XIAP deficiency in humans causes an X-linked lymphoproliferative syndrome

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BlankXIAP deficiency in humans causes an X-linked lymphoproliferative syndrome.

S Rigaud, MC Fondanèche, N Lambert, B Pasquier, V Mateo, P Soulas, L Galicier, F

Le Deist, F Rieux-Laucat, P Revy, A Fischer, G de Saint Basile, S Latour

[1] Inserm 768, Laboratoire du Développement Normal et Pathologique du Système

Immunitaire; Univ. René Descartes, Paris, F-75015, France [2] These authors

contributed equally to this work. 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.