235 results on '"Despina Moshous"'
Search Results
2. Sustained remission after haploidentical bone marrow transplantation in a child with refractory systemic juvenile idiopathic arthritis
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Guillaume Morelle, Martin Castelle, Graziella Pinto, Sylvain Breton, Matthieu Bendavid, Charlotte Boussard, Richard Mouy, Brigitte Bader-Meunier, Michaela Semeraro, Albert Faye, Marina Cavazzana, Bénédicte Neven, Stéphane Blanche, Pierre Quartier, and Despina Moshous
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Systemic juvenile idiopathic arthritis ,Still’s disease ,Allogenic hematopoietic stem cell transplantation ,Graft versus host disease ,Autoimmunity ,Pediatrics ,RJ1-570 ,Diseases of the musculoskeletal system ,RC925-935 - Abstract
Abstract Background Some patients with systemic juvenile idiopathic arthritis (SJIA) and severe, refractory disease achieved remission through intensive immunosuppressive treatment followed by autologous hematopoietic stem cell transplantation (HSCT). However, disease relapsed in most cases. More recently selected SJIA patients received allogenic HSCT from a HLA-identical sibling or a HLA matched unrelated donor. While most transplanted patients achieved sustained SJIA remission off-treatment, the procedure-related morbidity was high. Case report A girl presented SJIA with a severe disease course since the age of 15 months. She was refractory to the combination of methotrexate and steroids to anti-interleukin (IL)-1, then anti-IL-6, tumor necrosis factor alpha inhibitors, and thalidomide. Given the high disease burden and important treatment-related toxicity the indication for a haploidentical HSCT from her mother was validated, as no HLA matched donor was available. The patient received a T replete bone marrow graft at the age of 3.7 years. Conditioning regimen contained Rituximab, Alemtuzumab, Busulfan, and Fludarabine. Cyclophosphamide at D + 3 and + 4 post HSCT was used for graft-versus-host-disease prophylaxis, followed by Cyclosporin A and Mycophenolate Mofetil. Post HSCT complications included severe infections, grade 3 intestinal graft-versus-host-disease, autoimmune thyroiditis, and immune thrombocytopenia. Three years after HSCT, the child is alive and well, notwithstanding persistent hypothyroidy requiring substitution. Immune thrombocytopenia had resolved. Most importantly, SJIA was in complete remission, off immunosuppressive drugs. Conclusion Allogenic HSCT may be a therapeutic option, even with a HLA haplo-identical alternative donor, in patients with inflammatory diseases such as SJIA. Despite increased experience with this treatment, the risk of life-threatening complications restrains its indication to selected patients with severe, refractory disease.
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- 2021
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3. Bayesian Modeling Immune Reconstitution Apply to CD34+ Selected Stem Cell Transplantation for Severe Combined Immunodeficiency
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Jean-Sebastien Diana, Naïm Bouazza, Chloe Couzin, Martin Castelle, Alessandra Magnani, Elisa Magrin, Jeremie Rosain, Jean-Marc Treluyer, Capucine Picard, Despina Moshous, Stéphane Blanche, Bénédicte Neven, and Marina Cavazzana
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Bayesian prediction algorithm ,immune reconstitution ,severe combined immunodeficiency (SCID) ,hematopoietic stem cell transplantation ,CD34+ selection ,Pediatrics ,RJ1-570 - Abstract
Severe combined immunodeficiencies (SCIDs) correspond to the most severe form of primary immunodeficiency. Allogeneic hematopoietic stem cell transplantation (HSCT) and gene therapy are curative treatments, depending on the donor's availability and molecular diagnostics. A partially human leukocyte antigen (HLA)-compatible donor used has been developed for this specific HSCT indication in the absence of a matched donor. However, the CD34+ selected process induces prolonged post-transplant T-cell immunodeficiency. The aim here was to investigate a modeling approach to predict the time course and the extent of CD4+ T-cell immune reconstitution after CD34+ selected transplantation. We performed a Bayesian approach based on the age-related changes in thymic output and the cell proliferation/loss model. For that purpose, we defined specific individual covariates from the data collected from 10 years of clinical practice and then evaluated the model's predicted performances and accuracy. We have shown that this Bayesian modeling approach predicted the time course and extent of CD4+ T-cell immune reconstitution after SCID transplantation.
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- 2022
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4. Childhood Langerhans cell histiocytosis with severe lung involvement: a nationwide cohort study
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Solenne Le Louet, Mohamed-Aziz Barkaoui, Jean Miron, Claire Galambrun, Nathalie Aladjidi, Pascal Chastagner, Kamila Kebaili, Corinne Armari-Alla, Anne Lambilliotte, Julien Lejeune, Despina Moshous, Valeria Della Valle, Chiara Sileo, Hubert Ducou Le Pointe, Jean-François Chateil, Sylvain Renolleau, Jean-Eudes Piloquet, Aurelie Portefaix, Ralph Epaud, Raphaël Chiron, Emmanuelle Bugnet, Gwenaël Lorillon, Abdelatif Tazi, Jean-François Emile, Jean Donadieu, and Sébastien Héritier
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Childhood ,Pulmonary ,Langerhans cell histiocytosis ,Targeted therapy ,Intensive care ,Severe ,Medicine - Abstract
Abstract Background Lung involvement in childhood Langerhans cell histiocytosis (LCH) is infrequent and rarely life threatening, but occasionally, severe presentations are observed. Methods Among 1482 children (
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- 2020
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5. Thymic Epithelial Cell Alterations and Defective Thymopoiesis Lead to Central and Peripheral Tolerance Perturbation in MHCII Deficiency
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Francesca Ferrua, Ileana Bortolomai, Elena Fontana, Dario Di Silvestre, Rosita Rigoni, Genni Enza Marcovecchio, Elena Draghici, Francesca Brambilla, Maria Carmina Castiello, Gloria Delfanti, Despina Moshous, Capucine Picard, Tom Taghon, Victoria Bordon, Ansgar S. Schulz, Catharina Schuetz, Silvia Giliani, Annarosa Soresina, Andrew R. Gennery, Sara Signa, Blachy J. Dávila Saldaña, Ottavia M. Delmonte, Luigi D. Notarangelo, Chaim M. Roifman, Pietro Luigi Poliani, Paolo Uva, Pier Luigi Mauri, Anna Villa, and Marita Bosticardo
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thymus ,thymic epithelial cells ,primary immunodeficiency ,MHCII ,central tolerance ,Immunologic diseases. Allergy ,RC581-607 - Abstract
Major Histocompatibility Complex (MHC) class II (MHCII) deficiency (MHCII-D), also known as Bare Lymphocyte Syndrome (BLS), is a rare combined immunodeficiency due to mutations in genes regulating expression of MHCII molecules. MHCII deficiency results in impaired cellular and humoral immune responses, leading to severe infections and autoimmunity. Abnormal cross-talk with developing T cells due to the absence of MHCII expression likely leads to defects in thymic epithelial cells (TEC). However, the contribution of TEC alterations to the pathogenesis of this primary immunodeficiency has not been well characterized to date, in particular in regard to immune dysregulation. To this aim, we have performed an in-depth cellular and molecular characterization of TEC in this disease. We observed an overall perturbation of thymic structure and function in both MHCII−/− mice and patients. Transcriptomic and proteomic profiling of murine TEC revealed several alterations. In particular, we demonstrated that impairment of lymphostromal cross-talk in the thymus of MHCII−/− mice affects mTEC maturation and promiscuous gene expression and causes defects of central tolerance. Furthermore, we observed peripheral tolerance impairment, likely due to defective Treg cell generation and/or function and B cell tolerance breakdown. Overall, our findings reveal disease-specific TEC defects resulting in perturbation of central tolerance and limiting the potential benefits of hematopoietic stem cell transplantation in MHCII deficiency.
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- 2021
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6. Different Clinical Presentations and Outcomes of Disseminated Varicella in Children With Primary and Acquired Immunodeficiencies
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Paul Bastard, Aurélien Galerne, Alain Lefevre-Utile, Coralie Briand, André Baruchel, Philippe Durand, Judith Landman-Parker, Elodie Gouache, Nathalie Boddaert, Despina Moshous, Joel Gaudelus, Robert Cohen, Georges Deschenes, Alain Fischer, Stéphane Blanche, Loïc de Pontual, and Bénédicte Neven
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varicella ,primary immumunodeficiencies ,steroids ,innate immunity ,disseminated varicella ,Immunologic diseases. Allergy ,RC581-607 - Abstract
Primary infection with varicella-zoster virus (VZV) causes chickenpox, a benign and self-limited disease in healthy children. In patients with primary or acquired immunodeficiencies, primary infection can be life-threatening, due to rapid dissemination of the virus to various organs [lung, gastrointestinal tract, liver, eye, central nervous system (CNS)]. We retrospectively described and compared the clinical presentations and outcomes of disseminated varicella infection (DV) in patients with acquired (AID) (n= 7) and primary (PID) (n= 12) immunodeficiencies. Patients with AID were on immunosuppression (mostly steroids) for nephrotic syndrome, solid organ transplantation or the treatment of hemopathies, whereas those with PID had combined immunodeficiency (CID) or severe CID (SCID). The course of the disease was severe and fulminant in patients with AID, with multiple organ failure, no rash or a delayed rash, whereas patients with CID and SICD presented typical signs of chickenpox, including a rash, with dissemination to other organs, including the lungs and CNS. In the PID group, antiviral treatment was prolonged until immune reconstitution after bone marrow transplantation, which was performed in 10/12 patients. Four patients died, and three experienced neurological sequelae. SCID patients had the worst outcome. Our findings highlight substantial differences in the clinical presentation and course of DV between children with AID and PID, suggesting differences in pathophysiology. Prevention, early diagnosis and treatment are required to improve outcome.
