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Latour S. Human Immune Responses to Epstein-Barr Virus Highlighted by Immunodeficiencies. Annu Rev Immunol 2025; 43:723-749. [PMID: 40279309 DOI: 10.1146/annurev-immunol-082323-035455] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/27/2025]
Abstract
Inborn errors of immunity (IEIs) represent unique in natura models that uncover key components of immunity in humans, in particular those that predispose to infections. Epstein-Barr virus (EBV) is one of the most common opportunistic infectious agents in humans and is responsible for several diseases, including infectious mononucleosis, nonmalignant and malignant lymphoproliferative disorders, hemophagocytic lymphohistiocytosis, and smooth muscle and epithelial tumors. For most individuals, EBV infection persists for life without pathological consequences. IEIs that do not predispose to EBV infection suggest that innate and humoral responses are not necessary or redundant for the immune response to EBV. IEIs associated with high susceptibility to EBV infection provide unequivocal genetic proof of the central role of CD8+ T cell responses in immunity to EBV. They also highlight the distinct steps and pathways required for, on the one hand, the effector cytotoxic functions of CD8+ T cells and, on the other hand, the expansion and maturation of cytotoxic CD8+ T cells.
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Affiliation(s)
- Sylvain Latour
- Laboratory of Lymphocyte Activation and Susceptibility to EBV Infection, INSERM UMR 1163, Paris, France;
- Institut Imagine, Université Paris Cité, Paris, France
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2
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Rizzo AD, Sanz M, Roffe G, Sajaroff EO, Prado DA, Prieto E, Goris V, Rossi JG, Bernasconi AR. CD62-L down-regulation after L18-MDP stimulation as a complementary flow cytometry functional assay for the diagnosis of XIAP deficiency. CYTOMETRY. PART B, CLINICAL CYTOMETRY 2024; 106:383-391. [PMID: 38770762 DOI: 10.1002/cyto.b.22181] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/14/2023] [Revised: 04/26/2024] [Accepted: 05/06/2024] [Indexed: 05/22/2024]
Abstract
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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Affiliation(s)
- Agustín D Rizzo
- Laboratory Division, Cellular Immunology Laboratory, Hospital de Pediatría S.A.M.I.C. Prof. Dr. Juan P. Garrahan, Buenos Aires, Argentina
| | - Marianela Sanz
- Laboratory Division, Cellular Immunology Laboratory, Hospital de Pediatría S.A.M.I.C. Prof. Dr. Juan P. Garrahan, Buenos Aires, Argentina
| | - Georgina Roffe
- Laboratory Division, Cellular Immunology Laboratory, Hospital de Pediatría S.A.M.I.C. Prof. Dr. Juan P. Garrahan, Buenos Aires, Argentina
| | - Elisa O Sajaroff
- Laboratory Division, Cellular Immunology Laboratory, Hospital de Pediatría S.A.M.I.C. Prof. Dr. Juan P. Garrahan, Buenos Aires, Argentina
| | - Damian A Prado
- Laboratory Division, Cellular Immunology Laboratory, Hospital de Pediatría S.A.M.I.C. Prof. Dr. Juan P. Garrahan, Buenos Aires, Argentina
| | - Emma Prieto
- Immunology and Rheumatology Division, Molecular Immunology Laboratory, Hospital de Pediatría S.A.M.I.C. Prof. Dr. Juan P. Garrahan, Buenos Aires, Argentina
| | - Verónica Goris
- Immunology and Rheumatology Division, Molecular Immunology Laboratory, Hospital de Pediatría S.A.M.I.C. Prof. Dr. Juan P. Garrahan, Buenos Aires, Argentina
| | - Jorge G Rossi
- Laboratory Division, Cellular Immunology Laboratory, Hospital de Pediatría S.A.M.I.C. Prof. Dr. Juan P. Garrahan, Buenos Aires, Argentina
| | - Andrea R Bernasconi
- Laboratory Division, Cellular Immunology Laboratory, Hospital de Pediatría S.A.M.I.C. Prof. Dr. Juan P. Garrahan, Buenos Aires, Argentina
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Lee J, Sim KM, Kang M, Oh HJ, Choi HJ, Kim YE, Pack CG, Kim K, Kim KM, Oh SH, Kim I, Chang I. Understanding the molecular mechanism of pathogenic variants of BIR2 domain in XIAP-deficient inflammatory bowel disease. Sci Rep 2024; 14:853. [PMID: 38191507 PMCID: PMC10774423 DOI: 10.1038/s41598-023-50932-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2023] [Accepted: 12/28/2023] [Indexed: 01/10/2024] Open
Abstract
X-linked inhibitor of apoptosis protein (XIAP) deficiency causes refractory inflammatory bowel disease. The XIAP protein plays a pivotal role in the pro-inflammatory response through the nucleotide-binding oligomerization domain-containing signaling pathway that is important in mucosal homeostasis. We analyzed the molecular mechanism of non-synonymous pathogenic variants (PVs) of XIAP BIR2 domain. We generated N-terminally green fluorescent protein-tagged XIAP constructs of representative non-synonymous PVs. Co-immunoprecipitation and fluorescence cross-correlation spectroscopy showed that wild-type XIAP and RIP2 preferentially interacted in live cells, whereas all non-synonymous PV XIAPs failed to interact properly with RIP2. Structural analysis showed that various structural changes by mutations, such as hydrophobic core collapse, Zn-finger loss, and spatial rearrangement, destabilized the two loop structures (174-182 and 205-215) that critically interact with RIP2. Subsequently, it caused a failure of RIP2 ubiquitination and loss of protein deficiency by the auto-ubiquitination of all XIAP mutants. These findings could enhance our understanding of the role of XIAP mutations in XIAP-deficient inflammatory bowel disease and may benefit future therapeutic strategies.
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Affiliation(s)
- Juhwan Lee
- iProtein Therapeutics Inc., Munji-ro 281-9, Yuseong-gu, Daejeon, Korea
| | - Kyoung Mi Sim
- Department of Convergence Medicine, Asan Medical Center, Asan Institutes for Life Sciences, University of Ulsan College of Medicine, Seoul, Korea
| | - Mooseok Kang
- iProtein Therapeutics Inc., Munji-ro 281-9, Yuseong-gu, Daejeon, Korea
| | - Hyun Ju Oh
- Department of Pediatrics, Asan Medical Center Children's Hospital, University of Ulsan College of Medicine, 88, Olympic-ro 43-gil, Songpa-Gu, Seoul, 05505, Korea
| | - Ho Jung Choi
- Department of Pediatrics, Asan Medical Center Children's Hospital, University of Ulsan College of Medicine, 88, Olympic-ro 43-gil, Songpa-Gu, Seoul, 05505, Korea
| | - Yeong Eun Kim
- Department of Pediatrics, Asan Medical Center Children's Hospital, University of Ulsan College of Medicine, 88, Olympic-ro 43-gil, Songpa-Gu, Seoul, 05505, Korea
| | - Chan-Gi Pack
- Department of Convergence Medicine, Asan Medical Center, Asan Institutes for Life Sciences, University of Ulsan College of Medicine, Seoul, Korea
| | - Kyunggon Kim
- Department of Convergence Medicine, Asan Medical Center, Asan Institutes for Life Sciences, University of Ulsan College of Medicine, Seoul, Korea
| | - Kyung Mo Kim
- Department of Pediatrics, Asan Medical Center Children's Hospital, University of Ulsan College of Medicine, 88, Olympic-ro 43-gil, Songpa-Gu, Seoul, 05505, Korea
| | - Seak Hee Oh
- Department of Pediatrics, Asan Medical Center Children's Hospital, University of Ulsan College of Medicine, 88, Olympic-ro 43-gil, Songpa-Gu, Seoul, 05505, Korea.
| | - Inki Kim
- Department of Convergence Medicine, Asan Medical Center, Asan Institutes for Life Sciences, University of Ulsan College of Medicine, Seoul, Korea.
- Department of Pharmacology, University of Ulsan College of Medicine, 88, Olympic-ro 43-gil, Songpa-Gu, Seoul, 05505, Korea.
| | - Iksoo Chang
- Creative Research Initiatives Center for Proteome Biophysics, Department of Brain Sciences and Supercomputing Bigdata Center, DGIST, Daegu, 42988, Korea.
- Department of Brain Sciences and Supercomputing Big Data Center, DGIST, Daegu, 42988, Korea.
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Karageorgos S, Platt AS, Bassiri H. Genetics of Primary Hemophagocytic Lymphohistiocytosis. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2024; 1448:75-101. [PMID: 39117809 DOI: 10.1007/978-3-031-59815-9_7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 08/10/2024]
Abstract
Hemophagocytic lymphohistiocytosis (HLH) constitutes a rare, potentially life-threatening hyperinflammatory immune dysregulation syndrome that can present with a variety of clinical signs and symptoms, including fever, hepatosplenomegaly, and abnormal laboratory and immunological findings such as cytopenias, hyperferritinemia, hypofibrinogenemia, hypertriglyceridemia, elevated blood levels of soluble CD25 (interleukin (IL)-2 receptor α-chain), or diminished natural killer (NK)-cell cytotoxicity (reviewed in detail in Chapter 11 of this book). While HLH can be triggered by an inciting event (e.g., infections), certain monogenic causes have been associated with a significantly elevated risk of development of HLH, or recurrence of HLH in patients who have recovered from their disease episode. These monogenic predisposition syndromes are variably referred to as "familial" (FHL) or "primary" HLH (henceforth referred to as "pHLH") and are the focus of this chapter. Conversely, secondary HLH (sHLH) often occurs in the absence of monogenic etiologies that are commonly associated with pHLH and can be triggered by infections, malignancies, or rheumatological diseases; these triggers and the genetics associated with sHLH are discussed in more detail in other chapters in this book.
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Affiliation(s)
- Spyridon Karageorgos
- First Department of Pediatrics, "Aghia Sophia" Children's Hospital, National and Kapodistrian University of Athens, Athens, Greece
| | - Anna S Platt
- Roberts Individualized Medical Genetics Center and Immune Dysregulation Program, Children's Hospital of Philadelphia, Philadelphia, PA, USA
| | - Hamid Bassiri
- Immune Dysregulation Program and Division of Infectious Diseases, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
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Landy E, Carol H, Ring A, Canna S. Biological and clinical roles of IL-18 in inflammatory diseases. Nat Rev Rheumatol 2024; 20:33-47. [PMID: 38081945 DOI: 10.1038/s41584-023-01053-w] [Citation(s) in RCA: 49] [Impact Index Per Article: 49.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/27/2023] [Indexed: 12/23/2023]
Abstract
Several new discoveries have revived interest in the pathogenic potential and possible clinical roles of IL-18. IL-18 is an IL-1 family cytokine with potent ability to induce IFNγ production. However, basic investigations and now clinical observations suggest a more complex picture. Unique aspects of IL-18 biology at the levels of transcription, activation, secretion, neutralization, receptor distribution and signalling help to explain its pleiotropic roles in mucosal and systemic inflammation. Blood biomarker studies reveal a cytokine for which profound elevation, associated with detectable 'free IL-18', defines a group of autoinflammatory diseases in which IL-18 dysregulation can be a primary driving feature, the so-called 'IL-18opathies'. This impressive specificity might accelerate diagnoses and identify patients amenable to therapeutic IL-18 blockade. Pathogenically, human and animal studies identify a preferential activation of CD8+ T cells over other IL-18-responsive lymphocytes. IL-18 agonist treatments that leverage the site of production or subversion of endogenous IL-18 inhibition show promise in augmenting immune responses to cancer. Thus, the unique aspects of IL-18 biology are finally beginning to have clinical impact in precision diagnostics, disease monitoring and targeted treatment of inflammatory and malignant diseases.
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Affiliation(s)
- Emily Landy
- Program in Microbiology and Immunology, University of Pittsburgh, Pittsburgh, PA, USA
| | - Hallie Carol
- Division of Rheumatology and Immune Dysregulation Program, The Children's Hospital of Philadelphia, Philadelphia, PA, USA
- Institute for Immunology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
| | - Aaron Ring
- Translational Science and Therapeutics, Fred Hutchinson Cancer Center, Seattle, WA, USA
| | - Scott Canna
- Program in Microbiology and Immunology, University of Pittsburgh, Pittsburgh, PA, USA.
- Division of Rheumatology and Immune Dysregulation Program, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.
- Institute for Immunology, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
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Peng C, Jiang Y, Ou X, Liao L, Yang C, Zhou Q, Wei Y, Chang L, Fan X. Novel XIAP mutation with early-onset Crohn's disease complicated with acute heart failure: a case report. BMC Cardiovasc Disord 2023; 23:368. [PMID: 37479963 PMCID: PMC10362603 DOI: 10.1186/s12872-023-03386-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2023] [Accepted: 07/10/2023] [Indexed: 07/23/2023] Open
Abstract
BACKGROUND The X-linked inhibitor of apoptosis (XIAP) protein is encoded by the XIAP gene and is critical for multiple cell responses and plays a role in preventing cell death. XIAP mutations are associated with several diseases, primarily including hemophagocytic lymphohistiocytosis and inflammatory bowel disease (IBD). We report the clinical features and results associated with hemizygous mutation of the XIAP gene in a young male with Crohn's disease complicated with acute heart failure.This 16-year-old patient ultimately died of heart failure. CASE PRESENTATION A young male of 16 years of age was initially diagnosed with Crohn's disease based on evidences from endoscopic and histological findings. Although supportive care, anti-infective drugs and biologics were administered consecutively for 11 months, his clinical manifestations and laboratory indices (patient's condition) did not improved. Additionally, the patient exhibited a poor nutritional status and sustained weight loss. Subsequently, acute heart failure led to the exacerbation of the patient's condition. He was diagnosed with wet beriberi according to thiamine deficiency, but the standard medical therapy for heart failure and thiamine supplementation did not reverse the adverse outcomes. Comprehensive genetic analysis of peripheral blood-derived DNA revealed a novel hemizygous mutation of the XIAP gene (c.1259_1262 delACAG), which was inherited from his mother. CONCLUSION A novel XIAP mutation (c.1259_1262 delACAG) was identified in this study. It may be one of the potential pathogenic factors in Crohn's disease and plays an important role in the progression of heart failure. Additionally, thiamine deficiency triggers a vicious cycle.
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Affiliation(s)
- Chendong Peng
- Department of Cardiology, The Affiliated Hospital of Southwest Medical University, 25 Taiping Street, Jiangyang District, Luzhou, 646000, Sichuan, China
| | - Yuang Jiang
- Department of Cardiology, The Affiliated Hospital of Southwest Medical University, 25 Taiping Street, Jiangyang District, Luzhou, 646000, Sichuan, China
| | - Xianhong Ou
- Key Laboratory of Medical Electrophysiology of Ministry of Education and Medical Electrophysiological Key Laboratory of Sichuan Province, Collaborative Innovation Center for Prevention and Treatment of Cardiovascular Disease, Institute of Cardiovascular Research, Southwest Medical University, Luzhou, 646000, Sichuan, China
| | - Lei Liao
- Department of Cardiology, The Affiliated Hospital of Southwest Medical University, 25 Taiping Street, Jiangyang District, Luzhou, 646000, Sichuan, China
| | - Chengying Yang
- Department of Cardiology, The Affiliated Hospital of Southwest Medical University, 25 Taiping Street, Jiangyang District, Luzhou, 646000, Sichuan, China
| | - Qiao Zhou
- Department of Cardiology, The Affiliated Hospital of Southwest Medical University, 25 Taiping Street, Jiangyang District, Luzhou, 646000, Sichuan, China
| | - Yan Wei
- Key Laboratory of Medical Electrophysiology of Ministry of Education and Medical Electrophysiological Key Laboratory of Sichuan Province, Collaborative Innovation Center for Prevention and Treatment of Cardiovascular Disease, Institute of Cardiovascular Research, Southwest Medical University, Luzhou, 646000, Sichuan, China
| | - Lijia Chang
- Prenatal Diagnosis Center, Shijiazhuang Obstetrics and Gynecology Hospital, Key Laboratory of Maternal and Fetal Medicine of Hebei Province, 16 Tangu-North Street, Shijiazhuang, 050000, Hebei, China.
| | - Xinrong Fan
- Department of Cardiology, The Affiliated Hospital of Southwest Medical University, 25 Taiping Street, Jiangyang District, Luzhou, 646000, Sichuan, China.
- Key Laboratory of Medical Electrophysiology of Ministry of Education and Medical Electrophysiological Key Laboratory of Sichuan Province, Collaborative Innovation Center for Prevention and Treatment of Cardiovascular Disease, Institute of Cardiovascular Research, Southwest Medical University, Luzhou, 646000, Sichuan, China.
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7
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Witt A, Goncharov T, Lee YM, Kist M, Dohse M, Eastham J, Dugger D, Newton K, Webster JD, Vucic D. XIAP deletion sensitizes mice to TNF-induced and RIP1-mediated death. Cell Death Dis 2023; 14:262. [PMID: 37041175 PMCID: PMC10090100 DOI: 10.1038/s41419-023-05793-1] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2023] [Revised: 03/28/2023] [Accepted: 03/31/2023] [Indexed: 04/13/2023]
Abstract
XIAP is a caspase-inhibitory protein that blocks several cell death pathways, and mediates proper activation of inflammatory NOD2-RIP2 signaling. XIAP deficiency in patients with inflammatory diseases such as Crohn's disease, or those needing allogeneic hematopoietic cell transplantation, is associated with a worse prognosis. In this study, we show that XIAP absence sensitizes cells and mice to LPS- and TNF-mediated cell death without affecting LPS- or TNF-induced NF-κB and MAPK signaling. In XIAP deficient mice, RIP1 inhibition effectively blocks TNF-stimulated cell death, hypothermia, lethality, cytokine/chemokine release, intestinal tissue damage and granulocyte migration. By contrast, inhibition of the related kinase RIP2 does not affect TNF-stimulated events, suggesting a lack of involvement for the RIP2-NOD2 signaling pathway. Overall, our data indicate that in XIAP's absence RIP1 is a critical component of TNF-mediated inflammation, suggesting that RIP1 inhibition could be an attractive option for patients with XIAP deficiency.
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Affiliation(s)
- Axel Witt
- Department of Immunology Discovery, Genentech, South San Francisco, CA, 94080, USA
- Neovii Pharmaceutical AG, 8640, Rapperswil, Switzerland
| | - Tatiana Goncharov
- Department of Immunology Discovery, Genentech, South San Francisco, CA, 94080, USA
| | - Yujung Michelle Lee
- Department of Immunology Discovery, Genentech, South San Francisco, CA, 94080, USA
| | - Matthias Kist
- Department of Immunology Discovery, Genentech, South San Francisco, CA, 94080, USA
- CatalYm GmbH, Am Klopferspitz 19, 82152, Munich, Germany
| | - Monika Dohse
- Department of Pathology, Genentech, South San Francisco, CA, 94080, USA
| | - Jeff Eastham
- Department of Pathology, Genentech, South San Francisco, CA, 94080, USA
| | - Debra Dugger
- Department of Physiological Chemistry, Genentech, South San Francisco, CA, 94080, USA
| | - Kim Newton
- Department of Physiological Chemistry, Genentech, South San Francisco, CA, 94080, USA
| | - Joshua D Webster
- Department of Pathology, Genentech, South San Francisco, CA, 94080, USA
| | - Domagoj Vucic
- Department of Immunology Discovery, Genentech, South San Francisco, CA, 94080, USA.
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8
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Hughes SA, Lin M, Weir A, Huang B, Xiong L, Chua NK, Pang J, Santavanond JP, Tixeira R, Doerflinger M, Deng Y, Yu C, Silke N, Conos SA, Frank D, Simpson DS, Murphy JM, Lawlor KE, Pearson JS, Silke J, Pellegrini M, Herold MJ, Poon IKH, Masters SL, Li M, Tang Q, Zhang Y, Rashidi M, Geng L, Vince JE. Caspase-8-driven apoptotic and pyroptotic crosstalk causes cell death and IL-1β release in X-linked inhibitor of apoptosis (XIAP) deficiency. EMBO J 2023; 42:e110468. [PMID: 36647737 PMCID: PMC9975961 DOI: 10.15252/embj.2021110468] [Citation(s) in RCA: 31] [Impact Index Per Article: 15.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2021] [Revised: 12/08/2022] [Accepted: 12/19/2022] [Indexed: 01/18/2023] Open
Abstract
Genetic lesions in X-linked inhibitor of apoptosis (XIAP) pre-dispose humans to cell death-associated inflammatory diseases, although the underlying mechanisms remain unclear. Here, we report that two patients with XIAP deficiency-associated inflammatory bowel disease display increased inflammatory IL-1β maturation as well as cell death-associated caspase-8 and Gasdermin D (GSDMD) processing in diseased tissue, which is reduced upon patient treatment. Loss of XIAP leads to caspase-8-driven cell death and bioactive IL-1β release that is only abrogated by combined deletion of the apoptotic and pyroptotic cell death machinery. Namely, extrinsic apoptotic caspase-8 promotes pyroptotic GSDMD processing that kills macrophages lacking both inflammasome and apoptosis signalling components (caspase-1, -3, -7, -11 and BID), while caspase-8 can still cause cell death in the absence of both GSDMD and GSDME when caspase-3 and caspase-7 are present. Neither caspase-3 and caspase-7-mediated activation of the pannexin-1 channel, or GSDMD loss, prevented NLRP3 inflammasome assembly and consequent caspase-1 and IL-1β maturation downstream of XIAP inhibition and caspase-8 activation, even though the pannexin-1 channel was required for NLRP3 triggering upon mitochondrial apoptosis. These findings uncouple the mechanisms of cell death and NLRP3 activation resulting from extrinsic and intrinsic apoptosis signalling, reveal how XIAP loss can co-opt dual cell death programs, and uncover strategies for targeting the cell death and inflammatory pathways that result from XIAP deficiency.
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Matros ES, Karitskaya AI. Clinical Case of X-Linked Lymphoproliferative Syndrome Burdened with Hemophagocytic Lymphohistiocytosis and Crohn's Disease. PEDIATRIC PHARMACOLOGY 2023. [DOI: 10.15690/pf.v20i1.2522] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/05/2023]
Abstract
Background. X-linked lymphoproliferative (XLP) syndrome is hereditary disease with the incidence of 1-3 per 1 million born boys. This clinical case demonstrates a rare picture of XLP type 2 manifestation without prior Epstein-Barr virus.Clinical case description. Boy D., 15 years old, was admitted to Morozovskaya Children's City Hospital with complaints on fever, abdominal pain, loose stools, weight loss. The past medical history included hemophagocytic syndrome (remission) and acute erythema nodosum. We have performed several studies: abdominal ultrasound (hepatomegaly, dynamic changes in the intestine: parts of the small intestine were enlarged and walls were thickened, mass peristalsis, walls of transverse colon and descending colon are thickened up to 5 mm, mesenteric lymphadenopathy), rectosigmoidoscopy (high-activity ulcerative proctosigmoiditis corresponds to Crohn's disease), biochemical and clinical blood tests (active hemophagocytic syndrome), coagulogram (secondary hypocoagulation), myelogram (no data on hemoblastosis or aplastic condition). Virological blood tests (CMV, EBV, HHV-VI): negative. Laboratory and instrumental tests have revealed recurrence of hemophagocytic syndrome and Crohn's disease. The child was consulted by rheumatologist, hematologist, gastroenterologist, geneticist, neurologist, and clinical pharmacologist. The primary immune deficiency disease was suspected in this patient due to his medical history. Molecular genetic study was performed (deletion including the XIAP gene was revealed) and the diagnosis of primary immune deficiency was verified: X-linked lymphoproliferative syndrome type 2. Thus, allogeneic haematopoietic stem cell transplantation (HSCT) was performed.Conclusion. XLP diagnosis and management require multidisciplinary approach. The early diagnosis is crucial due to the high risk of secondary complications development that can significantly worsen the disease's prognosis. Allogeneic HSCT is the only effective treatment for the disease.
