Autoimmune lymphoproliferative syndrome due to somatic FAS mutation (ALPS-sFAS) combined with a germline caspase-10 (CASP10) variation.

Abstract

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 (TCRαβ+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.

• Authors: Ana Martínez-Feito, Josefa Melero, Sergio Mora-Díaz, Carmen Rodríguez-Vigil, Ramón Elduayen, Luis I González-Granado, Dolores Pérez-Méndez, Elena Sánchez-Zapardiel, Raquel Ruiz-García, Miguela Menchén, Josefa Díaz-Madroñero, Estela Paz-Artal, Rafael Del Orbe-Barreto, Marta Riñón, Luis M Allende
• Journal: Immunobiology (Immunobiology) Vol. 221 Issue 1 Pg. 40-7 (Jan 2016) ISSN: 1878-3279 [Electronic] Netherlands
• PMID: 26323380 (Publication Type: Case Reports, Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 Elsevier GmbH. All rights reserved.

Chemical References

• Antigens, CD
• FAS protein, human
• Phytohemagglutinins
• fas Receptor
• Perforin
• Caspase 10
• CASP10 protein, human

Topics

• Adolescent
• Antigens, CD (genetics, immunology)
• Autoimmune Lymphoproliferative Syndrome (genetics, immunology, pathology)
• B-Lymphocytes (immunology, pathology)
• CD4-Positive T-Lymphocytes (immunology, pathology)
• CD8-Positive T-Lymphocytes (immunology, pathology)
• Caspase 10 (genetics, immunology)
• Exons
• Female
• Gene Expression
• Humans
• Immunologic Memory
• Lymphatic Diseases (genetics, immunology, pathology)
• Lymphocyte Activation (drug effects)
• Male
• Middle Aged
• Mutation
• Perforin (genetics, immunology)
• Phytohemagglutinins (pharmacology)
• Primary Cell Culture
• Splenomegaly (genetics, immunology, pathology)
• fas Receptor (genetics, immunology)