34 results on '"I. Meyts"'
Search Results
2. Inborn errors of immunity reveal molecular requirements for generation and maintenance of human CD4 + IL-9-expressing cells.
- Author
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Rao G, Mack CD, Nguyen T, Wong N, Payne K, Worley L, Gray PE, Wong M, Hsu P, Stormon MO, Preece K, Suan D, O'Sullivan M, Blincoe AK, Sinclair J, Okada S, Hambleton S, Arkwright PD, Boztug K, Stepensky P, Cooper MA, Bezrodnik L, Nadeau KC, Abolhassani H, Abraham RS, Seppänen MRJ, Béziat V, Bustamante J, Forbes Satter LR, Leiding JW, Meyts I, Jouanguy E, Boisson-Dupuis S, Uzel G, Puel A, Casanova JL, Tangye SG, and Ma CS more...
- Abstract
Background: CD4
+ T cells play essential roles in adaptive immunity. Distinct CD4+ T-cell subsets-TH 1, TH</subscript> 2, T H 17, TH 22, T follicular helper, and regulatory T cells-have been identified, and their contributions to host defense and immune regulation are increasingly well defined. IL-9-producing TH 9 cells were first described in 2008 and appear to play both protective and pathogenic roles in human immunity. However, key requirements for generating human TH 9 cells remain incompletely defined., Objective: We sought to define signaling pathways that regulate IL-9 production by human CD4+ T cells., Methods: Human naive and memory CD4+ T cells were cultured under different conditions, and the molecular mechanisms regulating IL-9 induction were determined by assessing the ability of CD4+ T cells from a broad range of patients (n = 92) with pathogenic variants in key immune genes (n = 21) to differentiate into IL-9+ cells., Results: We identified 2 culture conditions that yielded IL-9-expressing cells from naive CD4+ T cells and amplified IL-9 production by in vivo-generated memory CD4+ T cells: TGF-β plus IL-4 (ie, TH 9 polarizing condition), and the combination of IL-21, IL-23, IL-6, IL-1β, and TGF-β (ie, TH 17 polarizing condition). Combining these conditions had a synergistic effect in generating IL-9+ CD4+ T cells. IL-9 induction required STAT3-activating cytokines as well as intact signaling via the T-cell receptor and STAT5. Importantly, IL-9 induction was restrained by IFN-γ/STAT1 and IL-10., Conclusions: Our findings revealed critical molecules involved in inducing/restraining IL-9 production by human CD4+ T cells, thereby identifying pathways that could be targeted to modulate IL-9 in health and disease., Competing Interests: Disclosure statement C.S.M. and S.G.T. are supported by the National Health and Medical Research Council of Australia (grants 2017463 and 1176665), the Allergy and Immunology Foundation of Australasia, and the Job Research Foundation. S.O. is supported by the Japan Agency for Medical Research and Development (AMED; grant number: JP23ek0109623 and JP24ek019754) and JSPS Program for Forming Japan's Peak Research Universities (JSPS J-PEAKS). I.M. is a senior clinical investigator at FWO Flanders. A.P. is supported by NIH grant (R01AI127564) and M.A.C. is supported by a NIH grant (P01AI155393). G.U. and her contribution are supported by NIAID intramural funds. J.L.C. is supported by grants from Institut National de la Santé et de la Recherche Médicale (INSERM), the Imagine Institute, Paris Cité University, St Giles Foundation, National Center for Advancing Translational Sciences (NCATS), NIH Clinical and Translational Science Award (CTSA) program (UL1TR001866), National Institute of Allergy and Infectious Diseases, NIH (R01AI095983), French National Research Agency (ANR) under “Investments for the future” program (ANR-10-IAHU-01), MAFMACRO (ANR-22-CE92-0008), Integrative Biology of Emerging Infectious Diseases Laboratory of Excellence (ANR-10-LABX-62-IBEID), French Foundation for Medical Research (FRM) (EQU201903007798), Square Foundation, Grandir - Fonds de solidarité pour l’enfance, and W. E. Ford, General Atlantic’s Chairman and Chief Executive Officer, G. Caillaux, General Atlantic’s Co-President, Managing Director and Head of business in EMEA, and the General Atlantic Foundation. Disclosure of potential conflict of interest: The authors declare that they have no relevant conflicts of interest., (Copyright © 2024 American Academy of Allergy, Asthma & Immunology. All rights reserved.) more...- Published
- 2024
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Catalog
3. Activated phosphoinositide 3-kinase δ syndrome: Update from the ESID Registry and comparison with other autoimmune-lymphoproliferative inborn errors of immunity.
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Maccari ME, Wolkewitz M, Schwab C, Lorenzini T, Leiding JW, Aladjdi N, Abolhassani H, Abou-Chahla W, Aiuti A, Azarnoush S, Baris S, Barlogis V, Barzaghi F, Baumann U, Bloomfield M, Bohynikova N, Bodet D, Boutboul D, Bucciol G, Buckland MS, Burns SO, Cancrini C, Cathébras P, Cavazzana M, Cheminant M, Chinello M, Ciznar P, Coulter TI, D'Aveni M, Ekwall O, Eric Z, Eren E, Fasth A, Frange P, Fournier B, Garcia-Prat M, Gardembas M, Geier C, Ghosh S, Goda V, Hammarström L, Hauck F, Heeg M, Heropolitanska-Pliszka E, Hilfanova A, Jolles S, Karakoc-Aydiner E, Kindle GR, Kiykim A, Klemann C, Koletsi P, Koltan S, Kondratenko I, Körholz J, Krüger R, Jeziorski E, Levy R, Le Guenno G, Lefevre G, Lougaris V, Marzollo A, Mahlaoui N, Malphettes M, Meinhardt A, Merlin E, Meyts I, Milota T, Moreira F, Moshous D, Mukhina A, Neth O, Neubert J, Neven B, Nieters A, Nove-Josserand R, Oksenhendler E, Ozen A, Olbrich P, Perlat A, Pac M, Schmid JP, Pacillo L, Parra-Martinez A, Paschenko O, Pellier I, Sefer AP, Plebani A, Plantaz D, Prader S, Raffray L, Ritterbusch H, Riviere JG, Rivalta B, Rusch S, Sakovich I, Savic S, Scheible R, Schleinitz N, Schuetz C, Schulz A, Sediva A, Semeraro M, Sharapova SO, Shcherbina A, Slatter MA, Sogkas G, Soler-Palacin P, Speckmann C, Stephan JL, Suarez F, Tommasini A, Trück J, Uhlmann A, van Aerde KJ, van Montfrans J, von Bernuth H, Warnatz K, Williams T, Worth AJJ, Ip W, Picard C, Catherinot E, Nademi Z, Grimbacher B, Forbes Satter LR, Kracker S, Chandra A, Condliffe AM, and Ehl S more...
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- Humans, Phosphatidylinositol 3-Kinases genetics, Class I Phosphatidylinositol 3-Kinases, CTLA-4 Antigen genetics, Mutation, Registries, Phosphatidylinositol 3-Kinase genetics, Primary Immunodeficiency Diseases genetics
- Abstract
Background: Activated phosphoinositide-3-kinase δ syndrome (APDS) is an inborn error of immunity (IEI) with infection susceptibility and immune dysregulation, clinically overlapping with other conditions. Management depends on disease evolution, but predictors of severe disease are lacking., Objectives: This study sought to report the extended spectrum of disease manifestations in APDS1 versus APDS2; compare these to CTLA4 deficiency, NFKB1 deficiency, and STAT3 gain-of-function (GOF) disease; and identify predictors of severity in APDS., Methods: Data was collected from the ESID (European Society for Immunodeficiencies)-APDS registry and was compared with published cohorts of the other IEIs., Results: The analysis of 170 patients with APDS outlines high penetrance and early onset of APDS compared to the other IEIs. The large clinical heterogeneity even in individuals with the same PIK3CD variant E1021K illustrates how poorly the genotype predicts the disease phenotype and course. The high clinical overlap between APDS and the other investigated IEIs suggests relevant pathophysiological convergence of the affected pathways. Preferentially affected organ systems indicate specific pathophysiology: bronchiectasis is typical of APDS1; interstitial lung disease and enteropathy are more common in STAT3 GOF and CTLA4 deficiency. Endocrinopathies are most frequent in STAT3 GOF, but growth impairment is also common, particularly in APDS2. Early clinical presentation is a risk factor for severe disease in APDS., Conclusions: APDS illustrates how a single genetic variant can result in a diverse autoimmune-lymphoproliferative phenotype. Overlap with other IEIs is substantial. Some specific features distinguish APDS1 from APDS2. Early onset is a risk factor for severe disease course calling for specific treatment studies in younger patients., (Copyright © 2023 American Academy of Allergy, Asthma & Immunology. All rights reserved.) more...
