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XIAP deficiency in humans causes an X-linked lymphoproliferative syndrome


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.

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We thank the patients and their families that participated in this study, E. Le Gall (Centre Hospitalier Universitaire de Rennes) and M. Hamidou (Centre Hospitalier Universitaire de Nantes) for the blood samples and their contribution to the follow up of patients from family 1 and 3; A. Veillette and C. Picard for discussions and critical reading of the manuscript; and P. Charneau, M. Bonneville and M. Leite-de-Moraes for their gift of reagents. We also acknowledge the contribution of C. Charon from the Centre National de Génotypage (CNG, Evry, France). This work was supported by grants from the Institut National de la Santé et de la Recherche Médicale (France), the Agence National de la Recherche (France), the Association pour la Recherche contre le Cancer (France), GIS-Institut des Maladies Rares (France) and La Ligue contre le Cancer (France). B.P. was supported by a fellowship from La Ligue contre le Cancer and V.M. by a European Molecular Biology Organization fellowship. S.L. and P.R. are scientists from the Centre National pour la Recherche Scientifique (France).

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Reprints and permissions information is available at www.nature.com/reprints. The authors declare no competing financial interests.

Correspondence to Sylvain Latour.

Supplementary information

  1. Supplementary Notes 1

    This file contains the Supplementary Table 1 and the Supplementary Figures and Legends 1–7. (PPT 1315 kb)

  2. Supplementary Notes 2

    This file contains the detailed Supplementary Methods and additional references and statistical values of Figures 2b and 3a–c. (DOC 32 kb)

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Figure 1: Identification of mutations in XIAP in affected individuals from XLP families without SAP mutations.
Figure 2: Deficiency in NKT cells in XIAP-deficient patients.
Figure 3: Enhanced apoptosis of XIAP-deficient T lymphocytes in response to apoptotic stimuli.


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