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- 2020
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7. Vasculitis as a Major Morbidity Factor in Patients With Partial RAG Deficiency
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Christoph B. Geier, Jocelyn R. Farmer, Zsofia Foldvari, Boglarka Ujhazi, Jolanda Steininger, John W. Sleasman, Suhag Parikh, Meredith A. Dilley, Sung-Yun Pai, Lauren Henderson, Melissa Hazen, Benedicte Neven, Despina Moshous, Svetlana O. Sharapova, Snezhina Mihailova, Petya Yankova, Elisaveta Naumova, Seza Özen, Kevin Byram, James Fernandez, Hermann M. Wolf, Martha M. Eibl, Luigi D. Notarangelo, Leonard H. Calabrese, and Jolan E. Walter
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vasculitis ,primary immumunodeficiencies ,rag deficiency ,severe combined immunodeficiencies (SCID) ,autoimmunity ,combined immunodeficiency with granuloma and/or autoimmunity ,Immunologic diseases. Allergy ,RC581-607 - Abstract
Vasculitis can be a life-threatening complication associated with high mortality and morbidity among patients with primary immunodeficiencies (PIDs), including variants of severe and combined immunodeficiencies ((S)CID). Our understanding of vasculitis in partial defects in recombination activating gene (RAG) deficiency, a prototype of (S)CIDs, is limited with no published systematic evaluation of diagnostic and therapeutic modalities. In this report, we sought to establish the clinical, laboratory features, and treatment outcome of patients with vasculitis due to partial RAG deficiency. Vasculitis was a major complication in eight (13%) of 62 patients in our cohort with partial RAG deficiency with features of infections and immune dysregulation. Vasculitis occurred early in life, often as first sign of disease (50%) and was complicated by significant end organ damage. Viral infections often preceded the onset of predominately non-granulomatous-small vessel vasculitis. Autoantibodies against cytokines (IFN-α, -ω, and IL-12) were detected in a large fraction of the cases tested (80%), whereas the majority of patients were anti-neutrophil cytoplasmic antibodies (ANCA) negative (>80%). Genetic diagnosis of RAG deficiency was delayed up to 2 years from the onset of vasculitis. Clinical cases with sole skin manifestation responded well to first-line steroid treatment, whereas systemic vasculitis with severe end-organ complications required second-line immunosuppression and/or hematopoietic stem cell transplantation (HSCT) for definitive management. In conclusion, our data suggest that vasculitis in partial RAG deficiency is prevalent among patients with partial RAG deficiency and is associated with high morbidity. Therefore, partial RAG deficiency should be included in the differential diagnosis of patients with early-onset systemic vasculitis. Diagnostic serology may be misleading with ANCA negative findings, and search for conventional autoantibodies should be extended to include those targeting cytokines.
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- 2020
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8. Safety and efficacy of brentuximab vedotin as a treatment for lymphoproliferative disorders in primary immunodeficiencies
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Thomas Pincez, Julie Bruneau, Laureline Berteloot, Eve Piekarski, Caroline Thomas, Ambroise Marçais, Amélie Trinquand, Martin Castelle, Nicolas Garcelon, Dominique Plantaz, Morgane Cheminant, Despina Moshous, Thierry Jo Molina, Olivier Hermine, Elizabeth Macintyre, Alain Fischer, Stéphane Blanche, Felipe Suarez, and Bénédicte Neven
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Published
- 2020
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9. Expanded circulating hematopoietic stem/progenitor cells as novel cell source for the treatment of TCIRG1 osteopetrosis
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Valentina Capo, Sara Penna, Ivan Merelli, Matteo Barcella, Serena Scala, Luca Basso-Ricci, Elena Draghici, Eleonora Palagano, Erika Zonari, Giacomo Desantis, Paolo Uva, Roberto Cusano, Lucia Sergi Sergi, Laura Crisafulli, Despina Moshous, Polina Stepensky, Katarzyna Drabko, Zühre Kaya, Ekrem Unal, Alper Gezdirici, Giuseppe Menna, Marta Serafini, Alessandro Aiuti, Silvia Laura Locatelli, Carmelo Carlo-Stella, Ansgar S. Schulz, Francesca Ficara, Cristina Sobacchi, Bernhard Gentner, and Anna Villa
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
Allogeneic hematopoietic stem cell transplantation is the treatment of choice for autosomal recessive osteopetrosis caused by defects in the TCIRG1 gene. Despite recent progress in conditioning, a relevant number of patients are not eligible for allogeneic stem cell transplantation because of the severity of the disease and significant transplant-related morbidity. We exploited peripheral CD34+ cells, known to circulate at high frequency in the peripheral blood of TCIRG1-deficient patients, as a novel cell source for autologous transplantation of gene corrected cells. Detailed phenotypical analysis showed that circulating CD34+ cells have a cellular composition that resembles bone marrow, supporting their use in gene therapy protocols. Transcriptomic profile revealed enrichment in genes expressed by hematopoietic stem and progenitor cells (HSPCs). To overcome the limit of bone marrow harvest/ HSPC mobilization and serial blood drawings in TCIRG1 patients, we applied UM171-based ex-vivo expansion of HSPCs coupled with lentiviral gene transfer. Circulating CD34+ cells from TCIRG1-defective patients were transduced with a clinically-optimized lentiviral vector (LV) expressing TCIRG1 under the control of phosphoglycerate promoter and expanded ex vivo. Expanded cells maintained long-term engraftment capacity and multi-lineage repopulating potential when transplanted in vivo both in primary and secondary NSG recipients. Moreover, when CD34+ cells were differentiated in vitro, genetically corrected osteoclasts resorbed the bone efficiently. Overall, we provide evidence that expansion of circulating HSPCs coupled to gene therapy can overcome the limit of stem cell harvest in osteopetrotic patients, thus opening the way to future gene-based treatment of skeletal diseases caused by bone marrow fibrosis.
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- 2020
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10. A gain-of-function RAC2 mutation is associated with bone-marrow hypoplasia and an autosomal dominant form of severe combined immunodeficiency
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Chantal Lagresle-Peyrou, Aurélien Olichon, Hanem Sadek, Philippe Roche, Claudine Tardy, Cindy Da Silva, Alexandrine Garrigue, Alain Fischer, Despina Moshous, Yves Collette, Capucine Picard, Jean Laurent Casanova, Isabelle André, and Marina Cavazzana
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
Severe combined immunodeficiencies (SCIDs) constitute a heterogeneous group of life-threatening genetic disorders that typically present in the first year of life. They are defined by the absence of autologous T cells and the presence of an intrinsic or extrinsic defect in the B-cell compartment. In three newborns presenting with frequent infections and profound leukopenia, we identified a private, heterozygous mutation in the RAC2 gene (p.G12R). This mutation was de novo in the index case, who had been cured by hematopoietic stem cell transplantation but had transmitted the mutation to her sick daughter. Biochemical assays showed that the mutation was associated with a gain of function. The results of in vitro differentiation assays showed that RAC2 is essential for the survival and differentiation of hematopoietic stem/progenitor cells. Therefore, screening for RAC2 gain-of-function mutations should be considered in patients with a SCID phenotype and who lack a molecular diagnosis.
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- 2020
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11. Haematopoietic Stem Cell Transplantation for Primary Haemophagocytic Lymphohistiocytosis
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Kai Lehmberg, Despina Moshous, and Claire Booth
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haemophagocytic lymhohistiocytosis ,macrophage activation syndrome ,haematopoietic stem cell transplantation ,gene therapy ,veno-occlusive disease ,mixed chimerism ,Pediatrics ,RJ1-570 - Abstract
Haematopoietic stem cell transplantation currently remains the only curative treatment of primary forms of haemophagocytic lymphohistiocytosis (HLH). Rapid diagnosis, efficient primary treatment of hyperinflammation, and conditioning regimens tailored to this demanding condition have substantially improved prognosis in the past 40 years. However, refractory hyperinflammation, central nervous system (CNS) involvement, unavailability of matched donors, susceptibility to conditioning-related toxicities, and a high frequency of mixed chimaerism remain a challenge in a substantial proportion of patients. Gene therapeutic approaches for several genetic defects of primary HLH are being developed at pre-clinical and translational levels.