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- 2023
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4. Homozygous DBF4 mutation as a cause of severe congenital neutropenia.
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Willemsen M, Barber JS, Nieuwenhove EV, Staels F, Gerbaux M, Neumann J, Prezzemolo T, Pasciuto E, Lagou V, Boeckx N, Filtjens J, De Visscher A, Matthys P, Schrijvers R, Tousseyn T, O'Driscoll M, Bucciol G, Schlenner S, Meyts I, Humblet-Baron S, and Liston A more...
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- Humans, Protein Serine-Threonine Kinases genetics, Mutation, Phosphorylation, Cell Cycle Proteins genetics, Saccharomyces cerevisiae Proteins genetics, Saccharomyces cerevisiae Proteins metabolism
- Abstract
Background: Severe congenital neutropenia presents with recurrent infections early in life as a result of arrested granulopoiesis. Multiple genetic defects are known to block granulocyte differentiation; however, a genetic cause remains unknown in approximately 40% of cases., Objective: We aimed to characterize a patient with severe congenital neutropenia and syndromic features without a genetic diagnosis., Methods: Whole exome sequencing results were validated using flow cytometry, Western blotting, coimmunoprecipitation, quantitative PCR, cell cycle and proliferation analysis of lymphocytes and fibroblasts and granulocytic differentiation of primary CD34
+ and HL-60 cells., Results: We identified a homozygous missense mutation in DBF4 in a patient with mild extra-uterine growth retardation, facial dysmorphism and severe congenital neutropenia. DBF4 is the regulatory subunit of the CDC7 kinase, together known as DBF4-dependent kinase (DDK), the complex essential for DNA replication initiation. The DBF4 variant demonstrated impaired ability to bind CDC7, resulting in decreased DDK-mediated phosphorylation, defective S-phase entry and progression and impaired differentiation of granulocytes associated with activation of the p53-p21 pathway. The introduction of wild-type DBF4 into patient CD34+ cells rescued the promyelocyte differentiation arrest., Conclusion: Hypomorphic DBF4 mutation causes autosomal-recessive severe congenital neutropenia with syndromic features., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.) more...- Published
- 2023
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5. Inherited and acquired errors of type I interferon immunity govern susceptibility to COVID-19 and multisystem inflammatory syndrome in children.
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Bucciol G and Meyts I
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- Child, Male, Young Adult, Humans, SARS-CoV-2, Post-Acute COVID-19 Syndrome, COVID-19, Interferon Type I
- Abstract
Since the beginning of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)/coronavirus disease 2019 (COVID-19) pandemic, global sequencing efforts have led in the field of inborn errors of immunity, and inspired particularly by previous research on life-threatening influenza, they have revealed that known and novel inborn errors affecting type I interferon immunity underlie critical COVID-19 in up to 5% of cases. In addition, neutralizing autoantibodies against type I interferons have been identified in up to 20% of patients with critical COVID-19 who are older than 80 years and 20% of fatal cases, with a higher prevalence in men and individuals older than 70 years. Also, inborn errors impairing regulation of type I interferon responses and RNA degradation have been found as causes of multisystem inflammatory syndrome in children, a life-threatening hyperinflammatory condition complicating otherwise mild initial SARS-CoV-2 infection in children and young adults. Better understanding of these immunologic mechanisms can aid in designing treatments for severe COVID-19, multisystem inflammatory syndrome in children, long COVID, and neuro-COVID., (Copyright © 2023. Published by Elsevier Inc.) more...
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- 2023
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6. DNA replication-associated inborn errors of immunity.
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Willemsen M, Staels F, Gerbaux M, Neumann J, Schrijvers R, Meyts I, Humblet-Baron S, and Liston A
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- Humans, Leukocytes, DNA Damage, Mutation, Immune System Diseases, Genetic Diseases, Inborn
- Abstract
Inborn errors of immunity are a heterogeneous group of monogenic immunologic disorders caused by mutations in genes with critical roles in the development, maintenance, or function of the immune system. The genetic basis is frequently a mutation in a gene with restricted expression and/or function in immune cells, leading to an immune disorder. Several classes of inborn errors of immunity, however, result from mutation in genes that are ubiquitously expressed. Despite the genes participating in cellular processes conserved between cell types, immune cells are disproportionally affected, leading to inborn errors of immunity. Mutations in DNA replication, DNA repair, or DNA damage response factors can result in monogenic human disease, some of which are classified as inborn errors of immunity. Genetic defects in the DNA repair machinery are a well-known cause of T
- B- NK+ severe combined immunodeficiency. An emerging class of inborn errors of immunity is those caused by mutations in DNA replication factors. Considerable heterogeneity exists within the DNA replication-associated inborn errors of immunity, with diverse immunologic defects and clinical manifestations observed. These differences are suggestive for differential sensitivity of certain leukocyte subsets to deficiencies in specific DNA replication factors. Here, we provide an overview of DNA replication-associated inborn errors of immunity and discuss the emerging mechanistic insights that can explain the observed immunologic heterogeneity., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.) more...- Published
- 2023
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7. Coronavirus disease 2019 in patients with inborn errors of immunity: An international study.
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Meyts I, Bucciol G, Quinti I, Neven B, Fischer A, Seoane E, Lopez-Granados E, Gianelli C, Robles-Marhuenda A, Jeandel PY, Paillard C, Sankaran VG, Demirdag YY, Lougaris V, Aiuti A, Plebani A, Milito C, Dalm VA, Guevara-Hoyer K, Sánchez-Ramón S, Bezrodnik L, Barzaghi F, Gonzalez-Granado LI, Hayman GR, Uzel G, Mendonça LO, Agostini C, Spadaro G, Badolato R, Soresina A, Vermeulen F, Bosteels C, Lambrecht BN, Keller M, Mustillo PJ, Abraham RS, Gupta S, Ozen A, Karakoc-Aydiner E, Baris S, Freeman AF, Yamazaki-Nakashimada M, Scheffler-Mendoza S, Espinosa-Padilla S, Gennery AR, Jolles S, Espinosa Y, Poli MC, Fieschi C, Hauck F, Cunningham-Rundles C, Mahlaoui N, Warnatz K, Sullivan KE, and Tangye SG more...
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- Adolescent, Adult, Aged, Child, Child, Preschool, Female, Humans, Infant, Infant, Newborn, Male, Middle Aged, Retrospective Studies, Risk Factors, Severity of Illness Index, Young Adult, COVID-19 epidemiology, Genetic Diseases, Inborn epidemiology, Immunologic Deficiency Syndromes epidemiology, SARS-CoV-2
- Abstract
Background: There is uncertainty about the impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in individuals with rare inborn errors of immunity (IEI), a population at risk of developing severe coronavirus disease 2019. This is relevant not only for these patients but also for the general population, because studies of IEIs can unveil key requirements for host defense., Objective: We sought to describe the presentation, manifestations, and outcome of SARS-CoV-2 infection in IEI to inform physicians and enhance understanding of host defense against SARS-CoV-2., Methods: An invitation to participate in a retrospective study was distributed globally to scientific, medical, and patient societies involved in the care and advocacy for patients with IEI., Results: We gathered information on 94 patients with IEI with SARS-CoV-2 infection. Their median age was 25 to 34 years. Fifty-three patients (56%) suffered from primary antibody deficiency, 9 (9.6%) had immune dysregulation syndrome, 6 (6.4%) a phagocyte defect, 7 (7.4%) an autoinflammatory disorder, 14 (15%) a combined immunodeficiency, 3 (3%) an innate immune defect, and 2 (2%) bone marrow failure. Ten were asymptomatic, 25 were treated as outpatients, 28 required admission without intensive care or ventilation, 13 required noninvasive ventilation or oxygen administration, 18 were admitted to intensive care units, 12 required invasive ventilation, and 3 required extracorporeal membrane oxygenation. Nine patients (7 adults and 2 children) died., Conclusions: This study demonstrates that (1) more than 30% of patients with IEI had mild coronavirus disease 2019 (COVID-19) and (2) risk factors predisposing to severe disease/mortality in the general population also seemed to affect patients with IEI, including more younger patients. Further studies will identify pathways that are associated with increased risk of severe disease and are nonredundant or redundant for protection against SARS-CoV-2., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.) more...