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Drabent P, Berrebi D. [Pediatric very early onset inflammatory bowel disease: Role of pathology]. Ann Pathol 2023. [PMID: 36863899 DOI: 10.1016/j.annpat.2023.02.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/04/2023]
Abstract
Inflammatory bowel diseases (IBD), including Crohn's disease and ulcerative colitis, are a heterogeneous group of multifactorial pathologies, often polygenic, due to a dysregulated immune response in a genetically susceptible host. In children under 6 years of age, a significant proportion of IBD, named "very early onset inflammatory bowel diseases" (VEO-IBD), are monogenic disorders in more than one third of cases. Over 80 genes have been linked to VEO-IBD and pathological descriptions are sparce. In this clarification, we describe the clinical aspects of monogenic VEO-IBD and the main causative genes, as well as the various histological patterns observed in intestinal biopsies. The management of a patient with VEO-IBD should be a coordinated effort by a multidisciplinary team including pediatric gastroenterologists, immunologists, geneticists, and of course pediatric pathologists.
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Affiliation(s)
- Philippe Drabent
- Service d'anatomie et cytologie pathologiques, hôpitaux universitaires Necker-Enfants malades et Robert Debré, AP-HP, université de Paris, 149, rue de Sèvres, 75015 Paris, France
| | - Dominique Berrebi
- Service d'anatomie et cytologie pathologiques, hôpitaux universitaires Necker-Enfants malades et Robert Debré, AP-HP, université de Paris, 149, rue de Sèvres, 75015 Paris, France.
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11
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Topal J, Panchal N, Barroeta A, Roppelt A, Mudde A, Gaspar HB, Thrasher AJ, Houghton BC, Booth C. Lentiviral Gene Transfer Corrects Immune Abnormalities in XIAP Deficiency. J Clin Immunol 2023; 43:440-451. [PMID: 36329240 PMCID: PMC9892131 DOI: 10.1007/s10875-022-01389-0] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2022] [Accepted: 10/19/2022] [Indexed: 11/06/2022]
Abstract
BACKGROUND X-linked inhibitor of apoptosis protein (XIAP) deficiency is a severe immunodeficiency with clinical features including hemophagocytic lymphohistiocytosis (HLH) and inflammatory bowel disease (IBD) due to defective NOD2 responses. Management includes immunomodulatory therapies and hematopoietic stem cell transplant (HSCT). However, this cohort is particularly susceptible to the chemotherapeutic regimens and acutely affected by graft-vs-host disease (GvHD), driving poor long-term survival in transplanted patients. Autologous HSC gene therapy could offer an alternative treatment option and would abrogate the risks of alloreactivity. METHODS Hematopoietic progenitor (Lin-ve) cells from XIAPy/- mice were transduced with a lentiviral vector encoding human XIAP cDNA before transplantation into irradiated XIAP y/- recipients. After 12 weeks animals were challenged with the dectin-1 ligand curdlan and recovery of innate immune function was evaluated though analysis of inflammatory cytokines, body weight, and splenomegaly. XIAP patient-derived CD14+ monocytes were transduced with the same vector and functional recovery was demonstrated using in vitro L18-MDP/NOD2 assays. RESULTS In treated XIAPy/- mice, ~40% engraftment of gene-corrected Lin-ve cells led to significant recovery of weight loss, splenomegaly, and inflammatory cytokine responses to curdlan, comparable to wild-type mice. Serum IL-6, IL-10, MCP-1, and TNF were significantly reduced 2-h post-curdlan administration in non-corrected XIAPy/- mice compared to wild-type and gene-corrected animals. Appropriate reduction of inflammatory responses was observed in gene-corrected mice, whereas non-corrected mice developed an inflammatory profile 9 days post-curdlan challenge. In gene-corrected patient CD14+ monocytes, TNF responses were restored following NOD2 activation with L18-MDP. CONCLUSION Gene correction of HSCs recovers XIAP-dependent immune defects and could offer a treatment option for patients with XIAP deficiency.
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Affiliation(s)
- Joseph Topal
- Molecular and Cellular Immunology Section, UCL Great Ormond Street Institute of Child Health, London, UK
| | - Neelam Panchal
- Molecular and Cellular Immunology Section, UCL Great Ormond Street Institute of Child Health, London, UK
| | - Amairelys Barroeta
- Molecular and Cellular Immunology Section, UCL Great Ormond Street Institute of Child Health, London, UK
| | - Anna Roppelt
- Molecular and Cellular Immunology Section, UCL Great Ormond Street Institute of Child Health, London, UK
- Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology, Moscow, Russian Federation
| | - Annelotte Mudde
- Molecular and Cellular Immunology Section, UCL Great Ormond Street Institute of Child Health, London, UK
| | - H Bobby Gaspar
- Molecular and Cellular Immunology Section, UCL Great Ormond Street Institute of Child Health, London, UK
- Orchard Therapeutics, London, UK
| | - Adrian J Thrasher
- Molecular and Cellular Immunology Section, UCL Great Ormond Street Institute of Child Health, London, UK
- Department of Immunology and Gene Therapy, Great Ormond Street Hospital for Children, NHS Foundation Trust, London, UK
| | - Benjamin C Houghton
- Molecular and Cellular Immunology Section, UCL Great Ormond Street Institute of Child Health, London, UK
| | - Claire Booth
- Molecular and Cellular Immunology Section, UCL Great Ormond Street Institute of Child Health, London, UK.
- Department of Immunology and Gene Therapy, Great Ormond Street Hospital for Children, NHS Foundation Trust, London, UK.
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12
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Quercetin ameliorates XIAP deficiency-associated hyperinflammation. Blood 2022; 140:706-715. [PMID: 35687753 DOI: 10.1182/blood.2021014335] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2021] [Accepted: 05/02/2022] [Indexed: 11/20/2022] Open
Abstract
XIAP (X-linked inhibitor of apoptosis) deficiency is a rare inborn error of immunity. XIAP deficiency causes hyperinflammatory disease manifestations due to dysregulated TNF (tumor necrosis factor)-receptor signaling and NLRP3 (NOD- [nucleotide-binding oligomerization domain], LRR- [leucine-rich repeat] and pyrin domain-containing protein 3) inflammasome function. Safe and effective long-term treatments are needed and are especially important to help prevent the need for high-risk allogeneic hematopoietic cell transplantation. Here we evaluated inflammasome inhibitors as potential therapeutics with a focus on the natural flavonoid antioxidant quercetin. Bone marrow (BM)-derived macrophages were derived from XIAP-deficient or wild-type (WT) mice. Human monocytes were obtained from control or XIAP-deficient patients. Cells were stimulated with TLR (Toll-like receptor) agonists or TNF-α ± inhibitors or quercetin. For in vivo lipopolysaccharide (LPS) challenge experiments, XIAP-deficient or WT mice were fed mouse chow ± supplemental quercetin (50 mg/kg per day exposure) for 7 days followed by a challenge with 10 ng/kg LPS. IL-1β (interleukin-1β) and IL-18 were measured by ELISA (enzyme-linked immunosorbent assay). In murine studies, quercetin prevented IL-1β secretion from XIAP knockout cells following TLR agonists or TNF-α stimulation (P < .05) and strongly reduced constitutive production of IL-18 by both WT and XIAP-deficient cells (P < .05). At 4 hours after in vivo LPS challenge, blood levels of IL-1β and IL-18 were significantly decreased in mice that had received quercetin-supplemented chow (P < .05). In experiments using human cells, quercetin greatly reduced IL-1β secretion by monocytes following TNF-α stimulation (P < .05). Our data suggest that quercetin may be an effective natural therapeutic for the prevention of XIAP deficiency-associated hyperinflammation. Clinical trials, including careful pharmacokinetic and pharmacodynamic studies to ensure that effective levels of quercetin can be obtained, are warranted.
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13
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Otagiri S, Katsurada T, Sakurai K, Sugita J, Sakamoto N. Endoscopic balloon dilations for strictures of rectum, ileocecal valve and duodenum in a patient with X-linked inhibitor of apoptosis deficiency: a case report. Intest Res 2022; 20:274-277. [PMID: 35124956 PMCID: PMC9081990 DOI: 10.5217/ir.2021.00029] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/18/2021] [Revised: 03/09/2021] [Accepted: 04/14/2021] [Indexed: 11/05/2022] Open
Abstract
X-linked inhibitor of apoptosis (XIAP) deficiency is a rare primary immunodeficiency and gastrointestinal (GI) lesions in XIAP deficiency are similar to Crohn's disease. For patients with Crohn's disease, endoscopic balloon dilation (EBD) is known to be a standard procedure for intestinal strictures including upper GI tract. However, there are no articles which mention the efficacy of EBDs for the strictures in upper GI tract in patients with XIAP deficiency. Herein, we describe an 18-year-old male with XIAP deficiency in whom EBDs for the rectum, ileocecal valve (ICV), and duodenum were performed. Before hematopoietic stem cell transplantation (HSCT), GI endoscopy revealed strictures of the rectum, ICV and duodenum with active ulcers. Although these ulcers healed after HSCT, the strictures progressed. Therefore, we performed EBDs for the strictures of the rectum, ICV, and duodenum. In contrast studies, we did not find any other strictures in the small intestine. Throughout the patient's clinical course, no complications of EBD occurred. He started eating after EBDs, but abdominal symptoms did not relapse without any dietary restrictions. Our case suggests that EBD could be an effective and safe procedure for intestinal strictures including upper GI tract after HSCT in patients with XIAP deficiency.
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Affiliation(s)
- Shinsuke Otagiri
- Department of Gastroenterology and Hepatology, Hokkaido University Graduate School of Medicine, Sapporo, Japan
| | - Takehiko Katsurada
- Department of Gastroenterology and Hepatology, Hokkaido University Hospital, Sapporo, Japan
| | - Kensuke Sakurai
- Department of Gastroenterology and Hepatology, Hokkaido University Graduate School of Medicine, Sapporo, Japan
| | - Junichi Sugita
- Department of Hematology, Hokkaido University Hospital, Sapporo, Japan
| | - Naoya Sakamoto
- Department of Gastroenterology and Hepatology, Hokkaido University Graduate School of Medicine, Sapporo, Japan
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14
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Zeiser R, Warnatz K, Rosshart S, Sagar, Tanriver Y. GVHD, IBD and primary immunodeficiencies: The gut as a target of immunopathology resulting from impaired immunity. Eur J Immunol 2022; 52:1406-1418. [PMID: 35339113 DOI: 10.1002/eji.202149530] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2021] [Revised: 12/10/2021] [Accepted: 01/21/2022] [Indexed: 11/11/2022]
Abstract
The intestinal tract is the largest immunological organ in the body and has a central function of regulating local immune responses, as the intestinal epithelial barrier is a location where the immune system interacts with the gut microbiome including bacteria, fungi and viruses. Impaired immunity in the intestinal tract can lead to immunopathology, which manifests in different diseases such as inflammatory bowel disease (IBD) or intestinal graft-versus-host disease (GVHD). A disturbed communication between epithelial cells, immune cells and microbiome will shape pathogenic immune responses to antigens, which need to be counterbalanced by tolerogenic mechanisms and repair mechanisms. Here, we review how impaired intestinal immune function leads to immunopathology with a specific focus on innate immune cells, the role of the microbiome and the resulting clinical manifestations including intestinal GVHD, IBD and enteropathy in primary immunodeficiency. This article is protected by copyright. All rights reserved.
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Affiliation(s)
- Robert Zeiser
- Department of Medicine I (Hematology, Oncology and Stem Cell Transplantation), Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.,Comprehensive Cancer Center Freiburg (CCCF), Medical Center- University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.,German Cancer Consortium (DKTK) Partner Site Freiburg and German Cancer Research Center (DKFZ), Heidelberg, Germany.,Signalling Research Centres BIOSS and CIBSS - Centre for Integrative Biological Signalling Studies, University of Freiburg, Freiburg, Germany
| | - Klaus Warnatz
- Department of Rheumatology and Clinical Immunology - Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.,Center for Chronic Immunodeficiency (CCI), Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Stephan Rosshart
- Department of Medicine II (Gastroenterology, Hepatology, Endocrinology and Infectious Diseases), Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Sagar
- Department of Medicine II (Gastroenterology, Hepatology, Endocrinology and Infectious Diseases), Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Yakup Tanriver
- Department of Medicine IV (Nephrology and Primary Care), Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.,Center for Microbiology and Hygiene, Institute for Microbiology and Hygiene, Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
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15
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Sasahara Y, Uchida T, Suzuki T, Abukawa D. Primary Immunodeficiencies Associated With Early-Onset Inflammatory Bowel Disease in Southeast and East Asia. Front Immunol 2022; 12:786538. [PMID: 35095863 PMCID: PMC8792847 DOI: 10.3389/fimmu.2021.786538] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2021] [Accepted: 12/21/2021] [Indexed: 12/02/2022] Open
Abstract
Background Causes of early-onset inflammatory bowel disease (IBD) vary, and primary immunodeficiency diseases (PIDs) are associated with early-onset IBD as monogenic disorders. Aim This review investigates the prevalence, clinical manifestation, genetic profile, and treatment of patients with early-onset IBD in Southeast and East Asia. Methods A systemic review of articles reporting PID patients associated with early-onset IBD in Southeast and East Asia was conducted. Results The prevalence of PID associated with IBD was higher than that reported in western nations, and the frequency of patients with bloody stools as an early symptom was relatively higher in monogenic diseases. A total 13 (12.0%) of 108 patients with early-onset IBD were diagnosed as PID by exome sequencing and targeted gene panel analysis in Japan, including four patients with XIAP, three with IL10RA, and two or one patient with other gene mutations. In addition, ten patients were reported as having IL-10 receptor alpha (IL-10RA) deficiency in China and Hong Kong. Allogeneic hematopoietic stem cell transplantation was performed in patients with X-linked inhibitor of apoptosis deficiency, IL-10RA deficiency, or other PID as a curative treatment, and the preferable outcome of reduced-intensity conditioning and complete resolution of IBD symptoms and dysbiosis were achieved. Conclusion Comprehensive molecular diagnosis has been widely applied to screen for patients with PID-associated IBD in Southeast and East Asia. These results contributed to the awareness of monogenic PID in early-onset IBD patients and their differences in clinical manifestations and genetic profiles compared to the patients in western counties.
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Affiliation(s)
- Yoji Sasahara
- Department of Pediatrics, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Takashi Uchida
- Department of Pediatrics, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Tasuku Suzuki
- Department of Pediatrics, Tohoku University Graduate School of Medicine, Sendai, Japan
| | - Daiki Abukawa
- Department of General Pediatrics, Gastroenterology and Hepatology, Miyagi Children's Hospital, Sendai, Japan
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16
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Tegtmeyer D, Flemming G, Klemann C. Chronisch-entzündliche Darmerkrankung. Monatsschr Kinderheilkd 2022. [DOI: 10.1007/s00112-022-01425-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
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17
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Ruan J, Schlüter D, Naumann M, Waisman A, Wang X. Ubiquitin-modifying enzymes as regulators of colitis. Trends Mol Med 2022; 28:304-318. [PMID: 35177326 DOI: 10.1016/j.molmed.2022.01.006] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2021] [Revised: 01/24/2022] [Accepted: 01/24/2022] [Indexed: 12/18/2022]
Abstract
Inflammatory bowel disease (IBD), including Crohn's disease (CD) and ulcerative colitis (UC), is a chronic inflammatory disorder of the gastrointestinal tract. Although the pathophysiology of IBD is multifaceted, ubiquitination, a post-translational modification, has been shown to have essential roles in its pathogenesis and development. Ubiquitin-modifying enzymes (UMEs) work in synergy to orchestrate the optimal ubiquitination of target proteins, thereby maintaining intestinal homeostasis. Genome-wide association studies (GWAS) have identified multiple UME genes as IBD susceptibility loci, implying the importance of UMEs in IBD. Furthermore, accumulative evidence demonstrates that UMEs affect intestinal inflammation by regulating various aspects, such as intestinal barrier functions and immune responses. Considering the significant functions of UMEs in IBD, targeting UMEs could become a favorable therapeutic approach for IBD.
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Affiliation(s)
- Jing Ruan
- Department of Pathology, The First Affiliated Hospital, Wenzhou Medical University, Wenzhou, China
| | - Dirk Schlüter
- Institute of Medical Microbiology and Hospital Epidemiology, Hannover Medical School, Hannover, Germany; Cluster of Excellence RESIST (EXC 2155), Hannover Medical School, Hannover, Germany
| | - Michael Naumann
- Institute of Experimental Internal Medicine, Otto-von-Guericke University Magdeburg, Magdeburg, Germany
| | - Ari Waisman
- Institute for Molecular Medicine, Johannes Gutenberg University Mainz, Mainz, Germany
| | - Xu Wang
- School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, China; Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision and Brain Health), Wenzhou, China; Institute of Medical Microbiology and Hospital Epidemiology, Hannover Medical School, Hannover, Germany.
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18
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Sbihi Z, Tanita K, Bachelet C, Bole C, Jabot-Hanin F, Tores F, Le Loch M, Khodr R, Hoshino A, Lenoir C, Oleastro M, Villa M, Spossito L, Prieto E, Danielian S, Brunet E, Picard C, Taga T, Abdrabou SSMA, Isoda T, Yamada M, Palma A, Kanegane H, Latour S. Identification of Germline Non-coding Deletions in XIAP Gene Causing XIAP Deficiency Reveals a Key Promoter Sequence. J Clin Immunol 2022; 42:559-571. [PMID: 35000057 DOI: 10.1007/s10875-021-01188-z] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2021] [Accepted: 11/21/2021] [Indexed: 11/24/2022]
Abstract
PURPOSE X-linked inhibitor of apoptosis protein (XIAP) deficiency, also known as the X-linked lymphoproliferative syndrome of type 2 (XLP-2), is a rare immunodeficiency characterized by recurrent hemophagocytic lymphohistiocytosis, splenomegaly, and inflammatory bowel disease. Variants in XIAP including missense, non-sense, frameshift, and deletions of coding exons have been reported to cause XIAP deficiency. We studied three young boys with immunodeficiency displaying XLP-2-like clinical features. No genetic variation in the coding exons of XIAP was identified by whole-exome sequencing (WES), although the patients exhibited a complete loss of XIAP expression. METHODS Targeted next-generation sequencing (NGS) of the entire locus of XIAP was performed on DNA samples from the three patients. Molecular investigations were assessed by gene reporter expression assays in HEK cells and CRISPR-Cas9 genome editing in primary T cells. RESULTS NGS of XIAP identified three distinct non-coding deletions in the patients that were predicted to be driven by repetitive DNA sequences. These deletions share a common region of 839 bp that encompassed the first non-coding exon of XIAP and contained regulatory elements and marks specific of an active promoter. Moreover, we showed that among the 839 bp, the exon was transcriptionally active. Finally, deletion of the exon by CRISPR-Cas9 in primary cells reduced XIAP protein expression. CONCLUSIONS These results identify a key promoter sequence contained in the first non-coding exon of XIAP. Importantly, this study highlights that sequencing of the non-coding exons that are not currently captured by WES should be considered in the genetic diagnosis when no variation is found in coding exons.
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Affiliation(s)
- Zineb Sbihi
- Laboratory of Lymphocyte Activation and Susceptibility to EBV Infection, INSERM UMR 1163, Imagine Institute, Paris, France
| | - Kay Tanita
- Department of Pediatrics and Developmental Biology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo, Japan
| | - Camille Bachelet
- Laboratory of Lymphocyte Activation and Susceptibility to EBV Infection, INSERM UMR 1163, Imagine Institute, Paris, France.,Université de Paris, Paris, France
| | - Christine Bole
- Genomics Core Facility, Institut Imagine-Structure Fédérative de Recherche Necker, INSERM UMR 1163, INSERM US24/CNRS UMS3633, Université de Paris, Paris, France
| | - Fabienne Jabot-Hanin
- Genomics Core Facility, Institut Imagine-Structure Fédérative de Recherche Necker, INSERM UMR 1163, INSERM US24/CNRS UMS3633, Université de Paris, Paris, France.,Bioinformatic Platform, INSERM UMR 1163, Institut Imagine, Paris, France
| | - Frederic Tores
- Genomics Core Facility, Institut Imagine-Structure Fédérative de Recherche Necker, INSERM UMR 1163, INSERM US24/CNRS UMS3633, Université de Paris, Paris, France.,Bioinformatic Platform, INSERM UMR 1163, Institut Imagine, Paris, France
| | - Marc Le Loch
- Service d'Histologie-Embryologie-Cytogénétique, Hôpital Necker-Enfants Malades, Paris, France
| | - Radi Khodr
- Laboratory of Lymphocyte Activation and Susceptibility to EBV Infection, INSERM UMR 1163, Imagine Institute, Paris, France
| | - Akihiro Hoshino
- Laboratory of Lymphocyte Activation and Susceptibility to EBV Infection, INSERM UMR 1163, Imagine Institute, Paris, France
| | - Christelle Lenoir
- Laboratory of Lymphocyte Activation and Susceptibility to EBV Infection, INSERM UMR 1163, Imagine Institute, Paris, France
| | - Matias Oleastro
- Immunology and Rheumatology Division, Hospital de Pediatria S.A.M.I.C. Prof. Dr. Juan P. Garrahan, Buenos Aires, Argentina
| | - Mariana Villa
- Immunology and Rheumatology Division, Hospital de Pediatria S.A.M.I.C. Prof. Dr. Juan P. Garrahan, Buenos Aires, Argentina
| | - Lucia Spossito
- Immunology and Rheumatology Division, Hospital de Pediatria S.A.M.I.C. Prof. Dr. Juan P. Garrahan, Buenos Aires, Argentina
| | - Emma Prieto
- Immunology and Rheumatology Division, Hospital de Pediatria S.A.M.I.C. Prof. Dr. Juan P. Garrahan, Buenos Aires, Argentina
| | - Silvia Danielian
- Immunology and Rheumatology Division, Hospital de Pediatria S.A.M.I.C. Prof. Dr. Juan P. Garrahan, Buenos Aires, Argentina
| | - Erika Brunet
- Laboratory of Dynamic of Genome and Immune System, INSERM UMR 1163, Imagine Institute, Paris, France
| | - Capucine Picard
- Laboratory of Lymphocyte Activation and Susceptibility to EBV Infection, INSERM UMR 1163, Imagine Institute, Paris, France.,Université de Paris, Paris, France.,Study Center for Primary Immunodeficiencies, Necker-Enfants Malades Hospital, APHP, Paris, France
| | - Takashi Taga
- Department of Pediatrics, Shiga University of Medical Science, Otsu, Japan
| | | | - Takeshi Isoda
- Department of Pediatrics and Developmental Biology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo, Japan
| | - Masafumi Yamada
- Department of Pediatrics, Faculty of Medicine, Graduate School of Medicine, Hokkaido University, Sapporo, Japan
| | - Alejandro Palma
- Immunology and Rheumatology Division, Hospital de Pediatria S.A.M.I.C. Prof. Dr. Juan P. Garrahan, Buenos Aires, Argentina
| | - Hirokazu Kanegane
- Department of Child Health and Development, Graduate School of Medical and Dental Sciences, TMDU, Tokyo, Japan
| | - Sylvain Latour
- Laboratory of Lymphocyte Activation and Susceptibility to EBV Infection, INSERM UMR 1163, Imagine Institute, Paris, France. .,Université de Paris, Paris, France.