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- 2019
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12. Proceedings of the 23rd Paediatric Rheumatology European Society Congress: part one
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F. De Benedetti, J. Anton, M. Gattorno, H. Lachmann, I. Kone-Paut, S. Ozen, J. Frenkel, A. Simon, A. Zeft, E. Ben-Chetrit, H. M. Hoffman, Y. Joubert, K. Lheritier, A. Speziale, J. Guido, Roberta Caorsi, Federica Penco, Alice Grossi, Antonella Insalaco, Maria Alessio, Giovanni Conti, Federico Marchetti, Alberto Tommasini, Silvana Martino, Romina Gallizzi, Annalisa Salis, Francesca Schena, Francesco Caroli, Alberto Martini, Gianluca Damonte, Isabella Ceccherini, Marco Gattorno, Marie-Louise Frémond, Carolina Uggenti, Lien Van Eyck, Isabelle Melki, Darragh Duffy, Vincent Bondet, Yoann Rose, Bénédicte Neven, Yanick Crow, Mathieu P. Rodero, Yvonne Kusche, Johannes Roth, Katarzyna Barczyk-Kahlert, Giovanna Ferrara, Annalisa Chiocchetti, Silvio Polizzi, Josef Vuch, Diego Vozzi, Anna Mondino, Erica Valencic, Serena Pastore, Andrea Taddio, Flavio Faletra, Umberto Dianzani, Ugo Ramenghi, Qing Zhou, Xiaomin Yu, Erkan Demirkaya, Natalie Deuitch, Deborah Stone, Wanxia Tsai, Amanda Ombrello, Tina Romeo, Elaine F. Remmers, JaeJin Chae, Massimo Gadina, Steven Welch, Seza Ozen, Rezan Topaloglu, Mario Abinun, Daniel L. Kastner, Ivona Aksentijevich, Donatella Vairo, Rosalba Monica Ferraro, Giulia Zani, Jessica Galli, Micaela De Simone, Marco Cattalini, Elisa Fazzi, Silvia Giliani, Ebun Omoyinmi, Ariane Standing, Dorota Rowczenio, Annette Keylock, Sonia Melo Gomes, Fiona Price-Kuehne, Sira Nanthapisal, Claire Murphy, Thomas Cullup, Lucy Jenkins, Kimberly Gilmour, Despina Eleftheriou, Helen Lachmann, Philip Hawkins, Nigel Klein, Paul Brogan, Anita Dhanrajani, Mercedes Chan, Stephanie Pau, Janet Ellsworth, Jaime Guzman, Florence A. Aeschlimann, Marinka Twilt, Simon W. Eng, Shehla Sheikh, Ronald M. Laxer, Diane Hebert, Damien Noone, Christian Pagnoux, Susanne M. Benseler, Rae S. Yeung, Christoph Kessel, Katrin Lippitz, Toni Weinhage, Claas Hinze, Helmut Wittkowski, Dirk Holzinger, Niklas Grün, Dirk Föll, Pieter Van Dijkhuizen, Federica Del Chierico, Clara Malattia, Alessandra Russo, Denise Pires Marafon, Nienke M. ter Haar, Silvia Magni-Manzoni, Sebastiaan J. Vastert, Bruno Dallapiccola, Berent Prakken, Fabrizio De Benedetti, Lorenza Putignani, Berna Eren Fidanci, Kenan Barut, Serap Arıcı, Dogan Simsek, Mustafa Cakan, Ezgi D. Batu, Sezgin Şahin, Ayşenur Kısaarslan, Ebru Yilmaz, Özge Basaran, Ferhat Demir, Kubra Ozturk, Zübeyde Gunduz, Betül Sozeri, Balahan Makay, Nuray Ayaz, Onder Yavascan, Ozlem Aydog, Yelda Bilginer, Zelal Ekinci, Dilek Yıldız, Faysal Gök, Muferret Erguven, Erbil Unsal, Ozgur Kasapcopur, For the FMF Arthritis Vasculitis and Orphan Disease Research in Paediatric Rheumatology (FAVOR), Hafize E. Sönmez, Betül Sözeri, Yonatan Butbul, Seza Özen, Claudia Bracaglia, Giusi Prencipe, Manuela Pardeo, Geneviève Lapeyre, Emiliano Marasco, Walter Ferlin, Robert Nelson, Cristina de Min, N. Ruperto, H. I. Brunner, P. Quartier, T. Constantin, E. Alexeeva, K. Marzan, N. Wulffraat, R. Schneider, S. Padeh, V. Chasnyk, C. Wouters, J. B. Kuemmerle-Deschner, T. Kallinich, B. Lauwerys, E. Haddad, E. Nasonov, M. Trachana, O. Vougiouka, K. Leon, E. Vritzali, A. Martini, D. Lovell, PRINTO/PRCSG, Stefano Volpi, Claudia Pastorino, Francesca Kalli, Alessia Omenetti, Sabrina Chiesa, Arinna Bertoni, Paolo Picco, Gilberto Filaci, Elisabetta Traggiai, Marie-Louise Fremond, Naoki Kitabayashi, Olivero Sacco, Isabelle Meyts, Marie-Anne Morren, Carine Wouters, Eric Legius, Isabelle Callebaut, Christine Bodemer, Frederic Rieux-Laucat, Mathieu Rodero, Nadia Jeremiah, Alexandre Belot, Eric Jeziorski, Didier Bessis, Guilhem Cros, Gillian I. Rice, Bruno Charbit, Anne Hulin, Nihel Khoudour, Consuelo Modesto Caballero, Monique Fabre, Laureline Berteloot, Muriel Le Bourgeois, Philippe Reix, Thierry Walzer, Despina Moshous, Stéphane Blanche, Alain Fischer, Brigitte Bader-Meunier, Frédéric Rieux-Laucat, K. Annink, N. ter Haar, S. Al-Mayouf, G. Amaryan, K. Barron, S. Benseler, P. Brogan, L. Cantarini, M. Cattalini, A. Cochino, F. Dedeoglu, A. De Jesus, O. Dellacasa, E. Demirkaya, P. Dolezalova, K. Durrant, G. Fabio, R. Gallizzi, R. Goldbach-Mansky, E. Hachulla, V. Hentgen, T. Herlin, M. Hofer, H. Hoffman, A. Insalaco, A. Jansson, I. Koné-Paut, A. Kozlova, J. Kuemmerle-Deschner, R. Laxer, S. Nielsen, I. Nikishina, A. Ombrello, E. Papadopoulou-Alataki, A. Ravelli, D. Rigante, R. Russo, Y. Uziel, Nienke ter Haar, Jerold Jeyaratnam, Anna Simon, Matteo Doglio, Jordi Anton, Consuelo Modesto, Pierre Quartier, Esther Hoppenreijs, Luca Cantarini, Loredana Lepore, Inmaculada Calvo Penades, Christina Boros, Rita Consolini, Donato Rigante, Ricardo Russo, Jana Pachlopnik Schmid, Thirusha Lane, Nicolino Ruperto, Joost Frenkel, Chiara Passarelli, Elisa Pisaneschi, Virginia Messia, Antonio Novelli, Fabrizio Debenedetti, P. A. Brogan, X. Wei, Martina Finetti, Francesca Orlando, Elisabetta Cortis, Angela Miniaci, Nicola Ruperto, Charlotte Eijkelboom, Pavla Dolezalova, Isabelle Koné-Paut, Marija Jelusic-Drazic, Liliana Bezrodnik, Mari Carmen Pinedo, Valda Stanevicha, Marielle van Gijn, Silvia Federici, Hermann Girschick, Gerd Ganser, Susan Nielsen, Troels Herlin, Sulaiman Mohammed Al-Mayouf, Michael Hofer, Jasmin Kuemmerle-Deschner, Susanne Schalm, Annette Jansson, on behalf of PRINTO and Eurofever registry, Marta Marchi, Chiara Marini, Angelo Ravelli, Alberto Garaventa, Sonia Carta, Enrica Balza, Patrizia Castellani, Caterina Pellecchia, Silvia Borghini, Maria Libera Trotta, Anna Rubartelli, Andrew Henrey, Thomas Loughin, Roberta Berard, Natalie Shiff, Roman Jurencak, Susanne Benseler, Lori Tucker, on behalf of ReACCh-Out Investigators, Charalampia Papadopoulou, Ying Hong, Petra Krol, Yiannis Ioannou, Clarissa Pilkington, Hema Chaplin, Stephania Simou, Marietta Charakida, Lucy Wedderburn, Lynn R. Spiegel, Sara Ahola Kohut, Jennifer Stinson, Paula Forgeron, Miriam Kaufman, Nadia Luca, Khush Amaria, Mary Bell, J Swart, F. Boris, E. Castagnola, A. Groll, G. Giancane, G. Horneff, H. I. Huppertz, T. Wolfs, E. Alekseeva, V. Panaviene, F. Uettwiller, V. Stanevicha, L. M. Ailioaie, E. Tsitami, S. Kamphuis, G. Susic, F. Sztajnbok, B. Flato, A. Pistorio, Stephanie J. W. Shoop, Suzanne M. M. Verstappen, Janet E. McDonagh, Wendy Thomson, Kimme L. Hyrich, CAPS, Maarit Tarkiainen, Pirjo Tynjala, Pekka Lahdenne, Janne Martikainen, Acute-JIA Study Group, Meredyth Wilkinson, Christopher Piper, Georg Otto, Claire T. Deakin, Stefanie Dowle, Stefania Simou, Daniel Kelberman, Claudia Mauri, Elizabeth Jury, David Isenberg, Lucy R. Wedderburn, Kiran Nistala, I. Foeldvari, D. J. Lovell, G. Simonini, M. Bereswill, J. Kalabic, Kiem Oen, Brian M. Feldman, Brenden Dufault, Jennifer Lee, Karen Watanabe Duffy, Ciaran Duffy, ReACCh-Out Investigators, N. Tzaribachev, G. Vega-Cornejo, I. Louw, A. Berman, I. Calvo, R. Cuttica, F. Avila-Zapata, R. Cimaz, E. Solau-Gervais, R. Joos, G. Espada, X. Li, M. Nys, R. Wong, S. Banerjee, For Pediatric Rheumatology International Trials Organization (PRINTO)/Pediatric Rheumatology Collaborative Study Group (PRCSG), Rebecca Nicolai, Margherita Verardo, Adele D’Amico, Luisa Bracci-Laudiero, Gian Marco Moneta, Gillian Rice, Anne-Laure Mathieu, Sulliman O. Omarjee, Tracy A. Briggs, James O’Sullivan, Simon Williams, Rolando Cimaz, Eve Smith, Michael W. Beresford, Yanick J. Crow, GENIAL Investigators, UK JSLE Study Group, Madeleine Rooney, Nick Bishop, joyce davidson, Clarissa pilkington, Michael Beresford, Jacqui Clinch, Rangaraj Satyapal, Helen Foster, Janet Gardner Medwin, Janet McDonagh, Sue Wyatt, On Behalf of the British Society for Paediatric and Adolescent Rheumatology, Valentina Litta Modignani, Francesco Baldo, Stefano Lanni, Alessandro Consolaro, Giovanni Filocamo, Helen J. Lachmann, on behalf of Eurofever Registry, Gianmarco Moneta, Camilla Celani, Bilade Cherqaoui, Linda Rossi-Semerano, Perrine Dusser, Véronique Hentgen, Claire Grimwood, Linda Rossi, Isabelle Kone Paut, Veronique Hentgen, Denise Lasigliè, Denise Ferrera, Giulia Amico, Marco Di Duca, Laura Obici, Roberto Ravazzolo, Ryuta Nishikomori, Juan Arostegui, Andrea Petretto, Chiara Lavarello, Elvira Inglese, Federica Vanoni, Michaël Hofer, on behalf of EUROFEVER PROJECT, P. N. Hawkins, T. van der Poll, U. A. Walker, H. H. Tilson, Pascal N. Tyrrell, Raphaela Goldbach-Mansky, Norbert Blank, Hal M. Hoffman, Elisabeth Weissbarth-Riedel, Boris Huegle, Tilmann Kallinich, Ahmet Gul, Marlen Oswald, Fatma Dedeoglu, Aki