Abstract
X-linked inhibitor of apoptosis (XIAP) deficiency is a rare inborn error of immunity first described in 2006. XIAP deficiency is characterised by immune dysregulation and a broad spectrum of clinical manifestations, including haemophagocytic lymphohistiocytosis (HLH), inflammatory bowel disease (IBD), hypogammaglobulinemia, susceptibility to infections, splenomegaly, cytopaenias, and other less common autoinflammatory phenomena. Since the first description of the disease, many XIAP deficient patients have been identified and our understanding of the disease has grown. Over 90 disease causing mutations have been described and more inflammatory disease manifestations, such as hepatitis, arthritis, and uveitis, are now well-recognised. Recently, following the introduction of reduced intensity conditioning (RIC), outcomes of allogeneic haematopoietic stem cell transplantation (HSCT), the only curative treatment option for XIAP deficiency, have improved. The pathophysiology of XIAP deficiency is not fully understood, however it is known that XIAP plays a role in both the innate and adaptive immune response and in immune regulation, most notably through modulation of tumour necrosis factor (TNF)-receptor signalling and regulation of NLRP3 inflammasome activity. In this review we will provide an up to date overview of both the clinical aspects and pathophysiology of XIAP deficiency.
Highlights
X-linked inhibitor of apoptosis (XIAP) deficiency is a rare inborn error of immunity caused by mutations in the XIAP/BIRC4 gene
Contrary to what is observed in SAP efficiency, invariant natural killer T cells (iNKT) cell numbers are normal in XIAP patients during wellness [52, 115, 116]
T and NK cell cytotoxic responses are normal in XIAP deficiency, which is again in contrast to what is observed in SAP deficiency [11, 12]
Summary
X-linked inhibitor of apoptosis (XIAP) deficiency is a rare inborn error of immunity caused by mutations in the XIAP/BIRC4 gene. T cells from XIAP deficient patients, invariant natural killer T cells (iNKT) and mucosal-associated invariant T (MAIT) cells which express elevated levels of caspases that are inhibited by XIAP, have an increased sensitivity to activation-induced cell death (AICD) [2,3,4, 51, 52] Dysregulation of inflammasome activation causes recurrent HLH, autoinflammation and elevated IL-18 levels in humans that have an activation mutation in the NLRC4 inflammasome [62] It seems that impaired NOD2 signalling is important for the development of IBD in XIAP deficiency. Immune dysregulation leads to a range of clinical manifestations in XIAP deficiency including recurrent HLH which is often triggered by EBV infection, IBD, splenomegaly, hypogammaglobulinemia, cytopaenias, and autoinflammatory phenomena [1,2,3, 21]. Absence of XIAP protein and/or XIAP function has been demonstrated in these asymptomatic individuals, once again highlighting the possible importance of other genetic and environmental factors on disease phenotype [4]
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