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19
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Abdrabou SSMA, Toita N, Ichihara S, Tozawa Y, Takahashi M, Fujiwara SI, Ashida T, Ohara O, Ariga T, Manabe A, Konno M, Yamada M. Absent X-linked inhibitor of apoptosis protein expression in T cell blasts and causal mutations including non-coding deletion. Pediatr Int 2022; 64:e14892. [PMID: 34145698 DOI: 10.1111/ped.14892] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/08/2021] [Revised: 06/15/2021] [Accepted: 06/17/2021] [Indexed: 11/30/2022]
Abstract
BACKGROUND X-linked inhibitor of apoptosis protein (XIAP) deficiency is one of inborn errors of immunity characterized by recurrent hemophagocytic lymphohistiocytosis and refractory inflammatory bowel disease (IBD), mimicking Crohn's disease. The aim of this study is to make an accurate diagnosis of XIAP deficiency based on genetic and XIAP expression studies and to investigate endoscopic findings shared by patients with this disease. METHODS Four male patients with recurrent hemophagocytic lymphohistiocytosis and long-term refractory IBD were studied for the diagnosis of XIAP deficiency. Endoscopic findings of the four patients were also studied in parallel. RESULTS These four patients were diagnosed with XIAP deficiency based on the absent XIAP expression in cultured T-cell blasts. Sequence analysis of the responsible gene, XIAP, demonstrated two novel nonsense mutations of p.Gln114X and p.Glu25X, and a previously reported nonsense mutation of p.Arg381X. Although no mutations in the coding region were detected in the fourth patient, further studies demonstrated a novel 2,199 bp deletion encompassing non-coding exon 1, presumably affecting transcription and stability of XIAP mRNA. All of the patients eventually underwent hematopoietic stem cell transplantation, leading to a complete or partial remission of IBD. These four patients shared an endoscopic finding of multiple wide and longitudinal ulcers with straight and non-raised edge in the colon. CONCLUSIONS X-linked inhibitor of apoptosis protein expression in T-cell blasts could facilitate the diagnosis of this disease, especially with causal mutations in non-coding regions.
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Affiliation(s)
| | - Nariaki Toita
- Department of Pediatrics, Sapporo Kosei General Hospital, Sapporo, Japan
| | - Shin Ichihara
- Department of Surgical Pathology, Sapporo Kosei General Hospital, Sapporo, Japan
| | - Yusuke Tozawa
- Department of Pediatrics, Division of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan
| | - Michiko Takahashi
- Department of Pediatrics, Sapporo Kosei General Hospital, Sapporo, Japan
| | - Shin-Ichi Fujiwara
- Department of Pediatrics, Sapporo Kosei General Hospital, Sapporo, Japan
| | | | - Osamu Ohara
- Department of Applied Genomics, Kazusa DNA Research Institute, Kisarazu, Japan
| | - Tadashi Ariga
- Department of Pediatrics, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan
| | - Atsushi Manabe
- Department of Pediatrics, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan
| | - Mutsuko Konno
- Department of Pediatrics, Sapporo Kosei General Hospital, Sapporo, Japan
| | - Masafumi Yamada
- Department of Pediatrics, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan
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20
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Yang L, Booth C, Speckmann C, Seidel MG, Worth AJ, Kindle G, Lankester AC, B G, Gennery AR, Seppanen MR, Morris EC, Burns SO. Phenotype, genotype, treatment, and survival outcomes in patients with X-linked inhibitor of apoptosis deficiency. J Allergy Clin Immunol 2021; 150:456-466. [PMID: 34920033 DOI: 10.1016/j.jaci.2021.10.037] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2021] [Revised: 10/06/2021] [Accepted: 10/13/2021] [Indexed: 11/27/2022]
Abstract
BACKGROUND X-linked inhibitor of apoptosis (XIAP) deficiency is a rare, primary immunodeficiency disease caused by XIAP gene mutations. A broad range of phenotype, severity, and age of onset present challenges for patient management. OBJECTIVE To characterize the phenotype, treatment, and survival outcomes of XIAP deficiency and assess parameters influencing prognosis. METHODS Data published from 2006-2020 were retrospectively analyzed. RESULTS 167 patients from 117 families with XIAP deficiency were reported with 90 different mutations. A wide spectrum of clinical features were seen, of which hemophagocytic lymphohistiocytosis (HLH) and inflammatory bowel disease (IBD) were the most common. Patients frequently developed multiple features with no clear genotype-phenotype correlation. 117 patients were managed conservatively and 50 underwent hematopoietic stem cell transplantation (HSCT), with respective overall survival probabilities of 90% and 53% at age 16 years. The predominant indication for HSCT was early-onset HLH. Active HLH and myeloablative conditioning regimens increased HSCT-related mortality, although HSCT outcome was much better after 2015 than before. For conservatively managed patients reaching adulthood, survival probabilities were 86% at age 30 years and 37% by age 52 years, with worse outcomes for patients developing the disease before the age of 5 years or with new disease features in adulthood. 9 asymptomatic mutation carriers were identified with a median age of 13.5 years. CONCLUSIONS Our study demonstrates the variable nature of XIAP deficiency which evolves over life for individual patients. Better therapeutic strategies and prospective studies are required to reduce morbidity and mortality and improve decision-making and long-term outcomes for patients with XIAP deficiency.
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Affiliation(s)
- Linlin Yang
- Department of Clinical Immunology, Royal Free London NHS Foundation Trust, London NW3 2PF, United Kingdom; Institute for Immunity and Transplantation, University College London, London NW3 2PF, United Kingdom; Department of Hematology, Shenzhen Second People's Hospital, The First Affiliated Hospital of Shenzhen University, Shenzhen, China
| | - Claire Booth
- Department of Immunology and Gene Therapy, Great Ormond Street Hospital for Children NHS Trust, London WC1N 1JH; Molecular and Cellular Immunology, UCL Great Ormond Street Institute of Child Health, London, United Kingdom
| | - Carsten Speckmann
- Institute for Immunodeficiency, Center for Chronic Immunodeficiency (CCI), Faculty of Medicine, Medical Center - University of Freiburg, Germany; Center for Pediatrics and Adolescent Medicine, Department of Pediatric Hematology and Oncology, Faculty of Medicine, Medical Center - University of Freiburg, Germany
| | - Markus G Seidel
- Research Unit for Pediatric Hematology and Immunology, Division of Pediatric Hematology-Oncology, Department of Pediatrics and Adolescent Medicine, Medical University of Graz, Graz, Austria
| | - Austen Jj Worth
- Department of Immunology and Gene Therapy, Great Ormond Street Hospital for Children NHS Trust, London WC1N 1JH
| | - Gerhard Kindle
- Institute for Immunodeficiency, Center for Chronic Immunodeficiency (CCI), Faculty of Medicine, Medical Center - University of Freiburg, Germany
| | - Arjan C Lankester
- Willem-Alexander Children's Hospital, Department of Pediatrics, Stem Cell Transplantation program, Leiden University Medical Center, Leiden, The Netherlands
| | - Grimbacher B
- Institute for Immunity and Transplantation, University College London, London NW3 2PF, United Kingdom; Institute for Immunodeficiency, Center for Chronic Immunodeficiency (CCI), Faculty of Medicine, Medical Center - University of Freiburg, Germany; DZIF - German Center for Infection Research, Satellite Center Freiburg, Germany; CIBSS - Centre for Integrative Biological Signalling Studies, Albert-Ludwigs University, Freiburg, Germany; RESIST - Cluster of Excellence 2155 to Hanover Medical School, Satellite Center Freiburg, Germany
| | | | - Andrew R Gennery
- Translational and Clinical Research Institute, Newcastle University and Pediatric Immunology + HSCT, Great North Children's Hospital, Newcastle upon Tyne, UK
| | - Mikko Rj Seppanen
- HUS Rare Disease Center, Children and Adolescents, University of Helsinki and Helsinki University Hospital, Finland
| | - Emma C Morris
- Department of Clinical Immunology, Royal Free London NHS Foundation Trust, London NW3 2PF, United Kingdom; Institute for Immunity and Transplantation, University College London, London NW3 2PF, United Kingdom
| | - Siobhan O Burns
- Department of Clinical Immunology, Royal Free London NHS Foundation Trust, London NW3 2PF, United Kingdom; Institute for Immunity and Transplantation, University College London, London NW3 2PF, United Kingdom.
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21
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Staels F, Collignon T, Betrains A, Gerbaux M, Willemsen M, Humblet-Baron S, Liston A, Vanderschueren S, Schrijvers R. Monogenic Adult-Onset Inborn Errors of Immunity. Front Immunol 2021; 12:753978. [PMID: 34867986 PMCID: PMC8635491 DOI: 10.3389/fimmu.2021.753978] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2021] [Accepted: 10/22/2021] [Indexed: 12/28/2022] Open
Abstract
Inborn errors of immunity (IEI) are a heterogenous group of disorders driven by genetic defects that functionally impact the development and/or function of the innate and/or adaptive immune system. The majority of these disorders are thought to have polygenic background. However, the use of next-generation sequencing in patients with IEI has led to an increasing identification of monogenic causes, unravelling the exact pathophysiology of the disease and allowing the development of more targeted treatments. Monogenic IEI are not only seen in a pediatric population but also in adulthood, either due to the lack of awareness preventing childhood diagnosis or due to a delayed onset where (epi)genetic or environmental factors can play a role. In this review, we discuss the mechanisms accounting for adult-onset presentations and provide an overview of monogenic causes associated with adult-onset IEI.
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Affiliation(s)
- Frederik Staels
- Department of Microbiology, Immunology and Transplantation, Laboratory of Adaptive Immunology, KU Leuven, Leuven, Belgium.,Department of Microbiology, Immunology and Transplantation, Allergy and Clinical Immunology Research Group, KU Leuven, Leuven, Belgium
| | | | - Albrecht Betrains
- Department of General Internal Medicine, University Hospitals Leuven, Leuven, Belgium.,Department of Microbiology, Immunology and Transplantation, Laboratory of Clinical Infectious and Inflammatory Disease, KU Leuven, Leuven, Belgium
| | - Margaux Gerbaux
- Department of Microbiology, Immunology and Transplantation, Laboratory of Adaptive Immunology, KU Leuven, Leuven, Belgium.,Vlaams Instituut voor Biotechnologie - Katholieke Universiteit (VIB-KU) Leuven Center for Brain and Disease Research, Leuven, Belgium
| | - Mathijs Willemsen
- Department of Microbiology, Immunology and Transplantation, Laboratory of Adaptive Immunology, KU Leuven, Leuven, Belgium.,Vlaams Instituut voor Biotechnologie - Katholieke Universiteit (VIB-KU) Leuven Center for Brain and Disease Research, Leuven, Belgium
| | - Stephanie Humblet-Baron
- Department of Microbiology, Immunology and Transplantation, Laboratory of Adaptive Immunology, KU Leuven, Leuven, Belgium
| | - Adrian Liston
- Department of Microbiology, Immunology and Transplantation, Laboratory of Adaptive Immunology, KU Leuven, Leuven, Belgium.,Laboratory of Lymphocyte Signalling and Development, Babraham Institute, Cambridge, United Kingdom
| | - Steven Vanderschueren
- Department of General Internal Medicine, University Hospitals Leuven, Leuven, Belgium.,Department of Microbiology, Immunology and Transplantation, Laboratory of Clinical Infectious and Inflammatory Disease, KU Leuven, Leuven, Belgium
| | - Rik Schrijvers
- Department of Microbiology, Immunology and Transplantation, Allergy and Clinical Immunology Research Group, KU Leuven, Leuven, Belgium.,Department of General Internal Medicine, University Hospitals Leuven, Leuven, Belgium
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22
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Ouahed J, Kelsen JR, Spessott WA, Kooshesh K, Sanmillan ML, Dawany N, Sullivan KE, Hamilton KE, Slowik V, Nejentsev S, Neves JF, Flores H, Chung WK, Wilson A, Anyane-Yeboa K, Wou K, Jain P, Field M, Tollefson S, Dent MH, Li D, Naito T, McGovern DPB, Kwong AC, Taliaferro F, Ordovas-Montanes J, Horwitz BH, Kotlarz D, Klein C, Evans J, Dorsey J, Warner N, Elkadri A, Muise AM, Goldsmith J, Thompson B, Engelhardt KR, Cant AJ, Hambleton S, Barclay A, Toth-Petroczy A, Vuzman D, Carmichael N, Bodea C, Cassa CA, Devoto M, Maas RL, Behrens EM, Giraudo CG, Snapper SB. Variants in STXBP3 are Associated with Very Early Onset Inflammatory Bowel Disease, Bilateral Sensorineural Hearing Loss and Immune Dysregulation. J Crohns Colitis 2021; 15:1908-1919. [PMID: 33891011 PMCID: PMC8575043 DOI: 10.1093/ecco-jcc/jjab077] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
BACKGROUND AND AIMS Very early onset inflammatory bowel disease [VEOIBD] is characterized by intestinal inflammation affecting infants and children less than 6 years of age. To date, over 60 monogenic aetiologies of VEOIBD have been identified, many characterized by highly penetrant recessive or dominant variants in underlying immune and/or epithelial pathways. We sought to identify the genetic cause of VEOIBD in a subset of patients with a unique clinical presentation. METHODS Whole exome sequencing was performed on five families with ten patients who presented with a similar constellation of symptoms including medically refractory infantile-onset IBD, bilateral sensorineural hearing loss and, in the majority, recurrent infections. Genetic aetiologies of VEOIBD were assessed and Sanger sequencing was performed to confirm novel genetic findings. Western analysis on peripheral blood mononuclear cells and functional studies with epithelial cell lines were employed. RESULTS In each of the ten patients, we identified damaging heterozygous or biallelic variants in the Syntaxin-Binding Protein 3 gene [STXBP3], a protein known to regulate intracellular vesicular trafficking in the syntaxin-binding protein family of molecules, but not associated to date with either VEOIBD or sensorineural hearing loss. These mutations interfere with either intron splicing or protein stability and lead to reduced STXBP3 protein expression. Knock-down of STXBP3 in CaCo2 cells resulted in defects in cell polarity. CONCLUSION Overall, we describe a novel genetic syndrome and identify a critical role for STXBP3 in VEOIBD, sensorineural hearing loss and immune dysregulation.
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Affiliation(s)
- Jodie Ouahed
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Boston Children's Hospital, and Harvard Medical School, Boston, MA, 02115, USA
| | - Judith R Kelsen
- Division of Gastroenterology, Hepatology, and Nutrition, The Children's Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA
| | - Waldo A Spessott
- Department of Microbiology and Immunology, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA, 19107, USA
| | - Kameron Kooshesh
- Brigham Genomic Medicine Program, Division of Genetics, Department of Medicine, Brigham & Women's Hospital and Harvard Medical School, Boston, MA, 02115, USA
| | - Maria L Sanmillan
- Department of Microbiology and Immunology, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA, 19107, USA
| | - Noor Dawany
- Department of Biomedical Health Informatics, The Children's Hospital of Philadelphia, Philadelphia, PA, 19104, USA
| | - Kathleen E Sullivan
- Division of Allergy and Immunology, The Children's Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA
| | - Kathryn E Hamilton
- Division of Gastroenterology, Hepatology, and Nutrition, The Children's Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA
| | - Voytek Slowik
- Department of Medicine, Division of Gastroenterology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA
| | - Sergey Nejentsev
- Division of Gastroenterology, Hepatology, and Nutrition, Children's Mercy Kansas City, Kansas City, MO, 64108, USA.,Department of Medicine, University of Cambridge, Cambridge, CB2 0QQ, UK
| | - João Farela Neves
- Department of Molecular Cell Biology and Immunology, Amsterdam University Medical Centers, Amsterdam, the Netherlands.,Primary Immunodeficiencies Unit; Hospital Dona Estefânia-CHLC, EPE, Lisbon, 1169, Portugal
| | - Helena Flores
- CEDOC, Chronic Diseases Research Center, NOVA Medical School, Lisbon, 1150, Portugal
| | - Wendy K Chung
- Gastroenterology Unit, Hospital Dona Estefânia-CHLC, EPE, Lisbon, 1169, Portugal
| | - Ashley Wilson
- Gastroenterology Unit, Hospital Dona Estefânia-CHLC, EPE, Lisbon, 1169, Portugal
| | - Kwame Anyane-Yeboa
- Gastroenterology Unit, Hospital Dona Estefânia-CHLC, EPE, Lisbon, 1169, Portugal
| | - Karen Wou
- Gastroenterology Unit, Hospital Dona Estefânia-CHLC, EPE, Lisbon, 1169, Portugal
| | - Preti Jain
- Department of Pediatrics, Columbia University Medical Center, New York, NY, 10032, USA.,Department of Medicine, Columbia University Medical Center, New York, NY, 10032, USA
| | - Michael Field
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Boston Children's Hospital, and Harvard Medical School, Boston, MA, 02115, USA
| | - Sophia Tollefson
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Boston Children's Hospital, and Harvard Medical School, Boston, MA, 02115, USA
| | - Maiah H Dent
- Department of Genetics, Yale University, New Haven, CT, 06510, USA
| | - Dalin Li
- F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA, 90048, USA
| | - Takeo Naito
- F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA, 90048, USA
| | - Dermot P B McGovern
- F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA, 90048, USA
| | - Andrew C Kwong
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Boston Children's Hospital, and Harvard Medical School, Boston, MA, 02115, USA.,Biological and Biomedical Sciences, Harvard Medical School, Boston, MA, 02115, USA.,Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA
| | - Faith Taliaferro
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Boston Children's Hospital, and Harvard Medical School, Boston, MA, 02115, USA.,Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA
| | - Jose Ordovas-Montanes
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Boston Children's Hospital, and Harvard Medical School, Boston, MA, 02115, USA.,Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA.,Program in Immunology, Harvard Medical School, Boston, MA, 02115, USA.,Harvard Stem Cell Institute, Cambridge, MA, 02138, USA
| | - Bruce H Horwitz
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Boston Children's Hospital, and Harvard Medical School, Boston, MA, 02115, USA.,Division of Emergency Medicine, Department of Pediatrics, Boston Children's Hospital, and Harvard Medical School, Boston, MA, 02115, USA
| | - Daniel Kotlarz
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Boston Children's Hospital, and Harvard Medical School, Boston, MA, 02115, USA.,Dr. von Hauner Children's Hospital, Department of Pediatrics, University Hospital LMU Munich, Munich, 80337, Germany
| | - Christoph Klein
- Dr. von Hauner Children's Hospital, Department of Pediatrics, University Hospital LMU Munich, Munich, 80337, Germany
| | - Jonathan Evans
- Department of Pediatrics, Nemours Children's Specialty Care, Jacksonville, FL 32207, USA
| | - Jill Dorsey
- Department of Pediatrics, Nemours Children's Specialty Care, Jacksonville, FL 32207, USA
| | - Neil Warner
- SickKids Inflammatory Bowel Disease Center and Cell Biology Program, Research Institute, Hospital for Sick Children, Toronto, ON, Canada.,Department of Pediatrics and Biochemistry, University of Toronto, Hospital for Sick Children, Toronto, ON, M5G 1X8, Canada
| | - Abdul Elkadri
- SickKids Inflammatory Bowel Disease Center and Cell Biology Program, Research Institute, Hospital for Sick Children, Toronto, ON, Canada.,Department of Pediatrics and Biochemistry, University of Toronto, Hospital for Sick Children, Toronto, ON, M5G 1X8, Canada
| | - Aleixo M Muise
- SickKids Inflammatory Bowel Disease Center and Cell Biology Program, Research Institute, Hospital for Sick Children, Toronto, ON, Canada.,Department of Pediatrics and Biochemistry, University of Toronto, Hospital for Sick Children, Toronto, ON, M5G 1X8, Canada
| | - Jeffrey Goldsmith
- Department of Pathology, Boston Children's Hospital, Harvard Medical School, Boston, MA, 02115, USA
| | - Benjamin Thompson
- Primary Immunodeficiency Group, III Theme, Institute of Cellular Medicine, Newcastle University, Newcastle, NE2 4HH, UK
| | - Karin R Engelhardt
- Primary Immunodeficiency Group, III Theme, Institute of Cellular Medicine, Newcastle University, Newcastle, NE2 4HH, UK
| | - Andrew J Cant
- Primary Immunodeficiency Group, III Theme, Institute of Cellular Medicine, Newcastle University, Newcastle, NE2 4HH, UK.,Children's Immunology Service, Great North Children's Hospital, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle, NE1 4LP, UK
| | - Sophie Hambleton
- Primary Immunodeficiency Group, III Theme, Institute of Cellular Medicine, Newcastle University, Newcastle, NE2 4HH, UK.,Children's Immunology Service, Great North Children's Hospital, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle, NE1 4LP, UK
| | - Andrew Barclay
- Department of Paediatric Gastroenterology, Royal Hospital for Children, Glasgow, G51 4TF, UK
| | - Agnes Toth-Petroczy
- Brigham Genomic Medicine Program, Division of Genetics, Department of Medicine, Brigham & Women's Hospital and Harvard Medical School, Boston, MA, 02115, USA.,Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany.,Center for Systems Biology Dresden, Dresden, Germany
| | - Dana Vuzman
- Brigham Genomic Medicine Program, Division of Genetics, Department of Medicine, Brigham & Women's Hospital and Harvard Medical School, Boston, MA, 02115, USA
| | - Nikkola Carmichael
- Brigham Genomic Medicine Program, Division of Genetics, Department of Medicine, Brigham & Women's Hospital and Harvard Medical School, Boston, MA, 02115, USA
| | - Corneliu Bodea
- Brigham Genomic Medicine Program, Division of Genetics, Department of Medicine, Brigham & Women's Hospital and Harvard Medical School, Boston, MA, 02115, USA
| | - Christopher A Cassa
- Brigham Genomic Medicine Program, Division of Genetics, Department of Medicine, Brigham & Women's Hospital and Harvard Medical School, Boston, MA, 02115, USA
| | - Marcella Devoto
- Division of Human Genetics, The Children's Hospital of Philadelphia, Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.,Department of Translational and Precision Medicine, University Sapienza, Rome 00185, Italy.,CNR-IRGB, Cagliari 09042, Italy
| | - Richard L Maas
- Brigham Genomic Medicine Program, Division of Genetics, Department of Medicine, Brigham & Women's Hospital and Harvard Medical School, Boston, MA, 02115, USA
| | - Edward M Behrens
- Division of Rheumatology, The Children's Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA
| | - Claudio G Giraudo
- Department of Microbiology and Immunology, Sidney Kimmel Medical College, Thomas Jefferson University, Philadelphia, PA, 19107, USA
| | - Scott B Snapper
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Boston Children's Hospital, and Harvard Medical School, Boston, MA, 02115, USA.,Division of Gastroenterology, Department of Medicine, Brigham & Women's Hospital and Harvard Medical School, Boston, MA, 02115, USA
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23
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Bachmann J, Le Thi G, Brückner A, Kalteis AL, Schwerd T, Koletzko S, Lurz E. Epstein-Barr Virus Prevalence at Diagnosis and Seroconversion during Follow-Up in Pediatric Inflammatory Bowel Disease. J Clin Med 2021; 10:jcm10215187. [PMID: 34768707 PMCID: PMC8584287 DOI: 10.3390/jcm10215187] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2021] [Revised: 10/30/2021] [Accepted: 11/03/2021] [Indexed: 12/14/2022] Open
Abstract
Primary Epstein-Barr virus infection in pediatric patients with inflammatory bowel disease during immunomodulation with thiopurines has been associated with increased risk for malignancies or hemophagocytic lymphohistiocytosis. We determined Epstein-Barr virus (EBV) seroprevalence at inflammatory bowel disease (IBD) diagnosis and seroconversion during follow-up in a large single center cohort of children with IBD. EBV serology results and patient characteristics were retrospectively retrieved from the hospital documentation system. EBV seronegative patients at IBD diagnosis were prospectively retested. We report on IBD patients with symptomatic active EBV infection and a complicated disease course, and those diagnosed with malignancy with respect to EBV status and drug exposure. Of 402 patients, 194 (48%) had available EBV serology results at time of IBD diagnosis at a median of 12 years (IQR 9-14 years). Thereof, 102 (53%) were EBV-positive. Of 92 EBV-negative patients, 66 were retested and 17% showed a seroconversion at a mean follow-up time of 4.3 years (SD 3 years). Three children treated with azathioprine experienced acute clinically relevant EBV infection 2, 2.5, and 4 years after IBD diagnosis, two developed signs of hemophagocytic lymphohistiocytosis. Three cases of malignancy occurred in the cohort, though none seemed to be triggered by EBV. In conclusion, almost 50% of pediatric IBD patients were EBV-naïve following diagnosis and may be at increased risk to develop severe EBV infection during immunosuppressive therapy, potentially associated with complications such as hemophagocytic lymphohistiocytosis or malignancy.