Hanaya, Takako Miyamae, Manabu Kawamoto, Yumi Tani, Takuma Hara, Yasushi Kawaguchi, Satoru Nagata, Hisashi Yamanaka, Almira Ćosićkić, Fahrija Skokić, Belkisa Čolić, Sanimir Suljendić, Anna Kozlova, Irina Mersiyanova, Mariya Panina, Lily Hachtryan, Vasiliy Burlakov, Elena Raikina, Alexey Maschan, Anna Shcherbina, Banu Acar, Meryem Albayrak, Betul Sozeri, Sezgin Sahin, Amra Adrovic, Nese Inan, Serhan Sevgi, Caroline M. Andreasen, Anne Grethe Jurik, Mia B. Glerup, Christian Høst, Birgitte T. Mahler, Ellen-Margrethe Hauge, Cecilia Lazea, Laura Damian, Calin Lazar, Rodica Manasia, Chloe M. Stephenson, Vimal Prajapati, Paivi M. Miettunen, Dilek Yılmaz, Yavuz Tokgöz, Yasin Bulut, Harun Çakmak, Ferah Sönmez, Elif Comak, Gülşah Kaya Aksoy, Mustafa Koyun, Sema Akman, Yunus Arıkan, Ender Terzioğlu, Osman Nidai Özdeş, İbrahim Keser, Hüseyin Koçak, Ayşen Bingöl, Aygen Yılmaz, Reha Artan, X. Xu, Fatemeh F. Mehregan, Vahid Ziaee, Mohammad H. Moradinejad, Francesco La Torre, Clotilde Alizzi, Pio D’Adamo, G. Junge, J. Gregson, Hasmik Sargsyan, Hulya Zengin, Berna E. Fidanci, Cagla Kaymakamgil, Dilek Konukbay, Dilek Yildiz, Faysal Gok, Iris Stoler, Judith Freytag, Banu Orak, Christine Seib, Lars Esmann, Eva Seipelt, Faekah Gohar, Dirk Foell, Ismail Dursun, Sebahat Tulpar, Sibel Yel, Demet Kartal, Murat Borlu, Funda Bastug, Hakan Poyrazoglu, Zubeyde Gunduz, Kader Kose, Mehmet E. Yuksel, Abdullah Calıskan, Ahmet B. Cekgeloglu, Ruhan Dusunsel, Katerina Bouchalova, Jana Franova, Marcel Schuller, Marie Macku, Katerina Theodoropoulou, Raffaella Carlomagno, Annette von Scheven-Gête, Claudia Poloni, Laura O. Damian, Dan Cosma, Amanda Radulescu, Dan Vasilescu, Liliana Rogojan, Simona Rednic, Mihaela Lupse, Lien De Somer, Pierre Moens, Rocio Galindo Zavala, Laura Martín Pedraz, Esmeralda Núñez Cuadros, Gisela Díaz-Cordovés Rego, Antonio L. Urda Cardona, Ilaria Dal Forno, Sara Pieropan, Ombretta Viapiana, Davide Gatti, Gloria Dallagiacoma, Paola Caramaschi, Domenico Biasi, Daniel Windschall, Ralf Trauzeddel, Hartwig Lehmann, Rainer Berendes, Maria Haller, Manuela Krumrey-Langkammerer, Antje Nimtz-Talaska, Philipp Schoof, Ralf Felix Trauzeddel, Christine Nirschl, Estefania Quesada-Masachs, Carla Aguilar Blancafort, Sara Marsal Barril, Francisca Aguiar, Rita Fonseca, Duarte Alves, Ana Vieira, Alberto Vieira, Jorge A. Dias, Iva Brito, Gordana Susic, Vera Milic, Goran Radunovic, Ivan Boricic, Pauline Marteau, Catherine Adamsbaum, Michel De Bandt, Irène Lemelle, Chantal Deslandre, Tu Anh Tran, Anne Lohse, Elisabeth Solau-Gervais, Pascal Pillet, Julien Wipff, Cécile Gaujoux-Viala, Sylvain Breton, Valérie Devauchelle-Pensec, Sandra Gran, Olesja Fehler, Stefanie Zenker, Michael Schäfers, Thomas Vogl, Severine Guillaume Czitrom, EH Pieter Van Dijkhuizen, Silvia Magni Manzoni, Francesca Magnaguagno, Laura Tanturri de Horatio, Nienke M. Ter Haar, Annemieke S. Littooij, Vitor A. Teixeira, Raquel Campanilho-Marques, Ana F. Mourão, Filipa O. Ramos, Manuela Costa, Wafa A. Madan, Orla G. Killeen, Adriana Rodriguez Vidal, Diana Sueiro Delgado, Maria Isabel Gonzalez Fernandez, Berta Lopez Montesinos, Aleksey Kozhevnikov, Nina Pozdeeva, Mikhail Konev, Evgeniy Melchenko, Vladimir Kenis, Gennadiy Novik, Aysenur Pac Kısaarslan, Butsabong Lerkvaleekul, Suphaneewan Jaovisidha, Witaya Sungkarat, Niyata Chitrapazt, Praman Fuangfa, Thumanoon Ruangchaijatuporn, Soamarat Vilaiyuk, Dan Ø. Pradsgaard, Arne Hørlyck, Anne H. Spannow, Carsten W. Heuck, Talia Diaz, Fernando Garcia, Lorenia De La Cruz, Nadina Rubio, Joanna Świdrowska-Jaros, Elzbieta Smolewska, Mirta Lamot, Lovro Lamot, Mandica Vidovic, Edi Paleka Bosak, Ivana Rados, Miroslav Harjacek, Nikolay Tzaribachev, Polymnia Louka, Romiesa Hagoug, Chiara Trentin, Olga Kubassova, Mark Hinton, Mikael Boesen, Olena A. Oshlianska, Illya A. Chaikovsky, G. Mjasnikov, A. Kazmirchyk, Umberto Garagiola, Irene Borzani, Paolo Cressoni, Fabrizia Corona, Eszter Dzsida, Giampietro Farronato, Antonella Petaccia, Alenka Gagro, Agneza Marija Pasini, Goran Roic, Ozren Vrdoljak, Lucija Lujic, Matija Zutelija-Fattorini, Monika M. Esser, Deepthi R. Abraham, Craig Kinnear, Glenda Durrheim, Mike Urban, Eileen Hoal, Victoria B. Nikolayenko, Kubilay Şahin, Yasar Karaaslan, Adele Civino, Giovanni Alighieri, Sergio Davì, Roberto Rondelli, Andrea Magnolato, Francesca Ricci, Alma Olivieri, Valeria Gerloni, Bianca Lattanzi, Francesca Soscia, Alessandro De Fanti, Stefania Citiso, Lorenzo Quartulli, Maria Cristina Maggio, Manuela Marsili, Maria Antonietta Pelagatti, Valentino Conter, Franca Fagioli, Andrea Pession, Marco Garrone, Mariangela Rinaldi, Jaime De Inocencio, Stella Garay, Daniel J. Lovell, Berit Flato, EPOCA Study Group, Angela Aquilani, Simona Cascioli, Ivan Caiello, Denise Pires-Marafón, Rita Carsetti, Emily Robinson, Salvatore Albani, Wilco de Jager, Sytze de Roock, Trang Duong, Justine Ellis, Kimme Hyrich, Laetitia Jervis, Daniel Lovell, Lucy Marshall, Elizabeth D. Mellins, Kirsten Minden, Jane Munro, Peter A. Nigrovic, Jason Palman, Sunil Sampath, Laura E. Schanberg, Susan D. Thompson, Richard Vesely, Chris Wallace, Chris Williams, Qiong Wu, Nico Wulffraat, Rae S. M. Yeung, M. B. Seyger, D. Arikan, J. K. Anderson, A. Lazar, D. A. Williams, C. Wang, R. Tarzynski-Potempa, J. S. Hymans, Gabriele Simonini, Erika Scoccimarro, Irene Pontikaki, Teresa Giani, Alessandro Ventura, Pier Luigi Meroni, Gaetana Minnone, Marzia Soligo, Luigi Manni, Luisa Bracci Laudiero, Noortje Groot, I. Grein, N. M. Wulffraat, R. Schepp, G. Berbers, C. C. Barbosa Sandoval de Souza, V. Paes Leme Ferriani, G. Pileggi, S. de Roock, Ingrid H. R. Grein, Silvia Scala, Elisa Patrone, Casper Schoemaker, on behalf of Dutch JIA patient organization, Wendy Costello, on behalf of ENCA, Suzanne Parsons, Jean-David Cohen, Damien Bentayou, Marc-Antoine Bernard Brunel, Sonia Trope, Jens Klotsche, Miriam Listing, Martina Niewerth, Gerd Horneff, Angelika Thon, Hans-Iko Huppertz, Kirsten Mönkemöller, Ivan Foeldvari, ICON study group, Achille Marino, Stefano Stagi, Niccolò Carli, Federico Bertini, Adriana S. Díaz-Maldonado, Sally Pino, Pilar Guarnizo, Alfonso Ragnar Torres-Jimenez, Berenice Sanchez-Jara, Eunice Solis-Vallejo, Adriana Ivonne Cespedes-Cruz, Maritza Zeferino-Cruz, Julia Veronica Ramirez-Miramontes, Ankur Kumar, Anju Gupta, Deepti Suri, Amit Rawat, Nandita Kakkar, Surjit Singh, Özge A. Gücenmez, Erbil Ünsal, Bo Magnusson, Karina Mördrup, Anna Vermé, Christina Peterson, Board of the Swedish Pediatric Rheumatology Registry, Caroline Freychet, Jean Louis Stephan, Cathryn E. Harkness, Leanne Foster, Emma Henry, Pauline Taggart, Coskun F. Ozkececi, Esra Kurt, Gokalp Basbozkurt, Daiva Gorczyca, Jacek Postępski, Aleksandra Czajkowska, Bogumiła Szponar, Mariola Paściak, Anna Gruenpeter, Iwona Lachór-Motyka, Daria Augustyniak, Edyta Olesińska, Emediong S. Asuka, Tatyana Golovko, Samuel U. Aliejim, Emilio Inarejos Clemente, Estibaliz Iglesias Jimenez, Joan Calzada Hernandez, Sergi Borlan Fernandez, Clara Gimenez Roca, David Moreno Romo, Natalia Rodriguez Nieva, Juan Manuel Mosquera Angarita, Jordi Anton Lopez, Esmeralda Nuñez-Cuadros, Gisela Diaz-Cordovés, Rocío Galindo-Zavala, Antonio Urda-Cardona, Antonio Fernández-Nebro, Daniel Álvarez de la Sierra, Marina Garcia Prat, Mónica Martínez Gallo, Ricardo Pujol Borrell, Ana M. Marín Sánchez, Etienne Merlin, Sylvie Fraitag, Jean-Louis Stephan, Federico Annoni, Giancarla Di Landro, Sofia Torreggiani, Marta Torcoletti, Georgina Tiller, Jo Buckle, Angela Cox, Peter Gowdie, Roger C. Allen, Jonathan D. Akikusa, Hayde G. Hernández-Huirache, Edel R. Rodea-Montero, William Fahy, Christelle Sordet, Karin B. Berggren, Johanna T. Kembe, Joyce Bos, Wineke Armbrust, Marco van Brussel, Jeanette Cappon, Pieter Dijkstra, Jan Geertzen, Elizabeth Legger, Marion van Rossum, Pieter Sauer, Otto Lelieveld, Levent Buluc, Gur Akansel, Bahar Muezzinoglu, Ljubov Rychkova, Tatyana Knyazeva, Anna Pogodina, Tatyana Belova, Tamara Mandzyak, Ekaterina Kulesh, Alessandro Cafarotti, Cosimo Giannini, Roberta Salvatore, Giuseppe Lapergola, Caterina Di Battista, Maria Loredana Marcovecchio, Raffaella Basilico, Piernicola Pelliccia, Francesco Chiarelli, Luciana Breda, Beverley Almeida, Sarah Tansley, Harsha Gunawardena, Neil McHugh, Juvenile Dermatomyositis Research Group (JDRG), Jessie Aouizerate, Marie De Antonio, Christine Barnerias, Guillaume Bassez, Isabelle Desguerre, Romain Gherardi, Jean-Luc Charuel, François-Jérôme Authier, Cyril Gitiaux, C. H. Spencer, Rabheh Abdul Aziz, Chack-Yung Yu, Brent Adler, Sharon Bout-Tabaku, Katherine Lintner, Melissa Moore-Clingenpeel, Liza McCann, Nicola Ambrose, Mario