Molecular genetic studies in lymphocyte apoptosis and human autoimmunity

Using a genetic approach, we have studied the molecular basis of human autoimmunity with special emphasis on a disease that is due to defective lymphocyte apoptosis. Recently, we and our collaborators have found that the autoimmune/lymphoproliferative syndrome (ALPS), an inherited disease of children comprising marked lymphoid hyperplasia and autoimmune manifestations, is due to abnormalities in the CD95 gene that cause defective lymphocyte apoptosis. Our recent investigations have shown that the mutations in most families with ALPS cause either global or local changes in the structure of a cytoplasmic portion of the molecule called the 'death domain'. These death domain alterations impair binding of the adapter protein FADD/MORT1 and result in a failure to activate apoptotic caspases after CD95 (Fas/APO-1) cross-linking. Mutations in apoptotic caspases may also contribute to the pathogenesis of ALPS in individuals that have no CD95 gene mutations.