifestations include
splenomegaly and
lymphadenopathy, in addition to recurrent sinopulmonary infections, recurrent
mucocutaneous herpesvirus, persistent warts and
molluscum contagiosum infections, and
hypogammaglobulinemia. There is sometimes lymphocytic infiltrative disease in
parenchymal organs, but
autoimmunity is minimal and
lymphoma has not been observed in the CEDS patients. CEDS is inherited in an autosomal recessive manner. The clinical phenotype of CEDS patients represented a
paradox since caspase-8 was considered to be chiefly a
proapoptotic protease, that was mainly involved in signal transduction from
Tumor necrosis factor receptor family death receptors such as Fas. The defect in lymphocyte activation and protective immunity suggested that caspase-8 had additional signaling roles in
lymphocytes. Further work revealed that caspase-8 was essential for the induction of the transcription factor “nuclear factor κB” (
NF-κB) after stimulation through
antigen receptors, Fc receptors, or Toll-like receptor 4 in T, B, and
natural killer cells. Biochemically, caspase-8 was found to enter the complex of the inhibitor of
NF-κB kinase (IKK) with the upstream Bcl10-MALT1 (mucosa-associated lymphatic tissue) adapter complex which were crucial for the induction of nuclear translocation of NF-κB. Moreover, the biochemical form of caspase-8 differed in the two pathways. For the death pathway, the caspase-8
zymogen is cleaved into subunits that assemble to form the mature, highly active caspase heterotetramer whereas for the activation pathway, the zymogen appears to remain intact perhaps to limit its proteolytic function but enhance its capability as an adapter protein. == Interactions ==