This pilot project is designed to evaluate the hypothesis that certain children with generalized lymphadenopathy, hypergammaglobulinemia and preponderant CD4 CD8 T lymphocytes (double-negative T-cells, DNTs) have a genetic defect in the Fas-Fas ligand apoptosis pathway similar to that seen in the autoimmune lpr and/or gld mutant mice. Preliminary studies suggest that lymphocytes from one such child as well as his parents have abnormal mRNA expression of Fas. We propose to evaluate the expression and nucleotide sequence of the fas and fas ligand cDNAs in patients with lymphoproliferation and increased CD4 CD8 circulating cells and to determine the underlying genetic basis of the fas or fas ligand defect(s) through analysis of genomic DNA. Simultaneously, we will test functional abnormalities in peripheral lymphocyte behavior stemming from defects in the apoptotic pathway. The long term goals of these studies involving fas and fas ligand mutations include the molecular include the molecular and cellular characterization of the novel human syndrome of generalized double negative T-cell lymphoproliferation associated with autoimmunity. Accomplishment of this goal will also improve our understanding of the importance of fas gene defects in other autoimmune diseases. Human diseases caused by fas and fas ligand defects may manifest as a wide spectrum of clinical phenomena as in the mouse model. Disease expression may depend on the molecular defects i these genes, allele dosage, as well as the influence exerted by other genes involved in T cell regulation (triggering, proliferation, apoptosis, etc.). Disease in humans will also be modified by required medical interventions. Development of a screening program for patients with unexplained lymphadenopathy and/or autoimmune disease and their families would help define the prevalence and importance of fas and fas ligand gene defects in humans.
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