- Published
- 2021
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8. Cutaneous barrier leakage and gut inflammation drive skin disease in Omenn syndrome.
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Rigoni R, Fontana E, Dobbs K, Marrella V, Taverniti V, Maina V, Facoetti A, D'Amico G, Al-Herz W, Cruz-Munoz ME, Schuetz C, Gennery AR, Garabedian EK, Giliani S, Draper D, Dbaibo G, Geha RS, Meyts I, Tousseyn T, Neven B, Moshous D, Fischer A, Schulz A, Finocchi A, Kuhns DB, Fink DL, Lionakis MS, Swamydas M, Guglielmetti S, Alejo J, Myles IA, Pittaluga S, Notarangelo LD, Villa A, and Cassani B more...
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- Animals, Cohort Studies, DNA-Binding Proteins genetics, Disease Models, Animal, Gastrointestinal Microbiome, Humans, Lymphocyte Activation, Mice, Mice, Inbred C57BL, Receptors, CCR4 metabolism, Dermatitis immunology, Inflammation immunology, Intestines immunology, Severe Combined Immunodeficiency immunology, Skin pathology, Th1 Cells immunology, Tight Junctions pathology
- Abstract
Background: Severe early-onset erythroderma and gut inflammation, with massive tissue infiltration of oligoclonal activated T cells are the hallmark of Omenn syndrome (OS)., Objective: The impact of altered gut homeostasis in the cutaneous manifestations of OS remains to be clarified., Methods: We analyzed a cohort of 15 patients with OS and the 129Sv/C57BL/6 knock-in Rag2
R229Q/R229Q (Rag2R229Q ) mouse model. Homing phenotypes of circulating lymphocytes were analyzed by flow cytometry. Inflammatory cytokines and chemokines were examined in the sera by ELISA and in skin biopsies by immunohistochemistry and in situ RNA hybridization. Experimental colitis was induced in mice by dextran sulfate sodium salt., Results: We show that memory/activated T cells from patients with OS and from the Rag2R229Q mouse model of OS abundantly express the skin homing receptors cutaneous lymphocyte associated antigen and CCR4 (Ccr4), associated with high levels of chemokine C-C motif ligands 17 and 22. Serum levels of LPS are also elevated. A broad Th 1/Th 2/Th 17 inflammatory signature is detected in the periphery and in the skin. Increased Tlr4 expression in the skin of Rag2R229Q mice is associated with enhanced cutaneous inflammation on local and systemic administration of LPS. Likewise, boosting colitis in Rag2R229Q mice results in increased frequency of Ccr4+ splenic T cells and worsening of skin inflammation, as indicated by epidermal thickening, enhanced epithelial cell activation, and dermal infiltration by Th 1 effector T cells., Conclusions: These results support the existence of an interplay between gut and skin that can sustain skin inflammation in OS., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.) more...- Published
- 2020
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9. Defective Sec61α1 underlies a novel cause of autosomal dominant severe congenital neutropenia.
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Van Nieuwenhove E, Barber JS, Neumann J, Smeets E, Willemsen M, Pasciuto E, Prezzemolo T, Lagou V, Seldeslachts L, Malengier-Devlies B, Metzemaekers M, Haßdenteufel S, Kerstens A, van der Kant R, Rousseau F, Schymkowitz J, Di Marino D, Lang S, Zimmermann R, Schlenner S, Munck S, Proost P, Matthys P, Devalck C, Boeckx N, Claessens F, Wouters C, Humblet-Baron S, Meyts I, and Liston A more...
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- Antigens, CD34 metabolism, Chromosome Disorders, Female, Genes, Dominant, HL-60 Cells, Humans, Neutropenia genetics, Pedigree, Single-Cell Analysis, Unfolded Protein Response genetics, Exome Sequencing, Young Adult, Congenital Bone Marrow Failure Syndromes genetics, Mutation genetics, Neutropenia congenital, Neutrophils physiology, SEC Translocation Channels genetics
- Abstract
Background: The molecular cause of severe congenital neutropenia (SCN) is unknown in 30% to 50% of patients. SEC61A1 encodes the α-subunit of the Sec61 complex, which governs endoplasmic reticulum protein transport and passive calcium leakage. Recently, mutations in SEC61A1 were reported to be pathogenic in common variable immunodeficiency and glomerulocystic kidney disease., Objective: Our aim was to expand the spectrum of SEC61A1-mediated disease to include autosomal dominant SCN., Methods: Whole exome sequencing findings were validated, and reported mutations were compared by Western blotting, Ca2
+ flux assays, differentiation of transduced HL-60 cells, in vitro differentiation of primary CD34 cells, quantitative PCR for unfolded protein response (UPR) genes, and single-cell RNA sequencing on whole bone marrow., Results: We identified a novel de novo missense mutation in SEC61A1 (c.A275G;p.Q92R) in a patient with SCN who was born to nonconsanguineous Belgian parents. The mutation results in diminished protein expression, disturbed protein translocation, and an increase in calcium leakage from the endoplasmic reticulum. In vitro differentiation of CD34+ cells recapitulated the patient's clinical arrest in granulopoiesis. The impact of Q92R-Sec61α1 on neutrophil maturation was validated by using HL-60 cells, in which transduction reduced differentiation into CD11b+ CD16+ cells. A potential mechanism for this defect is the uncontrolled initiation of the unfolded protein stress response, with single-cell analysis of primary bone marrow revealing perturbed UPR in myeloid precursors and in vitro differentiation of primary CD34+ cells revealing upregulation of CCAAT/enhancer-binding protein homologous protein and immunoglobulin heavy chain binding protein UPR-response genes., Conclusion: Specific mutations in SEC61A1 cause SCN through dysregulation of the UPR., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.) more...- Published
- 2020
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10. Long-term outcome of LRBA deficiency in 76 patients after various treatment modalities as evaluated by the immune deficiency and dysregulation activity (IDDA) score.
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Tesch VK, Abolhassani H, Shadur B, Zobel J, Mareika Y, Sharapova S, Karakoc-Aydiner E, Rivière JG, Garcia-Prat M, Moes N, Haerynck F, Gonzales-Granado LI, Santos Pérez JL, Mukhina A, Shcherbina A, Aghamohammadi A, Hammarström L, Dogu F, Haskologlu S, İkincioğulları AI, Köstel Bal S, Baris S, Kilic SS, Karaca NE, Kutukculer N, Girschick H, Kolios A, Keles S, Uygun V, Stepensky P, Worth A, van Montfrans JM, Peters AMJ, Meyts I, Adeli M, Marzollo A, Padem N, Khojah AM, Chavoshzadeh Z, Avbelj Stefanija M, Bakhtiar S, Florkin B, Meeths M, Gamez L, Grimbacher B, Seppänen MRJ, Lankester A, Gennery AR, and Seidel MG more...
- Subjects
- Adolescent, Adult, Aged, Child, Child, Preschool, Female, Humans, Immunologic Deficiency Syndromes mortality, Male, Middle Aged, Survival Analysis, Treatment Outcome, Young Adult, Adaptor Proteins, Signal Transducing deficiency, Hematopoietic Stem Cell Transplantation, Immunologic Deficiency Syndromes therapy
- Abstract
Background: Recent findings strongly support hematopoietic stem cell transplantation (HSCT) in patients with severe presentation of LPS-responsive beige-like anchor protein (LRBA) deficiency, but long-term follow-up and survival data beyond previous patient reports or meta-reviews are scarce for those patients who do not receive a transplant., Objective: This international retrospective study was conducted to elucidate the longitudinal clinical course of patients with LRBA deficiency who do and do not receive a transplant., Method: We assessed disease burden and treatment responses with a specially developed immune deficiency and dysregulation activity score, reflecting the sum and severity of organ involvement and infections, days of hospitalization, supportive care requirements, and performance indices., Results: Of 76 patients with LRBA deficiency from 29 centers (median follow-up, 10 years; range, 1-52), 24 underwent HSCT from 2005 to 2019. The overall survival rate after HSCT (median follow-up, 20 months) was 70.8% (17 of 24 patients); all deaths were due to nonspecific, early, transplant-related mortality. Currently, 82.7% of patients who did not receive a transplant (43 of 52; age range, 3-69 years) are alive. Of 17 HSCT survivors, 7 are in complete remission and 5 are in good partial remission without treatment (together, 12 of 17 [70.6%]). In contrast, only 5 of 43 patients who did not receive a transplant (11.6%) are without immunosuppression. Immune deficiency and dysregulation activity scores were significantly lower in patients who survived HSCT than in those receiving conventional treatment (P = .005) or in patients who received abatacept or sirolimus as compared with other therapies, and in patients with residual LRBA expression. Higher disease burden, longer duration before HSCT, and lung involvement were associated with poor outcome., Conclusion: The lifelong disease activity, implying a need for immunosuppression and risk of malignancy, must be weighed against the risks of HSCT., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.) more...
