RESUMEN
Autoimmune lymphoproliferative syndrome (ALPS) is a primary immunodeficiency caused by impaired Fas/FasL-mediated apoptosis of lymphocytes and is characterized by chronic nonmalignant or benign lymphoproliferation, autoimmune manifestations and expansion of double negative (DN) T-cells (TCRαß+CD4-CD8-). Most cases of ALPS are associated with germline (ALPS-FAS) or somatic (ALPS-sFAS) heterozygous FAS mutations or a combination of both. Here we report three unrelated patients with ALPS-sFAS. Only one of them showed impaired Fas function in PHA-activated T-cells. In this patient, the genetic analysis of the caspase-10 gene (CASP10) identified a heterozygous germline change in exon 9 (c.1337A>G) causing Y446C substitution in the caspase-10 protein. In addition, this patient had a dysregulated T- and B-cell phenotype; circulating lymphocytes showed expansion of T effector memory CD45RA+ (TEMRA) CD4 T-cells, effector memory CD8 T-cells, CD21(low) B-cells and reduced memory switched B-cells. Additionally, this patient showed altered expression in T-cells of several molecules that change during differentiation from naïve to effector cells (CD27, CD95, CD57 and perforin). Molecular alterations in genes of the Fas pathway are necessary for the development of ALPS and this syndrome could be influenced by the concurrent effect of other mutations hitting different genes involved in Fas or related pathways.