Characterization of Crohn disease in X-linked inhibitor of apoptosis–deficient male patients and female symptomatic carriers

Aguilar, Claire; Lenoir, Christelle; Lambert, Nathalie; Bègue, Bernadette; Brousse, Nicole; Canioni, Danielle; Berrebi, Dominique; Roy, Maryline; Gérart, Stéphane; Chapel, Helen; Schwerd, Tobias; Siproudhis, L.; Schäppi, Michela; Al-Ahmari, Ali; Mori, Masaaki; Yamaide, Akiko; Galicier, Lionel; Neven, Bénédicte; Routes, John M.; Uhlig, Holm H.; Koletzko, Sibylle; Patel, Smita Y.; Kanegane, Hirokazu; Pïcard, Capucine; Fischer, Alain; Cerf‐Bensussan, Nadine; Ruemmele, Frank M; Hugot, Jean‐Pierre; Latour, Sylvain

doi:10.1016/j.jaci.2014.04.031

Cited by 103 publications

(137 citation statements)

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“…IBD can occur before HLH and may be the first and the only symptom of the disease [9,8,11,10]. The age at onset of IBD varies greatly from 3 months to 41 years [9]. The clinical presentation and the biological and histological features are very similar to those observed in adult patients with Crohn's disease [9,10].…”

Section: Clinical Featuresmentioning

confidence: 85%

“…Worldwide, more than 70 XIAP-deficient patients have been reported in the literature [9,11,8,7,[26][27][28][29]. Over the last few years, we have identified additional patients and have been made aware of yet other patients by our collaborators (Aguilar and Latour, unpublished observations).…”

Section: Clinical Featuresmentioning

confidence: 94%

“…A few XLP-2 patients have developed variable, auto-inflammatory-like symptoms not shared by XLP-1 patients. Recently, young boys with earlyonset IBD as the only clinical trait were reported to be carriers of inactivating XIAP mutations -thus confirming the predominant role of XIAP deficiency in the occurrence of IBD [9][10][11]. Hence, XIAP deficiency should be now considered as one of the Mendelian determinants of inherited IBD in infancy [12].…”

mentioning

confidence: 88%

“…IBD is also a prevalent phenotype and affecting 25-30 % of patients. IBD can occur before HLH and may be the first and the only symptom of the disease [9,8,11,10]. The age at onset of IBD varies greatly from 3 months to 41 years [9].…”

Section: Clinical Featuresmentioning

confidence: 99%

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

2015

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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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Section: Clinical Featuresmentioning

confidence: 85%

Section: Clinical Featuresmentioning

confidence: 94%

mentioning

confidence: 88%

Section: Clinical Featuresmentioning

confidence: 99%

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

2015

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“…XIAP is the most potent caspase inhibitor and can prevent apoptosis by binding to and inhibiting caspase-3, 7, 9 and reducing the release of cytochrome C [13]. In addition to inhibiting caspase activity, XIAP also activates the expression of some anti-apoptotic genes through the nuclear factor kappalight-chain-enhancer of activated B cells (NF-κB) pathway and thereby inhibits apoptosis; it also reduces ischemia/hypoxia-induced oxidative stress and injury by upregulating the expression of mitochondrial antioxidants (superoxide dismutase, thioredoxin) [14]. XIAP is a macromolecule of 57 kDa; thus, it is difficult for it to cross the blood brain barrier, and its role in the central nervous system has been rarely studied.…”

Section: Discussionmentioning

confidence: 99%

The Effect of Hippocampal Cognitive Impairment and XIAP on Glucose and Lipids Metabolism in Rats