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Affiliation(s)
- Jennifer Bachmann
- Department of Pediatrics, Division of Gastroenterology and Hepatology, Dr. von Hauner Children’s Hospital, University Hospital, LMU Munich, 80337 Munich, Germany; (J.B.); (G.L.T.); (A.B.); (T.S.); (S.K.)
| | - Giang Le Thi
- Department of Pediatrics, Division of Gastroenterology and Hepatology, Dr. von Hauner Children’s Hospital, University Hospital, LMU Munich, 80337 Munich, Germany; (J.B.); (G.L.T.); (A.B.); (T.S.); (S.K.)
| | - Annecarin Brückner
- Department of Pediatrics, Division of Gastroenterology and Hepatology, Dr. von Hauner Children’s Hospital, University Hospital, LMU Munich, 80337 Munich, Germany; (J.B.); (G.L.T.); (A.B.); (T.S.); (S.K.)
| | - Anna-Lena Kalteis
- Max von Pettenkofer Institute & Gene Center, Virology, National Reference Center for Retroviruses, LMU Munich, 80336 Munich, Germany;
- German Center for Infection Research (DZIF), Partner Site Munich, 38124 Braunschweig, Germany
| | - Tobias Schwerd
- Department of Pediatrics, Division of Gastroenterology and Hepatology, Dr. von Hauner Children’s Hospital, University Hospital, LMU Munich, 80337 Munich, Germany; (J.B.); (G.L.T.); (A.B.); (T.S.); (S.K.)
| | - Sibylle Koletzko
- Department of Pediatrics, Division of Gastroenterology and Hepatology, Dr. von Hauner Children’s Hospital, University Hospital, LMU Munich, 80337 Munich, Germany; (J.B.); (G.L.T.); (A.B.); (T.S.); (S.K.)
- Department of Pediatric Gastroenterology and Nutrition, School of Medicine, Collegium Medicum University of Warmia and Mazury, 10-561 Olsztyn, Poland
| | - Eberhard Lurz
- Department of Pediatrics, Division of Gastroenterology and Hepatology, Dr. von Hauner Children’s Hospital, University Hospital, LMU Munich, 80337 Munich, Germany; (J.B.); (G.L.T.); (A.B.); (T.S.); (S.K.)
- Correspondence: ; Tel.: +49-89-4400-519060
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24
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Strigli A, Gopalakrishnan S, Zeissig Y, Basic M, Wang J, Schwerd T, Doms S, Peuker K, Hartwig J, Harder J, Hönscheid P, Arnold P, Kurth T, Rost F, Petersen BS, Forster M, Franke A, Kelsen JR, Rohlfs M, Klein C, Muise AM, Warner N, Nambu R, Mayerle J, Török HP, Linkermann A, Muders MH, Baretton GB, Hampe J, Aust DE, Baines JF, Bleich A, Zeissig S. Deficiency in X-linked inhibitor of apoptosis protein promotes susceptibility to microbial triggers of intestinal inflammation. Sci Immunol 2021; 6:eabf7473. [PMID: 34739342 DOI: 10.1126/sciimmunol.abf7473] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Inflammatory bowel disease (IBD) is characterized by inappropriate immune responses to the microbiota in genetically susceptible hosts, but little is known about the pathways that link individual genetic alterations to microbiota-dependent inflammation. Here, we demonstrated that the loss of X-linked inhibitor of apoptosis protein (XIAP), a gene associated with Mendelian IBD, rendered Paneth cells sensitive to microbiota-, tumor necrosis factor (TNF)–, receptor-interacting protein kinase 1 (RIPK1)–, and RIPK3-dependent cell death. This was associated with deficiency in Paneth cell–derived antimicrobial peptides and alterations in the stratification and composition of the microbiota. Loss of XIAP was not sufficient to elicit intestinal inflammation but provided susceptibility to pathobionts able to promote granulomatous ileitis, which could be prevented by administration of a Paneth cell–derived antimicrobial peptide. These data reveal a pathway critical for host-microbial cross-talk, which is required for intestinal homeostasis and the prevention of inflammation and which is amenable to therapeutic targeting.
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Affiliation(s)
- Anne Strigli
- Center for Regenerative Therapies, Technische Universität (TU) Dresden, 01307 Dresden, Germany.,Department of Medicine I, University Medical Center Dresden, Technische Universität (TU) Dresden, 01307 Dresden, Germany
| | - Shreya Gopalakrishnan
- Center for Regenerative Therapies, Technische Universität (TU) Dresden, 01307 Dresden, Germany.,Department of Medicine I, University Medical Center Dresden, Technische Universität (TU) Dresden, 01307 Dresden, Germany
| | - Yvonne Zeissig
- Department of General Pediatrics, University Medical Center Dresden, Technische Universität (TU) Dresden, 01307 Dresden, Germany
| | - Marijana Basic
- Institute for Laboratory Animal Science, Hannover Medical School, 30625 Hannover, Germany
| | - Jun Wang
- Max Planck Institute for Evolutionary Biology, 24306 Plön, Germany.,Institute for Experimental Medicine, Kiel University, 24105 Kiel, Germany.,CAS Key Laboratory for Pathogenic Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China
| | - Tobias Schwerd
- Department of Pediatrics, Dr von Hauner Children's Hospital, LMU Munich, 80337 Munich, Germany
| | - Shauni Doms
- Max Planck Institute for Evolutionary Biology, 24306 Plön, Germany.,Institute for Experimental Medicine, Kiel University, 24105 Kiel, Germany
| | - Kenneth Peuker
- Center for Regenerative Therapies, Technische Universität (TU) Dresden, 01307 Dresden, Germany.,Department of Medicine I, University Medical Center Dresden, Technische Universität (TU) Dresden, 01307 Dresden, Germany
| | - Jelka Hartwig
- Center for Regenerative Therapies, Technische Universität (TU) Dresden, 01307 Dresden, Germany
| | - Jürgen Harder
- Department of Dermatology, University Medical Center Schleswig-Holstein, 24105 Kiel, Germany
| | - Pia Hönscheid
- Institute of Pathology, University Medical Center Dresden, Technische Universität (TU) Dresden, 01307 Dresden, Germany
| | - Philipp Arnold
- Institute of Functional and Clinical Anatomy, Friedrich-Alexander-University Erlangen-Nürnberg (FAU), 91054 Erlangen, Germany
| | - Thomas Kurth
- Center for Molecular and Cellular Bioengineering (CMCB), Technology Platform, Technische Universität (TU) Dresden, 01307 Dresden, Germany
| | - Fabian Rost
- Center for Molecular and Cellular Bioengineering (CMCB), Technology Platform, Technische Universität (TU) Dresden, 01307 Dresden, Germany.,Center for Information Services and High Performance Computing (ZIH), Technische Universität (TU) Dresden, 01602 Dresden, Germany
| | | | - Michael Forster
- Institute for Clinical Molecular Biology, Kiel University, 24105 Kiel, Germany
| | - Andre Franke
- Institute for Clinical Molecular Biology, Kiel University, 24105 Kiel, Germany
| | - Judith R Kelsen
- Division of Gastroenterology, Hepatology, and Nutrition, Children's Hospital of Philadelphia, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Meino Rohlfs
- Department of Pediatrics, Dr von Hauner Children's Hospital, LMU Munich, 80337 Munich, Germany
| | - Christoph Klein
- Department of Pediatrics, Dr von Hauner Children's Hospital, LMU Munich, 80337 Munich, Germany
| | - Aleixo M Muise
- SickKids Inflammatory Bowel Disease Center, Hospital for Sick Children, Toronto, ON M5G 1X8, Canada.,Cell Biology Program, Research Institute, Hospital for Sick Children, Toronto, ON M5G 1X8, Canada.,Department of Pediatrics, Institute of Medical Science and Biochemistry, University of Toronto, Hospital for Sick Children, Toronto, ON M5G 1X8, Canada
| | - Neil Warner
- SickKids Inflammatory Bowel Disease Center, Hospital for Sick Children, Toronto, ON M5G 1X8, Canada
| | - Ryusuke Nambu
- SickKids Inflammatory Bowel Disease Center, Hospital for Sick Children, Toronto, ON M5G 1X8, Canada.,Division of Gastroenterology and Hepatology, Saitama Children's Medical Center, Saitama 330-8777, Japan
| | - Julia Mayerle
- Department of Medicine II, University Hospital, LMU Munich, 80337 Munich, Germany
| | - Helga-Paula Török
- Department of Medicine II, University Hospital, LMU Munich, 80337 Munich, Germany
| | - Andreas Linkermann
- Division of Nephrology, Department of Medicine III, University Medical Center Dresden, Technische Universität (TU) Dresden, 01307 Dresden, Germany
| | - Michael H Muders
- Institute of Pathology, University Medical Center Dresden, Technische Universität (TU) Dresden, 01307 Dresden, Germany
| | - Gustavo B Baretton
- Institute of Pathology, University Medical Center Dresden, Technische Universität (TU) Dresden, 01307 Dresden, Germany
| | - Jochen Hampe
- Center for Regenerative Therapies, Technische Universität (TU) Dresden, 01307 Dresden, Germany.,Department of Medicine I, University Medical Center Dresden, Technische Universität (TU) Dresden, 01307 Dresden, Germany
| | - Daniela E Aust
- Institute of Pathology, University Medical Center Dresden, Technische Universität (TU) Dresden, 01307 Dresden, Germany.,Tumor and Normal Tissue Bank of the University Cancer Center (UCC), University Medical Center Dresden, Technische Universität (TU) Dresden, 01307 Dresden, Germany
| | - John F Baines
- Max Planck Institute for Evolutionary Biology, 24306 Plön, Germany.,Institute for Experimental Medicine, Kiel University, 24105 Kiel, Germany
| | - André Bleich
- Institute for Laboratory Animal Science, Hannover Medical School, 30625 Hannover, Germany
| | - Sebastian Zeissig
- Center for Regenerative Therapies, Technische Universität (TU) Dresden, 01307 Dresden, Germany.,Department of Medicine I, University Medical Center Dresden, Technische Universität (TU) Dresden, 01307 Dresden, Germany
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Arnold DE, Nofal R, Wakefield C, Lehmberg K, Wustrau K, Albert MH, Morris EC, Heimall JR, Bunin NJ, Kumar A, Jordan MB, Cole T, Choo S, Brettig T, Speckmann C, Ehl S, Salamonowicz M, Wahlstrom J, Rao K, Booth C, Worth A, Marsh RA. Reduced-Intensity/Reduced-Toxicity Conditioning Approaches Are Tolerated in XIAP Deficiency but Patients Fare Poorly with Acute GVHD. J Clin Immunol 2021; 42:36-45. [PMID: 34586554 PMCID: PMC8478634 DOI: 10.1007/s10875-021-01103-6] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2021] [Accepted: 07/16/2021] [Indexed: 12/01/2022]
Abstract
X-linked inhibitor of apoptosis (XIAP) deficiency is an inherited primary immunodeficiency characterized by chronic inflammasome overactivity and associated with hemophagocytic lymphohistiocytosis (HLH) and inflammatory bowel disease (IBD). Allogeneic hematopoietic cell transplantation (HCT) with fully myeloablative conditioning may be curative but has been associated with poor outcomes. Reports of reduced-intensity conditioning (RIC) and reduced-toxicity conditioning (RTC) regimens suggest these approaches are well tolerated, but outcomes are not well established. Retrospective data were collected from an international cohort of 40 patients with XIAP deficiency who underwent HCT with RIC or RTC. Thirty-three (83%) patients had a history of HLH, and thirteen (33%) patients had IBD. Median age at HCT was 6.5 years. Grafts were from HLA-matched (n = 30, 75%) and HLA-mismatched (n = 10, 25%) donors. There were no cases of primary graft failure. Two (5%) patients experienced secondary graft failure, and three (8%) patients ultimately received a second HCT. Nine (23%) patients developed grade II–IV acute GVHD, and 3 (8%) developed extensive chronic GVHD. The estimated 2-year overall and event-free survival rates were 74% (CI 55–86%) and 64% (CI 46–77%), respectively. Recipient and donor HLA mismatch and grade II–IV acute GVHD were negatively associated with survival on multivariate analysis with hazard ratios of 5.8 (CI 1.5–23.3, p = 0.01) and 8.2 (CI 2.1–32.7, p < 0.01), respectively. These data suggest that XIAP patients tolerate RIC and RTC with survival rates similar to HCT of other genetic HLH disorders. Every effort should be made to prevent acute GVHD in XIAP-deficient patients who undergo allogeneic HCT.
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Affiliation(s)
- Danielle E Arnold
- Division of Bone Marrow Transplantation and Immune Deficiency, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, 3333 Burnet Ave, Cincinnati, OH, 45229, USA
| | | | - Connor Wakefield
- Rush Medical College, Rush University Medical Center, Chicago, IL, USA
| | - Kai Lehmberg
- Division of Pediatric Stem Cell Transplantation and Immunology, University Medical Center Hamburg, Hamburg, Germany
| | - Katharina Wustrau
- Division of Pediatric Stem Cell Transplantation and Immunology, University Medical Center Hamburg, Hamburg, Germany
| | - Michael H Albert
- Dr. Von Hauner Children's Hospital, University Hospital, Ludwig-Maximilians University, Munich, Germany
| | - Emma C Morris
- Institute of Immunity and Transplantation, University College London, London, UK
| | - Jennifer R Heimall
- Division of Allergy and Immunology, Children's Hospital of Philadelphia, Philadelphia, PA, USA
| | - Nancy J Bunin
- Division of Oncology, Children's Hospital of Philadelphia, Philadelphia, PA, USA
| | - Ashish Kumar
- Division of Bone Marrow Transplantation and Immune Deficiency, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, 3333 Burnet Ave, Cincinnati, OH, 45229, USA
| | - Michael B Jordan
- Division of Bone Marrow Transplantation and Immune Deficiency, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, 3333 Burnet Ave, Cincinnati, OH, 45229, USA
| | - Theresa Cole
- Department of Allergy and Immunology, The Royal Children's Hospital, Melbourne, VIC, Australia
| | - Sharon Choo
- Department of Allergy and Immunology, The Royal Children's Hospital, Melbourne, VIC, Australia
| | - Tim Brettig
- Department of Allergy and Immunology, The Royal Children's Hospital, Melbourne, VIC, Australia
| | - Carsten Speckmann
- Institute for Immunodeficiency, Center for Chronic Immunodeficiency, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Stephan Ehl
- Institute for Immunodeficiency, Center for Chronic Immunodeficiency, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Malgorzata Salamonowicz
- Department of Pediatric Stem Cell Transplantation, Hematology and Oncology, Medical University, Wroclaw, Poland
| | - Justin Wahlstrom
- Blood and Marrow Transplantation Program, Benioff Children's Hospital, University of California San Francisco, San Francisco, CA, USA
| | - Kanchan Rao
- Department of Bone Marrow Transplantation, Great Ormond Street Hospital for Children, London, UK
| | - Claire Booth
- Department of Pediatric Immunology, Great Ormond Street Hospital, London, UK
| | - Austen Worth
- Department of Pediatric Immunology, Great Ormond Street Hospital, London, UK
| | - Rebecca A Marsh
- Division of Bone Marrow Transplantation and Immune Deficiency, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, 3333 Burnet Ave, Cincinnati, OH, 45229, USA.
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Intestinal immunoregulation: lessons from human mendelian diseases. Mucosal Immunol 2021; 14:1017-1037. [PMID: 33859369 DOI: 10.1038/s41385-021-00398-3] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2020] [Revised: 03/03/2021] [Accepted: 03/04/2021] [Indexed: 02/04/2023]
Abstract
The mechanisms that maintain intestinal homeostasis despite constant exposure of the gut surface to multiple environmental antigens and to billions of microbes have been scrutinized over the past 20 years with the goals to gain basic knowledge, but also to elucidate the pathogenesis of inflammatory bowel diseases (IBD) and to identify therapeutic targets for these severe diseases. Considerable insight has been obtained from studies based on gene inactivation in mice as well as from genome wide screens for genetic variants predisposing to human IBD. These studies are, however, not sufficient to delineate which pathways play key nonredundant role in the human intestinal barrier and to hierarchize their respective contribution. Here, we intend to illustrate how such insight can be derived from the study of human Mendelian diseases, in which severe intestinal pathology results from single gene defects that impair epithelial and or hematopoietic immune cell functions. We suggest that these diseases offer the unique opportunity to study in depth the pathogenic mechanisms leading to perturbation of intestinal homeostasis in humans. Furthermore, molecular dissection of monogenic intestinal diseases highlights key pathways that might be druggable and therapeutically targeted in common forms of IBD.
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Ku C, Chen I, Lai M. Infection-induced inflammation from specific inborn errors of immunity to COVID-19. FEBS J 2021; 288:5021-5041. [PMID: 33971084 PMCID: PMC8236961 DOI: 10.1111/febs.15961] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2021] [Revised: 04/10/2021] [Accepted: 05/07/2021] [Indexed: 01/07/2023]
Abstract
Inborn errors of immunity (IEIs) are a group of genetically defined disorders leading to defective immunity. Some IEIs have been linked to mutations of immune receptors or signaling molecules, resulting in defective signaling of respective cascades essential for combating specific pathogens. However, it remains incompletely understood why in selected IEIs, such as X-linked lymphoproliferative syndrome type 2 (XLP-2), hypo-immune response to specific pathogens results in persistent inflammation. Moreover, mechanisms underlying the generation of anticytokine autoantibodies are mostly unknown. Recently, IEIs have been associated with coronavirus disease 2019 (COVID-19), with a small proportion of patients that contract severe COVID-19 displaying loss-of-function mutations in genes associated with type I interferons (IFNs). Moreover, approximately 10% of patients with severe COVID-19 possess anti-type I IFN-neutralizing autoantibodies. Apart from IEIs that impair immune responses to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), SARS-CoV-2 encodes several proteins that suppress early type I IFN production. One primary consequence of the lack of type I IFNs during early SARS-CoV-2 infection is the increased inflammation associated with COVID-19. In XLP-2, resolution of inflammation rescued experimental subjects from infection-induced mortality. Recent studies also indicate that targeting inflammation could alleviate COVID-19. In this review, we discuss infection-induced inflammation in IEIs, using XLP-2 and COVID-19 as examples. We suggest that resolving inflammation may represent an effective therapeutic approach to these diseases.
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Affiliation(s)
- Cheng‐Lung Ku
- Laboratory of Human Immunology and Infectious DiseasesGraduate Institute of Clinical Medical SciencesChang Gung UniversityTaoyuanTaiwan
- Department of NephrologyLinkou Chang Gung Memorial HospitalTaoyuanTaiwan
| | - I‐Ting Chen
- Institute of Molecular BiologyAcademia SinicaTaipeiTaiwan
| | - Ming‐Zong Lai
- Institute of Molecular BiologyAcademia SinicaTaipeiTaiwan
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Chang I, Park S, Lee HJ, Kim I, Park S, Ahn MK, Lee J, Kang M, Baek IJ, Sung YH, Pack CG, Kang HJ, Lee K, Im HJ, Seo EJ, Kim KM, Yang SK, Song K, Oh SH. Interpretation of XIAP Variants of Uncertain Significance in Paediatric Patients with Refractory Crohn's Disease. J Crohns Colitis 2021; 15:1291-1304. [PMID: 33460440 DOI: 10.1093/ecco-jcc/jjab013] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
BACKGROUND AND AIMS Mutations in XIAP can lead to the development of treatment-refractory severe paediatric Crohn's disease [CD], for which haematopoietic stem cell transplantation is the primary therapeutic option. The interpretation of variants of uncertain significance [VUSs] in XIAP needs to be scrutinized. METHODS Targeted next-generation sequencing was performed for 33 male paediatric patients with refractory CD admitted at a tertiary referral hospital. To obtain functional data, biomolecular cell assays and supercomputing molecular dynamics simulations were performed. RESULTS Nine unrelated male patients harboured hemizygous XIAP variants. Four known pathogenic variants and one novel pathogenic variant [p.Lys168Serfs*12] were identified in five patients, and two novel VUSs [p.Gly205del and p.Pro260Ser] and one known VUS [p.Glu350del] were identified in the remaining four. Among children with VUSs, only the subject with p.Gly205del exhibited defective NOD2 signalling. Using molecular dynamics simulation, we determined that the altered backbone torsional energy of C203 in XIAP of p.G205del was ~2 kcal/mol, suggesting loss of zinc binding in the mutant XIAP protein and poor coordination between the mutant XIAP and RIP2 proteins. Elevated auto-ubiquitination of zinc-depleted p.G205del XIAP protein resulted in XIAP protein deficiency. CONCLUSION A high prevalence of XIAP deficiency was noted among children with refractory CD. Advanced functional studies decreased the subjectivity in the case-level interpretation of XIAP VUSs and directed consideration of haematopoietic stem cell transplantation.