- Published
- 2020
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11. Activating mutations in PIK3CD disrupt the differentiation and function of human and murine CD4 + T cells.
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Bier J, Rao G, Payne K, Brigden H, French E, Pelham SJ, Lau A, Lenthall H, Edwards ESJ, Smart JM, Cole TS, Choo S, Joshi AY, Abraham RS, O'Sullivan M, Boztug K, Meyts I, Gray PE, Berglund LJ, Hsu P, Wong M, Holland SM, Notarangelo LD, Uzel G, Ma CS, Brink R, Tangye SG, and Deenick EK more...
- Subjects
- Animals, Cytokines metabolism, Gain of Function Mutation, Humans, Mice, Phenotype, CD4-Positive T-Lymphocytes metabolism, Cell Differentiation, Phosphatidylinositol 3-Kinases genetics
- Abstract
Background: Gain-of-function (GOF) mutations in PIK3CD cause a primary immunodeficiency characterized by recurrent respiratory tract infections, susceptibility to herpesvirus infections, and impaired antibody responses. Previous work revealed defects in CD8
+ T and B cells that contribute to this clinical phenotype, but less is understood about the role of CD4+ T cells in disease pathogenesis., Objective: We sought to dissect the effects of increased phosphoinositide 3-kinase (PI3K) signaling on CD4+ T-cell function., Methods: We performed detailed ex vivo, in vivo, and in vitro phenotypic and functional analyses of patients' CD4+ T cells and a novel murine disease model caused by overactive PI3K signaling., Results: PI3K overactivation caused substantial increases in numbers of memory and follicular helper T (TFH ) cells and dramatic changes in cytokine production in both patients and mice. Furthermore, PIK3CD GOF human TFH cells had dysregulated phenotype and function characterized by increased programmed cell death protein 1, CXCR3, and IFN-γ expression, the phenotype of a TFH cell subset with impaired B-helper function. This was confirmed in vivo in which Pik3cd GOF CD4+ T cells also acquired an aberrant TFH phenotype and provided poor help to support germinal center reactions and humoral immune responses by antigen-specific wild-type B cells. The increase in numbers of both memory and TFH cells was largely CD4+ T-cell extrinsic, whereas changes in cytokine production and TFH cell function were cell intrinsic., Conclusion: Our studies reveal that CD4+ T cells with overactive PI3K have aberrant activation and differentiation, thereby providing mechanistic insight into dysfunctional antibody responses in patients with PIK3CD GOF mutations., (Copyright © 2019 American Academy of Allergy, Asthma & Immunology. All rights reserved.) more...- Published
- 2019
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12. Hematopoietic stem cell transplantation for CD40 ligand deficiency: Results from an EBMT/ESID-IEWP-SCETIDE-PIDTC study.
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Ferrua F, Galimberti S, Courteille V, Slatter MA, Booth C, Moshous D, Neven B, Blanche S, Cavazzana M, Laberko A, Shcherbina A, Balashov D, Soncini E, Porta F, Al-Mousa H, Al-Saud B, Al-Dhekri H, Arnaout R, Formankova R, Bertrand Y, Lange A, Smart J, Wolska-Kusnierz B, Aquino VM, Dvorak CC, Fasth A, Fouyssac F, Heilmann C, Hoenig M, Schuetz C, Kelečić J, Bredius RGM, Lankester AC, Lindemans CA, Suarez F, Sullivan KE, Albert MH, Kałwak K, Barlogis V, Bhatia M, Bordon V, Czogala W, Alonso L, Dogu F, Gozdzik J, Ikinciogullari A, Kriván G, Ljungman P, Meyts I, Mustillo P, Smith AR, Speckmann C, Sundin M, Keogh SJ, Shaw PJ, Boelens JJ, Schulz AS, Sedlacek P, Veys P, Mahlaoui N, Janda A, Davies EG, Fischer A, Cowan MJ, and Gennery AR more...
- Subjects
- Child, Child, Preschool, Humans, Infant, Infant, Newborn, Treatment Outcome, X-Linked Combined Immunodeficiency Diseases mortality, CD40 Ligand deficiency, Hematopoietic Stem Cell Transplantation, X-Linked Combined Immunodeficiency Diseases therapy
- Abstract
Background: CD40 ligand (CD40L) deficiency, an X-linked primary immunodeficiency, causes recurrent sinopulmonary, Pneumocystis and Cryptosporidium species infections. Long-term survival with supportive therapy is poor. Currently, the only curative treatment is hematopoietic stem cell transplantation (HSCT)., Objective: We performed an international collaborative study to improve patients' management, aiming to individualize risk factors and determine optimal HSCT characteristics., Methods: We retrospectively collected data on 130 patients who underwent HSCT for CD40L deficiency between 1993-2015. We analyzed outcome and variables' relevance with respect to survival and cure., Results: Overall survival (OS), event-free survival (EFS), and disease-free survival (DFS) were 78.2%, 58.1%, and 72.3% 5 years after HSCT. Results were better in transplantations performed in 2000 or later and in children less than 10 years old at the time of HSCT. Pre-existing organ damage negatively influenced outcome. Sclerosing cholangitis was the most important risk factor. After 2000, superior OS was achieved with matched donors. Use of myeloablative regimens and HSCT at 2 years or less from diagnosis associated with higher OS and DFS. EFS was best with matched sibling donors, myeloablative conditioning (MAC), and bone marrow-derived stem cells. Most rejections occurred after reduced-intensity or nonmyeloablative conditioning, which associated with poor donor cell engraftment. Mortality occurred mainly early after HSCT, predominantly from infections. Among survivors who ceased immunoglobulin replacement, T-lymphocyte chimerism was 50% or greater donor in 85.2%., Conclusion: HSCT is curative in patients with CD40L deficiency, with improved outcome if performed before organ damage development. MAC is associated with better OS, EFS, and DFS. Prospective studies are required to compare the risks of HSCT with those of lifelong supportive therapy., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.) more...
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- 2019
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13. Combined liver and hematopoietic stem cell transplantation in patients with X-linked hyper-IgM syndrome.
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Bucciol G, Nicholas SK, Calvo PL, Cant A, Edgar JDM, Español T, Ferrua F, Galicchio M, Gennery AR, Hadzic N, Hanson IC, Kusminsky G, Lange A, Lanternier F, Mahlaoui N, Moshous D, Nademi Z, Neven B, Oleastro M, Porta F, Quarello P, Silva M, Slatter MA, Soncini E, Stefanowicz M, Tandoi F, Teisseyre M, Torgerson TR, Veys P, Weinacht KG, Wolska-Kuśnierz B, Pirenne J, de la Morena MT, and Meyts I more...
- Subjects
- Adolescent, Adult, Anti-Bacterial Agents therapeutic use, Child, Cholangitis, Sclerosing genetics, Fatal Outcome, Humans, Hyper-IgM Immunodeficiency Syndrome genetics, Immunoglobulins therapeutic use, Lung Diseases genetics, Lung Diseases therapy, Young Adult, Cholangitis, Sclerosing therapy, Hematopoietic Stem Cell Transplantation, Hyper-IgM Immunodeficiency Syndrome therapy, Liver Transplantation
- Published
- 2019
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14. Lessons learned from the study of human inborn errors of innate immunity.
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Bucciol G, Moens L, Bosch B, Bossuyt X, Casanova JL, Puel A, and Meyts I
- Subjects
- Animals, Communicable Diseases immunology, Humans, Interferons metabolism, NF-kappa B genetics, Phagocytosis, Signal Transduction, Toll-Like Receptors genetics, Communicable Diseases genetics, Genetic Diseases, Inborn immunology, Immunity, Innate genetics, Leukocytes physiology, Mutation genetics
- Abstract
Innate immunity contributes to host defense through all cell types and relies on their shared germline genetic background, whereas adaptive immunity operates through only 3 main cell types, αβ T cells, γδ T cells, and B cells, and relies on their somatic genetic diversification of antigen-specific responses. Human inborn errors of innate immunity often underlie infectious diseases. The range and nature of infections depend on the mutated gene, the deleteriousness of the mutation, and other ill-defined factors. Most known inborn errors of innate immunity to infection disrupt the development or function of leukocytes other than T and B cells, but a growing number of inborn errors affect cells other than circulating and tissue leukocytes. Here we review inborn errors of innate immunity that have been recently discovered or clarified. We highlight the immunologic implications of these errors., (Copyright © 2018 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.) more...
