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 (TCR...

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Published in:	Immunobiology (1979) Vol. 221; no. 1; pp. 40 - 47
Main Authors:	Martínez-Feito, Ana, Melero, Josefa, Mora-Díaz, Sergio, Rodríguez-Vigil, Carmen, Elduayen, Ramón, González-Granado, Luis I, Pérez-Méndez, Dolores, Sánchez-Zapardiel, Elena, Ruiz-García, Raquel, Menchén, Miguela, Díaz-Madroñero, Josefa, Paz-Artal, Estela, del Orbe-Barreto, Rafael, Riñón, Marta, Allende, Luis M
Format:	Journal Article
Language:	English
Published:	Netherlands Elsevier GmbH 01-01-2016
Subjects:	Adolescent Advanced Basic Science Allergy and Immunology ALPS Antigens, CD - genetics Antigens, CD - immunology Apoptosis Autoimmune Lymphoproliferative Syndrome - genetics Autoimmune Lymphoproliferative Syndrome - immunology Autoimmune Lymphoproliferative Syndrome - pathology B-Lymphocytes - immunology B-Lymphocytes - pathology CASP10 Caspase 10 - genetics Caspase 10 - immunology CD4-Positive T-Lymphocytes - immunology CD4-Positive T-Lymphocytes - pathology CD8-Positive T-Lymphocytes - immunology CD8-Positive T-Lymphocytes - pathology Exons FAS fas Receptor - genetics fas Receptor - immunology Female Gene Expression Humans Immunodeficiency Immunologic Memory Lymphatic Diseases - genetics Lymphatic Diseases - immunology Lymphatic Diseases - pathology Lymphocyte Activation - drug effects Male Middle Aged Mutation Perforin - genetics Perforin - immunology Phytohemagglutinins - pharmacology Primary Cell Culture Splenomegaly - genetics Splenomegaly - immunology Splenomegaly - pathology ALPS FAS CASP10 Immunodeficiency Apoptosis
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Summary:	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 (TCR α β + 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, CD21low 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.
Bibliography:	ObjectType-Case Study-2 SourceType-Scholarly Journals-1 ObjectType-Feature-4 content type line 23 ObjectType-Report-1 ObjectType-Article-3
ISSN:	0171-2985 1878-3279
DOI:	10.1016/j.imbio.2015.08.004