Most cases of autoimmune lymphoproliferative syndrome (ALPS) are associated with heterozygous mutations in the genes encoding CD95 (Fas receptor), CD95 ligand and the apoptotic enzyme caspase-10. These mutations lead to defects in lymphocyte apoptosis, lymphadenopathy and autoimmunity. In the September 26
Chun et al. studied two patients who have ALPS-related disorders but lack mutations in the CD95, CD95L or caspase-10 genes. They identified a homozygous C to T mutation in the capsase-8 gene that reduced the protein's stability and destroyed its enzymatic activity. The mutation also affected T-cell activation and proliferation, natural killer cell activation and immunoglobulin production. They confirmed the role of caspase-8 in T cell functions using RNAi experiments in normal human lymphocytes and rescue experiments in the patient's cells.
The authors conclude that caspase-8 plays a ...