- Published
- 2019
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15. Activating PIK3CD mutations impair human cytotoxic lymphocyte differentiation and function and EBV immunity.
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Edwards ESJ, Bier J, Cole TS, Wong M, Hsu P, Berglund LJ, Boztug K, Lau A, Gostick E, Price DA, O'Sullivan M, Meyts I, Choo S, Gray P, Holland SM, Deenick EK, Uzel G, and Tangye SG
- Subjects
- Adolescent, Adult, Aged, B-Lymphocytes immunology, CD8-Positive T-Lymphocytes pathology, Cell Differentiation genetics, Cellular Senescence genetics, Cellular Senescence immunology, Child, Child, Preschool, Genetic Diseases, Inborn genetics, Genetic Diseases, Inborn pathology, Humans, Immunologic Surveillance genetics, Killer Cells, Natural pathology, Male, Middle Aged, CD8-Positive T-Lymphocytes immunology, Cell Differentiation immunology, Class I Phosphatidylinositol 3-Kinases genetics, Class I Phosphatidylinositol 3-Kinases immunology, Epstein-Barr Virus Infections genetics, Epstein-Barr Virus Infections immunology, Epstein-Barr Virus Infections pathology, Gain of Function Mutation, Genetic Diseases, Inborn immunology, Herpesvirus 4, Human immunology, Killer Cells, Natural immunology
- Abstract
Background: Germline gain-of function (GOF) mutations in PIK3CD, encoding the catalytic p110δ subunit of phosphoinositide 3-kinase (PI3K), result in hyperactivation of the PI3K-AKT-mechanistic target of rapamycin pathway and underlie a novel inborn error of immunity. Affected subjects exhibit perturbed humoral and cellular immunity, manifesting as recurrent infections, autoimmunity, hepatosplenomegaly, uncontrolled EBV and/or cytomegalovirus infection, and increased incidence of B-cell lymphoproliferation, lymphoma, or both. Mechanisms underlying disease pathogenesis remain unknown., Objective: Understanding the cellular and molecular mechanisms underpinning inefficient surveillance of EBV-infected B cells is required to understand disease in patients with PIK3CD GOF mutations, identify key molecules required for cell-mediated immunity against EBV, and develop immunotherapeutic interventions for the treatment of this and other EBV-opathies., Methods: We studied the consequences of PIK3CD GOF mutations on the generation, differentiation, and function of CD8
+ T cells and natural killer (NK) cells, which are implicated in host defense against infection with herpesviruses, including EBV., Results: PIK3CD GOF total and EBV-specific CD8+ T cells were skewed toward an effector phenotype, with exaggerated expression of markers associated with premature immunosenescence/exhaustion and increased susceptibility to reactivation-induced cell death. These findings were recapitulated in a novel mouse model of PI3K GOF mutations. NK cells in patients with PIK3CD GOF mutations also exhibited perturbed expression of differentiation-associated molecules. Both CD8+ T and NK cells had reduced capacity to kill EBV-infected B cells. PIK3CD GOF B cells had increased expression of CD48, programmed death ligand 1/2, and CD70., Conclusions: PIK3CD GOF mutations aberrantly induce exhaustion, senescence, or both and impair cytotoxicity of CD8+ T and NK cells. These defects might contribute to clinical features of affected subjects, such as impaired immunity to herpesviruses and tumor surveillance., (Copyright © 2018 American Academy of Allergy, Asthma & Immunology. All rights reserved.) more...- Published
- 2019
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16. A kindred with mutant IKAROS and autoimmunity.
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Van Nieuwenhove E, Garcia-Perez JE, Helsen C, Rodriguez PD, van Schouwenburg PA, Dooley J, Schlenner S, van der Burg M, Verhoeyen E, Gijsbers R, Frietze S, Schjerven H, Meyts I, Claessens F, Humblet-Baron S, Wouters C, and Liston A more...
- Subjects
- Animals, Antibodies, Antinuclear metabolism, Autoimmunity genetics, Cell Differentiation genetics, Child, Female, Gene Frequency, Humans, Lupus Coagulation Inhibitor metabolism, Lupus Erythematosus, Systemic genetics, Mice, NIH 3T3 Cells, Pedigree, Polymorphism, Genetic, Sialic Acid Binding Ig-like Lectin 2 metabolism, B-Lymphocytes pathology, Ikaros Transcription Factor genetics, Lupus Erythematosus, Systemic diagnosis, Mutation genetics
- Published
- 2018
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17. Abnormal differentiation of B cells and megakaryocytes in patients with Roifman syndrome.
- Author
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Heremans J, Garcia-Perez JE, Turro E, Schlenner SM, Casteels I, Collin R, de Zegher F, Greene D, Humblet-Baron S, Lesage S, Matthys P, Penkett CJ, Put K, Stirrups K, Thys C, Van Geet C, Van Nieuwenhove E, Wouters C, Meyts I, Freson K, and Liston A more...
- Subjects
- Adolescent, Cell Differentiation, Cell Lineage, Cell Proliferation, Cells, Cultured, Child, Child, Preschool, Humans, Infant, Mitogen-Activated Protein Kinase 1 metabolism, Pedigree, Primary Immunodeficiency Diseases, Protein Splicing genetics, Signal Transduction genetics, Exome Sequencing, B-Lymphocytes physiology, Blood Platelets physiology, Cardiomyopathies genetics, Immunologic Deficiency Syndromes genetics, Megakaryocytes physiology, Mental Retardation, X-Linked genetics, Mitogen-Activated Protein Kinase 1 genetics, Osteochondrodysplasias genetics, Precursor Cells, B-Lymphoid physiology, RNA, Small Nuclear genetics, Retinal Diseases genetics
- Abstract
Background: Roifman syndrome is a rare inherited disorder characterized by spondyloepiphyseal dysplasia, growth retardation, cognitive delay, hypogammaglobulinemia, and, in some patients, thrombocytopenia. Compound heterozygous variants in the small nuclear RNA gene RNU4ATAC, which is necessary for U12-type intron splicing, were identified recently as driving Roifman syndrome., Objective: We studied 3 patients from 2 unrelated kindreds harboring compound heterozygous or homozygous stem II variants in RNU4ATAC to gain insight into the mechanisms behind this disorder., Methods: We systematically profiled the immunologic and hematologic compartments of the 3 patients with Roifman syndrome and performed RNA sequencing to unravel important splicing defects in both cell lineages., Results: The patients exhibited a dramatic reduction in B-cell numbers, with differentiation halted at the transitional B-cell stage. Despite abundant B-cell activating factor availability, development past this B-cell activating factor-dependent stage was crippled, with disturbed minor splicing of the critical mitogen-activated protein kinase 1 signaling component. In the hematologic compartment patients with Roifman syndrome demonstrated defects in megakaryocyte differentiation, with inadequate generation of proplatelets. Platelets from patients with Roifman syndrome were rounder, with increased tubulin and actin levels, and contained increased α-granule and dense granule markers. Significant minor intron retention in 354 megakaryocyte genes was observed, including DIAPH1 and HPS1, genes known to regulate platelet and dense granule formation, respectively., Conclusion: Together, our results provide novel molecular and cellular data toward understanding the immunologic and hematologic features of Roifman syndrome., (Copyright © 2018 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.) more...
- Published
- 2018
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18. Treatment of severe forms of LPS-responsive beige-like anchor protein deficiency with allogeneic hematopoietic stem cell transplantation.
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Seidel MG, Böhm K, Dogu F, Worth A, Thrasher A, Florkin B, İkincioğulları A, Peters A, Bakhtiar S, Meeths M, Stepensky P, Meyts I, Sharapova SO, Gámez-Díaz L, Hammarström L, Ehl S, Grimbacher B, and Gennery AR more...
