Autoimmune lymphoproliferative syndrome

The autoimmune lymphoproliferative syndrome is a recently identified human disorder of lymphocyte apoptosis that has provided important information about Fas-mediated lymphocyte apoptosis. In this review we summarize current information regarding the diagnosis, management and underlying molecular basis of the syndrome.

The genetic basis of autoimmune lymphoproliferative syndrome has continued to expand with the recently identified defects in caspase-8 and caspase-10 along with the more frequent defect in Fas and unusual Fas ligand deficiency. Genotype-phenotype links and differences continue to be assessed while the variation in penetrance remains to be fully defined. An increased risk for lymphoreticular malignancy has clearly been established in those autoimmune lymphoproliferative syndrome patients with defects in the gene encoding for the death domain of Fas. Therapy remains directed at managing acute problems although a preliminary report suggests sulphadoxine-pyrimethamine treatment may be successful in patients with the syndrome or autoimmune lymphoproliferative syndrome-like disease and this approach is presently being studied in a controlled trial.

Defects in multiple molecules within the Fas apoptotic pathway may result in autoimmune lymphoproliferative syndrome and, despite recent advances, a number of patients remain with unidentified genetic defects. There is also clear need for improved understanding of mechanisms underlying the development of autoimmunity in this disorder and to provide early evidence for development of malignancy. This syndrome is the first human disorder linked to a germline defect in lymphocyte apoptosis and it continues to be an area of productive research and new information regarding this process of lymphocyte homeostasis and its role in human disease.