Decreased activation-induced cell death by EBV-transformed B-cells from a patient with autoimmune lymphoproliferative syndrome caused by a novel FASLG mutation.
BACKGROUND
Autoimmune lymphoproliferative syndrome (ALPS) is a primary immunodeficiency characterized by chronic lymphoproliferation, autoimmune manifestations, expansion of double-negative T-cells, and susceptibility to malignancies. Most cases of ALPS are caused by germline or somatic FAS mutations. We report the case of an ALPS patient due to a novel homozygous Fasligand gene mutation (ALPS-FASLG).


METHODS
ALPS biomarkers were measured and FASLG mutation was identified. Functional characterization was carried out based on activation-induced cell death (AICD) and cytotoxicity assays.


RESULTS
This report describes the cases of a patient who presented a severe form of ALPS-FASLG, and his brother who had died due to complications related to ALPS. Moreover, in another family, we present the first case of lymphoma in a patient with ALPS-FASLG. Functional studies showed defective Fasligand-mediated apoptosis, cytotoxicity, and AICD in T-cell blasts. Otherwise, expression of the FASLG gene and corresponding protein was normal, but the shedding of the Fasligand was impaired in T-cells. Additionally, analyzing Epstein-Barr virus (EBV)-transformed B-cells, our results indicate impaired AICD in ALPS-FASLG patients.


CONCLUSIONS
Patients with autosomal recessive inheritance of ALPS-FASLG have a severe phenotype and a partial defect in AICD in T- and B-cell lines. The Fasligand could play a key role in immune surveillance preventing malignancy.
Servicio de Inmunología, Hospital Universitario 12 de Octubre, Madrid, Spain.
Raquel
R
Ruiz-García
Servicio de Inmunología, Hospital Universitario 12 de Octubre, Madrid, Spain.
Sergio
S
Mora
UGC de Pediatría, Hospital Materno-Infantil, Hospital Regional Universitario, Málaga, Spain.
Gema
G
Lozano-Sánchez
Departamento de Bioquímica, Biología Molecular y Celular, Universidad de Zaragoza, Zaragoza, Spain.
Luis
L
Martínez-Lostao
Servicio de Inmunología, Hospital Universitario 12 de Octubre, Madrid, Spain.|Instituto de Investigación I+12, Madrid, Spain.|Facultad de Medicina, Universidad Complutense y Sección de Inmunología, Universidad San Pablo CEU, Madrid, Spain.
Estela
E
Paz-Artal
Instituto de Investigación I+12, Madrid, Spain.|Unidad de Inmunodeficiencias, Departamento de Pediatría, Hospital Universitario 12 de Octubre, Madrid, Spain.
Jesús
J
Ruiz-Contreras
Departamento de Bioquímica, Biología Molecular y Celular, Universidad de Zaragoza, Zaragoza, Spain.
Alberto
A
Anel
Instituto de Investigación I+12, Madrid, Spain.|Unidad de Inmunodeficiencias, Departamento de Pediatría, Hospital Universitario 12 de Octubre, Madrid, Spain.
Luis I
LI
González-Granado
UGC de Pediatría, Hospital Materno-Infantil, Hospital Regional Universitario, Málaga, Spain.
David
D
Moreno-Pérez
Servicio de Inmunología, Hospital Universitario 12 de Octubre, Madrid, Spain.|Instituto de Investigación I+12, Madrid, Spain.
Luis M
LM
Allende
D000328:Adult; D017209:Apoptosis; D056735:Autoimmune Lymphoproliferative Syndrome / Q000175:diagnosis / Q000188:drug therapy / Q000235:genetics* / Q000276:immunology; D001402:B-Lymphocytes / Q000276:immunology / Q000473:pathology / Q000821:virology*; D002472:Cell Transformation, Viral; D002675:Child, Preschool; D003241:Consanguinity; D003602:Cytotoxicity, Immunologic; D004252:DNA Mutational Analysis; D053222:Fas Ligand Protein / Q000235:genetics* / Q000276:immunology; D005260:Female; D020022:Genetic Predisposition to Disease; D057809:HEK293 Cells; D004854:Herpesvirus 4, Human / Q000472:pathogenicity*; D006720:Homozygote; D006801:Humans; D007223:Infant; D019169:Jurkat Cells; D008223:Lymphoma / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D008297:Male; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D013601:T-Lymphocytes / Q000276:immunology / Q000473:pathology; D014162:Transfection
C505661:FASLG protein, human; D053222:Fas Ligand Protein