- Subjects
- Allografts, Child, Child, Preschool, Common Variable Immunodeficiency pathology, Female, Humans, Infant, Male, Adaptor Proteins, Signal Transducing deficiency, Common Variable Immunodeficiency genetics, Common Variable Immunodeficiency immunology, Common Variable Immunodeficiency therapy, Hematopoietic Stem Cell Transplantation
- Published
- 2018
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- View/download PDF
19. Clinical characteristics of patients with low functional IL-6 production upon TLR/IL-1R stimulation.
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Frans G, Van der Werff Ten Bosch J, Moens L, Wuyts G, Schaballie H, Tuerlinckx D, De Bie M, Vermeulen F, Schrijvers R, Meert W, Hestand MS, Delanghe J, Vermeesch JR Ir, Meyts I, and Bossuyt X
- Subjects
- Bacterial Infections pathology, Female, Humans, Male, Bacterial Infections genetics, Bacterial Infections immunology, Interleukin-6 genetics, Interleukin-6 immunology, Receptors, Interleukin-1 Type I genetics, Receptors, Interleukin-1 Type I immunology, Toll-Like Receptors genetics, Toll-Like Receptors immunology
- Published
- 2018
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20. Disease-associated mutations identify a novel region in human STING necessary for the control of type I interferon signaling.
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Melki I, Rose Y, Uggenti C, Van Eyck L, Frémond ML, Kitabayashi N, Rice GI, Jenkinson EM, Boulai A, Jeremiah N, Gattorno M, Volpi S, Sacco O, Terheggen-Lagro SWJ, Tiddens HAWM, Meyts I, Morren MA, De Haes P, Wouters C, Legius E, Corveleyn A, Rieux-Laucat F, Bodemer C, Callebaut I, Rodero MP, and Crow YJ more...
- Subjects
- Adolescent, Adult, Amino Acid Substitution, Child, Female, HEK293 Cells, Humans, Interferon Type I metabolism, Male, Mutation, STAT1 Transcription Factor metabolism, Signal Transduction, Inflammation genetics, Interferon Type I genetics, Membrane Proteins genetics
- Abstract
Background: Gain-of-function mutations in transmembrane protein 173 (TMEM173) encoding stimulator of interferon genes (STING) underlie a recently described type I interferonopathy called STING-associated vasculopathy with onset in infancy (SAVI)., Objectives: We sought to define the molecular and cellular pathology relating to 3 individuals variably exhibiting the core features of the SAVI phenotype including systemic inflammation, destructive skin lesions, and interstitial lung disease., Methods: Genetic analysis, conformational studies, in vitro assays and ex vivo flow-cytometry were performed., Results: Molecular and in vitro data demonstrate that the pathology in these patients is due to amino acid substitutions at positions 206, 281, and 284 of the human STING protein. These mutations confer cGAMP-independent constitutive activation of type I interferon signaling through TBK1 (TANK-binding kinase), independent from the alternative STING pathway triggered by membrane fusion of enveloped RNA viruses. This constitutive activation was abrogated by ex vivo treatment with the janus kinase 1/2 inhibitor ruxolitinib., Conclusions: Structural analysis indicates that the 3 disease-associated mutations at positions 206, 281, and 284 of the STING protein define a novel cluster of amino acids with functional importance in the regulation of type I interferon signaling., (Copyright © 2016 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.) more...
- Published
- 2017
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21. A novel kindred with inherited STAT2 deficiency and severe viral illness.
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Moens L, Van Eyck L, Jochmans D, Mitera T, Frans G, Bossuyt X, Matthys P, Neyts J, Ciancanelli M, Zhang SY, Gijsbers R, Casanova JL, Boisson-Dupuis S, Meyts I, and Liston A
- Subjects
- Alleles, Female, Genotype, Humans, Male, Pedigree, Severity of Illness Index, Whole Genome Sequencing, Genetic Association Studies, Genetic Predisposition to Disease, STAT2 Transcription Factor deficiency, Virus Diseases diagnosis, Virus Diseases etiology
- Published
- 2017
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22. Long-term outcomes of 176 patients with X-linked hyper-IgM syndrome treated with or without hematopoietic cell transplantation.
- Author
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de la Morena MT, Leonard D, Torgerson TR, Cabral-Marques O, Slatter M, Aghamohammadi A, Chandra S, Murguia-Favela L, Bonilla FA, Kanariou M, Damrongwatanasuk R, Kuo CY, Dvorak CC, Meyts I, Chen K, Kobrynski L, Kapoor N, Richter D, DiGiovanni D, Dhalla F, Farmaki E, Speckmann C, Español T, Shcherbina A, Hanson IC, Litzman J, Routes JM, Wong M, Fuleihan R, Seneviratne SL, Small TN, Janda A, Bezrodnik L, Seger R, Raccio AG, Edgar JD, Chou J, Abbott JK, van Montfrans J, González-Granado LI, Bunin N, Kutukculer N, Gray P, Seminario G, Pasic S, Aquino V, Wysocki C, Abolhassani H, Dorsey M, Cunningham-Rundles C, Knutsen AP, Sleasman J, Costa Carvalho BT, Condino-Neto A, Grunebaum E, Chapel H, Ochs HD, Filipovich A, Cowan M, Gennery A, Cant A, Notarangelo LD, and Roifman CM more...
- Subjects
- Adolescent, Adult, Child, Child, Preschool, Cohort Studies, Female, Follow-Up Studies, Humans, Infant, Kaplan-Meier Estimate, Male, Middle Aged, Proportional Hazards Models, Retrospective Studies, Time, Young Adult, Hematopoietic Stem Cell Transplantation mortality, Hyper-IgM Immunodeficiency Syndrome mortality, Hyper-IgM Immunodeficiency Syndrome therapy
- Abstract
Background: X-linked hyper-IgM syndrome (XHIGM) is a primary immunodeficiency with high morbidity and mortality compared with those seen in healthy subjects. Hematopoietic cell transplantation (HCT) has been considered a curative therapy, but the procedure has inherent complications and might not be available for all patients., Objectives: We sought to collect data on the clinical presentation, treatment, and follow-up of a large sample of patients with XHIGM to (1) compare long-term overall survival and general well-being of patients treated with or without HCT along with clinical factors associated with mortality and (2) summarize clinical practice and risk factors in the subgroup of patients treated with HCT., Methods: Physicians caring for patients with primary immunodeficiency diseases were identified through the Jeffrey Modell Foundation, United States Immunodeficiency Network, Latin American Society for Immunodeficiency, and Primary Immune Deficiency Treatment Consortium. Data were collected with a Research Electronic Data Capture Web application. Survival from time of diagnosis or transplantation was estimated by using the Kaplan-Meier method compared with log-rank tests and modeled by using proportional hazards regression., Results: Twenty-eight clinical sites provided data on 189 patients given a diagnosis of XHIGM between 1964 and 2013; 176 had valid follow-up and vital status information. Sixty-seven (38%) patients received HCT. The average follow-up time was 8.5 ± 7.2 years (range, 0.1-36.2 years). No difference in overall survival was observed between patients treated with or without HCT (P = .671). However, risk associated with HCT decreased for diagnosis years 1987-1995; the hazard ratio was significantly less than 1 for diagnosis years 1995-1999. Liver disease was a significant predictor of overall survival (hazard ratio, 4.9; 95% confidence limits, 2.2-10.8; P < .001). Among survivors, those treated with HCT had higher median Karnofsky/Lansky scores than those treated without HCT (P < .001). Among patients receiving HCT, 27 (40%) had graft-versus-host disease, and most deaths occurred within 1 year of transplantation., Conclusion: No difference in survival was observed between patients treated with or without HCT across all diagnosis years (1964-2013). However, survivors treated with HCT experienced somewhat greater well-being, and hazards associated with HCT decreased, reaching levels of significantly less risk in the late 1990s. Among patients treated with HCT, treatment at an early age is associated with improved survival. Optimism remains guarded as additional evidence accumulates., (Copyright © 2016 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.) more...
- Published
- 2017
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23. Homozygous N-terminal missense mutation in TRNT1 leads to progressive B-cell immunodeficiency in adulthood.
- Author
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Frans G, Moens L, Schaballie H, Wuyts G, Liston A, Poesen K, Janssens A, Rice GI, Crow YJ, Meyts I, and Bossuyt X
- Subjects
- Disease Progression, Genetic Markers, Homozygote, Humans, Immunologic Deficiency Syndromes diagnosis, Immunologic Deficiency Syndromes immunology, Male, Young Adult, B-Lymphocytes immunology, Immunologic Deficiency Syndromes genetics, Mutation, Missense, Nucleotidyltransferases genetics
- Published
- 2017
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- View/download PDF
24. Successful hematopoietic stem cell transplantation for myelofibrosis in an adult with warts-hypogammaglobulinemia-immunodeficiency-myelokathexis syndrome.
