Autoimmune lymphoproliferative syndrome due to somatic FAS mutation (ALPS-sFAS) combined with a germline caspase-10 (CASP10) variation.
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.
Servicio de Inmunología, Hospital Universitario 12 de Octubre, Madrid, Spain.
Ana
A
Martínez-Feito
Servicio de Inmunología, Hospital Universitario Infanta Cristina, Badajoz, Spain.
Josefa
J
Melero
Servicio de Inmunología, Hospital Universitario 12 de Octubre, Madrid, Spain.
Sergio
S
Mora-Díaz
Servicio de Hemato-Oncología Pediátrica, Hospital Universitario Miguel Servet, Zaragoza, Spain.
Carmen
C
Rodríguez-Vigil
Servicio de Hematología, Hospital Universitario Infanta Cristina, Badajoz, Spain.
Ramón
R
Elduayen
Unidad de Inmunodeficiencias e Infecciosas pediátricas, Unidad de Hemato-Oncología Pediátrica, Hospital Universitario 12 Octubre, Madrid, Spain; Instituto de Investigación i+12, Madrid, Spain.
Luis I
LI
González-Granado
Servicio de Inmunología, Hospital Universitario 12 de Octubre, Madrid, Spain.
Dolores
D
Pérez-Méndez
Servicio de Inmunología, Hospital Universitario 12 de Octubre, Madrid, Spain.
Elena
E
Sánchez-Zapardiel
Servicio de Inmunología, Hospital Universitario 12 de Octubre, Madrid, Spain.
Raquel
R
Ruiz-García
Servicio de Inmunología, Hospital Universitario 12 de Octubre, Madrid, Spain.
Miguela
M
Menchén
Servicio de Inmunología, Hospital Universitario 12 de Octubre, Madrid, Spain.
Josefa
J
Díaz-Madroñero
Servicio de Inmunología, Hospital Universitario 12 de Octubre, Madrid, Spain; Instituto de Investigación i+12, Madrid, Spain.
Estela
E
Paz-Artal
Servicio de Hematología, Hospital Universitario de Cruces, Bilbao, Spain.
Rafael
R
Del Orbe-Barreto
Servicio de Inmunología, Hospital Universitario de Cruces, Bilbao, Spain.
Marta
M
Riñón
Servicio de Inmunología, Hospital Universitario 12 de Octubre, Madrid, Spain; Instituto de Investigación i+12, Madrid, Spain. Electronic address: luis.allende@salud.madrid.org.
Luis M
LM
Allende
D000293:Adolescent; D015703:Antigens, CD / Q000235:genetics / Q000276:immunology; D056735:Autoimmune Lymphoproliferative Syndrome / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D001402:B-Lymphocytes / Q000276:immunology* / Q000473:pathology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000473:pathology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000473:pathology; D053455:Caspase 10 / Q000235:genetics* / Q000276:immunology; D005091:Exons; D005260:Female; D015870:Gene Expression; D006801:Humans; D007156:Immunologic Memory; D008206:Lymphatic Diseases / Q000235:genetics / Q000276:immunology / Q000473:pathology; D008213:Lymphocyte Activation / Q000187:drug effects; D008297:Male; D008875:Middle Aged; D009154:Mutation; D054353:Perforin / Q000235:genetics / Q000276:immunology; D010835:Phytohemagglutinins / Q000494:pharmacology; D061251:Primary Cell Culture; D013163:Splenomegaly / Q000235:genetics / Q000276:immunology / Q000473:pathology; D019014:fas Receptor / Q000235:genetics* / Q000276:immunology
D015703:Antigens, CD; C491901:FAS protein, human; D010835:Phytohemagglutinins; D019014:fas Receptor; D054353:Perforin; D053455:Caspase 10; C506438:CASP10 protein, human
ALPS; Apoptosis; CASP10; FAS; Immunodeficiency