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X-linked Inhibitor of Apoptosis Protein Deficiency: More than an X-linked Lymphoproliferative Syndrome

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Abstract

X-linked inhibitor of apoptosis (XIAP) deficiency (also known as X-linked lymphoproliferative syndrome type 2, XLP-2) is a rare primary immunodeficiency. Since the disease was first described in 2006, more than 70 patients suffering from XIAP-deficiency have been reported, thus extending the clinical presentations of the disease. The main clinical features of XLP-2 are (i) elevated susceptibility to hemophagocytic lymphohistiocytosis (HLH, frequently in response to infection with Epstein-Barr virus (EBV)), (ii) recurrent splenomegaly and (iii) inflammatory bowel disease (IBD) with the characteristics of Crohn’s disease. XIAP deficiency is now considered to be one of the genetic causes of IBD in infancy. Although XIAP is an anti-apoptotic molecule, it is also involved in many other pathways, including the regulation of innate immunity and inflammation. XIAP is required for signaling through the Nod-like receptors NOD1 and 2, which are intracellular sensors of bacterial infection. XIAP-deficient T cells (including innate natural killer T cells and mucosal-associated invariant T cells) are overly sensitive to apoptosis. NOD2 function is impaired in XIAP-deficient monocytes. However, the physiopathological mechanisms underlying the clinical phenotypes in XIAP deficiency, notably the HLH and the EBV susceptibility, are not well understood. Here, we review the clinical aspects, molecular etiology and physiopathology of XIAP deficiency.

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Acknowledgments

We thank our collaborators for sharing their clinical observations.

S.L. is a senior scientist at the Centre National de la Recherche Scientifique (France) and C.A. received a fellowship from the Fondation ARC pour la Recherche sur le Cancer (France).

This work was funded by grants from INSERM, the Agence Nationale de la Recherche (ANR) (ANR-08-MIEN-012-01, ANR-2010-MIDI-005-02 and ANR-10-IAHU-01), the Fondation ARC pour la Recherche sur le Cancer (France), the European Research Council (ERC-2009-AdG_20090506 n°FP7-249816), the Rare Diseases Foundation (France) and the François Aupetit Association (France).

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Authors and Affiliations

  1. Laboratory of Lymphocyte Activation and Susceptibility to EBV Infection, INSERM UMR 1163, Descartes-Sorbonne Paris Cité University of Paris and Institut Imagine, Paris, France

    Claire Aguilar

  2. Laboratory of Lymphocyte Activation and Susceptibility to EBV Infection, Imagine – Institut des maladies génétiques - INSERM UMR 1163, 24, boulevard du Montparnasse, 75015, Paris, France

    Sylvain Latour

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  1. Claire Aguilar
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Correspondence to Sylvain Latour.

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Aguilar, C., Latour, S. X-linked Inhibitor of Apoptosis Protein Deficiency: More than an X-linked Lymphoproliferative Syndrome. J Clin Immunol 35, 331–338 (2015). https://doi.org/10.1007/s10875-015-0141-9

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