- Author
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Moens L, Frans G, Bosch B, Bossuyt X, Verbinnen B, Poppe W, Boeckx N, Slatter M, Brusselmans C, Diaz G, Tousseyn T, Flipts H, Corveleyn A, Dierickx D, and Meyts I
- Subjects
- Adolescent, Agammaglobulinemia therapy, Female, Hematopoietic Stem Cell Transplantation methods, Humans, Neutropenia therapy, Primary Immunodeficiency Diseases, Primary Myelofibrosis therapy, Immunologic Deficiency Syndromes therapy, Warts therapy
- Published
- 2016
- Full Text
- View/download PDF
25. Exome and genome sequencing for inborn errors of immunity.
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Meyts I, Bosch B, Bolze A, Boisson B, Itan Y, Belkadi A, Pedergnana V, Moens L, Picard C, Cobat A, Bossuyt X, Abel L, and Casanova JL
- Subjects
- Genetic Variation, High-Throughput Nucleotide Sequencing, Humans, Exome genetics, Genetic Diseases, Inborn, Genome, Human genetics, Immunologic Deficiency Syndromes genetics
- Abstract
The advent of next-generation sequencing (NGS) in 2010 has transformed medicine, particularly the growing field of inborn errors of immunity. NGS has facilitated the discovery of novel disease-causing genes and the genetic diagnosis of patients with monogenic inborn errors of immunity. Whole-exome sequencing (WES) is presently the most cost-effective approach for research and diagnostics, although whole-genome sequencing offers several advantages. The scientific or diagnostic challenge consists in selecting 1 or 2 candidate variants among thousands of NGS calls. Variant- and gene-level computational methods, as well as immunologic hypotheses, can help narrow down this genome-wide search. The key to success is a well-informed genetic hypothesis on 3 key aspects: mode of inheritance, clinical penetrance, and genetic heterogeneity of the condition. This determines the search strategy and selection criteria for candidate alleles. Subsequent functional validation of the disease-causing effect of the candidate variant is critical. Even the most up-to-date dry lab cannot clinch this validation without a seasoned wet lab. The multifariousness of variations entails an experimental rigor even greater than traditional Sanger sequencing-based approaches in order not to assign a condition to an irrelevant variant. Finding the needle in the haystack takes patience, prudence, and discernment., (Copyright © 2016 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.) more...
- Published
- 2016
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26. A novel hypomorphic mutation in STIM1 results in a late-onset immunodeficiency.
- Author
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Schaballie H, Rodriguez R, Martin E, Moens L, Frans G, Lenoir C, Dutré J, Canioni D, Bossuyt X, Fischer A, Latour S, Meyts I, and Picard C
- Subjects
- Age of Onset, Bacterial Infections complications, Bacterial Infections immunology, Bacterial Infections pathology, Cell Proliferation, Child, Consanguinity, Female, Humans, Immunologic Deficiency Syndromes complications, Immunologic Deficiency Syndromes immunology, Immunologic Deficiency Syndromes pathology, Immunophenotyping, Male, Membrane Proteins immunology, Neoplasm Proteins immunology, Opportunistic Infections complications, Opportunistic Infections immunology, Opportunistic Infections pathology, Siblings, Stromal Interaction Molecule 1, T-Lymphocytes immunology, T-Lymphocytes pathology, Young Adult, Bacterial Infections genetics, Immunologic Deficiency Syndromes genetics, Membrane Proteins genetics, Mutation, Neoplasm Proteins genetics, Opportunistic Infections genetics
- Published
- 2015
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27. Multicenter experience in hematopoietic stem cell transplantation for serious complications of common variable immunodeficiency.
- Author
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Wehr C, Gennery AR, Lindemans C, Schulz A, Hoenig M, Marks R, Recher M, Gruhn B, Holbro A, Heijnen I, Meyer D, Grigoleit G, Einsele H, Baumann U, Witte T, Sykora KW, Goldacker S, Regairaz L, Aksoylar S, Ardeniz Ö, Zecca M, Zdziarski P, Meyts I, Matthes-Martin S, Imai K, Kamae C, Fielding A, Seneviratne S, Mahlaoui N, Slatter MA, Güngör T, Arkwright PD, van Montfrans J, Sullivan KE, Grimbacher B, Cant A, Peter HH, Finke J, Gaspar HB, Warnatz K, and Rizzi M more...
- Subjects
- Adolescent, Adult, Cause of Death, Child, Common Variable Immunodeficiency complications, Common Variable Immunodeficiency mortality, Female, Follow-Up Studies, Graft Survival, Graft vs Host Disease etiology, Graft vs Host Disease prevention & control, Humans, Male, Middle Aged, Retrospective Studies, Transplantation Conditioning, Treatment Outcome, Young Adult, Common Variable Immunodeficiency therapy, Hematopoietic Stem Cell Transplantation adverse effects, Hematopoietic Stem Cells
- Abstract
Background: Common variable immunodeficiency (CVID) is usually well controlled with immunoglobulin substitution and immunomodulatory drugs. A subgroup of patients has a complicated disease course with high mortality. For these patients, investigation of more invasive, potentially curative treatments, such as allogeneic hematopoietic stem cell transplantation (HSCT), is warranted., Objective: We sought to define the outcomes of HSCT for patients with CVID., Methods: Retrospective data were collected from 14 centers worldwide on patients with CVID receiving HSCT between 1993 and 2012., Results: Twenty-five patients with CVID, which was defined according to international criteria, aged 8 to 50 years at the time of transplantation were included in the study. The indication for HSCT was immunologic dysregulation in the majority of patients. The overall survival rate was 48%, and the survival rate for patients undergoing transplantation for lymphoma was 83%. The major causes of death were treatment-refractory graft-versus-host disease accompanied by poor immune reconstitution and infectious complications. Immunoglobulin substitution was stopped in 50% of surviving patients. In 92% of surviving patients, the condition constituting the indication for HSCT resolved., Conclusion: This multicenter study demonstrated that HSCT in patients with CVID was beneficial in most surviving patients; however, there was a high mortality associated with the procedure. Therefore this therapeutic approach should only be considered in carefully selected patients in whom there has been extensive characterization of the immunologic and/or genetic defect underlying the CVID diagnosis. Criteria for patient selection, refinement of the transplantation protocol, and timing are needed for an improved outcome., (Copyright © 2014 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.) more...
- Published
- 2015
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28. Hematopoietic stem cell transplantation rescues the immunologic phenotype and prevents vasculopathy in patients with adenosine deaminase 2 deficiency.
- Author
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Van Eyck L Jr, Hershfield MS, Pombal D, Kelly SJ, Ganson NJ, Moens L, Frans G, Schaballie H, De Hertogh G, Dooley J, Bossuyt X, Wouters C, Liston A, and Meyts I
- Subjects
- Adenosine Deaminase blood, Adenosine Deaminase genetics, Adenosine Deaminase immunology, Agammaglobulinemia blood, Agammaglobulinemia genetics, Agammaglobulinemia immunology, Child, Preschool, Humans, Infant, Intercellular Signaling Peptides and Proteins blood, Intercellular Signaling Peptides and Proteins genetics, Interleukin-6 blood, Lymphocyte Count, Male, Mutation, Phenotype, Severe Combined Immunodeficiency blood, Severe Combined Immunodeficiency genetics, Severe Combined Immunodeficiency immunology, Adenosine Deaminase deficiency, Agammaglobulinemia therapy, Hematopoietic Stem Cell Transplantation, Intercellular Signaling Peptides and Proteins deficiency, Severe Combined Immunodeficiency therapy
- Published
- 2015
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29. Gain-of-function mutations in signal transducer and activator of transcription 1 (STAT1): chronic mucocutaneous candidiasis accompanied by enamel defects and delayed dental shedding.
- Author
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Frans G, Moens L, Schaballie H, Van Eyck L, Borgers H, Wuyts M, Dillaerts D, Vermeulen E, Dooley J, Grimbacher B, Cant A, Declerck D, Peumans M, Renard M, De Boeck K, Hoffman I, François I, Liston A, Claessens F, Bossuyt X, and Meyts I more...