Cortina-Borja, Juvenile Dermatomyositis Cohort and Biomarker Study (JCDBS), Prasad T. Oommen, Fabian Speth, Johannes-Peter Haas, Working Group “Juvenile Dermatomyositis” of the German Society for Paediatric and Adolescent Rheumatology (GKJR), Claudio Lavarello, Gabriella Giancane, Angela Pistorio, Lisa Rider, Rohit Aggarwal, Sheila K. Oliveira, Ruben Cuttica, Michel Fischbach, Gary Sterba, Karine Brochard, Frank Dressler, Patrizia Barone, Ruben Burgos-Vargas, Elizabeth Candell Chalom, Marine Desjonqueres, Graciela Espada, Anders Fasth, Stella Maris Garay, Rose-Marie Herbigneaux, Claire Hoyoux, Chantal Job Deslandre, Frederick W. Miller, Jiri Vencovsky, Erdal Sag, Gulsev Kale, Haluk Topaloglu, Beril Talim, Francesco Zulian, Tadej Avcin, Roberto Marini, Anne Pagnier, Michel Rodiere, Christine Soler, Rebecca Ten Cate, Yosef Uziel, Jelena Vojinovic, Ana V. Villarreal, Nydia Acevedo, Yuridiana Ramirez, Enrique Faugier, Rocio Maldonado, Bita Arabshahi, John H. Lee, Ian Leibowitz, Lawrence O. Okong’o, Jo Wilmshurst, Monika Esser, Christiaan Scott, Ezgi Deniz Batu, Nagehan Emiroglu, Hafize Emine Sonmez, Gokcen Dilsa Tugcu, Zehra Serap Arici, Ebru Yalcin, Deniz Dogru, Ugur Ozcelik, Mithat Haliloglu, Nural Kiper, Masato Yashiro, Mutsuko Yamada, Toshihiko Yabuuchi, Tomonobu Kikkawa, Nobuyuki Nosaka, Yosuke Fujii, Yukie Saito, Hirokazu Tsukahara, Sulaiman M. Al-Mayouf, Nora AlMutiari, Mohammed Muzaffer, Rawiah shehata, Adel Al-Wahadneh, Reem Abdwani, Safia Al-Abrawi, Mohammed Abu-shukair, Zeyad El-Habahbeh, Abdullah Alsonbul, Aleksandra Szabat, Monika Chęć, Violetta Opoka-Winiarska, Biman Saikia, Ranjana W. Minz, Christine Arango, Clara Malagon, Maria D. P. Gomez, Angela C. Mosquera, Ricardo Yepez, Tatiana Gonzalez, Camilo Vargas, GRIP study group, Marta Balzarin, Biagio Castaldi, Elena Reffo, Francesca Sperotto, Giorgia Martini, Alessandra Meneghel, Ornella Milanesi, Ozgur Kasapçopur, Maria Teresa Terreri, Ekaterina Alexeeva, Maria Katsicas, Mikhail Kostik, Thomas Lehman, W.-Alberto Sifuentes-Giraldo, Vanessa Smith, Flavio Sztajnbok, Tadey Avcin, Maria Jose Santos, Dana Nemcova, Cristina Battagliotti, Liora Harel, Mahesh Janarthanan, Kathryn Torok, Nicola Helmus, Eileen Baildem, Michael Blakley, Kim Fligelstone, Antonia Kienast, Clare Pain, Amanda Saracino, Gabriele Simoni, Lisa Weibel, Maria K. Osminina, Nathalia A. Geppe, Olga V. Niconorova, Olesya V. Karashtina, Oksana V. Abbyasova, Olga V. Shpitonkova, Sinem Durmus, Hafize Uzun, Angela Mauro, Eleonora Fanti, Fabio Voller, Franca Rusconi, Fernando Garcia-Rodriguez, Ana V. Villarreal-Treviño, Angel J. Flores-Pineda, Paola B. Lara-Herrea, Diego R. Salinas-Encinas, Talia Diaz-Prieto, Maria R. Maldonado-Velazquez, Sarbelio Moreno-Espinosa, Enrique Faugier-Fuentes, Mirella Crapanzano, Ilaria Parissenti, Man S. Parihar, Pandiarajan Vignesh, ManojKumar Rohit, Kavitha Gopalan, Savita V. Attri, Alan Salama, David Jayne, Mark Little, Yulia Kostina, Galina Lyskina, Olga Shpitonkova, Alena Torbyak, Olga Shirinsky, Maria Francesca Gicchino, Maria Cristina Smaldone, Mario Diplomatico, Alma Nunzia Olivieri, C H. Spencer, Richard McClead, Hiren Patel, Chung-Yung Yu, Dita Cebecauerová, Tomáš Dallos, Edita Kabíčková, Martin Kynčl, Daniela Chroustová, Jozef Hoza, Dana Němcová, Vladimír Tesař, Pavla Doležalová, Tuncay Hazirolan, Fatih Ozaltin, Fabiola Almeida, Isabela H. Faria de Paula, Maíra M. Sampaio, Fernando N. Arita, Andressa G. Alves, Maria Carolina Santos, Eunice M. Okuda, Silvana B. Sacchetti, Fernanda Falcini, Marini Francesca, Gemma Lepri, Marco Matucci-Cerinic, Maria Luisa Brandi, Hakan Kisaoglu, Sema Misir, Selim Demir, Yuksel Aliyazicioglu, Mukaddes Kalyoncu, Carlos Eduardo Ramalho, Fabiola D. Almeida, Joan Calzada-Hernández, Rosa Bou, Estíbaliz Iglesias, Judith Sánchez-Manubens, Fredy Hermógenes Prada Martínez, Clara Giménez Roca, Sergi Borlan Fernández, Marek Bohm, Kamran Mahmood, Valentina Leone, Mark Wood, Ken-Ichi Yamaguchi, Satoshi Fujikawa, Working Group of Behçet’s Disease, Pediatric Rheumatology Association of Japan (PRAJ), Kyu Yeun Kim, Do Young Kim, Dong Soo Kim, Maka Ioseliani, Ivane Chkhaidze, Maia Lekishvili, Nana Tskhakaia, Shorena Tvalabeishvili, Aleksandre Kajrishvili, Maiko Takakura, Masaki Shimizu, Natsumi Inoue, Mao Mizuta, Akihiro Yachie, Giovanni Corsello, Maryam Piram, Carla Maldini, Sandra Biscardi, Nathalie Desuremain, Catherine Orzechowski, Emilie Georget, Delphine Regnard, Isabelle Kone-Paut, Alfred Mahr, Mihaela Sparchez, Zeno Sparchez, Nydia Acevedo Silva, Ana V. Villarreal Treviño, Yuridiana Ramirez Loyola, Talia Diaz Prieto, Enrique Faugier Fuentes, Maria D. R. Maldonado Velazquez, Pilar Perez, Sagar Bhattad, Ranjana Minz, Jitendra Shandilya, Pediatric Allergy and Immunology Unit, PGIMER, Chandigarh, Ana Villarreal, Yuridiana Ramírez, Zeynep Birsin Özçakar, Suat Fitoz, Fatos Yalcinkaya, Annacarin Horne, Francesca Minoia, Francesca Bovis, Sergio Davi, Priyankar Pal, Kimo Stein, Sandra Enciso, Michael Jeng, Despoina Maritsi, Randy C. Cron, Anne Thorwarth, Sae Lim von Stuckrad, Angela Rösen-Wolff, Hella Luksch, Patrick Hundsdoerfer, Peter Krawitz, Nuray Aktay Ayaz, Doğan Simsek, Şebnem Sara Kılıc, Emine Sonmez, Aysenur Pac Kisaarslan, Ozge Altug Gucenmez, Z. Serap Arıcı, Fatih Kelesoglu, Zelal Ekinci Ekinci, Maria Miranda-Garcia, Carolin Pretzer, Michael Frosch, F. Gohar, Angela McArdle, Niamh Callan, Belinda Hernandez, Miha Lavric, Oliver FitzGerald, Stephen R. Pennington, Joachim Peitz, Joern Kekow, Ariane Klein, Anna C. Schulz, Frank Weller-Heinemann, Anton Hospach, J-Peter Haas, BIKER collaborative group, Karen Put, Jessica Vandenhaute, Anneleen Avau, Annemarie van Nieuwenhuijze, Ellen Brisse, Tim Dierckx, Omer Rutgeerts, Josselyn E. Garcia-Perez, Jaan Toelen, Mark Waer, Georges Leclercq, An Goris, Johan Van Weyenbergh, Adrian Liston, Patrick Matthys, Carine H. Wouters, Yasuo Nakagishi, Michael J. Ombrello, Victoria Arthur, Anne Hinks, Patricia Woo, International Childhood Arthritis Genetics (INCHARGE) Consortium, Barbara Stanimirovic, Biljana Djurdjevic-Banjac, Olivera Ljuboja, Boris Hugle, MArgarita Onoufriou, Olga Vougiouka, Kenza Bouayed, Sanae El Hani, Imane Hafid, Nabiha Mikou, Nunu Shelia, Mari Laan, Jaanika Ilisson, and Chris Pruunsild
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Pediatrics ,RJ1-570 ,Diseases of the musculoskeletal system ,RC925-935 - Published
- 2017
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13. Extended clinical and genetic spectrum associated with biallelic RTEL1 mutations
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Fabien Touzot, Laetitia Kermasson, Laurent Jullien, Despina Moshous, Christelle Ménard, Aydan Ikincioğullari, Figen Doğu, Sinan Sari, Vannina Giacobbi-Milet, Amos Etzioni, Jean Soulier, Arturo Londono-Vallejo, Alain Fischer, Isabelle Callebaut, Jean-Pierre de Villartay, Thierry Leblanc, Caroline Kannengiesser, and Patrick Revy
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Specialties of internal medicine ,RC581-951 - Abstract
Abstract: Telomeres are repetitive hexameric sequences located at the end of linear chromosomes. They adopt a lariat-like structure, the T-loop, to prevent them from being recognized as DNA breaks by the DNA repair machinery. RTEL1 is a DNA helicase required for proper telomere replication and stability. In particular, it has been postulated that RTEL1 is involved in the opening of the T-loop during telomere replication to avoid sudden telomere deletion and telomere circle (T-circle) formation. In humans, biallelic RTEL1 mutations cause Hoyeraal-Hreidarsson syndrome (HH), a rare and severe telomere biology disorder characterized by intrauterine growth retardation, bone marrow failure, microcephaly and/or cerebellar hypoplasia, and immunodeficiency. To date, 18 different RTEL1 mutations have been described in 19 cases of HH with short telomeres. The impaired T-loop resolution has been proposed to be a major cause of telomere shortening in RTEL1 deficiency. However, the biological and clinical consequences of this disorder remain incompletely documented. Here, we describe 4 new patients harboring biallelic RTEL1 mutations, including 2 novel missense mutations located in the C-terminal end of RTEL1 (p.Cys1268Arg and p.Val1294Phe). Clinical characteristics from these 4 patients were collected as those from 4 other RTEL1-deficient patients previously reported. In addition, we assessed whether T-circles, the product of improper T-loop resolution, were detected in our RTEL1-deficient patients. Overall, our study broadens and refines the clinical and biological spectrum of human RTEL1 deficiency.
