In 1990 we identified a child with a disorder involving dramatic enlargement of all her lymph node chains, hepatomegaly, splenomegaly, autoimmune hemolytic anemia and marked expansion of CD3+/CD4-/CD8- T cells. We have termed this disorder autoimmune lymphoproliferative syndrome, or ALPS. We subsequently identified eight additional children with similar disorders; their clinical and immunologic features were well-studied. During the past year, we discovered heritable, functional mutations-in the first 5 cases tested-in the gene encoding Fas, a cell surface protein involved in lymphocyte apoptosis. This is the first genetic disorder involving apoptosis and the first human gene in which a defect leads to autoimmune disease. We will be analyzing other proteins related to apoptosis to determine whether they contribute to ALPS.
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