In 1990, we identified and began to characterize a new chronic disorder we have termed autoimmune lymphoproliferative syndrome, or ALPS. It manifests as chronic nonmalignant adenopathy and splenomegaly; the expansion of an unusual population of CD4-CD8-T cells (DNT?s); and the development of autoimmune disease including but not limited to hemolytic anemia, thrombocytopenia and neutropenia. Through our family-based association studies involving over 700 members in 200 families, we learned to identify and diagnose the syndrome and to identify and treat most of its major complications effectively. We have documented a variety of humoral and cellular immunologic 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 genes involving lymphocyte apoptosis pathways. Inherited mutations in genes that regulate cell death, a process referred to as apoptosis, is causal in the development of ALPS and related disease. Mutations in a total of four genes associated with ALPS have been identified to date. Most cases of ALPS (over 70 percent) are classified as Type Ia, these involve heterozygous mutations in TNFRSF6 (Tumor necrosis Factor Receptor SuperFamily-6), the gene that encodes the lymphocyte surface protein Fas (CD95, APO-1); Type Ib is associated with mutations in Fas ligand, Type IIa with caspase-10 and Type IIb with caspase-8. Patients for whom the involved apoptotic gene has yet to be identified are classified as Type III, comprising 35 percent of our families. We determined that inherited mutations in TNFRSF6 represent a novel risk factor for the subsequent development of B and T cell lymphomas. The risk of non-Hodgkin and Hodgkin lymphomas compared to that of the general population, matched by age, are 14 and 51 fold elevated, respectively. 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 discriminate ALPS nodes from lymphomatous nodes. We are also exploring new therapeutic options for ALPS both in animal models and in patients. We are testing agents that stimulate lymphocyte apoptosis in MRL/lpr mice bearing homozygous deletions of the TNFRSF6 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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