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- 2016
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14. Late effects after hematopoietic stem cell transplantation for β-thalassemia major: the French national experience
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Ilhem Rahal, Claire Galambrun, Yves Bertrand, Nathalie Garnier, Catherine Paillard, Pierre Frange, Corinne Pondarré, Jean Hugues Dalle, Regis Peffault de Latour, Mauricette Michallet, Dominique Steschenko, Despina Moshous, Patrick Lutz, Jean Louis Stephan, Pierre Simon Rohrlich, Ibrahim Yakoub-Agha, Françoise Bernaudin, Christophe Piguet, Nathalie Aladjidi, Catherine Badens, Claire Berger, Gérard Socié, Cécile Dumesnil, Marie Pierre Castex, Marilyne Poirée, Anne Lambilliotte, Caroline Thomas, Pauline Simon, Pascal Auquier, Gérard Michel, Anderson Loundou, Imane Agouti, and Isabelle Thuret
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
In this retrospective study, we evaluate long-term complications in nearly all β-thalassemia-major patients who successfully received allogeneic hematopoietic stem cell transplantation in France. Ninety-nine patients were analyzed with a median age of 5.9 years at transplantation. The median duration of clinical follow up was 12 years. All conditioning regimens were myeloablative, most were based on busulfan combined with cyclophosphamide, and more than 90% of patients underwent a transplant from a matched sibling donor. After transplantation, 11% of patients developed thyroid dysfunction, 5% diabetes, and 2% heart failure. Hypogonadism was present in 56% of females and 14% of males. Female patients who went on to normal puberty after transplant were significantly younger at transplantation than those who experienced delayed puberty (median age 2.5 vs. 8.7 years). Fertility was preserved in 9 of 27 females aged 20 years or older and 2 other patients became pregnant following oocyte donation. In addition to patient’s age and higher serum ferritin levels at transplantation, time elapsed since transplant was significantly associated with decreased height growth in multivariate analysis. Weight growth increased after transplantation particularly in females, 36% of adults being overweight at last evaluation. A comprehensive long-term monitoring, especially of endocrine late effects, is required after hematopoietic stem cell transplantation for thalassemia.
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- 2018
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15. Disease Evolution and Response to Rapamycin in Activated Phosphoinositide 3-Kinase δ Syndrome: The European Society for Immunodeficiencies-Activated Phosphoinositide 3-Kinase δ Syndrome Registry
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Maria Elena Maccari, Hassan Abolhassani, Asghar Aghamohammadi, Alessandro Aiuti, Olga Aleinikova, Catherine Bangs, Safa Baris, Federica Barzaghi, Helen Baxendale, Matthew Buckland, Siobhan O. Burns, Caterina Cancrini, Andrew Cant, Pascal Cathébras, Marina Cavazzana, Anita Chandra, Francesca Conti, Tanya Coulter, Lisa A. Devlin, J. David M. Edgar, Saul Faust, Alain Fischer, Marina Garcia Prat, Lennart Hammarström, Maximilian Heeg, Stephen Jolles, Elif Karakoc-Aydiner, Gerhard Kindle, Ayca Kiykim, Dinakantha Kumararatne, Bodo Grimbacher, Hilary Longhurst, Nizar Mahlaoui, Tomas Milota, Fernando Moreira, Despina Moshous, Anna Mukhina, Olaf Neth, Benedicte Neven, Alexandra Nieters, Peter Olbrich, Ahmet Ozen, Jana Pachlopnik Schmid, Capucine Picard, Seraina Prader, William Rae, Janine Reichenbach, Stephan Rusch, Sinisa Savic, Alessia Scarselli, Raphael Scheible, Anna Sediva, Svetlana O. Sharapova, Anna Shcherbina, Mary Slatter, Pere Soler-Palacin, Aurelie Stanislas, Felipe Suarez, Francesca Tucci, Annette Uhlmann, Joris van Montfrans, Klaus Warnatz, Anthony Peter Williams, Phil Wood, Sven Kracker, Alison Mary Condliffe, and Stephan Ehl
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activated phosphoinositide 3-kinase δ syndrome ,PIK3CD ,PIK3R1 ,registry ,natural history ,rapamycin ,Immunologic diseases. Allergy ,RC581-607 - Abstract
Activated phosphoinositide 3-kinase (PI3K) δ Syndrome (APDS), caused by autosomal dominant mutations in PIK3CD (APDS1) or PIK3R1 (APDS2), is a heterogeneous primary immunodeficiency. While initial cohort-descriptions summarized the spectrum of clinical and immunological manifestations, questions about long-term disease evolution and response to therapy remain. The prospective European Society for Immunodeficiencies (ESID)-APDS registry aims to characterize the disease course, identify outcome predictors, and evaluate treatment responses. So far, 77 patients have been recruited (51 APDS1, 26 APDS2). Analysis of disease evolution in the first 68 patients pinpoints the early occurrence of recurrent respiratory infections followed by chronic lymphoproliferation, gastrointestinal manifestations, and cytopenias. Although most manifestations occur by age 15, adult-onset and asymptomatic courses were documented. Bronchiectasis was observed in 24/40 APDS1 patients who received a CT-scan compared with 4/15 APDS2 patients. By age 20, half of the patients had received at least one immunosuppressant, but 2–3 lines of immunosuppressive therapy were not unusual before age 10. Response to rapamycin was rated by physician visual analog scale as good in 10, moderate in 9, and poor in 7. Lymphoproliferation showed the best response (8 complete, 11 partial, 6 no remission), while bowel inflammation (3 complete, 3 partial, 9 no remission) and cytopenia (3 complete, 2 partial, 9 no remission) responded less well. Hence, non-lymphoproliferative manifestations should be a key target for novel therapies. This report from the ESID-APDS registry provides comprehensive baseline documentation for a growing cohort that will be followed prospectively to establish prognostic factors and identify patients for treatment studies.
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- 2018
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16. Mutations in the adaptor-binding domain and associated linker region of p110δ cause Activated PI3K-δ Syndrome 1 (APDS1)
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Lucie Heurtier, Hicham Lamrini, Loïc Chentout, Marie-Céline Deau, Amine Bouafia, Jérémie Rosain, Jean-Marc Plaza, Mélanie Parisot, Benoit Dumont, Delphine Turpin, Etienne Merlin, Despina Moshous, Nathalie Aladjidi, Bénédicte Neven, Capucine Picard, Marina Cavazzana, Alain Fischer, Anne Durandy, Jean-Louis Stephan, and Sven Kracker
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Published
- 2017
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17. The syndrome of hemophagocytic lymphohistiocytosis in primary immunodeficiencies: implications for differential diagnosis and pathogenesis
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Sebastian FN Bode, Sandra Ammann, Waleed Al-Herz, Mihaela Bataneant, Christopher C Dvorak, Stephan Gehring, Andrew Gennery, Kimberly C Gilmour, Luis I Gonzalez-Granado, Ute Groß-Wieltsch, Marianne Ifversen, Jenny Lingman-Framme, Susanne Matthes-Martin, Rolf Mesters, Isabelle Meyts, Joris M van Montfrans, Jana Pachlopnik Schmid, Sung-Yun Pai, Pere Soler-Palacin, Uta Schuermann, Volker Schuster, Markus G. Seidel, Carsten Speckmann, Polina Stepensky, Karl-Walter Sykora, Bianca Tesi, Thomas Vraetz, Catherine Waruiru, Yenan T. Bryceson, Despina Moshous, Kai Lehmberg, Michael B Jordan, and Stephan Ehl
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Diseases of the blood and blood-forming organs ,RC633-647.5 - Abstract
Hemophagocytic lymphohistiocytosis is a hyperinflammatory syndrome defined by clinical and laboratory criteria. Current criteria were created to identify patients with familial hemophagocytic lmyphohistiocytosis in immediate need of immunosuppressive therapy. However, these criteria also identify patients with infection-associated hemophagocytic inflammatory states lacking genetic defects typically predisposing to hemophagocytic lymphohistiocytosis. These patients include those with primary immunodeficiencies, in whom the pathogenesis of the inflammatory syndrome may be distinctive and aggressive immunosuppression is contraindicated. To better characterize hemophagocytic inflammation associated with immunodeficiencies, we combined an international survey with a literature search and identified 63 patients with primary immunodeficiencies other than cytotoxicity defects or X-linked lymphoproliferative disorders, presenting with conditions fulfilling current criteria for hemophagocytic lymphohistiocytosis. Twelve patients had severe combined immunodeficiency with
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- 2015
- Full Text
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18. Coronin 1 regulates cognition and behavior through modulation of cAMP/protein kinase A signaling.