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Affiliation(s)
- Iksoo Chang
- Supercomputing & Big Data Center, DGIST, Daegu, Korea.,Department of Brain and Cognitive Sciences, DGIST, Daegu, Korea
| | - Seongjun Park
- Department of Emerging Materials Science, DGIST, Daegu, Korea
| | - Hye-Jin Lee
- Department of Pediatrics, Asan Medical Center Children's Hospital, University of Ulsan College of Medicine, Seoul, Korea
| | - Inki Kim
- Department of Convergence Medicine, Asan Institutes for Life Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Sojung Park
- Department of Convergence Medicine, Asan Institutes for Life Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Mi Kyoung Ahn
- Department of Pediatrics, Asan Medical Center Children's Hospital, University of Ulsan College of Medicine, Seoul, Korea
| | - Juhwan Lee
- Supercomputing & Big Data Center, DGIST, Daegu, Korea
| | - Mooseok Kang
- Department of Brain and Cognitive Sciences, DGIST, Daegu, Korea
| | - In-Jeoung Baek
- Department of Convergence Medicine, Asan Institutes for Life Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Young Hoon Sung
- Department of Convergence Medicine, Asan Institutes for Life Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Chan-Gi Pack
- Department of Convergence Medicine, Asan Institutes for Life Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Hyo-Jeong Kang
- Department of Pathology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Kunsong Lee
- Department of Pediatrics, Dankook University College of Medicine, Dankook University Hospital, Chungnam, Korea
| | - Ho Joon Im
- Department of Pediatrics, Asan Medical Center Children's Hospital, University of Ulsan College of Medicine, Seoul, Korea
| | - Eul Ju Seo
- Department of Laboratory Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Kyung Mo Kim
- Department of Pediatrics, Asan Medical Center Children's Hospital, University of Ulsan College of Medicine, Seoul, Korea
| | - Suk-Kyun Yang
- Department of Gastroenterology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea
| | - Kyuyoung Song
- Department of Biochemistry and Molecular Biology, University of Ulsan College of Medicine, Seoul, Korea
| | - Seak Hee Oh
- Department of Pediatrics, Asan Medical Center Children's Hospital, University of Ulsan College of Medicine, Seoul, Korea
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Zacharias SA, Seshadri P, Hwang S, Baker L, Powell J, Fernando del Rosario J, Molle-Rios Z. Delayed Diagnosis of X-linked Lymphoproliferative Syndrome Type 2 in a 17-year-old Male With Severe Crohn's Disease and Recurrent Skin Infections. JPGN REPORTS 2021; 2:e102. [PMID: 37205951 PMCID: PMC10191492 DOI: 10.1097/pg9.0000000000000102] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 12/18/2020] [Accepted: 06/02/2021] [Indexed: 05/21/2023]
Abstract
X-linked lymphoproliferative syndrome type 2 (XLP2) is a rare genetic primary immunodeficiency disease caused by mutations in the XIAP gene that lead to deficiency of the X-linked inhibitor of apoptosis protein. XLP2 is characterized by dysregulated immune responses and can result in an inflammatory bowel disease (IBD)-like phenotype, a form of monogenic IBD. Patients with XLP2 often succumb to fulminant hemophagocytic lymphohistiocytosis or Epstein-Barr virus infections. Hematopoietic stem cell transplantation (HSCT) is currently the only definitive treatment for XLP2. We report an adolescent with a delayed diagnosis of XLP2 in the setting of severe Crohn's disease diagnosed at age 9 years and recurrent skin infections. He is under evaluation for HSCT. Gastroenterologists must recognize monogenic IBD in patients of all ages with severe disease and signs of an underlying primary immunodeficiency disease. Patients with suspected monogenic IBD should undergo immunologic and genetic analysis at diagnosis to initiate potentially life-saving treatment.
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Affiliation(s)
- Stephanie A. Zacharias
- From the Division of Gastroenterology and Nutrition, Nemours/Alfred I. duPont Hospital for Children, Wilmington, DE
- Sidney Kimmel College of Medicine at Thomas Jefferson University, Philadelphia, PA
| | - Priyanka Seshadri
- From the Division of Gastroenterology and Nutrition, Nemours/Alfred I. duPont Hospital for Children, Wilmington, DE
- Sidney Kimmel College of Medicine at Thomas Jefferson University, Philadelphia, PA
| | - Sharon Hwang
- From the Division of Gastroenterology and Nutrition, Nemours/Alfred I. duPont Hospital for Children, Wilmington, DE
- Sidney Kimmel College of Medicine at Thomas Jefferson University, Philadelphia, PA
| | - Laura Baker
- From the Division of Gastroenterology and Nutrition, Nemours/Alfred I. duPont Hospital for Children, Wilmington, DE
| | - Jonathan Powell
- From the Division of Gastroenterology and Nutrition, Nemours/Alfred I. duPont Hospital for Children, Wilmington, DE
- Sidney Kimmel College of Medicine at Thomas Jefferson University, Philadelphia, PA
| | - J. Fernando del Rosario
- From the Division of Gastroenterology and Nutrition, Nemours/Alfred I. duPont Hospital for Children, Wilmington, DE
- Sidney Kimmel College of Medicine at Thomas Jefferson University, Philadelphia, PA
| | - Zarela Molle-Rios
- From the Division of Gastroenterology and Nutrition, Nemours/Alfred I. duPont Hospital for Children, Wilmington, DE
- Sidney Kimmel College of Medicine at Thomas Jefferson University, Philadelphia, PA
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Hematopoietic Cell Transplantation Rescues Inflammatory Bowel Disease and Dysbiosis of Gut Microbiota in XIAP Deficiency. THE JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY-IN PRACTICE 2021; 9:3767-3780. [PMID: 34246792 DOI: 10.1016/j.jaip.2021.05.045] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/05/2021] [Revised: 05/22/2021] [Accepted: 05/25/2021] [Indexed: 12/15/2022]
Abstract
BACKGROUND X-linked inhibitor of apoptosis protein (XIAP) deficiency is an infrequent inborn error of immunity that is often associated with refractory inflammatory bowel disease (IBD). The natural course of XIAP deficiency is typically associated with poor prognosis, and hematopoietic cell transplantation (HCT) is the only curative treatment. OBJECTIVE To study (1) the effect of HCT on patients with XIAP deficiency undergoing HCT, (2) the status of XIAP deficiency-associated IBD after HCT, and (3) the gut microbiota of XIAP deficiency-associated IBD before and after HCT. METHODS A nationwide survey of patients with XIAP deficiency was conducted. A spreadsheet questionnaire was collected from the physicians. Feces samples collected from the patients before and after HCT and their healthy family members were analyzed. RESULTS Twenty-six patients with XIAP deficiency underwent HCT by the end of March 2020, and 22 patients (84.6%) survived. All the survivors underwent a fludarabine-based reduced-intensity condition regimen. Acute graft-versus-host disease was observed in 17 patients (65.4%). Nineteen patients experienced refractory IBD before undergoing HCT. IBD improved remarkably after HCT. After HCT, the colonoscopic and pathological symptoms were restored to normal, and the pediatric ulcerative colitis activity index improved significantly. Gut microbiota indicated dysbiosis before HCT; however, it was improved to resemble that of the healthy family members after HCT. CONCLUSIONS This study revealed that HCT has a favorable outcome for XIAP deficiency. HCT rescues gut inflammation and dysbiosis in patients with XIAP deficiency.
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Ahmari AA, Alsmadi O, Sheereen A, Elamin T, Jabr A, El-Baik L, Alhissi S, Saud BA, Al-Awwami M, Fawaz IA, Ayas M, Siddiqui K, Hawwari A. Genetic and clinical characteristics of pediatric patients with familial hemophagocytic lymphohistiocytosis. Blood Res 2021; 56:86-101. [PMID: 34083498 PMCID: PMC8246041 DOI: 10.5045/br.2021.2020308] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2020] [Revised: 05/02/2021] [Accepted: 05/18/2021] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND Our study was designed to investigate the frequencies and distributions of familial hemophagocytic lymphohistiocytosis (FHL) associated genes in Saudi patients. METHODS FHL associated gene screening was performed on 87 Saudi patients who were diagnosed with hemophagocytic lymphohistiocytosis (HLH) between 1995 and 2014. The clinical and biochemical profiles were also retrospectively captured and analyzed. RESULTS Homozygous mutations and mono-allelic variants were identified in 66 (75.9%) and 3 (3.5%) of the study participants, respectively. STXBP2 was the most frequently mutated gene (36% of patients) and mutations in STXBP2 and STX11 accounted for 58% of all FHL cases and demonstrated a specific geographical pattern. Patients in the FHL group presented at a significantly younger age than those belonging to the unknown-genetics group (median, 3.9 vs. 9.4 mo; P=0.005). The presenting clinical features were similar among the various genetic groups and the 5-year overall survival (OS) was 55.4% with a 5.6 year median follow-up. Patients with PRF1 mutations had a significantly poorer 5-year OS (21.4%, P =0.008) and patients undergoing hematopoietic stem cell transplant (72.4%) had a significantly better 5-year OS (66.5% vs. 0%, P =0.001). CONCLUSION Our study revealed the predominance of the STXBP2 mutations in Saudi patients with FHL. A genetic diagnosis was possible in 80% of the cohort and our data showed improved survival in FHL patients who underwent hematopoietic stem cell transplant.
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Affiliation(s)
- Ali Al Ahmari
- Department of Pediatric Hematology/Oncology, Research Center, Riyadh, Saudi Arabia
- College of Medicine, AlFaisal University, Riyadh, Saudi Arabia
| | - Osama Alsmadi
- Department of Section of Immunogenetics, Department of Genetics, Research Center, Riyadh, Saudi Arabia
- Cell Therapy, Applied Genomics, King Hussein Cancer Center, Amman, Jordan, Arabia
| | - Atia Sheereen
- Department of Section of Immunogenetics, Department of Genetics, Research Center, Riyadh, Saudi Arabia
| | - Tanziel Elamin
- Department of Section of Immunogenetics, Department of Genetics, Research Center, Riyadh, Saudi Arabia
| | - Amal Jabr
- Department of Section of Immunogenetics, Department of Genetics, Research Center, Riyadh, Saudi Arabia
| | - Lina El-Baik
- Department of Section of Immunogenetics, Department of Genetics, Research Center, Riyadh, Saudi Arabia
| | - Safa Alhissi
- Department of Section of Immunogenetics, Department of Genetics, Research Center, Riyadh, Saudi Arabia
| | - Bandar Al Saud
- Department of Pediatric Allergy/Immunology, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
| | - Moheeb Al-Awwami
- Department of Pathology and Laboratory Medicine, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia
| | - Ibrahim Al Fawaz
- Department of Pediatric Hematology/Oncology, Research Center, Riyadh, Saudi Arabia
- College of Medicine, AlFaisal University, Riyadh, Saudi Arabia
| | - Mouhab Ayas
- Department of Pediatric Hematology/Oncology, Research Center, Riyadh, Saudi Arabia
- College of Medicine, AlFaisal University, Riyadh, Saudi Arabia
| | - Khawar Siddiqui
- Department of Pediatric Hematology/Oncology, Research Center, Riyadh, Saudi Arabia
| | - Abbas Hawwari
- Department of Section of Immunogenetics, Department of Genetics, Research Center, Riyadh, Saudi Arabia
- King Abdullah International Medical Research Center (KAIMRC), King Saud bin Abdulaziz University for Health Sciences, King Abdulaziz Medical City Hospital, Al-Ahsa, Saudi Arabia
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Rispoli F, Valencic E, Girardelli M, Pin A, Tesser A, Piscianz E, Boz V, Faletra F, Severini GM, Taddio A, Tommasini A. Immunity and Genetics at the Revolving Doors of Diagnostics in Primary Immunodeficiencies. Diagnostics (Basel) 2021; 11:532. [PMID: 33809703 PMCID: PMC8002250 DOI: 10.3390/diagnostics11030532] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2021] [Revised: 03/12/2021] [Accepted: 03/14/2021] [Indexed: 12/14/2022] Open
Abstract
Primary immunodeficiencies (PIDs) are a large and growing group of disorders commonly associated with recurrent infections. However, nowadays, we know that PIDs often carry with them consequences related to organ or hematologic autoimmunity, autoinflammation, and lymphoproliferation in addition to simple susceptibility to pathogens. Alongside this conceptual development, there has been technical advancement, given by the new but already established diagnostic possibilities offered by new genetic testing (e.g., next-generation sequencing). Nevertheless, there is also the need to understand the large number of gene variants detected with these powerful methods. That means advancing beyond genetic results and resorting to the clinical phenotype and to immunological or alternative molecular tests that allow us to prove the causative role of a genetic variant of uncertain significance and/or better define the underlying pathophysiological mechanism. Furthermore, because of the rapid availability of results, laboratory immunoassays are still critical to diagnosing many PIDs, even in screening settings. Fundamental is the integration between different specialties and the development of multidisciplinary and flexible diagnostic workflows. This paper aims to tell these evolving aspects of immunodeficiencies, which are summarized in five key messages, through introducing and exemplifying five clinical cases, focusing on diseases that could benefit targeted therapy.
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Affiliation(s)
- Francesco Rispoli
- Department of Medical, Surgical and Health Sciences, University of Trieste, 34149 Trieste, Italy; (F.R.); (V.B.); (A.T.); (A.T.)
| | - Erica Valencic
- Department of Pediatrics, Institute for Maternal and Child Health—IRCCS “Burlo Garofolo”, 34137 Trieste, Italy; (M.G.); (A.P.); (A.T.); (E.P.); (G.M.S.)
| | - Martina Girardelli
- Department of Pediatrics, Institute for Maternal and Child Health—IRCCS “Burlo Garofolo”, 34137 Trieste, Italy; (M.G.); (A.P.); (A.T.); (E.P.); (G.M.S.)
| | - Alessia Pin
- Department of Pediatrics, Institute for Maternal and Child Health—IRCCS “Burlo Garofolo”, 34137 Trieste, Italy; (M.G.); (A.P.); (A.T.); (E.P.); (G.M.S.)
| | - Alessandra Tesser
- Department of Pediatrics, Institute for Maternal and Child Health—IRCCS “Burlo Garofolo”, 34137 Trieste, Italy; (M.G.); (A.P.); (A.T.); (E.P.); (G.M.S.)
| | - Elisa Piscianz
- Department of Pediatrics, Institute for Maternal and Child Health—IRCCS “Burlo Garofolo”, 34137 Trieste, Italy; (M.G.); (A.P.); (A.T.); (E.P.); (G.M.S.)
| | - Valentina Boz
- Department of Medical, Surgical and Health Sciences, University of Trieste, 34149 Trieste, Italy; (F.R.); (V.B.); (A.T.); (A.T.)
| | - Flavio Faletra
- Department of Diagnostics, Institute for Maternal and Child Health—IRCCS “Burlo Garofolo”, 34137 Trieste, Italy;
| | - Giovanni Maria Severini
- Department of Pediatrics, Institute for Maternal and Child Health—IRCCS “Burlo Garofolo”, 34137 Trieste, Italy; (M.G.); (A.P.); (A.T.); (E.P.); (G.M.S.)
| | - Andrea Taddio
- Department of Medical, Surgical and Health Sciences, University of Trieste, 34149 Trieste, Italy; (F.R.); (V.B.); (A.T.); (A.T.)
- Department of Pediatrics, Institute for Maternal and Child Health—IRCCS “Burlo Garofolo”, 34137 Trieste, Italy; (M.G.); (A.P.); (A.T.); (E.P.); (G.M.S.)
| | - Alberto Tommasini
- Department of Medical, Surgical and Health Sciences, University of Trieste, 34149 Trieste, Italy; (F.R.); (V.B.); (A.T.); (A.T.)
- Department of Pediatrics, Institute for Maternal and Child Health—IRCCS “Burlo Garofolo”, 34137 Trieste, Italy; (M.G.); (A.P.); (A.T.); (E.P.); (G.M.S.)
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Uhlig HH, Charbit-Henrion F, Kotlarz D, Shouval DS, Schwerd T, Strisciuglio C, de Ridder L, van Limbergen J, Macchi M, Snapper SB, Ruemmele FM, Wilson DC, Travis SP, Griffiths AM, Turner D, Klein C, Muise AM, Russell RK. Clinical Genomics for the Diagnosis of Monogenic Forms of Inflammatory Bowel Disease: A Position Paper From the Paediatric IBD Porto Group of European Society of Paediatric Gastroenterology, Hepatology and Nutrition. J Pediatr Gastroenterol Nutr 2021; 72:456-473. [PMID: 33346580 PMCID: PMC8221730 DOI: 10.1097/mpg.0000000000003017] [Citation(s) in RCA: 77] [Impact Index Per Article: 19.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
BACKGROUND It is important to identify patients with monogenic IBD as management may differ from classical IBD. In this position statement we formulate recommendations for the use of genomics in evaluating potential monogenic causes of IBD across age groups. METHODS The consensus included paediatric IBD specialists from the Paediatric IBD Porto group of the European Society of Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) and specialists from several monogenic IBD research consortia. We defined key topics and performed a systematic literature review to cover indications, technologies (targeted panel, exome and genome sequencing), gene panel setup, cost-effectiveness of genetic screening, and requirements for the clinical care setting. We developed recommendations that were voted upon by all authors and Porto group members (32 voting specialists). RESULTS We recommend next-generation DNA-sequencing technologies to diagnose monogenic causes of IBD in routine clinical practice embedded in a setting of multidisciplinary patient care. Routine genetic screening is not recommended for all IBD patients. Genetic testing should be considered depending on age of IBD-onset (infantile IBD, very early-onset IBD, paediatric or young adult IBD), and further criteria, such as family history, relevant comorbidities, and extraintestinal manifestations. Genetic testing is also recommended in advance of hematopoietic stem cell transplantation. We developed a diagnostic algorithm that includes a gene panel of 75 monogenic IBD genes. Considerations are provided also for low resource countries. CONCLUSIONS Genomic technologies should be considered an integral part of patient care to investigate patients at risk for monogenic forms of IBD.
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Affiliation(s)
- Holm H. Uhlig
- Translational Gastroenterology Unit, University of Oxford, Oxford, United Kingdom
- Department of Pediatrics, University of Oxford, Oxford, United Kingdom
- Biomedical Research Center, University of Oxford, Oxford, United Kingdom
| | - Fabienne Charbit-Henrion
- Université de Paris, INSERM UMR 1163 Immunité Intestinale, APHP, Hôpital Necker Enfants Malades, Service de Génétique moléculaire, Paris, France
| | - Daniel Kotlarz
- Department of Pediatrics, Dr. von Hauner Children’s Hospital, University Hospital, LMU Munich, Munich, Germany
| | - Dror S. Shouval
- Department of Pediatrics, Dr. von Hauner Children’s Hospital, University Hospital, LMU Munich, Munich, Germany
| | - Tobias Schwerd
- Department of Pediatrics, Dr. von Hauner Children’s Hospital, University Hospital, LMU Munich, Munich, Germany
| | | | - Lissy de Ridder
- Department of Paediatric Gastroenterology, Erasmus University Medical Center Sophia Children’s Hospital, Rotterdam, the Netherlands
| | - Johan van Limbergen
- Amsterdam University Medical Centres, Emma Children’s Hospital, The Netherlands and Tytgat Institute for Liver and Intestinal Research, Amsterdam Gastroenterology and Metabolism, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands
| | - Marina Macchi
- Translational Gastroenterology Unit, University of Oxford, Oxford, United Kingdom
| | - Scott B. Snapper
- Division of Gastroenterology, Hepatology, and Nutrition, Boston Children’s Hospital and Harvard Medical School, Boston, Massachusetts, USA
| | - Frank M. Ruemmele
- Université de Paris, APHP, Hôpital Necker Enfants Malades, Service de Gastroentérologie pédiatrique, Paris, France
| | - David C. Wilson
- Child Life and Health, University of Edinburgh, Department of Paediatric Gastroenterology, The Royal Hospital for Sick Children, Edinburgh
| | - Simon P.L. Travis
- Translational Gastroenterology Unit, University of Oxford, Oxford, United Kingdom
- Biomedical Research Center, University of Oxford, Oxford, United Kingdom
| | - Anne M. Griffiths
- The Hospital for Sick Children, University of Toronto
- SickKids Inflammatory Bowel Disease Centre and Cell Biology Program, Research Institute, The Hospital for Sick Children
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Toronto, Ontario, Canada
| | - Dan Turner
- Shaare Zedek Medical Center, The Hebrew University of Jerusalem, Israel
| | - Christoph Klein
- Department of Pediatrics, Dr. von Hauner Children’s Hospital, University Hospital, LMU Munich, Munich, Germany
| | - Aleixo M. Muise
- The Hospital for Sick Children, University of Toronto
- SickKids Inflammatory Bowel Disease Centre and Cell Biology Program, Research Institute, The Hospital for Sick Children
- Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Toronto, Ontario, Canada
| | - Richard K. Russell
- Child Life and Health, University of Edinburgh, Department of Paediatric Gastroenterology, The Royal Hospital for Sick Children, Edinburgh
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Mudde ACA, Booth C, Marsh RA. Evolution of Our Understanding of XIAP Deficiency. Front Pediatr 2021; 9:660520. [PMID: 34222142 PMCID: PMC8247594 DOI: 10.3389/fped.2021.660520] [Citation(s) in RCA: 57] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/29/2021] [Accepted: 05/17/2021] [Indexed: 12/17/2022] Open
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.
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Affiliation(s)
- Anne C A Mudde
- Molecular and Cellular Immunology Section, UCL Great Ormond Street Institute of Child Health, London, United Kingdom
| | - Claire Booth
- Molecular and Cellular Immunology Section, UCL Great Ormond Street Institute of Child Health, London, United Kingdom.,Department of Immunology and Gene Therapy, Great Ormond Street Hospital, London, United Kingdom
| | - Rebecca A Marsh
- Division of Bone Marrow Transplantation and Immune Deficiency, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, United States.,Department of Pediatrics, University of Cincinnati, Cincinnati, OH, United States
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35
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Durkee-Shock JR, Kuehn HS, Stoddard J, Niemela JE, Sun G, Keller MD, Rosenzweig S, Milner JD. Recurrent lymphadenitis in a female XIAP/BIRC4 mutation carrier with normal lyonization. THE JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY-IN PRACTICE 2020; 9:1002-1005.e2. [PMID: 33212241 DOI: 10.1016/j.jaip.2020.10.062] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/18/2020] [Revised: 09/16/2020] [Accepted: 10/01/2020] [Indexed: 11/18/2022]
Affiliation(s)
- Jessica R Durkee-Shock
- Center for Cancer and Immunology Research, Children's National Health System, Washington, DC; National Institutes of Health, Bethesda, MD
| | - Hye Sun Kuehn
- Immunology Service, Department of Laboratory Medicine, Clinical Center, National Institutes of Health, Bethesda, MD
| | - Jennifer Stoddard
- Immunology Service, Department of Laboratory Medicine, Clinical Center, National Institutes of Health, Bethesda, MD
| | - Julie E Niemela
- Immunology Service, Department of Laboratory Medicine, Clinical Center, National Institutes of Health, Bethesda, MD
| | - Guangping Sun
- Department of Pediatrics, Columbia University Irving Medical Center, New York, NY
| | - Michael D Keller
- Center for Cancer and Immunology Research, Children's National Health System, Washington, DC; GW Cancer Center, George Washington University, Washington, DC; Division of Allergy and Immunology, Children's National Health System, Washington, DC
| | - Sergio Rosenzweig
- Immunology Service, Department of Laboratory Medicine, Clinical Center, National Institutes of Health, Bethesda, MD
| | - Joshua D Milner
- Department of Pediatrics, Columbia University Irving Medical Center, New York, NY.
