In 1990, we identified and began to characterize a new chronic disorder we have termed autoimmune lymphoproliferative syndrome, or ALPS. It is manifested by chronic non-malignant adenopathy and splenomegaly and a variety of autoimmune phenomena.Through our investigations of nearly 400 members of 94 families, we have learned to identify and diagnose the syndrome and treat most of its complications effectively. We have documented a variety of cellular and humoral mmunologic abnormalities in ALPS patients, including circulation of multiple autoantibodies, alterations in lymphocyte subsets anddisordered regulation of cytokines including IL-10.In vitro studies with human cells and cell lines showed that ALPS is associated with inherited defects in lymphocyte apoptosis. About 75% of patients possess ALPS Type Ia, associated with functional mutations in the gene encoding Fas, a protein that triggers apoptosis, the programmed death of lymphocytes. Because Fas is critical to lymphocyte apoptosis, the cells persist when no longer appropriate; leading to accumulation of cells infiltrating tissues; including cells with reactivity against self-antigens. Initial studies showed that Fas is expressed on the surfaces of our patients cells, but some of it is abnormal, arising from one mutated copy of the pair of Fas genes. The defective Fas protein that is expressed interferes with the function of the normal Fas protein. Many relatives of ALPS patient have Fas mutations but are completely well. Recent studies showed that the risk of manifesting clinical features of ALPS is significantly greater in individuals who inherit mutations in exon 9 encoding the cytoplasmic signaling domain of Fas. Fas mutations are not responsible, however, for ALPS in about 20 of our affected families. Mutations in the fas-ligand are responsible for disease in 2 families. Mutations in caspases 8 and 10 are associated with defective apoptosis and ALPS in 3 of our other families. Other, still unidentified, genetic defects must underlie ALPS in our remaining families. During the past year, through collaborations, we determined that inherited mutations in Fas represent a novel risk factor for the subsequent development of B and T cell lymphomas. The risk of non-Hodgkin's and Hodgkin's lymphomas are 14-51 fold elevated over age and gender-matched controls. This represents a challenge that we will address by defining an algorithm for patient follow up and lymphoma detection.
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