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 including autoimmune hemolytic anemia, immune thrombocytopenia and neutropenia. Through our investigations of nearly 650 members of over 160 families, we 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 leading to immune cytopenias, alterations in lymphocyte subsets and disordered regulation of cytokines. 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 in patients with Fas gene mutation even when no longer appropriate; leading to accumulation of cells infiltrating tissues, including cells with reactivity against self-antigens. Fas mutations are not responsible, however, for ALPS in about 45 of our affected families. Mutations in the Fas-ligand are responsible for disease in 1 family. Mutations in caspases 8 and 10 are associated with defective apoptosis and ALPS in 7 of our other families. Other, still unidentified, genetic defects must underlie ALPS in our remaining families. 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 are addressing by defining an algorithm for patient follow up and lymphoma detection under a protocol in which PET scanning is being evaluated for its ability to distinguish reactive ALPS nodes from normal nodes, and hopefully lymphomatous nodes from ALPS nodes. During the past year we began to explore new therapeutic options for ALPS< b oth in animal models and in patients. We are testing agents that stimulate lymphocyte apoptosis in MRL/lpr mice bearing homozygous deletions of the gene encoding Fas. And, increasingly, mycophenylate mofitil is being used as a steroid sparing and spleen salvaging agent in patients with refractory autoimmune cytopenias.
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