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

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.

Severe Epstein–Barr virus infection in primary immunodeficiency and the normal host

“…A number of case series have now been published which confirm the main clinical features as HLH (frequently recurrent and of a more indolent course than seen in other primary HLH diseases), splenomegaly, colitis and periodic fevers Yang et al, 2012;Speckmann et al, 2013;Aguilar & Latour, 2015). In contrast to XLP patients, lymphoma has not been reported in patients with XIAP deficiency.…”

Severe infectious diseases of childhood as monogenic inborn errors of immunity

“…At any rate, XLP provides a fine example of a life-threatening infection or virus-induced cancer that also is strictly Mendelian. It paved the way for the discovery of other related recessive disorders, X-linked inhibitor of apoptosis (XIAP) deficiency and X-linked magnesium transporter 1 (MAGT1) deficiency, conditions that also often manifest clinically upon EBV infection (64)(65)(66)(67).…”

The role of monogenic disease in children with very early onset inflammatory bowel disease

“…XIAP is involved in NOD2 mediated NFKB signaling, and therefore these children may have an impaired ability to sense bacteria. In addition, as an inhibitor of apoptosis, it prevents apoptosis of activated T cells, thus allowing for expansion and survival of T cells in response to pathogens 90,91 . Therefore, in XIAP deficiency, due to the inability to clear pathogens, there is a hyperinflammatory state, with increased production of cytokines resulting in an IBD phenotype 89,91 .…”

“…In addition, as an inhibitor of apoptosis, it prevents apoptosis of activated T cells, thus allowing for expansion and survival of T cells in response to pathogens 90,91 . Therefore, in XIAP deficiency, due to the inability to clear pathogens, there is a hyperinflammatory state, with increased production of cytokines resulting in an IBD phenotype 89,91 . Children with these mutations can present with severe colonic and perianal fistualizing disease 18,92 , and of great concern, EBV infection can result in fatal hemophagocytic lymphohistiocytosis 92 .…”