XIAP deficiency in humans causes an X-linked lymphoproliferative syndrome

Stéphanie Rigaud, Marie-Claude Fondanèche, Nathalie Lambert, Benoit Pasquier, Véronique Mateo, Pauline Soulas, Lionel Galicier, Françoise Le Deist, Frédéric Rieux-Laucat, Patrick Revy, Alain Fischer, Geneviève de Saint Basile and Sylvain Latour ()
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Stéphanie Rigaud: Inserm 768, Laboratoire du Développement Normal et Pathologique du Système Immunitaire; Univ. René Descartes
Marie-Claude Fondanèche: Inserm 768, Laboratoire du Développement Normal et Pathologique du Système Immunitaire; Univ. René Descartes
Nathalie Lambert: Inserm 768, Laboratoire du Développement Normal et Pathologique du Système Immunitaire; Univ. René Descartes
Benoit Pasquier: Inserm 768, Laboratoire du Développement Normal et Pathologique du Système Immunitaire; Univ. René Descartes
Véronique Mateo: Inserm 768, Laboratoire du Développement Normal et Pathologique du Système Immunitaire; Univ. René Descartes
Pauline Soulas: Inserm 768, Laboratoire du Développement Normal et Pathologique du Système Immunitaire; Univ. René Descartes
Lionel Galicier: AP-HP, Hôpital Saint-Louis, Service d’Immuno-Hématologie
Françoise Le Deist: Inserm 768, Laboratoire du Développement Normal et Pathologique du Système Immunitaire; Univ. René Descartes
Frédéric Rieux-Laucat: Inserm 768, Laboratoire du Développement Normal et Pathologique du Système Immunitaire; Univ. René Descartes
Patrick Revy: Inserm 768, Laboratoire du Développement Normal et Pathologique du Système Immunitaire; Univ. René Descartes
Alain Fischer: Inserm 768, Laboratoire du Développement Normal et Pathologique du Système Immunitaire; Univ. René Descartes
Geneviève de Saint Basile: Inserm 768, Laboratoire du Développement Normal et Pathologique du Système Immunitaire; Univ. René Descartes
Sylvain Latour: Inserm 768, Laboratoire du Développement Normal et Pathologique du Système Immunitaire; Univ. René Descartes

Nature, 2006, vol. 444, issue 7115, 110-114

Abstract: Abstract The homeostasis of the immune response requires tight regulation of the proliferation and apoptosis of activated lymphocytes1,2. 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)3,4,5. Mutations in the signalling lymphocyte activation molecule (SLAM)-associated protein SAP, a signalling adaptor molecule, underlie 60% of cases of familial XLP6,7,8. 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)9,10, 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.

Date: 2006
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DOI: 10.1038/nature05257

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