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Rajesh Jayachandran, Xiaolong Liu, Somdeb Bosedasgupta, Philipp Müller, Chun-Lei Zhang, Despina Moshous, Vera Studer, Jacques Schneider, Christel Genoud, Catherine Fossoud, Frédéric Gambino, Malik Khelfaoui, Christian Müller, Deborah Bartholdi, Helene Rossez, Michael Stiess, Xander Houbaert, Rolf Jaussi, Daniel Frey, Richard A Kammerer, Xavier Deupi, Jean-Pierre de Villartay, Andreas Lüthi, Yann Humeau, and Jean Pieters
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Biology (General) ,QH301-705.5 - Abstract
Cognitive and behavioral disorders are thought to be a result of neuronal dysfunction, but the underlying molecular defects remain largely unknown. An important signaling pathway involved in the regulation of neuronal function is the cyclic AMP/Protein kinase A pathway. We here show an essential role for coronin 1, which is encoded in a genomic region associated with neurobehavioral dysfunction, in the modulation of cyclic AMP/PKA signaling. We found that coronin 1 is specifically expressed in excitatory but not inhibitory neurons and that coronin 1 deficiency results in loss of excitatory synapses and severe neurobehavioral disabilities, including reduced anxiety, social deficits, increased aggression, and learning defects. Electrophysiological analysis of excitatory synaptic transmission in amygdala revealed that coronin 1 was essential for cyclic-AMP-protein kinase A-dependent presynaptic plasticity. We further show that upon cell surface stimulation, coronin 1 interacted with the G protein subtype Gαs to stimulate the cAMP/PKA pathway. The absence of coronin 1 or expression of coronin 1 mutants unable to interact with Gαs resulted in a marked reduction in cAMP signaling. Strikingly, synaptic plasticity and behavioral defects of coronin 1-deficient mice were restored by in vivo infusion of a membrane-permeable cAMP analogue. Together these results identify coronin 1 as being important for cognition and behavior through its activity in promoting cAMP/PKA-dependent synaptic plasticity and may open novel avenues for the dissection of signal transduction pathways involved in neurobehavioral processes.
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- 2014
- Full Text
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19. Hematopoietic stem cell transplantation for adolescents and adults with inborn errors of immunity: an EBMT IEWP study
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Michael H. Albert, Tiarlan Sirait, Dirk-Jan Eikema, Katerina Bakunina, Claudia Wehr, Felipe Suarez, Maria Laura Fox, Nizar Mahlaoui, Andrew R. Gennery, Arjan C. Lankester, Rita Beier, Maria Ester Bernardo, Venetia Bigley, Caroline A. Lindemans, Siobhan O. Burns, Ben Carpenter, Jaroslaw Dybko, Tayfun Güngör, Fabian Hauck, Su Han Lum, Dmitry Balashov, Roland Meisel, Despina Moshous, Ansgar Schulz, Carsten Speckmann, Mary A. Slatter, Brigitte Strahm, Duygu Uckan-Cetinkaya, Isabelle Meyts, Tanja C. Vallée, Robert Wynn, Bénédicte Neven, Emma C. Morris, Alessandro Aiuti, Alexei Maschan, Mahmoud Aljurf, Tobias Gedde-Dahl, Gunhan Gurman, Victoria Bordon, Gergely Kriván, Franco Locatelli, Fulvio Porta, David Valcárcel, Yves Beguin, Maura Faraci, Nicolaus Kröger, Aleksandr Kulagin, Peter J. Shaw, Joan Hendrik Veelken, Cristina Diaz de Heredia, Franca Fagioli, Matthias Felber, Bernd Gruhn, Wolfgang Holter, Claudia Rössig, Petr Sedlacek, Jane Apperley, Mouhab Ayas, Ivana Bodova, Goda Choi, J.J. Cornelissen, Anne Sirvent, Anjum Khan, Alphan Kupesiz, Stig Lenhoff, Hakan Ozdogu, Nicolas von der Weid, Montserrat Rovira, Rik Schots, Donald C. Vinh, Clinical sciences, and Hematology
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Adult ,Adolescent ,adolescenti ,Trapianto ,Immunology ,Graft vs Host Disease ,Biochemistry ,Bronchiectasis/etiology ,Humans ,Transplantation, Homologous ,Hematopoietic Stem Cell Transplantation/adverse effects ,Child ,Retrospective Studies ,cellule staminali ematopoietiche ,Hematopoietic Stem Cell Transplantation ,Infant ,Trapianto, cellule staminali ematopoietiche, adolescenti ,Inborn errors of immunity ,Cell Biology ,Hematology ,Middle Aged ,Bronchiectasis ,surgical procedures, operative ,Settore MED/38 - PEDIATRIA GENERALE E SPECIALISTICA ,HSCT ,young adult - Abstract
Allogeneic hematopoietic stem cell transplantation (HSCT) is the gold standard curative therapy for infants and children with many inborn errors of immunity (IEI), but adolescents and adults with IEI are rarely referred for transplant. Lack of published HSCT outcome data outside small, single-center studies and perceived high risk of transplant-related mortality have delayed the adoption of HSCT for IEI patients presenting or developing significant organ damage later in life. This large retrospective, multicenter HSCT outcome study reports on 329 IEI patients (age range, 15-62.5 years at HSCT). Patients underwent first HSCT between 2000 and 2019. Primary endpoints were overall survival (OS) and event-free survival (EFS). We also evaluated the influence of IEI-subgroup and IEI-specific risk factors at HSCT, including infections, bronchiectasis, colitis, malignancy, inflammatory lung disease, splenectomy, hepatic dysfunction, and systemic immunosuppression. At a median follow-up of 44.3 months, the estimated OS at 1 and 5 years post-HSCT for all patients was 78% and 71%, and EFS was 65% and 62%, respectively, with low rates of severe acute (8%) or extensive chronic (7%) graft-versus-host disease. On univariate analysis, OS and EFS were inferior in patients with primary antibody deficiency, bronchiectasis, prior splenectomy, hepatic comorbidity, and higher hematopoietic cell transplant comorbidity index scores. On multivariable analysis, EFS was inferior in those with a higher number of IEI-associated complications. Neither age nor donor had a significant effect on OS or EFS. We have identified age-independent risk factors for adverse outcome, providing much needed evidence to identify which patients are most likely to benefit from HSCT. ispartof: BLOOD vol:140 issue:14 pages:1635-1649 ispartof: location:United States status: published
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- 2022
20. Partial RAG deficiency in humans induces dysregulated peripheral lymphocyte development and humoral tolerance defect with accumulation of T-bet+ B cells
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Krisztian Csomos, Boglarka Ujhazi, Peter Blazso, Jose L. Herrera, Christopher M. Tipton, Tomoki Kawai, Sumai Gordon, Maryssa Ellison, Kevin Wu, Matthew Stowell, Lauren Haynes, Rachel Cruz, Bence Zakota, Johnny Nguyen, Michelle Altrich, Christoph B. Geier, Svetlana Sharapova, Joseph F. Dasso, Jennifer W. Leiding, Grace Smith, Waleed Al-Herz, Mayra de Barros Dorna, Olajumoke Fadugba, Eva Fronkova, Veronika Kanderova, Michael Svaton, Sarah E. Henrickson, Joseph D. Hernandez, Taco Kuijpers, Snezhina Mihailova Kandilarova, Elizaveta Naumova, Tomas Milota, Anna Sediva, Despina Moshous, Benedicte Neven, Tara Saco, Ravishankar Sargur, Sinisa Savic, John Sleasman, Gauri Sunkersett, Brant R. Ward, Masanobu Komatsu, Stefania Pittaluga, Attila Kumanovics, Manish J. Butte, Michael P. Cancro, Shiv Pillai, Eric Meffre, Luigi D. Notarangelo, Jolan E. Walter, Paediatric Infectious Diseases / Rheumatology / Immunology, AII - Inflammatory diseases, and ARD - Amsterdam Reproduction and Development
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Homeodomain Proteins ,B-Lymphocytes ,1.1 Normal biological development and functioning ,Immunology ,Nuclear Proteins ,Cell Differentiation ,DNA-Binding Proteins ,Infectious Diseases ,Underpinning research ,Immune Tolerance ,Humans ,Immunology and Allergy ,Lymphocyte Count ,Biotechnology - Abstract
The recombination-activating genes (RAG) 1 and 2 are indispensable for diversifying the primary B cell receptor repertoire and pruning self-reactive clones via receptor editing in the bone marrow; however, the impact ofRAG1/RAG2on peripheral tolerance is unknown. Partial RAG deficiency (pRD) manifesting with late-onset immune dysregulation represents an ‘experiment of nature’ to explore this conundrum. By studying B cell development and subset-specific repertoires in pRD, we demonstrate that reduced RAG activity impinges on peripheral tolerance through the generation of a restricted primary B cell repertoire, persistent antigenic stimulation and an inflammatory milieu with elevated B cell-activating factor. This unique environment gradually provokes profound B cell dysregulation with widespread activation, remarkable extrafollicular maturation and persistence, expansion and somatic diversification of self-reactive clones. Through the model of pRD, we reveal aRAG-dependent ‘domino effect’ that impacts stringency of tolerance and B cell fate in the periphery.
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- 2022
21. Determinants of long-term outcomes of splenectomy in pediatric autoimmune cytopenias
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Thomas Pincez, Nathalie Aladjidi, Sébastien Héritier, Nathalie Garnier, Mony Fahd, Wadih Abou Chahla, Helder Fernandes, Claire Dichamp, Stéphane Ducassou, Marlène Pasquet, Sophie Bayart, Despina Moshous, Nathalie Cheikh, Catherine Paillard, Dominique Plantaz, Eric Jeziorski, Caroline Thomas, Corinne Guitton, Marianna Deparis, Aude Marie Cardine, Jean-Louis Stephan, Isabelle Pellier, Eric Doré, Joy Benadiba, Claire Pluchart, Claire Briandet, Vincent Barlogis, Guy Leverger, and Thierry Leblanc
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Cohort Studies ,Immunology ,Splenectomy ,Humans ,Anemia, Hemolytic, Autoimmune ,Cell Biology ,Hematology ,Child ,Thrombocytopenia ,Biochemistry - Abstract
Splenectomy is effective in ∼70% to 80% of pediatric chronic immune thrombocytopenia (cITP) cases, and few data exist about it in autoimmune hemolytic anemia (AIHA) and Evans syndrome (ES). Because of the irreversibility of the procedure and the lack of predictions regarding long-term outcomes, the decision to undertake splenectomy is difficult in children. We report here factors associated with splenectomy outcomes from the OBS’CEREVANCE cohort, which prospectively includes French children with autoimmune cytopenia (AIC) since 2004. The primary outcome was failure-free survival (FFS), defined as the time from splenectomy to the initiation of a second-line treatment (other than steroids and intravenous immunoglobulins) or death. We included 161 patients (cITP, n = 120; AIHA, n = 19; ES, n = 22) with a median (minimum-maximum) follow-up of 6.8 years (1.0-33.3) after splenectomy. AIC subtype was not associated with FFS. We found that immunopathological manifestations (IMs) were strongly associated with unfavorable outcomes. Diagnosis of an IM before splenectomy was associated with a lower FFS (hazard ratio [HR], 0.39; 95% confidence interval [CI], 0.21-0.72, P = .003, adjusted for AIC subtype). Diagnosis of an IM at any timepoint during follow-up was associated with an even lower FFS (HR, 0.22; 95% CI, 0.12-0.39; P = 2.8 × 10−7, adjusted for AIC subtype) as well as with higher risk of recurrent or severe bacterial infections and thrombosis. In conclusion, our results support the search for associated IMs when considering a splenectomy to refine the risk-benefit ratio. After the procedure, monitoring IMs helps to identify patients with higher risk of unfavorable outcomes.
