Review
XIAP deficiency syndrome in humans

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Abstract

The X-linked inhibitor of apoptosis (XIAP) deficiency, also known as the X-linked lymphoproliferative syndrome type 2 (XLP-2), is a rare primary immunodeficiency. XIAP deficiency is characterized by a key triad of clinical manisfestations, which consist of a high susceptibility to develop hemophagocytic lymphohistiocytosis (HLH) frequently triggered by Epstein–Barr virus (EBV) infection, recurrent splenomegaly and inflammatory bowel disease (IBD) with the features of a Crohn's disease. XIAP deficiency can be considered as one of the genetic causes for inherited IBD. XIAP is an anti-apoptotic molecule, but it is also involved in many other pathways. Recent findings demonstrate the role of XIAP in innate immunity and in the negative regulation of inflammation. In this review, we focus on the clinical aspects, the molecular etiology and the immunopathogenesis of XIAP deficiency. We also discuss recent progress in the understanding of XIAP function in relation to the pathophysiology of XLP-2.

Introduction

In 2006, 12 boys of three non-related families were identified as carriers of deleterious mutations in XIAP leading to loss of XIAP protein expression and function. These boys all suffered from immunodeficiency and most of them had developed hemophagocytic lymphohistiocytosis (HLH) subsequently to Epstein–Barr Virus infection (also termed virus-associated hemophagocytic syndrome (VAHS)) [1]. Some boys had also hypogammaglobulinemia and two developed inflammatory bowel disease (IBD). The susceptibility to EBV infection that triggers HLH, and the hypogammaglobulinemia, were reminiscent of the clinical phenotypes associated with the X-linked lymphoproliferative (XLP) syndrome caused by mutations in the gene SH2D1A (also named SAP deficiency) [2]. Based on these clinical similarities, XIAP deficiency was defined as a second genetic cause of XLP and denoted as XLP type 2 (XLP-2), while SAP deficiency was termed XLP-1. Furthermore and interestingly enough, SH2D1A and XIAP are both localized in Xq25 in the same vicinity and are only separated by a region of 2 Mb containing a single gene. At that time, it was tempting to hypothetize that SH2D1A and XIAP could form a functional cluster. Since then, however, a growing body of evidence has suggested that XLP-1 and XLP-2 are non-functionally related diseases, even if they share some striking similarities at first sight. The most convincing common feature is HLH, also known as macrophage activation syndrome (MAS). HLH is a life-threatening immunodeficiency characterized by hyperinflammation caused by an uncontrolled and ineffective immune response, in which activated T lymphocytes and macrophages accumulate in organs, and produce massive amounts of pro-inflammatory cytokines, such as IFN-γ, TNF-α and IL-6, resulting in tissue damage and organ failure [3], [4]. HLH is triggered in most cases by infectious pathogens, in particular viruses.

Section snippets

Functions of XIAP

XIAP belongs to the Inhibitor of Apoptosis Protein (IAP) gene family and shares important functional and structural features with two other cellular IAPs, cIAP-1 and cIAP-2. It is composed of 3 BIR domains (Baculovirus Inhibitor of apoptosis Repeats), an Ubiquitin-associated domain (UBA), and a C-terminal RING domain which has E3 ubiquitin ligase activity. XIAP is ubiquitously expressed and its expression is significantly increased in cancer cells. Originally, the first function ascribed to

Mouse models of XIAP deficiency

Xiap-deficient mouse models have been developed, and the first characterization of these models did not reveal any obvious phenotype or abnormalities, in particular regarding apoptosis [28], [29]. However, the following recent studies reveal that Xiap-deficient mice have compromised immunity leading to decreased survival when infected with certain pathogens. Those include intracellular gram-negative and -positive bacteria, such as Listeria monocytogenes [30], Chlamydophilia pneumonia [31] and

Clinical features

Since its original discovery, more than 70 male patients from different countries have been diagnosed with an XLP-2/XIAP deficiency [1], [36], [37], [38], [39], [40]. XIAP deficiency is mostly a pediatric disease and boys can be affected very early in their life (during the first months) with symptoms which are especially severe – the younger the patient is. The most frequent clinical manifestations are HLH (54%), recurrent splenomegaly (57%) and IBD (26%). EBV is very often the trigger of HLH

Conclusion and perspectives

The recent findings revealing that XIAP (as well as cIAP-1 and cIAP-2) is an important player in innate immunity and in the negative regulation of inflammation provide new insights into the immunopathogenesis of XIAP deficiency in humans. These studies also open novel perspectives for the treatment of the XIAP deficiency or related diseases. TNF-α and IL-18 appear to be important cytokines associated with the disease, thus they may represent potential therapeutic targets for inflammation

Acknowledgements

S. L. is a senior scientist at the Centre National de la Recherche Scientifique-CNRS (France) and C.A. is an M.D./Ph.D. and was a fellowship recipient of the Fondation ARC pour la Recherche sur le Cancer. This work was supported by grants from INSERM, the Agence Nationale de la Recherche (ANR) (ANR-14-CE14-0028-01, ANR-2010-MIDI-005-02, ANR-10-IAHU-01 and ANR-08-MIEN-012-01), the Fondation ARC pour la Recherche sur le Cancer (France), the European Research Council (ERC-2009-AdG_20090506 n°

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