XIAP is an anti-apoptotic molecule, but it is also involved in many other pathways. 2021. https://www.frontiersin.org/articles/10.3389/fped.2021.660520/full. Evolution of Our Understanding of XIAP Deficiency Published in: Frontiers in Pediatrics, June 2021 DOI: 10.3389/fped.2021.660520: . 1997; Rigaud et al. XIAP deficiency is therefore frequently referred to as XLP-2 [2], [3], [4], [5]. HLH is a serious condition where the body . Front Pediatr, 9:660520, 17 Jun 2021 Cited by: 3 articles | PMID: 34222142 | PMCID: PMC8247594. The estimated incidence is 1-2 cases per million of live-born children. 2012).XIAP inhibits caspase-3, caspase-7, and caspase-9 in response to apoptotic stimuli, such as CD95 cross-linking (Deveraux et al. Entrance Pediatr. Mudde ACA, Booth C, Marsh RA. By damaging your immune system, HIV interferes with your body's ability to fight infection and disease. XIAP deficiency is an example of an X-linked disorder, which means that it almost exclusively affects males. In all metazoans, the intestinal tract is an essential organ to integrate nutritional signaling, hormonal cues and immunometabolic networks. XIAP deficiency compromises epithelial barrier function, with Paneth cell loss or dysfunction causing a reduced secretion of antimicrobial peptides. Neurodegenerative Disease GSK-3 has well documented roles in neurodegenerative diseases, established through extensive mechanistic studies of GSK-3 in neurological models. Apoptosis is the classical (type I) form of programmed cell death that results in the dismantling of the entire cell within the context of membrane-enclosed vesicles that are recognized and engulfed by phagocytes; this prevents the release of intracellular components from dying cells and the activation of innate immune responses. . Review Free to read & use Europe PMC is an archive of life sciences journal literature. Clinical trials, including careful pharmacokinetic and pharmacodynamic studies to ensure that effective levels of quercetin can be obtained, are warranted. May 16, 2022. Deficiency of X-linked inhibitor of apoptosis (XIAP), caused by BIRC4 gene mutations, was discovered to be associated with X-linked lymphoproliferative disease (XLP) phenotypes among 12 patients from 3 families by Rigaud et al in 2006. Consistently with the observation of Crohn's disease (CD) in XIAP deficiency, the RING activity of XIAP was recently shown to be required for NOD2 . This causes an altered microbial diversity (i.e., loss of protective Clostridia species) and susceptibility to pathogenic bacteria (such as H. hepaticus infection). Since the first description of the disease, many XIAP deficient patients have been identified and our understanding of the disease has grown. Signs and symptoms of XIAP deficiency. Overview of Histiocytic Disorders; COVID-19 Information; Hemophagocytic Syndromes; Langerhans cell Histiocytosis in Adults; Langerhans cell Histiocytosis in Children Such females are healthy carriers of XIAP deficiency. GENETICS XIAP is encoded by the XIAP/BIRC4gene, which consists of 6 coding exons. Patients with deficiency of the X-linked inhibitor of apoptosis (XIAP) were initially identified among patients with X-linked lymphoproliferative disease (XLP) but normal sequence in SH2D1A, defective in XLP-1 [1]. 2-4 Patients with SAP deficiency . October 22, 2022 0 13 Mudde ACA, Sales space C, Marsh RA. XIAP deficiency is a rare primary immunodeficiency, also known as X-linked lymphoproliferative syndrome type 2 (XLP-2), caused by mutations in the XIAP (BIRC4) gene. 9B) Comparison of FACS and in silico sorting experiments. The XIAP gene provides instructions for making a protein that is found in many types of cells, including immune cells. Alzheimer's Disease and Related Tauopathies The genetic adaptive mechanisms of action of ITH include activating "cellular plasticity", through which tumor cells create a tumor-supportive microenvironment in which they can proliferate and cause increased damage. Representative genes and top terms from gene-set enrichment analysis for each group (right). Over 90 disease causing mutations have been described and more inflammatory disease manifestations, such as hepatitis, arthritis, and uveitis, are now well-recognised. The dysregulation of intestinal epithelium functions can impact organism physiology and, in humans, leads to devastating and complex diseases, such as inflammatory bowel diseases, intestinal cancers, and obesity. Genome-Wide Identification and Expression Analysis of Senescence-Associated Genes in Grapevine (Vitis vinifera L.) Reveal Their Potential Functions in Leaf Senescence Order recurrent fevers, a rash and low blood count (haemophagocytic lymphohistiocytosis (HLH*), often triggered by the glandular fever virus (Epstein-Barr virus; EBV) inflammatory bowel disease, with symptoms of abdominal pain and diarrhoea, sometimes containing blood. The