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Abstract
PURPOSE OF REVIEW Very early-onset inflammatory bowel disease (VEO-IBD) is a rare presentation defined as onset of intestinal inflammation at the age of <6 years. Some of these young children develop IBD because of inherent defects in immune or epithelial cell function resulting from deleterious mutations in genes involved in mucosal homeostasis. Here, we provide an overview of the clinical, genetic and immunologic approach in patients with VEO-IBD. RECENT FINDINGS More than 50 different monogenic disorders directly causing IBD have been identified in the last decade; most of them present with unique clinical features in the first years of life. Such a diagnosis may facilitate the administration of targeted therapies and is important for genetic counseling. Nevertheless, a monogenic disorder is identified only in a minority of patients with VEO-IBD. Consequently, different demographic, clinical and histologic features should prompt a detailed genetic and immunologic workup in patients with IBD. SUMMARY A diagnosis of monogenic IBD can have a huge impact on patient's care, enabling in some cases to provide personalized therapies. Clinicians should be aware of unique features of such disorders, and complete a detailed genetic and immune workup in selected cases, even when disease manifests beyond a young age.
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Abstract
Crohn's disease [CD] is an inflammatory bowel disease of unknown aetiology. During recent decades, significant technological advances led to development of -omic datasets allowing a detailed description of the disease. Unfortunately these have not, to date, resolved the question of the aetiology of CD. Thus, it may be necessary to [re]consider hypothesis-driven approaches to resolve the aetiology of CD. According to the cold chain hypothesis, the development of industrial and domestic refrigeration has led to frequent exposure of human populations to bacteria capable of growing in the cold. These bacteria, at low levels of exposure, particularly those of the genus Yersinia, are believed to be capable of inducing exacerbated inflammation of the intestine in genetically predisposed subjects. We discuss the consistency of this working hypothesis in light of recent data from epidemiological, clinical, pathological, microbiological, and molecular studies.
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Affiliation(s)
- Jean-Pierre Hugot
- Centre de recherche sur l’inflammation, UMR1149 INSERM and Université de Paris, Paris, France,Service des maladies digestives et respiratoires de l’enfant, Hôpital Robert Debré, Assistance Publique Hôpitaux de Paris, Paris, France,Corresponding author: Jean-Pierre Hugot, MD, PhD, Service des maladies digestives et respiratoires de l’enfant, Hôpital Robert Debré, 48 Bd Sérurier, F75019 Paris, France. Tel.: [33] 1 40 03 57 12; fax: [33] 1 40 03 57 66;
| | - Anne Dumay
- Centre de recherche sur l’inflammation, UMR1149 INSERM and Université de Paris, Paris, France
| | - Frédérick Barreau
- IRSD, UMR1220, Université de Toulouse, INSERM, INRA, ENVT, UPS, Toulouse, France
| | - Ulrich Meinzer
- Centre de recherche sur l’inflammation, UMR1149 INSERM and Université de Paris, Paris, France,Service des maladies digestives et respiratoires de l’enfant, Hôpital Robert Debré, Assistance Publique Hôpitaux de Paris, Paris, France
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38
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Yang J, Zhu GH, Wang B, Zhang R, Jia CG, Yan Y, Ma HH, Qin MQ. Haploidentical Hematopoietic Stem Cell Transplantation for XIAP Deficiency: a Single-Center Report. J Clin Immunol 2020; 40:893-900. [PMID: 32627096 DOI: 10.1007/s10875-020-00795-6] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2019] [Accepted: 05/25/2020] [Indexed: 12/12/2022]
Abstract
PURPOSE X-linked inhibitor of apoptosis (XIAP) deficiency caused by mutations in the XIAP/BIRC4 gene is a rare inherited primary immunodeficiency also known as X-linked lymphoproliferative syndrome type 2 (XLP2). Hematopoietic stem cell transplantation (HSCT) is currently the only curative strategy available. However, few studies of haploidentical HSCT have been published regarding the outcomes in patients with this syndrome. METHODS We evaluated the XIAP gene analysis and clinical characteristics of four Chinese patients with XIAP who underwent haploidentical HSCT. RESULTS The mutations in the two of four patients had not yet been reported in the literature. All of the patients had recurrent hemophagocytic lymphohistiocytosis but did not have a good matched donor and underwent haploidentical HSCT at BCH in China between September 2016 and December 2018. All four patients received antithymocyte globulin with fludarabine-based regimens. Two patients underwent reduced intensity conditioning (RIC), and the other two received modified myeloablative conditioning (MAC) regimens. Three of the four patients survived. Three patients experienced complications with mixed chimerism. One of the four patients who underwent RIC had early graft loss and then developed grade IV acute graft-versus-host disease (GVHD) after donor lymphocyte infusion with bone marrow. The two patients who received MAC survived with no or mild GVHD, even though one of them developed hepatic veno-occlusive disease in the early stage of transplantation. CONCLUSIONS Haploidentical HSCT may be a treatment option for patients with XIAP deficiency who lack a good matched donor. More studies are needed to determine whether modified MAC with reduced toxicity is more suitable for haploidentical transplantation.
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Affiliation(s)
- Jun Yang
- Beijing Key Laboratory of Pediatric Hematology Oncology; National Key Discipline of Pediatrics (Capital Medical University); Key Laboratory of Major Diseases in Children, Ministry of Education; Hematology Oncology Center, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing, P.R., China.,National Key Discipline of Pediatrics, Capital Medical University, Beijing, China.,Key Laboratory of Major Diseases in Children, Ministry of Education, Capital Medical University, 56 Nanlishi Road, Beijing, China.,Hematology Oncology Center, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, 56 Nanlishi Road, Beijing, China
| | - Guang-Hua Zhu
- Beijing Key Laboratory of Pediatric Hematology Oncology; National Key Discipline of Pediatrics (Capital Medical University); Key Laboratory of Major Diseases in Children, Ministry of Education; Hematology Oncology Center, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing, P.R., China.,National Key Discipline of Pediatrics, Capital Medical University, Beijing, China.,Key Laboratory of Major Diseases in Children, Ministry of Education, Capital Medical University, 56 Nanlishi Road, Beijing, China.,Hematology Oncology Center, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, 56 Nanlishi Road, Beijing, China
| | - Bin Wang
- Beijing Key Laboratory of Pediatric Hematology Oncology; National Key Discipline of Pediatrics (Capital Medical University); Key Laboratory of Major Diseases in Children, Ministry of Education; Hematology Oncology Center, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing, P.R., China.,National Key Discipline of Pediatrics, Capital Medical University, Beijing, China.,Key Laboratory of Major Diseases in Children, Ministry of Education, Capital Medical University, 56 Nanlishi Road, Beijing, China.,Hematology Oncology Center, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, 56 Nanlishi Road, Beijing, China
| | - Rui Zhang
- Beijing Key Laboratory of Pediatric Hematology Oncology; National Key Discipline of Pediatrics (Capital Medical University); Key Laboratory of Major Diseases in Children, Ministry of Education; Hematology Oncology Center, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing, P.R., China.,National Key Discipline of Pediatrics, Capital Medical University, Beijing, China.,Key Laboratory of Major Diseases in Children, Ministry of Education, Capital Medical University, 56 Nanlishi Road, Beijing, China.,Hematology Oncology Center, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, 56 Nanlishi Road, Beijing, China
| | - Chen-Guang Jia
- Beijing Key Laboratory of Pediatric Hematology Oncology; National Key Discipline of Pediatrics (Capital Medical University); Key Laboratory of Major Diseases in Children, Ministry of Education; Hematology Oncology Center, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing, P.R., China.,National Key Discipline of Pediatrics, Capital Medical University, Beijing, China.,Key Laboratory of Major Diseases in Children, Ministry of Education, Capital Medical University, 56 Nanlishi Road, Beijing, China.,Hematology Oncology Center, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, 56 Nanlishi Road, Beijing, China
| | - Yan Yan
- Beijing Key Laboratory of Pediatric Hematology Oncology; National Key Discipline of Pediatrics (Capital Medical University); Key Laboratory of Major Diseases in Children, Ministry of Education; Hematology Oncology Center, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing, P.R., China.,National Key Discipline of Pediatrics, Capital Medical University, Beijing, China.,Key Laboratory of Major Diseases in Children, Ministry of Education, Capital Medical University, 56 Nanlishi Road, Beijing, China.,Hematology Oncology Center, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, 56 Nanlishi Road, Beijing, China
| | - Hong-Hao Ma
- Beijing Key Laboratory of Pediatric Hematology Oncology; National Key Discipline of Pediatrics (Capital Medical University); Key Laboratory of Major Diseases in Children, Ministry of Education; Hematology Oncology Center, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing, P.R., China.,National Key Discipline of Pediatrics, Capital Medical University, Beijing, China.,Key Laboratory of Major Diseases in Children, Ministry of Education, Capital Medical University, 56 Nanlishi Road, Beijing, China.,Hematology Oncology Center, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, 56 Nanlishi Road, Beijing, China
| | - Mao-Quan Qin
- Beijing Key Laboratory of Pediatric Hematology Oncology; National Key Discipline of Pediatrics (Capital Medical University); Key Laboratory of Major Diseases in Children, Ministry of Education; Hematology Oncology Center, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing, P.R., China. .,National Key Discipline of Pediatrics, Capital Medical University, Beijing, China. .,Key Laboratory of Major Diseases in Children, Ministry of Education, Capital Medical University, 56 Nanlishi Road, Beijing, China. .,Hematology Oncology Center, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, 56 Nanlishi Road, Beijing, China.
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Takeuchi I, Kawai T, Nambu M, Migita O, Yoshimura S, Nishimura K, Yoshioka T, Ogura M, Kyodo R, Shimizu H, Ito S, Kato M, Onodera M, Hata K, Matsubara Y, Arai K. X-linked inhibitor of apoptosis protein deficiency complicated with Crohn's disease-like enterocolitis and Takayasu arteritis: A case report. Clin Immunol 2020; 217:108495. [PMID: 32540394 DOI: 10.1016/j.clim.2020.108495] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2020] [Revised: 06/04/2020] [Accepted: 06/07/2020] [Indexed: 01/17/2023]
Abstract
X-linked inhibitor of apoptosis protein (XIAP) deficiency results in monogenic inflammatory bowel disease. To date, no vasculitis associated with XIAP deficiency has been reported. A 10-year-old boy was diagnosed with Crohn's disease and he responded poorly to conventional treatment for Crohn's disease. He was dependent on corticosteroids and parenteral nutrition. To manage severe colitis, he underwent ileostomy followed by ileocolectomy for an ileo-sigmoid fistula. At the age of 15 years, he developed IgA vasculitis and at the age of 17 years, he developed refractory Takayasu arteritis (TAK), which was resistant to corticosteroid and immunosuppressive therapy. Whole-exome sequencing revealed a novel mutation of the splice acceptor site in XIAP (c.1057-1G > A) at the age of 19 years. Allogeneic hematopoietic stem cell transplantation was successful with subsequent withdrawal of intensive immunosuppressive therapy and clinical remission of both enterocolitis and TAK. This case suggests that patients with XIAP deficiency could develop intractable inflammatory disease involving the intestinal tract and blood vessels.
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Affiliation(s)
- Ichiro Takeuchi
- Center for Pediatric Inflammatory Bowel Disease, Division of Gastroenterology, National Center for Child Health and Development, Tokyo, Japan.
| | - Toshinao Kawai
- Division of Immunology, National Center for Child Health and Development, Tokyo, Japan
| | - Meika Nambu
- Division of Immunology, National Center for Child Health and Development, Tokyo, Japan
| | - Ohsuke Migita
- Department of Maternal-Fetal Biology, National Research Institute for Child Health and Development, Tokyo, Japan
| | - Satoshi Yoshimura
- Department of Transplantation and Cell Therapy, Children's Cancer Center, National Center for Child Health and Development, Tokyo, Japan
| | - Kenichi Nishimura
- Department of Pediatrics, Yokohama City University Graduate School of Medicine, Kanagawa, Japan
| | - Takako Yoshioka
- Department of Pathology, Children's Cancer Center, National Center for Child Health and Development, Tokyo, Japan
| | - Masao Ogura
- Division of Nephrology and Rheumatology, National Center for Child Health and Development, Tokyo, Japan
| | - Reiko Kyodo
- Center for Pediatric Inflammatory Bowel Disease, Division of Gastroenterology, National Center for Child Health and Development, Tokyo, Japan
| | - Hirotaka Shimizu
- Center for Pediatric Inflammatory Bowel Disease, Division of Gastroenterology, National Center for Child Health and Development, Tokyo, Japan
| | - Shuichi Ito
- Department of Pediatrics, Yokohama City University Graduate School of Medicine, Kanagawa, Japan
| | - Motohiro Kato
- Department of Transplantation and Cell Therapy, Children's Cancer Center, National Center for Child Health and Development, Tokyo, Japan
| | - Masafumi Onodera
- Division of Immunology, National Center for Child Health and Development, Tokyo, Japan
| | - Kenichiro Hata
- Department of Maternal-Fetal Biology, National Research Institute for Child Health and Development, Tokyo, Japan
| | - Yoichi Matsubara
- National Research Institute for Child Health and Development, Tokyo, Japan
| | - Katsuhiro Arai
- Center for Pediatric Inflammatory Bowel Disease, Division of Gastroenterology, National Center for Child Health and Development, Tokyo, Japan
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40
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Parackova Z, Milota T, Vrabcova P, Smetanova J, Svaton M, Freiberger T, Kanderova V, Sediva A. Novel XIAP mutation causing enhanced spontaneous apoptosis and disturbed NOD2 signalling in a patient with atypical adult-onset Crohn's disease. Cell Death Dis 2020; 11:430. [PMID: 32514016 PMCID: PMC7280281 DOI: 10.1038/s41419-020-2652-4] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2020] [Revised: 05/07/2020] [Accepted: 05/11/2020] [Indexed: 12/12/2022]
Abstract
X-linked inhibitor of apoptosis (XIAP) is the most potent human inhibitor of apoptosis, and is also involved in NOD2-dependent NFκB and MAPK signalling cascade activation. The absence or defective function of XIAP leads to the development of a rare and severe primary immunodeficiency known as X-linked lymphoproliferative syndrome type 2 (XLP-2), which is characterized by a triad of clinical manifestations, including a high incidence of haemophagocytic lymphohistiocytosis (HLH), lymphoproliferation and inflammatory bowel disease (IBD), usually with very early onset. Here, we present a novel XIAP mutation identified in a patient with atypical adult-onset IBD complicated by relapsing HLH, splenomegaly and sarcoid-like disease. The c.266delA mutation in the XIAP gene creates a premature stop codon, and causes a severe reduction in XIAP protein expression. The mutation is also associated with impaired spontaneous and staurosporine- and PMA-induced apoptosis accompanied by significantly increased expression of pro-apoptotic genes. We also confirmed the negative impact of this particular XIAP mutation on NOD2-dependent NFκB and MAPK activation, while NOD2-independent activation was found to be unaffected. Moreover, we assume that the mutation has an impact on the overproduction of IL-12 and IFNγ, the shift towards the Th1 immune response and increased numbers of central memory and effector memory CD4+ and CD8+ T cells. All these changes contribute to immune dysregulation and the clinical manifestation of XLP-2.
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Affiliation(s)
- Zuzana Parackova
- Department of Immunology, 2nd Faculty of Medicine Charles University, University Hospital in Motol, V Uvalu 84, Prague, Czech Republic.
| | - Tomas Milota
- Department of Immunology, 2nd Faculty of Medicine Charles University, University Hospital in Motol, V Uvalu 84, Prague, Czech Republic
| | - Petra Vrabcova
- Department of Immunology, 2nd Faculty of Medicine Charles University, University Hospital in Motol, V Uvalu 84, Prague, Czech Republic
| | - Jitka Smetanova
- Department of Immunology, 2nd Faculty of Medicine Charles University, University Hospital in Motol, V Uvalu 84, Prague, Czech Republic
| | - Michael Svaton
- CLIP-Childhood Leukaemia Investigation Prague, Department of Paediatric Haematology and Oncology, 2nd Faculty of Medicine, Charles University and University Hospital Motol, Prague, Czech Republic
| | - Tomas Freiberger
- Molecular Genetics Laboratory, Center of Cardiovascular Surgery and Transplantation, Brno, Czech Republic.,Faculty of Medicine, Masaryk University, Brno, Czech Republic
| | - Veronika Kanderova
- CLIP-Childhood Leukaemia Investigation Prague, Department of Paediatric Haematology and Oncology, 2nd Faculty of Medicine, Charles University and University Hospital Motol, Prague, Czech Republic
| | - Anna Sediva
- Department of Immunology, 2nd Faculty of Medicine Charles University, University Hospital in Motol, V Uvalu 84, Prague, Czech Republic
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41
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Ouahed J, Spencer E, Kotlarz D, Shouval DS, Kowalik M, Peng K, Field M, Grushkin-Lerner L, Pai SY, Bousvaros A, Cho J, Argmann C, Schadt E, Mcgovern DPB, Mokry M, Nieuwenhuis E, Clevers H, Powrie F, Uhlig H, Klein C, Muise A, Dubinsky M, Snapper SB. Very Early Onset Inflammatory Bowel Disease: A Clinical Approach With a Focus on the Role of Genetics and Underlying Immune Deficiencies. Inflamm Bowel Dis 2020; 26:820-842. [PMID: 31833544 PMCID: PMC7216773 DOI: 10.1093/ibd/izz259] [Citation(s) in RCA: 119] [Impact Index Per Article: 23.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/06/2019] [Indexed: 12/12/2022]
Abstract
Very early onset inflammatory bowel disease (VEO-IBD) is defined as IBD presenting before 6 years of age. When compared with IBD diagnosed in older children, VEO-IBD has some distinct characteristics such as a higher likelihood of an underlying monogenic etiology or primary immune deficiency. In addition, patients with VEO-IBD have a higher incidence of inflammatory bowel disease unclassified (IBD-U) as compared with older-onset IBD. In some populations, VEO-IBD represents the age group with the fastest growing incidence of IBD. There are contradicting reports on whether VEO-IBD is more resistant to conventional medical interventions. There is a strong need for ongoing research in the field of VEO-IBD to provide optimized management of these complex patients. Here, we provide an approach to diagnosis and management of patients with VEO-IBD. These recommendations are based on expert opinion from members of the VEO-IBD Consortium (www.VEOIBD.org). We highlight the importance of monogenic etiologies, underlying immune deficiencies, and provide a comprehensive description of monogenic etiologies identified to date that are responsible for VEO-IBD.
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Affiliation(s)
- Jodie Ouahed
- Division of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Boston Children’s Hospital, Boston, MA, USA
| | - Elizabeth Spencer
- Division of Gastroenterology, Hepatology and Nutrition, Mount Sinai Hospital, New York City, NY, USA
| | - Daniel Kotlarz
- Department of Pediatrics, Dr. Von Haunder Children’s Hospital, University Hospital, Ludwig-Maximillians-University Munich, Munich, Germany
| | - Dror S Shouval
- Pediatric Gastroenterology Unit, Edmond and Lily Safra Children’s Hospital, Sheba Medical Center, Tel Hashomer, Ramat-Gan, Israel; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Matthew Kowalik
- Division of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Boston Children’s Hospital, Boston, MA, USA
| | - Kaiyue Peng
- Division of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Boston Children’s Hospital, Boston, MA, USA,Department of Gastroenterology, Pediatric Inflammatory Bowel Disease Research Center, Children’s Hospital of Fudan University, Shanghai, China
| | - Michael Field
- Division of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Boston Children’s Hospital, Boston, MA, USA
| | - Leslie Grushkin-Lerner
- Division of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Boston Children’s Hospital, Boston, MA, USA
| | - Sung-Yun Pai
- Division of Hematology-Oncology, Boston Children’s Hospital, Dana-Farber Cancer Institute, Boston, MA USA
| | - Athos Bousvaros
- Division of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Boston Children’s Hospital, Boston, MA, USA
| | - Judy Cho
- Icahn School of Medicine at Mount Sinai, Dr. Henry D. Janowitz Division of Gastroenterology, New York, NY, USA
| | - Carmen Argmann
- Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, USA
| | - Eric Schadt
- Icahn Institute for Genomics and Multiscale Biology, Icahn School of Medicine at Mount Sinai, New York, USA,Sema4, Stamford, CT, USA
| | - Dermot P B Mcgovern
- F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA
| | - Michal Mokry
- Division of Pediatrics, Wilhelmina Children’s Hospital, University Medical Center Utrecht, Utrecht, the Netherlands
| | - Edward Nieuwenhuis
- Division of Pediatrics, Wilhelmina Children’s Hospital, University Medical Center Utrecht, Utrecht, the Netherlands
| | - Hans Clevers
- Hubrecht Institute-Royal Netherlands Academy of Arts and Sciences, Utrecht, the Netherlands
| | - Fiona Powrie
- University of Oxford, Kennedy Institute of Rheumatology, Oxford, UK
| | - Holm Uhlig
- Translational Gastroenterology Unit, University of Oxford, Oxford, UK; Department of Pediatrics, University of Oxford, Oxford, UK
| | - Christoph Klein
- Pediatric Gastroenterology Unit, Edmond and Lily Safra Children’s Hospital, Sheba Medical Center, Tel Hashomer, Ramat-Gan, Israel; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Aleixo Muise
- SickKids Inflammatory Bowel Disease Center and Cell Biology Program, Research Institute, Hospital for Sick Children, Toronto, ON, Canada. Department of Pediatrics and Biochemistry, University of Toronto, Hospital for Sick Children, Toronto, ON, Canada
| | - Marla Dubinsky
- Division of Gastroenterology, Hepatology and Nutrition, Mount Sinai Hospital, New York City, NY, USA
| | - Scott B Snapper
- Division of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Boston Children’s Hospital, Boston, MA, USA,Address correspondence to: Scott B. Snapper, MD, PhD, Children's Hospital Boston, Boston, Massachusetts, USA.