Xia

Zhu²,

Shao³

et al. 2016

Cell Physiol Biochem

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Background/Aims: To investigate the effect of cognitive impairment and X-linked inhibitor of apoptosis protein (XIAP) on glucolipid metabolism. Materials and Methods: β-amyloid (Aβ 1-42) was injected into the hippocampus of rats to establish a cognitive impairment model. Trans-activator of transcription (TAT)-XIAP fusion protein (the TAT-XIAP group), PBS (the model group), or XIAP antisense oligonucleotides (the ASODN group) was injected into the lateral ventricles of the rats to increase and decrease the activity of XIAP in the hippocampus. To determine the level of blood glucose and lipids, adenosine monophosphate-activated protein kinase (AMPK) expression of liver and hipppocamual neuronal apoptosis. Results: The levels of FPG, TG, TC and LDL were significantly higher in the TAT-XIAP group, the model group and the ASODN group than in the blank group (P < 0.05); however, the HDL level showed no significant change in all groups of rats. The apoptosis indexes of the rat hippocampal CA1 neuron were 68.44 ± 4.31%, 13.21 ± 2.30%, 56.68 ± 4.771%, and 87.51 ± 6.63% in the model group, the blank group, the TAT-XIAP group and the ASODN group, respectively. Gastrointestinal motility was less frequent (per time unit) in the model group, the ASODN group and the TAT-XIAP group than in the blank group. Compared with the model group, gastrointestinal motility was significantly less frequent in the ASODN group and was significantly more frequent in the TAT-XIAP group. Compared with the blank group, the model group had a significantly lower gastric emptying rate and intestinal propulsive rate. Compared with the model group, the gastric emptying rate and intestinal propulsive rate were significantly lower in the ASODN group and were significantly higher in the TAT-XIAP group. Compared with the blank group, the expressions of AMPK mRNA, and AMPK protein were significantly reduced in the model group, the TAT-XIAP group, and the ASODN group. AMPK expression was significantly increased in the TAT-XIAP group and was significantly decreased in the ASODN group than in the model group. Conclusion: Cognitive impairment and hippocampal neuron apoptosis can cause glucose and lipids metabolic abnormalities, possibly by regulating gastrointestinal motility and AMPK expression in the liver. The changes in the function of XIAP, which is an anti-apoptotic protein in the hippocampus, may affect the metabolism of glucose and lipids.

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CD62‐L down‐regulation after L18‐MDP stimulation as a complementary flow cytometry functional assay for the diagnosis of XIAP deficiency

Rizzo,

Sanz,

Roffe

et al. 2024

Cytometry Part B Clinical

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X‐linked inhibitor of apoptosis (XIAP) deficiency is an infrequent inborn error of immunity caused by mutations in XIAP gene. Most cases present with absence of XIAP protein which can be detected by flow cytometry (FC), representing a rapid diagnostic method. However, since some genetic defects may not preclude protein expression, it is important to include a complementary functional test in the laboratory workup of these patients. L‐selectin (CD62‐L) is a molecule that is cleaved from the surface membrane of leukocytes upon stimulation of different receptors such as toll like receptors (TLRs) and nucleotide‐binding oligomerization domain‐like receptors (NLRs), including NOD2. Considering that XIAP deficiency impairs NOD2 signaling, we decided to assess CD62‐L down‐regulation by FC post‐stimulation of neutrophils and monocytes with L18‐muramyl Di‐Peptide (L18‐MDP), a NOD2 specific agonist, in order to develop a novel assay for the functional evaluation of patients with suspicion of XIAP defects. Whole blood samples from 20 healthy controls (HC) and four patients with confirmed molecular diagnosis of XIAP deficiency were stimulated with 200 ng/mL of L18‐MDP for 2 h. Stimulation with 100 ng/mL of lipopolysaccharide (LPS) was carried out in parallel as a positive control of CD62‐L shedding. CD62‐L expression was evaluated by FC using an anti CD62‐L‐ antibody and down‐regulation was assessed by calculating the difference in CD62‐L expression before and after stimulation, both in terms of percentage of CD62‐L expressing cells (Δ%CD62‐L) and median fluorescence intensity (ΔMFI%). Neutrophils and monocytes from XIAP deficient patients displayed a significantly diminished response to L18‐MDP stimulation compared with HC (p < 0.0001), indicating a severely altered mechanism of CD62‐L down‐regulation following activation of NOD2‐XIAP axis. On the other hand, the response to LPS stimulation was comparable between patients and heathy controls, suggesting preserved CD62‐L shedding with a different stimulus. FC detection of CD62‐L down‐regulation in monocytes and neutrophils after whole blood stimulation with L18‐MDP results in an effective and rapid functional test for the identification of XIAP deficient patients.

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Characterization of Crohn disease in X-linked inhibitor of apoptosis–deficient male patients and female symptomatic carriers

Cited by 103 publications

References 39 publications

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

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

The Effect of Hippocampal Cognitive Impairment and XIAP on Glucose and Lipids Metabolism in Rats

CD62‐L down‐regulation after L18‐MDP stimulation as a complementary flow cytometry functional assay for the diagnosis of XIAP deficiency

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