- Subjects
- Adolescent, Candidiasis, Chronic Mucocutaneous pathology, Humans, Male, Tooth Abnormalities pathology, Candidiasis, Chronic Mucocutaneous genetics, Dental Enamel abnormalities, Mutation, STAT1 Transcription Factor genetics, Tooth Abnormalities genetics
- Published
- 2014
- Full Text
- View/download PDF
30. Clinical picture and treatment of 2212 patients with common variable immunodeficiency.
- Author
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Gathmann B, Mahlaoui N, Gérard L, Oksenhendler E, Warnatz K, Schulze I, Kindle G, Kuijpers TW, van Beem RT, Guzman D, Workman S, Soler-Palacín P, De Gracia J, Witte T, Schmidt RE, Litzman J, Hlavackova E, Thon V, Borte M, Borte S, Kumararatne D, Feighery C, Longhurst H, Helbert M, Szaflarska A, Sediva A, Belohradsky BH, Jones A, Baumann U, Meyts I, Kutukculer N, Wågström P, Galal NM, Roesler J, Farmaki E, Zinovieva N, Ciznar P, Papadopoulou-Alataki E, Bienemann K, Velbri S, Panahloo Z, and Grimbacher B more...
- Subjects
- Adolescent, Adult, Age of Onset, Autoimmunity, Bronchiectasis pathology, Child, Child, Preschool, Common Variable Immunodeficiency drug therapy, Common Variable Immunodeficiency immunology, Common Variable Immunodeficiency mortality, Delayed Diagnosis, Europe, Female, Humans, Immunoglobulins, Intravenous therapeutic use, Lymphoproliferative Disorders drug therapy, Lymphoproliferative Disorders immunology, Lymphoproliferative Disorders mortality, Male, Pneumonia drug therapy, Pneumonia immunology, Pneumonia mortality, Retrospective Studies, Splenomegaly pathology, Survival Analysis, Common Variable Immunodeficiency complications, Lymphoproliferative Disorders complications, Pneumonia complications
- Abstract
Background: Common variable immunodeficiency (CVID) is an antibody deficiency with an equal sex distribution and a high variability in clinical presentation. The main features include respiratory tract infections and their associated complications, enteropathy, autoimmunity, and lymphoproliferative disorders., Objective: This study analyzes the clinical presentation, association between clinical features, and differences and effects of immunoglobulin treatment in Europe., Methods: Data on 2212 patients with CVID from 28 medical centers contributing to the European Society for Immunodeficiencies Database were analyzed retrospectively., Results: Early disease onset (<10 years) was very frequent in our cohort (33.7%), especially in male subjects (39.8%). Male subjects with early-onset CVID were more prone to pneumonia and less prone to other complications suggesting a distinct disease entity. The diagnostic delay of CVID ranges between 4 and 5 years in many countries and is particularly high in subjects with early-onset CVID. Enteropathy, autoimmunity, granulomas, and splenomegaly formed a set of interrelated features, whereas bronchiectasis was not associated with any other clinical feature. Patient survival in this cohort was associated with age at onset and age at diagnosis only. There were different treatment strategies in Europe, with considerable differences in immunoglobulin dosing, ranging from 130 up to 750 mg/kg/mo. Patients with very low trough levels of less than 4 g/L had poor clinical outcomes, whereas higher trough levels were associated with a reduced frequency of serious bacterial infections., Conclusion: Patients with CVID are being managed differently throughout Europe, affecting various outcome measures. Clinically, CVID is a truly variable antibody deficiency syndrome., (Copyright © 2014 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.) more...
- Published
- 2014
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31. Human CD20+CD43+CD27+CD5- B cells generate antibodies to capsular polysaccharides of Streptococcus pneumoniae.
- Author
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Verbinnen B, Covens K, Moens L, Meyts I, and Bossuyt X
- Subjects
- Adult, Antibodies, Bacterial biosynthesis, Antibody Specificity, Antigens, CD classification, Antigens, CD metabolism, Antigens, CD20 immunology, Antigens, CD20 metabolism, B-Lymphocytes classification, B-Lymphocytes metabolism, CD5 Antigens metabolism, Child, Preschool, Humans, Leukosialin immunology, Leukosialin metabolism, Polysaccharides, Bacterial immunology, Tumor Necrosis Factor Receptor Superfamily, Member 7 immunology, Tumor Necrosis Factor Receptor Superfamily, Member 7 metabolism, Antibodies, Bacterial blood, Antigens, CD immunology, B-Lymphocytes immunology, Bacterial Capsules immunology, CD5 Antigens immunology, Streptococcus pneumoniae immunology
- Published
- 2012
- Full Text
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32. Granulomatous inflammation in cartilage-hair hypoplasia: risks and benefits of anti-TNF-α mAbs.
- Author
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Moshous D, Meyts I, Fraitag S, Janssen CE, Debré M, Suarez F, Toelen J, De Boeck K, Roskams T, Deschildre A, Picard C, Bodemer C, Wouters C, and Fischer A
- Subjects
- Antibodies, Monoclonal adverse effects, Antibodies, Monoclonal immunology, Child, Child, Preschool, Female, Hair abnormalities, Hair immunology, Hair pathology, Hematopoietic Stem Cell Transplantation, Humans, Inflammation immunology, Inflammation pathology, Inflammation therapy, Leukoencephalopathy, Progressive Multifocal immunology, Leukoencephalopathy, Progressive Multifocal pathology, Leukoencephalopathy, Progressive Multifocal therapy, Male, Osteochondrodysplasias immunology, Osteochondrodysplasias pathology, Osteochondrodysplasias therapy, Primary Immunodeficiency Diseases, Retrospective Studies, Risk Factors, Transplantation, Homologous, Tumor Necrosis Factor-alpha immunology, Antibodies, Monoclonal administration & dosage, Dermatitis immunology, Dermatitis pathology, Dermatitis therapy, Granuloma immunology, Granuloma pathology, Granuloma therapy, Hirschsprung Disease immunology, Hirschsprung Disease pathology, Hirschsprung Disease therapy, Immunologic Deficiency Syndromes immunology, Immunologic Deficiency Syndromes pathology, Immunologic Deficiency Syndromes therapy, Osteochondrodysplasias congenital, Tumor Necrosis Factor-alpha antagonists & inhibitors
- Abstract
Background: Cartilage-hair hypoplasia (CHH) is a rare autosomal recessive disorder characterized by short-limbed skeletal dysplasia. Some patients also have defects in cell-mediated immunity and antibody production. Granulomatous inflammation has been described in patients with various forms of primary immunodeficiencies but has not been reported in patients with CHH., Objective: We sought to describe granulomatous inflammation as a novel feature in patients with CHH, assess associated immunodeficiency, and evaluate treatment options., Methods: In a retrospective observational study we collected clinical data on 21 patients with CHH to identify and further characterize patients with granulomatous inflammation., Results: Four unrelated patients with CHH (with variable degrees of combined immunodeficiency) had epithelioid cell granulomatous inflammation in the skin and visceral organs. Anti-TNF-α mAb therapy in 3 of these patients led to significant regression of granulomas. However, 1 treated patient had fatal progressive multifocal leukoencephalopathy caused by the JC polyomavirus. In 2 patients immune reconstitution after allogeneic hematopoietic stem cell transplantation led to the complete disappearance of granulomas., Conclusion: To the best of our knowledge, this is the first report of granulomatous inflammation in patients with CHH. Although TNF-α antagonists can effectively suppress granulomas, the risk of severe infectious complications limits their use in immunodeficient patients., (Copyright © 2011 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.) more...
- Published
- 2011
- Full Text
- View/download PDF
33. Age- and serotype-dependent antibody response to pneumococcal polysaccharides.
- Author
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Bossuyt X, Borgers H, Moens L, Verbinnen B, and Meyts I
- Subjects
- Age Factors, Antibodies, Bacterial blood, Humans, Infant, Antibodies, Bacterial immunology, Antibody Formation immunology, Pneumococcal Vaccines immunology, Polysaccharides, Bacterial immunology, Streptococcus pneumoniae immunology
- Published
- 2011
- Full Text
- View/download PDF
34. Determination of IgG subclasses: a need for standardization.
- Author
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Bossuyt X, Mariën G, Meyts I, Proesmans M, and De Boeck K
- Subjects
- Adolescent, Adult, Child, Female, Humans, Male, Reference Standards, Reference Values, Reproducibility of Results, Respiratory Tract Infections immunology, Enzyme-Linked Immunosorbent Assay standards, Immunoglobulin G blood, Isoantibodies blood
- Published
- 2005
- Full Text
- View/download PDF
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