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Takeuchi I, Kaburaki Y, Arai K, Shimizu H, Hirano Y, Nagata S, Shimizu T. Infliximab for very early-onset inflammatory bowel disease: A tertiary center experience in Japan. J Gastroenterol Hepatol 2020; 35:593-600. [PMID: 31425641 DOI: 10.1111/jgh.14836] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/24/2019] [Revised: 07/30/2019] [Accepted: 08/08/2019] [Indexed: 12/12/2022]
Abstract
BACKGROUND AND AIM Very early-onset inflammatory bowel disease (VEO-IBD), defined as IBD diagnosed before 6 years of age, tends to be refractory to conventional treatment for IBD. However, there have been a few reports about the usage of infliximab for VEO-IBD. This study aimed to evaluate the efficacy and safety of infliximab for VEO-IBD. METHODS Medical records of a cohort of children with VEO-IBD who had received infliximab in a Japanese tertiary children's hospital were retrospectively reviewed for their disease characteristics and clinical course. Subjects were categorized into three groups for the descriptive comparison: ulcerative colitis type (UCT), non-UCT with perianal disease (NUC-PD), and non-UCT without perianal disease (NUC-NPD). RESULTS Seventeen VEO-IBD patients (five UCT, five NUC-PD, and seven NUC-NPD) had received infliximab as their first biologic. In the UCT group, infliximab was continued over 54 weeks in two patients, and three eventually required surgery. In contrast, all patients in the NUC-PD and NUC-NPD groups followed up over 54 weeks remained on infliximab, and two of three patients and three of five patients were in remission at week 54, respectively. Infusion reactions occurred in all five UCT, three of five NUC-PD, and two of seven NUC-NPD patients; however, except for two patients with severe reactions, infliximab was continued with premedication and slow infusions. CONCLUSIONS Infliximab appeared useful for children with VEO-IBD. Children with NUC-PD and NUC-NPD responded better with less infusion reaction compared with that with UCT.
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Affiliation(s)
- Ichiro Takeuchi
- Center for Pediatric Inflammatory Bowel Disease Division of Gastroenterology, National Center for Child Health and Development, Tokyo, Japan
| | - Yoichiro Kaburaki
- Center for Pediatric Inflammatory Bowel Disease Division of Gastroenterology, National Center for Child Health and Development, Tokyo, Japan.,Department of Pediatrics, Tokyo Women's Medical University, Tokyo, Japan
| | - Katsuhiro Arai
- Center for Pediatric Inflammatory Bowel Disease Division of Gastroenterology, National Center for Child Health and Development, Tokyo, Japan
| | - Hirotaka Shimizu
- Center for Pediatric Inflammatory Bowel Disease Division of Gastroenterology, National Center for Child Health and Development, Tokyo, Japan.,Department of Pediatrics and Adolescent Medicine, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Yuri Hirano
- Center for Pediatric Inflammatory Bowel Disease Division of Gastroenterology, National Center for Child Health and Development, Tokyo, Japan
| | - Satoru Nagata
- Department of Pediatrics, Tokyo Women's Medical University, Tokyo, Japan
| | - Toshiaki Shimizu
- Department of Pediatrics and Adolescent Medicine, Juntendo University Graduate School of Medicine, Tokyo, Japan
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Latour S, Fischer A. Signaling pathways involved in the T-cell-mediated immunity against Epstein-Barr virus: Lessons from genetic diseases. Immunol Rev 2020; 291:174-189. [PMID: 31402499 DOI: 10.1111/imr.12791] [Citation(s) in RCA: 86] [Impact Index Per Article: 17.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2019] [Revised: 06/05/2019] [Accepted: 06/10/2019] [Indexed: 12/13/2022]
Abstract
Primary immunodeficiencies (PIDs) provide researchers with unique models to understand in vivo immune responses in general and immunity to infections in particular. In humans, impaired immune control of Epstein-Barr virus (EBV) infection is associated with the occurrence of several different immunopathologic conditions; these include non-malignant and malignant B-cell lymphoproliferative disorders, hemophagocytic lymphohistiocytosis (HLH), a severe inflammatory condition, and a chronic acute EBV infection of T cells. Studies of PIDs associated with a predisposition to develop severe, chronic EBV infections have led to the identification of key components of immunity to EBV - notably the central role of T-cell expansion and its regulation in the pathophysiology of EBV-associated diseases. On one hand, the defective expansion of EBV-specific CD8 T cells results from mutations in genes involved in T-cell activation (such as RASGRP1, MAGT1, and ITK), DNA metabolism (CTPS1) or co-stimulatory pathways (CD70, CD27, and TNFSFR9 (also known as CD137/4-1BB)) leads to impaired elimination of proliferating EBV-infected B cells and the occurrence of lymphoma. On the other hand, protracted T-cell expansion and activation after the defective killing of EBV-infected B cells is caused by genetic defects in the components of the lytic granule exocytosis pathway or in the small adapter protein SH2D1A (also known as SAP), a key activator of T- and NK cell-cytotoxicity. In this setting, the persistence of EBV-infected cells results in HLH, a condition characterized by unleashed T-cell and macrophage activation. Moreover, genetic defects causing selective vulnerability to EBV infection have highlighted the role of co-receptor molecules (CD27, CD137, and SLAM-R) selectively involved in immune responses against infected B cells via specific T-B cell interactions.
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Affiliation(s)
- Sylvain Latour
- Laboratory of Lymphocyte Activation and Susceptibility to EBV infection, Inserm UMR 1163, Paris, France.,University Paris Descartes Sorbonne Paris Cité, Imagine Institut, Paris, France
| | - Alain Fischer
- University Paris Descartes Sorbonne Paris Cité, Imagine Institut, Paris, France.,Department of Pediatric Immunology, Hematology and Rheumatology, Necker-Enfants Malades Hospital, Assistance Publique-Hôpitaux de Paris (APHP), Paris, France.,Collège de France, Paris, France.,Inserm UMR 1163, Paris, France
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Jensen S, Seidelin JB, LaCasse EC, Nielsen OH. SMAC mimetics and RIPK inhibitors as therapeutics for chronic inflammatory diseases. Sci Signal 2020; 13:13/619/eaax8295. [PMID: 32071170 DOI: 10.1126/scisignal.aax8295] [Citation(s) in RCA: 41] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
New therapeutic approaches for chronic inflammatory diseases such as inflammatory bowel disease, rheumatoid arthritis, and psoriasis are needed because current treatments are often suboptimal in terms of both efficacy and the risks of serious adverse events. Inhibitor of apoptosis proteins (IAPs) are E3 ubiquitin ligases that inhibit cell death pathways and are themselves inhibited by second mitochondria-derived activator of caspases (SMAC). SMAC mimetics (SMs), small-molecule antagonists of IAPs, are being evaluated as cancer therapies in clinical trials. IAPs are also crucial regulators of inflammatory pathways because they influence both the activation of inflammatory genes and the induction of cell death through the receptor-interacting serine-threonine protein kinases (RIPKs), nuclear factor κB (NF-κB)-inducing kinase, and mitogen-activated protein kinases (MAPKs). Furthermore, there is an increasing interest in specifically targeting the substrates of IAP-mediated ubiquitylation, especially RIPK1, RIPK2, and RIPK3, as druggable nodes in inflammation control. Several studies have revealed an anti-inflammatory potential of RIPK inhibitors that either block inflammatory signaling or block the form of inflammatory cell death known as necroptosis. Expanding research on innate immune signaling through pattern recognition receptors that stimulate proinflammatory NF-κB and MAPK signaling may further contribute to uncovering the complex molecular roles used by IAPs and downstream RIPKs in inflammatory signaling. This may benefit and guide the development of SMs or selective RIPK inhibitors as anti-inflammatory therapeutics for various chronic inflammatory conditions.
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Affiliation(s)
- Simone Jensen
- Department of Gastroenterology, Medical Section, Herlev Hospital, University of Copenhagen, 1 Borgmester Ib Juuls Vej, DK-2730 Herlev, Denmark
| | - Jakob Benedict Seidelin
- Department of Gastroenterology, Medical Section, Herlev Hospital, University of Copenhagen, 1 Borgmester Ib Juuls Vej, DK-2730 Herlev, Denmark.
| | - Eric Charles LaCasse
- Apoptosis Research Centre, Children's Hospital of Eastern Ontario Research Institute, 401 Smyth Road, Ottawa, Ontario K1H 8L1, Canada
| | - Ole Haagen Nielsen
- Department of Gastroenterology, Medical Section, Herlev Hospital, University of Copenhagen, 1 Borgmester Ib Juuls Vej, DK-2730 Herlev, Denmark
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Nambu R, Muise AM. Advanced Understanding of Monogenic Inflammatory Bowel Disease. Front Pediatr 2020; 8:618918. [PMID: 33553075 PMCID: PMC7862769 DOI: 10.3389/fped.2020.618918] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/19/2020] [Accepted: 12/31/2020] [Indexed: 12/29/2022] Open
Abstract
Inflammatory bowel disease (IBD) is a group of chronic disorders that cause relapsing inflammation in the gastrointestinal tract and comprise three major subgroups of Crohn's disease (CD), ulcerative colitis (UC), and IBD-unclassified (IBDU). Recent advances in genomic technologies have furthered our understanding of IBD pathogenesis. It includes differentiation rare monogenic disorders exhibiting IBD and IBD-like inflammation (monogenic IBD) from patients with the common polygenic form of IBD. Several novel genes responsible for monogenic IBD have been elucidated, and the number of reports has increased due to advancements in molecular functional analysis. Identification of these pathogenic genetic mutations has helped in elucidating the details of the immune response associated with gastrointestinal inflammation and in providing individualized treatments for patients with severe IBD that is often unresponsive to conventional therapy. The majority of monogenic IBD studies have focused on young children diagnosed <6 years of age (very early-onset IBD); however, a recent study revealed high prevalence of monogenic IBD in older children aged >6 years of age as well. Meanwhile, although patients with monogenic IBD generally show co-morbidities and/or extraintestinal manifestation at the time of diagnosis, cases of IBD developing as the initial symptom with unremarkable prodromal symptoms have been reported. It is crucial that the physicians properly match genetic analytical data with clinical diagnosis and/or differential diagnosis. In this review, we summarize the essential clues that may physicians make a correct diagnosis of monogenic disease, including classification, prevalence and clinical phenotype based on available literatures.
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Affiliation(s)
- Ryusuke Nambu
- Cell Biology Program, Research Institute, The Hospital for Sick Children, Toronto, ON, Canada.,SickKids Inflammatory Bowel Disease Center, The Hospital for Sick Children, Toronto, ON, Canada.,Department of Gastroenterology and Hepatology, Saitama Children's Medical Center, Saitama, Japan
| | - Aleixo M Muise
- Cell Biology Program, Research Institute, The Hospital for Sick Children, Toronto, ON, Canada.,SickKids Inflammatory Bowel Disease Center, The Hospital for Sick Children, Toronto, ON, Canada.,Department of Pediatrics, Institute of Medical Science and Biochemistry, The Hospital for Sick Children, University of Toronto, Toronto, ON, Canada
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X-linked lymphoproliferative syndrome in mainland China: review of clinical, genetic, and immunological characteristic. Eur J Pediatr 2020; 179:327-338. [PMID: 31754776 PMCID: PMC6970958 DOI: 10.1007/s00431-019-03512-7] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/15/2019] [Revised: 09/07/2019] [Accepted: 10/21/2019] [Indexed: 12/21/2022]
Abstract
X-linked lymphoproliferative syndrome (XLP) is a rare primary immunodeficiency disease that can be divided into two types: SAP deficiency (XLP1) and XIAP deficiency (XLP2), caused by mutations in the SH2D1A and XIAP genes, respectively. Few cases of XLP (particularly XIAP deficiency) have been reported in mainland China; hence, little is known about the characteristics of Chinese patients with XLP. We identified 13 and 7 patients with SAP and XIAP deficiency, respectively, in our center. Of our 20 patients, 19/20 (95%) presented with disease symptoms at a very early age: six in infancy and 13 in childhood. One XIAP- and three SAP-deficient patients died, while 3/7(42.9%) and 4/13(30.8%), respectively, developed hemophagocytic lymphohistiocytosis (HLH). Epstein-Barr virus (EBV) infection was significantly more common in SAP-deficient 10/13 (76.9%) than XIAP-deficient 2/7 (28.6%) patients, as was hypogammaglobulinemia (10/13 (76.9%) vs. 1/7 (14.3%)). None of the seven XIAP-deficient patients had colitis or lymphoma. Nine SAP-deficient patients and five XIAP-deficient patients showed markedly deficient SAP and XIAP expression, respectively, in lymphocytes. Significantly reduced levels of switched memory B cells were observed in six SAP-deficient patients with persistent hypogammaglobulinemia. One of 13 (7.7%) SAP-deficient patients and 1 of 7 (12.3%) XIAP-deficient patients have received HSCT treatment and are now alive and well; the other alive patients were waiting for HSCT. We also summarized clinical, genetic, and immunological characteristics of all 55 patients (including our 20 patients) reported in the literature in mainland China today.Conclusion: The overall characteristics of SAP deficiency in mainland China were consistent with those in previous reports, whereas manifestations of XIAP deficiency varied significantly. None of inflammatory bowel disease (IBD) has been reported among XIAP-deficient patients in our center; however, whether Chinese XIAP-deficient patients will develop colitis in the future warrants further investigation. HSCT is the only curative therapy for XLP and this therapy should be urgently considered.What is Known:• SAP and XIAP deficiencies share common clinical feature, HLH, whereas they also have their own specific manifestations.• IBD affects 25-30% of XIAP-deficient patients, which has been reported in other countries especially in European country and Japan.What is New:• This is the largest patient cohort study of XLP in China.• We firstly summarized the clinical features and outcomes of Chinese XIAP-deficient patients and found only 1 in 22 patients developed IBD and diet background may contribute to it; Asian SAP-deficient patients carrying SH2D1A R55X mutation were more prone to HLH.
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Shabani M, Razaghian A, Alimadadi H, Shiari R, Shahrooei M, Parvaneh N. Different phenotypes of the same XIAP mutation in a family: A case of XIAP deficiency with juvenile idiopathic arthritis. Pediatr Blood Cancer 2019; 66:e27593. [PMID: 30604482 DOI: 10.1002/pbc.27593] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/08/2018] [Accepted: 12/13/2018] [Indexed: 01/04/2023]
Affiliation(s)
- Mahsima Shabani
- Division of Allergy and Clinical Immunology, Department of Pediatrics, Tehran University of Medical Sciences, Tehran, Iran.,Research Center for Immunodeficiencies, Tehran University of Medical Sciences, Tehran, Iran
| | - Anahita Razaghian
- Division of Allergy and Clinical Immunology, Department of Pediatrics, Tehran University of Medical Sciences, Tehran, Iran
| | - Hosein Alimadadi
- Department of Pediatric Gastroeneterology, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran
| | - Reza Shiari
- Department of Pediatric Rheumatology, Mofid Children Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mohammad Shahrooei
- Department of Microbiology and Immunology, Laboratory of Clinical Bacteriology and Mycology, KU Leuven, Leuven, Belgium.,Specialized Immunology Laboratory, Ahvaz, Iran
| | - Nima Parvaneh
- Division of Allergy and Clinical Immunology, Department of Pediatrics, Tehran University of Medical Sciences, Tehran, Iran.,Research Center for Immunodeficiencies, Tehran University of Medical Sciences, Tehran, Iran
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48
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Lipinski S, Petersen BS, Barann M, Piecyk A, Tran F, Mayr G, Jentzsch M, Aden K, Stengel ST, Klostermeier UC, Sheth V, Ellinghaus D, Rausch T, Korbel JO, Nothnagel M, Krawczak M, Gilissen C, Veltman JA, Forster M, Forster P, Lee CC, Fritscher-Ravens A, Schreiber S, Franke A, Rosenstiel P. Missense variants in NOX1 and p22phox in a case of very-early-onset inflammatory bowel disease are functionally linked to NOD2. Cold Spring Harb Mol Case Stud 2019; 5:mcs.a002428. [PMID: 30709874 PMCID: PMC6371741 DOI: 10.1101/mcs.a002428] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2017] [Accepted: 10/29/2018] [Indexed: 02/07/2023] Open
Abstract
Whole-genome and whole-exome sequencing of individual patients allow the study of rare and potentially causative genetic variation. In this study, we sequenced DNA of a trio comprising a boy with very-early-onset inflammatory bowel disease (veoIBD) and his unaffected parents. We identified a rare, X-linked missense variant in the NAPDH oxidase NOX1 gene (c.C721T, p.R241C) in heterozygous state in the mother and in hemizygous state in the patient. We discovered that, in addition, the patient was homozygous for a common missense variant in the CYBA gene (c.T214C, p.Y72H). CYBA encodes the p22phox protein, a cofactor for NOX1. Functional assays revealed reduced cellular ROS generation and antibacterial capacity of NOX1 and p22phox variants in intestinal epithelial cells. Moreover, the identified NADPH oxidase complex variants affected NOD2-mediated immune responses, and p22phox was identified as a novel NOD2 interactor. In conclusion, we detected missense variants in a veoIBD patient that disrupt the host response to bacterial challenges and reduce protective innate immune signaling via NOD2. We assume that the patient's individual genetic makeup favored disturbed intestinal mucosal barrier function.
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Affiliation(s)
- Simone Lipinski
- Institute of Clinical Molecular Biology (IKMB), Christian-Albrechts-University, 24105 Kiel, Germany
| | - Britt-Sabina Petersen
- Institute of Clinical Molecular Biology (IKMB), Christian-Albrechts-University, 24105 Kiel, Germany
| | - Matthias Barann
- Institute of Clinical Molecular Biology (IKMB), Christian-Albrechts-University, 24105 Kiel, Germany
| | - Agnes Piecyk
- Institute of Clinical Molecular Biology (IKMB), Christian-Albrechts-University, 24105 Kiel, Germany
| | - Florian Tran
- Institute of Clinical Molecular Biology (IKMB), Christian-Albrechts-University, 24105 Kiel, Germany.,Department of General Internal Medicine, Christian-Albrechts-University, University Hospital Schleswig-Holstein, 24105 Kiel, Germany
| | - Gabriele Mayr
- Institute of Clinical Molecular Biology (IKMB), Christian-Albrechts-University, 24105 Kiel, Germany
| | - Marlene Jentzsch
- Institute of Clinical Molecular Biology (IKMB), Christian-Albrechts-University, 24105 Kiel, Germany
| | - Konrad Aden
- Institute of Clinical Molecular Biology (IKMB), Christian-Albrechts-University, 24105 Kiel, Germany.,Department of General Internal Medicine, Christian-Albrechts-University, University Hospital Schleswig-Holstein, 24105 Kiel, Germany
| | - Stephanie T Stengel
- Institute of Clinical Molecular Biology (IKMB), Christian-Albrechts-University, 24105 Kiel, Germany
| | - Ulrich C Klostermeier
- Institute of Clinical Molecular Biology (IKMB), Christian-Albrechts-University, 24105 Kiel, Germany
| | - Vrunda Sheth
- Life Technologies, Beverly, Massachusetts 01915, USA
| | - David Ellinghaus
- Institute of Clinical Molecular Biology (IKMB), Christian-Albrechts-University, 24105 Kiel, Germany
| | - Tobias Rausch
- European Molecular Biology Laboratory (EMBL), Genome Biology Unit, 69117 Heidelberg, Germany
| | - Jan O Korbel
- European Molecular Biology Laboratory (EMBL), Genome Biology Unit, 69117 Heidelberg, Germany
| | - Michael Nothnagel
- Institute of Medical Informatics and Statistics (IMIS), Christian-Albrechts University, 24105 Kiel, Germany
| | - Michael Krawczak
- Institute of Medical Informatics and Statistics (IMIS), Christian-Albrechts University, 24105 Kiel, Germany
| | - Christian Gilissen
- Department of Human Genetics, Donders Institute for Brain, Cognition and Behavior, Radboud University Medical Center, Nijmegen 6525, The Netherlands
| | - Joris A Veltman
- Department of Human Genetics, Donders Institute for Brain, Cognition and Behavior, Radboud University Medical Center, Nijmegen 6525, The Netherlands.,Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne NE1 3BZ, United Kingdom
| | - Michael Forster
- Institute of Clinical Molecular Biology (IKMB), Christian-Albrechts-University, 24105 Kiel, Germany
| | - Peter Forster
- Murray Edwards College, University of Cambridge, Cambridge CB3 0DF, United Kingdom
| | - Clarence C Lee
- Department of General Internal Medicine, Christian-Albrechts-University, University Hospital Schleswig-Holstein, 24105 Kiel, Germany
| | - Annette Fritscher-Ravens
- Department of General Internal Medicine, Christian-Albrechts-University, University Hospital Schleswig-Holstein, 24105 Kiel, Germany
| | - Stefan Schreiber
- Institute of Clinical Molecular Biology (IKMB), Christian-Albrechts-University, 24105 Kiel, Germany.,Department of General Internal Medicine, Christian-Albrechts-University, University Hospital Schleswig-Holstein, 24105 Kiel, Germany
| | - Andre Franke
- Institute of Clinical Molecular Biology (IKMB), Christian-Albrechts-University, 24105 Kiel, Germany
| | - Philip Rosenstiel
- Institute of Clinical Molecular Biology (IKMB), Christian-Albrechts-University, 24105 Kiel, Germany
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Abstract
The inhibitor of apoptosis proteins (IAPs) are a family of proteins that were chiefly known for their ability to inhibit apoptosis by blocking caspase activation or activity. Recent research has shown that cellular IAP1 (cIAP1), cIAP2, and X-linked IAP (XIAP) also regulate signaling by receptors of the innate immune system by ubiquitylating their substrates. These IAPs thereby act at the intersection of pathways leading to cell death and inflammation. Mutation of IAP genes can impair tissue homeostasis and is linked to several human diseases. Small-molecule IAP antagonists have been developed to treat certain malignant, infectious, and inflammatory diseases. Here, we will discuss recent advances in our understanding of the functions of cIAP1, cIAP2, and XIAP; the consequences of their mutation or dysregulation; and the therapeutic potential of IAP antagonist drugs.
