title: XIAP deficiency in humans causes an X-linked lymphoproliferative syndrome.
abstract: The homeostasis of the immune response requires tight regulation of the proliferation and apoptosis of activated lymphocytes. In humans, defects in immune homeostasis result in lymphoproliferation disorders including autoimmunity, haemophagocytic lymphohystiocytosis and lymphomas. The X-linked lymphoproliferative syndrome (XLP) is a rare, inherited immunodeficiency that is characterized by lymphohystiocytosis, hypogammaglobulinaemia and lymphomas, and that usually develops in response to infection with Epstein-Barr virus (EBV). Mutations in the signalling lymphocyte activation molecule (SLAM)-associated protein SAP, a signalling adaptor molecule, underlie 60% of cases of familial XLP. Here, we identify mutations in the gene that encodes the X-linked inhibitor-of-apoptosis XIAP (also termed BIRC4) in patients with XLP from three families without mutations in SAP. These mutations lead to defective expression of XIAP. We show that apoptosis of lymphocytes from XIAP-deficient patients is enhanced in response to various stimuli including the T-cell antigen receptor (TCR)-CD3 complex, the death receptor CD95 (also termed Fas or Apo-1) and the TNF-associated apoptosis-inducing ligand receptor (TRAIL-R). We also found that XIAP-deficient patients, like SAP-deficient patients, have low numbers of natural killer T-lymphocytes (NKT cells), indicating that XIAP is required for the survival and/or differentiation of NKT cells. The observation that XIAP-deficiency and SAP-deficiency are both associated with a defect in NKT cells strengthens the hypothesis that NKT cells have a key role in the immune response to EBV. Furthermore, by identifying an XLP immunodeficiency that is caused by mutations in XIAP, we show that XIAP is a potent regulator of lymphocyte homeostasis in vivo.
authors.affiliation: Inserm 768, Laboratoire du Développement Normal et Pathologique du Système Immunitaire, Univ. René Descartes, Paris, F-75015, France.
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Rigaud
authors.forename: Marie-Claude
authors.initials: MC
authors.lastname: Fondanèche
authors.forename: Nathalie
authors.initials: N
authors.lastname: Lambert
authors.forename: Benoit
authors.initials: B
authors.lastname: Pasquier
authors.forename: Véronique
authors.initials: V
authors.lastname: Mateo
authors.forename: Pauline
authors.initials: P
authors.lastname: Soulas
authors.forename: Lionel
authors.initials: L
authors.lastname: Galicier
authors.forename: Françoise
authors.initials: F
authors.lastname: Le Deist
authors.forename: Frédéric
authors.initials: F
authors.lastname: Rieux-Laucat
authors.forename: Patrick
authors.initials: P
authors.lastname: Revy
authors.forename: Alain
authors.initials: A
authors.lastname: Fischer
authors.forename: Geneviève
authors.initials: G
authors.lastname: de Saint Basile
authors.forename: Sylvain
authors.initials: S
authors.lastname: Latour
mesh_terms: D000328:Adult; D017209:Apoptosis; D001483:Base Sequence; D002648:Child; D002675:Child, Preschool; D005260:Female; D006706:Homeostasis; D006801:Humans; D007223:Infant; D008232:Lymphoproliferative Disorders / Q000235:genetics* / Q000276:immunology / Q000473:pathology*; D008297:Male; D009154:Mutation / Q000235:genetics; D010375:Pedigree; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000473:pathology; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000172:deficiency* / Q000235:genetics*
chemical_list: D051636:X-Linked Inhibitor of Apoptosis Protein