molecule contains three baculovirus inhibitor of apoptosis repeat (BIR) domains (Yang et al. This is because the XIAP gene is on the X chromosome. To. Evolution of Our Understanding of XIAP Deficiency. Recent findings demonstrate the role of XIAP in innate immunity and in the negative regulation of inflammation. Inhibitor of apoptosis proteins or IAPs (XIAP and BIRC2), and NOTCH signaling proteins are known to be involved in anti- apoptosis process and are elevated in many cancer cells, especially breast cancer [52-54]. Overview of Histiocytic Disorders; COVID-19 Information; Hemophagocytic Syndromes; Langerhans cell Histiocytosis in Adults; Langerhans cell Histiocytosis in Children Enter the email address you signed up with and we'll email you a reset link. Ryner Lai, MBBS. Acquired immunodeficiency syndrome (AIDS) is a chronic, potentially life-threatening condition caused by the human immunodeficiency virus (HIV). In fact, XIAP deficiency is recognized as a highly heterogeneous disorder, whose expression probably depends upon the different type of mutation, environmental and infectious factors. Two decades ago, the discovery of an . Over 90 disease causing mutations have been described and more inflammatory disease manifestations, such as hepatitis, arthritis, and uveitis, are now well-recognised. Since the first description of the disease, many XIAP deficient patients have been identified and our understanding of the disease has grown. Today, XIAP deciency is regarded primarily as a disorder of immune dysregulation and hyperinammation. 1 Before this, XLP was known only to be associated with mutations in SH2D1A, which encodes SLAM-Associated Protein (SAP). It helps protect these cells from self-destructing (undergoing apoptosis) by blocking (inhibiting) the action of certain enzymes called caspases, which are necessary for apoptosis. The popular anti-cancer agents, doxorubicin and cisplatin, are associated with XIAP via protein kinase B (Akt) (Fig 6) [55]. Evolution of our understanding of XIAP deficiency. Our data suggest that quercetin may be an effective natural therapeutic for the prevention of XIAP deficiency-associated hyperinflammation. It involves both multiple vascular and nonvascular cell types and depends on several pathogenic events (i.e., genetic susceptibility, hypoxia, inflammation, viral infection, DNA damage, and shear stress, among others) for disease manifestation and progression ( 1, 2 ). 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 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. More importantly, xIAP deficiency also abrogated the formation of TAB1.IkappaB kinase beta complexes in 4T1 breast cancer cells, thereby diminishing their activation of NF-kappaB, their expression . Thus, although this is a serious primary immunodeficiency, the indication for HSCT is not always an easy issue, due to high transplantation related risks [ 23 ]. Rigaud S, Fondanche MC, Lambert N, Pasquier B, Mateo V, Soulas P, et al. Scatterplot shows reprogramming efficiencies determined by FACS sort and growth experiments (blue triangles) (16) and our computationally inferred trajectories (red squares). 2006; Obexer and Ausserlechner 2014). XIAP deficiency in people causes an X-linked lymphoproliferative syndrome. Females have two X chromosomes, so a problem in one copy of the XIAP gene can be compensated for by the second copy. In this review, we focus on the clinical aspects, the molecular etiology and the immunopathogenesis of XIAP deficiency. These highly plastic cells are located in the tumor microenvironment (TME) and undergo extreme changes to resist therapeutic drugs. 4.2.1. This is our high-level measure of the quality and quantity of online attention that it has received. XIAP deficiency is characterised by immune dysregulation and a broad spectrum of clinical manifestations, including haemophagocytic lymphohistiocytosis (HLH), inflammatory bowel disease (IBD),. Below, we provide a brief overview of the literature regarding GSK-3, neurodegenerative disease, and therapeutic insights. |. (FIG. The Continuing Evolution of Our Understanding of IPF. Sir, We read with interest the review by Holm Uhlig on monogenic diseases associated with intestinal inflammation.1 XIAP deficiency, caused by X-linked inherited mutations in BIRC4 , is highlighted as a mendelian cause of very early onset IBD. The initial understanding of XIAP function focused upon its role in control of apoptosis. 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. Evolution of Our Understanding of XIAP Deficiency. Human immunodeficiency virus (HIV) is the virus that causes AIDS. One of the most important aspects of the scientific process is that assumptions are tested, and discarded when discredited, and new hypotheses take their place, with the same stringent measures firmly in place to ensure that they are rigorously tested as well.