Autoimmune lymphoproliferative syndrome. A human disorder of abnormal lymphocyte survival

The importance of Fas in the homeostatic balance between lymphocyte survival and death is underscored by the three main consequences of defective Fas-mediated apoptosis, as experienced by patients with ALPS: (1) abnormal accumulation of lymphocytes results in lymphadenopathy, hepatosplenomegaly, and hypersplenism; (2) failure of removal of potentially autoreactive lymphocytes, a process normally used to eliminate lymphocytes that have escaped negative selection in the thymus and bone marrow (see article by Fleisher and Blessing, p. 1197), is associated with the appearance of autoimmune manifestations; and (3) inappropriate survival of lymphocytes may lead to the development of malignancies. As with other "experiments of nature," the many aspects of ALPS have provided valuable new insights into the immune system and the importance of a proper balance between life and death of lymphocytes. ALPS is an example of how a mouse disease model was applied directly to the identification of the molecular basis and the understanding of a remarkable disease in humans. It is also an example of clinical observations being linked to basic scientific data to unlock the underlying defect(s) causing a disease. Despite the difficulty in fully understanding the complex nature of the clinical course, the immunologic abnormalities, and the genetic aspects of ALPS, the accumulated experience in diagnosis, treatment, and follow-up of patients and relatives has generated a "road map" that can be used as a guide for their care. As examples, the appreciation that manifestations of lymphoproliferation usually subside over time has allowed a "wait-and-see" approach in many patients who might previously have been treated aggressively. The appreciation that these patients are at increased risk for malignancies has mandated the adoption of careful and lifelong follow-up. Future efforts directed at careful clinical follow-up and scientific investigation are required to learn more about the incidence and natural history of ALPS, therapeutic interventions directed at altering the consequences of TNFRSF6 mutations, and the identification of other genetic and environmental factors that may have a role in the pathogenesis of ALPS.