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Affiliation(s)
- Najoua Lalaoui
- Cell Signalling and Cell Death, The Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, 3052, Australia.,Department of Medical Biology, The University of Melbourne, Melbourne, Victoria, 3050, Australia
| | - David Lawrence Vaux
- Cell Signalling and Cell Death, The Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria, 3052, Australia.,Department of Medical Biology, The University of Melbourne, Melbourne, Victoria, 3050, Australia
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50
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Charbit-Henrion F, Parlato M, Hanein S, Duclaux-Loras R, Nowak J, Begue B, Rakotobe S, Bruneau J, Fourrage C, Alibeu O, Rieux-Laucat F, Lévy E, Stolzenberg MC, Mazerolles F, Latour S, Lenoir C, Fischer A, Picard C, Aloi M, Dias JA, Hariz MB, Bourrier A, Breuer C, Breton A, Bronsky J, Buderus S, Cananzi M, Coopman S, Crémilleux C, Dabadie A, Dumant-Forest C, Gurkan OE, Fabre A, Fischer A, Diaz MG, Gonzalez-Lama Y, Goulet O, Guariso G, Gurcan N, Homan M, Hugot JP, Jeziorski E, Karanika E, Lachaux A, Lewindon P, Lima R, Magro F, Major J, Malamut G, Mas E, Mattyus I, Mearin LM, Melek J, Navas-Lopez VM, Paerregaard A, Pelatan C, Pigneur B, Pais IP, Rebeuh J, Romano C, Siala N, Strisciuglio C, Tempia-Caliera M, Tounian P, Turner D, Urbonas V, Willot S, Ruemmele FM, Cerf-Bensussan N. Diagnostic Yield of Next-generation Sequencing in Very Early-onset Inflammatory Bowel Diseases: A Multicentre Study. J Crohns Colitis 2018; 12:1104-1112. [PMID: 29788237 PMCID: PMC6113703 DOI: 10.1093/ecco-jcc/jjy068] [Citation(s) in RCA: 61] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/13/2017] [Revised: 03/14/2018] [Accepted: 05/16/2018] [Indexed: 12/11/2022]
Abstract
BACKGROUND AND AIMS An expanding number of monogenic defects have been identified as causative of severe forms of very early-onset inflammatory bowel diseases [VEO-IBD]. The present study aimed at defining how next-generation sequencing [NGS] methods can be used to improve identification of known molecular diagnosis and to adapt treatment. METHODS A total of 207 children were recruited in 45 paediatric centres through an international collaborative network [ESPGHAN GENIUS working group] with a clinical presentation of severe VEO-IBD [n = 185] or an anamnesis suggestive of a monogenic disorder [n = 22]. Patients were divided at inclusion into three phenotypic subsets: predominantly small bowel inflammation, colitis with perianal lesions, and colitis only. Methods to obtain molecular diagnosis included functional tests followed by specific Sanger sequencing, custom-made targeted NGS, and in selected cases whole exome sequencing [WES] of parents-child trios. Genetic findings were validated clinically and/or functionally. RESULTS Molecular diagnosis was achieved in 66/207 children [32%]: 61% with small bowel inflammation, 39% with colitis and perianal lesions, and 18% with colitis only. Targeted NGS pinpointed gene mutations causative of atypical presentations, and identified large exonic copy number variations previously missed by WES. CONCLUSIONS Our results lead us to propose an optimised diagnostic strategy to identify known monogenic causes of severe IBD.
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Affiliation(s)
- Fabienne Charbit-Henrion
- INSERM, UMR1163, Laboratory of Intestinal Immunity, and Imagine Institute, Paris, France
- Université Paris Descartes-Sorbonne Paris Cité, Paris, France
- Paediatric Gastroenterology, Hepatology and Nutrition Unit, Hôpital Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris, Paris, France
- GENIUS Group [GENetically ImmUne–mediated enteropathieS] from the European Society for Paediatric Gastroenterology, Hepatology and Nutrition [ESPGHAN]
| | - Marianna Parlato
- INSERM, UMR1163, Laboratory of Intestinal Immunity, and Imagine Institute, Paris, France
- Université Paris Descartes-Sorbonne Paris Cité, Paris, France
- GENIUS Group [GENetically ImmUne–mediated enteropathieS] from the European Society for Paediatric Gastroenterology, Hepatology and Nutrition [ESPGHAN]
| | - Sylvain Hanein
- INSERM, UMR 1163 Translational Genetic, and Imagine Institute, Paris, France
| | - Rémi Duclaux-Loras
- INSERM, UMR1163, Laboratory of Intestinal Immunity, and Imagine Institute, Paris, France
- Université Paris Descartes-Sorbonne Paris Cité, Paris, France
- GENIUS Group [GENetically ImmUne–mediated enteropathieS] from the European Society for Paediatric Gastroenterology, Hepatology and Nutrition [ESPGHAN]
| | - Jan Nowak
- INSERM, UMR1163, Laboratory of Intestinal Immunity, and Imagine Institute, Paris, France
- Université Paris Descartes-Sorbonne Paris Cité, Paris, France
- GENIUS Group [GENetically ImmUne–mediated enteropathieS] from the European Society for Paediatric Gastroenterology, Hepatology and Nutrition [ESPGHAN]
- Department of Paediatric Gastroenterology and Metabolic Diseases, Poznan University of Medical Sciences, Poznan, Poland
| | - Bernadette Begue
- INSERM, UMR1163, Laboratory of Intestinal Immunity, and Imagine Institute, Paris, France
- Université Paris Descartes-Sorbonne Paris Cité, Paris, France
- GENIUS Group [GENetically ImmUne–mediated enteropathieS] from the European Society for Paediatric Gastroenterology, Hepatology and Nutrition [ESPGHAN]
| | - Sabine Rakotobe
- INSERM, UMR1163, Laboratory of Intestinal Immunity, and Imagine Institute, Paris, France
- Université Paris Descartes-Sorbonne Paris Cité, Paris, France
- GENIUS Group [GENetically ImmUne–mediated enteropathieS] from the European Society for Paediatric Gastroenterology, Hepatology and Nutrition [ESPGHAN]
| | - Julie Bruneau
- Université Paris Descartes-Sorbonne Paris Cité, Paris, France
- Pathology Department, Hôpital Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris, Paris, France
| | - Cécile Fourrage
- Université Paris Descartes-Sorbonne Paris Cité, Paris, France
- Bioinformatics Platform, Imagine Institute Paris, France
| | - Olivier Alibeu
- Université Paris Descartes-Sorbonne Paris Cité, Paris, France
- Genomic Platform, Imagine Institute, Paris, France
| | - Frédéric Rieux-Laucat
- Université Paris Descartes-Sorbonne Paris Cité, Paris, France
- INSERM, UMR1163, Immunogenetics of Paediatric Autoimmunity, and Imagine Institute, Paris, France
| | - Eva Lévy
- Université Paris Descartes-Sorbonne Paris Cité, Paris, France
- INSERM, UMR1163, Immunogenetics of Paediatric Autoimmunity, and Imagine Institute, Paris, France
| | - Marie-Claude Stolzenberg
- Université Paris Descartes-Sorbonne Paris Cité, Paris, France
- INSERM, UMR1163, Immunogenetics of Paediatric Autoimmunity, and Imagine Institute, Paris, France
| | - Fabienne Mazerolles
- Université Paris Descartes-Sorbonne Paris Cité, Paris, France
- INSERM, UMR1163, Immunogenetics of Paediatric Autoimmunity, and Imagine Institute, Paris, France
| | - Sylvain Latour
- Université Paris Descartes-Sorbonne Paris Cité, Paris, France
- INSERM, UMR1163, Lymphocyte activation and EBV susceptibility, and Imagine Institute, Paris, France
| | - Christelle Lenoir
- Université Paris Descartes-Sorbonne Paris Cité, Paris, France
- INSERM, UMR1163, Lymphocyte activation and EBV susceptibility, and Imagine Institute, Paris, France
| | - Alain Fischer
- Université Paris Descartes-Sorbonne Paris Cité, Paris, France
- Collège de France, Médecine expérimentale, Paris, France
- INSERM UMR 1163 and Imagine Institute, Paris, France
| | - Capucine Picard
- Université Paris Descartes-Sorbonne Paris Cité, Paris, France
- INSERM, UMR1163, Lymphocyte activation and EBV susceptibility, and Imagine Institute, Paris, France
- Investigation Centre for Immunodeficiency, Hôpital Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris and Imagine Institute, Paris, France
| | - Marina Aloi
- GENIUS Group [GENetically ImmUne–mediated enteropathieS] from the European Society for Paediatric Gastroenterology, Hepatology and Nutrition [ESPGHAN]
- Sapienza University of Rome, Paediatric Gastroenterology and Liver Unit, Department of Pediatrics, Rome, Italy
| | - Jorge Amil Dias
- GENIUS Group [GENetically ImmUne–mediated enteropathieS] from the European Society for Paediatric Gastroenterology, Hepatology and Nutrition [ESPGHAN]
- Department of Paediatrics, Centro Hospitalar São João, Porto, Portugal
| | - Mongi Ben Hariz
- GENIUS Group [GENetically ImmUne–mediated enteropathieS] from the European Society for Paediatric Gastroenterology, Hepatology and Nutrition [ESPGHAN]
- Department of Paediatrics, Hopital La Marsa, Tunisia
| | - Anne Bourrier
- Department of Gastroenterology, Hôpital St Antoine, Assistance Publique-Hôpitaux de Paris, Paris, France
| | - Christian Breuer
- GENIUS Group [GENetically ImmUne–mediated enteropathieS] from the European Society for Paediatric Gastroenterology, Hepatology and Nutrition [ESPGHAN]
- Department of Paediatrics, Universitätsklinikum Hamburg, Hamburg, Germany
| | - Anne Breton
- GENIUS Group [GENetically ImmUne–mediated enteropathieS] from the European Society for Paediatric Gastroenterology, Hepatology and Nutrition [ESPGHAN]
- Department of Paediatrics, Gastroenterology, Hepatology, Nutrition, and Diabetes, Centre Hospitalier Universitaire de Toulouse, Toulouse, France
| | - Jiri Bronsky
- GENIUS Group [GENetically ImmUne–mediated enteropathieS] from the European Society for Paediatric Gastroenterology, Hepatology and Nutrition [ESPGHAN]
- University Hospital Motol, Prague, Czech Republic
| | - Stephan Buderus
- GENIUS Group [GENetically ImmUne–mediated enteropathieS] from the European Society for Paediatric Gastroenterology, Hepatology and Nutrition [ESPGHAN]
- St. Marien Hospital, Bonn, Germany
| | - Mara Cananzi
- GENIUS Group [GENetically ImmUne–mediated enteropathieS] from the European Society for Paediatric Gastroenterology, Hepatology and Nutrition [ESPGHAN]
- Unit of Paediatric Hepatology, Department of Woman and Child Health, University Hospital of Padova, Padova, Italy
| | - Stéphanie Coopman
- GENIUS Group [GENetically ImmUne–mediated enteropathieS] from the European Society for Paediatric Gastroenterology, Hepatology and Nutrition [ESPGHAN]
- Division of Gastroenterology, Hepatology and Nutrition, Department of Paediatrics, Jeanne De Flandre Children’s Hospital, Lille University Faculty of Medicine, Lille, France
| | - Clara Crémilleux
- GENIUS Group [GENetically ImmUne–mediated enteropathieS] from the European Society for Paediatric Gastroenterology, Hepatology and Nutrition [ESPGHAN]
- Department of Paediatrics, Centre Hospitalo-Universitaire de St-Etienne, St-Etienne, France
| | - Alain Dabadie
- GENIUS Group [GENetically ImmUne–mediated enteropathieS] from the European Society for Paediatric Gastroenterology, Hepatology and Nutrition [ESPGHAN]
- Service de médecine de l’enfant et de l’adolescent, Hôpital Sud – Centre Hospitalo-Universitaire de Rennes, Rennes, France
| | - Clémentine Dumant-Forest
- GENIUS Group [GENetically ImmUne–mediated enteropathieS] from the European Society for Paediatric Gastroenterology, Hepatology and Nutrition [ESPGHAN]
- Department of Paediatrics, Centre Hospitalo-Universitaire Charles Nicolle, Rouen, France
| | - Odul Egritas Gurkan
- GENIUS Group [GENetically ImmUne–mediated enteropathieS] from the European Society for Paediatric Gastroenterology, Hepatology and Nutrition [ESPGHAN]
- Paediatric Gastroenterology, Hepatology and Nutrition, Gazi University, Ankara, Turkey
| | - Alexandre Fabre
- GENIUS Group [GENetically ImmUne–mediated enteropathieS] from the European Society for Paediatric Gastroenterology, Hepatology and Nutrition [ESPGHAN]
- Department of Paediatrics, Assistance publique Hôpitaux de Marseille, Hôpital de la Timone, Marseille, France
| | - Aude Fischer
- GENIUS Group [GENetically ImmUne–mediated enteropathieS] from the European Society for Paediatric Gastroenterology, Hepatology and Nutrition [ESPGHAN]
- Department of Paediatrics, Centre Hospitalo-Universitaire Sud Réunion, St Pierre, France
| | - Marta German Diaz
- GENIUS Group [GENetically ImmUne–mediated enteropathieS] from the European Society for Paediatric Gastroenterology, Hepatology and Nutrition [ESPGHAN]
- Unit of Paediatric Nutrition, Hospital Universitario 12 de Octubre, Madrid, Spain
| | - Yago Gonzalez-Lama
- Inflammatory Bowel Disease Unit, Hospital Universitario Puerta de Hierro–Majadahonda, Madrid, Spain
| | - Olivier Goulet
- Université Paris Descartes-Sorbonne Paris Cité, Paris, France
- Paediatric Gastroenterology, Hepatology and Nutrition Unit, Hôpital Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris, Paris, France
- GENIUS Group [GENetically ImmUne–mediated enteropathieS] from the European Society for Paediatric Gastroenterology, Hepatology and Nutrition [ESPGHAN]
| | - Graziella Guariso
- GENIUS Group [GENetically ImmUne–mediated enteropathieS] from the European Society for Paediatric Gastroenterology, Hepatology and Nutrition [ESPGHAN]
- University of Padua, Italy
| | - Neslihan Gurcan
- GENIUS Group [GENetically ImmUne–mediated enteropathieS] from the European Society for Paediatric Gastroenterology, Hepatology and Nutrition [ESPGHAN]
- Paediatric Gastroenterology, Hepatology and Nutrition, Gazi University, Ankara, Turkey
| | - Matjaz Homan
- GENIUS Group [GENetically ImmUne–mediated enteropathieS] from the European Society for Paediatric Gastroenterology, Hepatology and Nutrition [ESPGHAN]
- Department of Gastroenterology, Hepatology and Nutrition, University Children’s Hospital, Ljubljana, Slovenia
| | - Jean-Pierre Hugot
- GENIUS Group [GENetically ImmUne–mediated enteropathieS] from the European Society for Paediatric Gastroenterology, Hepatology and Nutrition [ESPGHAN]
- Departments of Paediatric Digestive and Respiratory Diseases, Hôpital Robert-Debré, Assistance Publique-Hôpitaux de Paris, Paris, France
| | - Eric Jeziorski
- GENIUS Group [GENetically ImmUne–mediated enteropathieS] from the European Society for Paediatric Gastroenterology, Hepatology and Nutrition [ESPGHAN]
- Department of Paediatrics, Infectious diseases and Immunology, Centre Hospitalo-Universitaire de Montpellier, Montpellier, France
| | - Evi Karanika
- GENIUS Group [GENetically ImmUne–mediated enteropathieS] from the European Society for Paediatric Gastroenterology, Hepatology and Nutrition [ESPGHAN]
- Department of Paediatrics, University General Hospital of Thessaloniki, Thessaloniki, Greece
| | - Alain Lachaux
- GENIUS Group [GENetically ImmUne–mediated enteropathieS] from the European Society for Paediatric Gastroenterology, Hepatology and Nutrition [ESPGHAN]
- Department of Paediatric Gastroenterology, Hepatology and Nutrition, Centre de Nutrition parentérale à domicile, Hôpital Femme–Mère–Enfant CHU de Lyon HCL - GH Est, Bron, France
| | - Peter Lewindon
- GENIUS Group [GENetically ImmUne–mediated enteropathieS] from the European Society for Paediatric Gastroenterology, Hepatology and Nutrition [ESPGHAN]
- Department of Gastroenterology and Hepatology, Lady Cilento Children’s Hospital and the Faculty of Medicine and Biomedical Sciences, TUniversity of Queensland, Brisbane, Australia
| | - Rosa Lima
- GENIUS Group [GENetically ImmUne–mediated enteropathieS] from the European Society for Paediatric Gastroenterology, Hepatology and Nutrition [ESPGHAN]
- Department of Paediatrics, Centro Hospitalar São João, Porto, Portugal
| | - Fernando Magro
- Gastroenterology Department, Hospital de São João, Institute of Pharmacology and Therapeutics Faculty of Medicine and MedInUP - Centre for Drug Discovery and Innovative Medicines, University of Porto, Porto, Portugal
| | - Janos Major
- GENIUS Group [GENetically ImmUne–mediated enteropathieS] from the European Society for Paediatric Gastroenterology, Hepatology and Nutrition [ESPGHAN]
- MRE Bethesda Gyermekkórháza; Department of Pediatrics, Budapest, Hungary
| | - Georgia Malamut
- INSERM, UMR1163, Laboratory of Intestinal Immunity, and Imagine Institute, Paris, France
- Université Paris Descartes-Sorbonne Paris Cité, Paris, France
- Department of Gastroenterology, Hôpital Européen Georges Pompidou, Assistance Publique-Hôpitaux de Paris, Paris, France
| | - Emmanuel Mas
- GENIUS Group [GENetically ImmUne–mediated enteropathieS] from the European Society for Paediatric Gastroenterology, Hepatology and Nutrition [ESPGHAN]
- Department of Paediatrics, Gastroenterology, Hepatology, Nutrition, and Diabetes, Centre Hospitalier Universitaire de Toulouse, Toulouse, France
| | - Istvan Mattyus
- GENIUS Group [GENetically ImmUne–mediated enteropathieS] from the European Society for Paediatric Gastroenterology, Hepatology and Nutrition [ESPGHAN]
- Semmelweis University; Department of Paediatrics, Budapest, Hungary
| | - Luisa M Mearin
- GENIUS Group [GENetically ImmUne–mediated enteropathieS] from the European Society for Paediatric Gastroenterology, Hepatology and Nutrition [ESPGHAN]
- Leiden University Medical Centre, Department of Paediatrics, Leiden, The Netherlands
| | - Jan Melek
- GENIUS Group [GENetically ImmUne–mediated enteropathieS] from the European Society for Paediatric Gastroenterology, Hepatology and Nutrition [ESPGHAN]
- University Hospital, Hradec Kralove, Czech Republic
| | - Victor Manuel Navas-Lopez
- GENIUS Group [GENetically ImmUne–mediated enteropathieS] from the European Society for Paediatric Gastroenterology, Hepatology and Nutrition [ESPGHAN]
- Hospital Regional Universitario de Málaga, Departamento de Pediatría, Malaga, Spain
| | - Anders Paerregaard
- GENIUS Group [GENetically ImmUne–mediated enteropathieS] from the European Society for Paediatric Gastroenterology, Hepatology and Nutrition [ESPGHAN]
- Hvidovre University Hospital, Department of Paediatrics, Copenhagen, Denmark
| | - Cecile Pelatan
- GENIUS Group [GENetically ImmUne–mediated enteropathieS] from the European Society for Paediatric Gastroenterology, Hepatology and Nutrition [ESPGHAN]
- Department of Paediatrics, Centre Hospitalier du Mans, Le Mans, France
| | - Bénédicte Pigneur
- INSERM, UMR1163, Laboratory of Intestinal Immunity, and Imagine Institute, Paris, France
- Université Paris Descartes-Sorbonne Paris Cité, Paris, France
- Paediatric Gastroenterology, Hepatology and Nutrition Unit, Hôpital Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris, Paris, France
- GENIUS Group [GENetically ImmUne–mediated enteropathieS] from the European Society for Paediatric Gastroenterology, Hepatology and Nutrition [ESPGHAN]
| | - Isabel Pinto Pais
- GENIUS Group [GENetically ImmUne–mediated enteropathieS] from the European Society for Paediatric Gastroenterology, Hepatology and Nutrition [ESPGHAN]
- Centro Hospitalar Gaia Espinho, Department of Paediatrics, Vila Nova de Gaia, Portugal
| | - Julie Rebeuh
- GENIUS Group [GENetically ImmUne–mediated enteropathieS] from the European Society for Paediatric Gastroenterology, Hepatology and Nutrition [ESPGHAN]
- Department of Paediatrics, Centre Hospitalo-Universitaire de Strasbourg, Strasbourg, France
| | - Claudio Romano
- GENIUS Group [GENetically ImmUne–mediated enteropathieS] from the European Society for Paediatric Gastroenterology, Hepatology and Nutrition [ESPGHAN]
- Department of Paediatrics, Hospital of Messina, University of Messina, Messina, Italy
| | - Nadia Siala
- GENIUS Group [GENetically ImmUne–mediated enteropathieS] from the European Society for Paediatric Gastroenterology, Hepatology and Nutrition [ESPGHAN]
- Department of Paediatrics, Hôpital Mongi Slim, La Marsa, Tunisia
| | - Caterina Strisciuglio
- GENIUS Group [GENetically ImmUne–mediated enteropathieS] from the European Society for Paediatric Gastroenterology, Hepatology and Nutrition [ESPGHAN]
- Department of Woman, Child and General and Specialized Surgery, Second University of Naples, Naples, Italy
| | - Michela Tempia-Caliera
- GENIUS Group [GENetically ImmUne–mediated enteropathieS] from the European Society for Paediatric Gastroenterology, Hepatology and Nutrition [ESPGHAN]
- Department of Paediatrics, FMH Pédiatrie et FA Gastroentérologie et hépatologie, Clinique des Grangettes, Geneva, Switzerland
| | - Patrick Tounian
- GENIUS Group [GENetically ImmUne–mediated enteropathieS] from the European Society for Paediatric Gastroenterology, Hepatology and Nutrition [ESPGHAN]
- Department of Paediatric Nutrition and Gastroenterology, Hôpital Armand Trousseau, Assistance Publique-Hôpitaux de Paris, Paris, France
| | - Dan Turner
- GENIUS Group [GENetically ImmUne–mediated enteropathieS] from the European Society for Paediatric Gastroenterology, Hepatology and Nutrition [ESPGHAN]
- Shaare Zedek Medical Centre, Jerusalem, Israel
| | - Vaidotas Urbonas
- GENIUS Group [GENetically ImmUne–mediated enteropathieS] from the European Society for Paediatric Gastroenterology, Hepatology and Nutrition [ESPGHAN]
- Department of Paediatric Gastroenterology, Vilnius University Clinic for Children’s Diseases, Vilnius, Lithuania
| | - Stéphanie Willot
- GENIUS Group [GENetically ImmUne–mediated enteropathieS] from the European Society for Paediatric Gastroenterology, Hepatology and Nutrition [ESPGHAN]
- Department of Paediatrics, Centre hospitalier régional universitaire, Hôpital Clocheville, Tours, France
| | - Frank M Ruemmele
- INSERM, UMR1163, Laboratory of Intestinal Immunity, and Imagine Institute, Paris, France
- Université Paris Descartes-Sorbonne Paris Cité, Paris, France
- Paediatric Gastroenterology, Hepatology and Nutrition Unit, Hôpital Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris, Paris, France
- GENIUS Group [GENetically ImmUne–mediated enteropathieS] from the European Society for Paediatric Gastroenterology, Hepatology and Nutrition [ESPGHAN]
| | - Nadine Cerf-Bensussan
- INSERM, UMR1163, Laboratory of Intestinal Immunity, and Imagine Institute, Paris, France
- Université Paris Descartes-Sorbonne Paris Cité, Paris, France
- GENIUS Group [GENetically ImmUne–mediated enteropathieS] from the European Society for Paediatric Gastroenterology, Hepatology and Nutrition [ESPGHAN]
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