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- 2022
22. JAK inhibition in Aicardi-Goutières syndrome: a monocentric multidisciplinary real-world approach study
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Marie-Louise Frémond, Marie Hully, Benjamin Fournier, Rémi Barrois, Romain Lévy, Mélodie Aubart, Martin Castelle, Delphine Chabalier, Clarisse Gins, Eugénie Sarda, Buthaina Al Adba, Sophie Couderc, Céline D’ Almeida, Claire-Marine Berat, Chloé Durrleman, Caroline Espil, Laetitia Lambert, Cécile Méni, Maximilien Périvier, Pascal Pillet, Laura Polivka, Manuel Schiff, Calina Todosi, Florence Uettwiller, Alice Lepelley, Gillian I. Rice, Luis Seabra, Sylvia Sanquer, Anne Hulin, Claire Pressiat, Lauriane Goldwirt, Vincent Bondet, Darragh Duffy, Despina Moshous, Brigitte Bader-Meunier, Christine Bodemer, Florence Robin-Renaldo, Nathalie Boddaert, Stéphane Blanche, Isabelle Desguerre, Yanick J. Crow, Bénédicte Neven, CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Université Paris Cité (UPCité), Neurogénétique et neuroinflammation = Neurogenetics and neuroinflammation (Equipe Inserm U1163), Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Sidra Medicine [Doha, Qatar], Centre hospitalier intercommunal de Poissy/Saint-Germain-en-Laye - CHIPS [Poissy], Centre Hospitalier Intercommunal Castres-Mazamet (CHIC-CM), CHU Bordeaux [Bordeaux], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), University of Manchester [Manchester], Hôpital Henri Mondor, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Hopital Saint-Louis [AP-HP] (AP-HP), Immunologie Translationnelle - Translational Immunology lab, Institut Pasteur [Paris] (IP)-Université Paris Cité (UPCité), CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), University of Edinburgh, Immunogenetics of pediatric autoimmune diseases (Equipe Inserm U1163), M.-L. F. received a grant from the Institut National de la Santé et de la Recherche Médicale (reference: 000427993). Y. J. C. acknowledges the European Research Council (GA309449 and 786142-E-T1IFNs) and a state subsidy managed by the National Research Agency (France) under the 'Investments for the Future' program bearing the reference ANR-10-IAHU-01. Y. J. C. is supported by a UK Medical Research Council Human Genetics Unit core grant (MRC, U127580972). Y. J. C. and D. D. acknowledge the ANR (grant CE17001002). D. D. thanks ImmunoQure AG for the provision of antibodies for the Simoa assay. The project was supported by MSDAVENIR (Devo-Decode Project)., ANR-10-IAHU-0001,Imagine,Institut Hospitalo-Universitaire Imagine(2010), and European Project: 786142,ERC-2017-ADG,E-T1IFNs(2018)
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JAK inhibitors ,[SDV]Life Sciences [q-bio] ,Aicardi-Goutières syndrome (AGS) ,Immunology ,Immunology and Allergy ,interferon - Abstract
The paradigm type I interferonopathy Aicardi-Goutières syndrome (AGS) is most typically characterized by severe neurological involvement. AGS is considered an immune-mediated disease, poorly responsive to conventional immunosuppression. Premised on a chronic enhancement of type I interferon signaling, JAK1/2 inhibition has been trialed in AGS, with clear improvements in cutaneous and systemic disease manifestations. Contrastingly, treatment efficacy at the level of the neurological system has been less conclusive. Here, we report our real-word approach study of JAK1/2 inhibition in 11 patients with AGS, providing extensive assessments of clinical and radiological status; interferon signaling, including in cerebrospinal fluid (CSF); and drug concentrations in blood and CSF. Over a median follow-up of 17 months, we observed a clear benefit of JAK1/2 inhibition on certain systemic features of AGS, and reproduced results reported using the AGS neurologic severity scale. In contrast, there was no change in other scales assessing neurological status; using the caregiver scale, only patient comfort, but no other domain of everyday-life care, was improved. Serious bacterial infections occurred in 4 out of the 11 patients. Overall, our data lead us to conclude that other approaches to treatment are urgently required for the neurologic features of AGS. We suggest that earlier diagnosis and adequate central nervous system penetration likely remain the major factors determining the efficacy of therapy in preventing irreversible brain damage, implying the importance of early and rapid genetic testing and the consideration of intrathecal drug delivery.
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- 2023
23. Clinical, Immunological Features, Treatments, and Outcomes of Autoimmune Hemolytic Anemia in Patients with RAG Deficiency
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Chen Wang, Bijun Sun, Kevin Wu, Jocelyn Farmer, Boglarka Ujhazi, Christoph B. Geier, Sumai Gordon, Emma Westermann-Clark, Sinisa Savic, Sargur Ravishankar, Karin Chen, Cullen M Dutmer, Maria G Kanariou, Mehdi Adeli, Paolo Palma, Carmem Bonfim, Evangelia Lycopoulou, Beata Wolska-Kusnierz, Dbaibo Ghassan, Jack Bleesing, Despina Moshous, Benedicte Neven, Catharina Schuetz, Geha Raif, Luigi D. Notarangelo, Maurizio Miano, David K. Buchbinder, Krisztian Csomos, Wenjie Wang, Ji-Yang Wang, Xiaochuan Wang, and Jolan E. Walter
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Immunology ,Cell Biology ,Hematology ,Biochemistry - Published
- 2022
24. DOCK11 deficiency in patients with X-linked actinopathy and autoimmunity
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Charlotte Boussard, Laure Delage, Tania Gajardo, Alexandre Kauskot, Maxime Batignes, Nicolas Goudin, Marie-Claude Stolzenberg, Camille Brunaud, Patricia Panikulam, Quentin Riller, Maryse Moya-Nilges, Jean Solarz, Christelle Reperant, Béatrice Durel, Jean-Claude Bordet, Olivier Pellé, Corinne Lebreton, Aude Magerus-Chatinet, Vithura Pirabakaran, Pablo Vargas, Sébastien Dupichaud, Marie Jeanpierre, Angélique Vinit, Mohammed Zarhrate, Cécile Masson, Nathalie Aladjidi, Peter D Arkwright, Brigitte Bader-Meunier, Sandrine Baron Joly, Joy Benadiba, Elise Bernard, Dominique Berrebi, Christine Bodemer, Martin Castelle, Fabienne Charbit-Henrion, Marwa Chbihi, Agathe Debray, Philippe Drabent, Sylvie Fraitag, Miguel Hié, Judith Landman-Parker, Ludovic Lhermitte, Despina Moshous, Pierre Rohrlich, Frank M Ruemmele, Anne Welfringer-Morin, Maud Tusseau, Alexandre Belot, Nadine Cerf-Bensussan, Marie Roelens, Capucine Picard, Bénédicte Neven, Alain Fischer, Isabelle Callebaut, Mickaël Mathieu Ménager, Fernando E Sepulveda, Frédéric Adam, and Frédéric Rieux-Laucat
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Immunology ,Cell Biology ,Hematology ,Biochemistry - Abstract
Dedicator of cytokinesis (DOCK) proteins play a central role in actin cytoskeleton regulation. This is highlighted by the DOCK2 and DOCK8 deficiencies leading to actinopathies and immune deficiencies. DOCK8 and DOCK11 activate CDC42, a RHO-GTPase involved in actin cytoskeleton dynamics, among many cellular functions. The role of DOCK11 in human immune disease has been long suspected but has never been described so far. We studied eight male patients, from seven unrelated families, with hemizygous DOCK11 missense variants leading to reduced DOCK11 expression. The patients were presenting with early-onset autoimmunity, including cytopenia, systemic lupus erythematosus, skin, and digestive manifestations. Patients' platelets exhibited abnormal ultrastructural morphology and spreading as well as impaired CDC42 activity. In vitro activated T cells and B lymphoblastoid cell lines (B-LCL) of patients exhibited aberrant protrusions and abnormal migration speed in confined channels concomitant with altered actin polymerization during migration. A DOCK11 knock-down recapitulated these abnormal cellular phenotypes in monocytes-derived dendritic cells (MDDC) and primary activated T cells from healthy controls. Lastly, in line with the patients' autoimmune manifestations, we also observed abnormal regulatory T cells (Tregs) phenotype with profoundly reduced FOXP3 and IKZF2 expression. Moreover, we found a reduced T cell proliferation and an impaired STAT5B phosphorylation upon IL2 stimulation of the patients' lymphocytes. In conclusion, DOCK11 deficiency is a new X-linked immune-related actinopathy leading to impaired CDC42 activity and STAT5 activation, and associated with abnormal actin cytoskeleton remodeling as well as Tregs phenotype culminating in immune dysregulation and severe early-onset autoimmunity.
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- 2023
25. Late-onset enteric virus infection associated with hepatitis (EVAH) in transplanted SCID patients
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Quentin Riller, Jacques Fourgeaud, Julie Bruneau, Suk See De Ravin, Grace Smith, Mathieu Fusaro, Samy Meriem, Aude Magerus, Marine Luka, Ghaith Abdessalem, Ludovic Lhermitte, Anne Jamet, Emmanuelle Six, Alessandra Magnani, Martin Castelle, Romain Lévy, Mathilde M. Lecuit, Benjamin Fournier, Sarah Winter, Michaela Semeraro, Graziella Pinto, Hanène Abid, Nizar Mahlaoui, Nathalie Cheikh, Benoit Florkin, Pierre Frange, Eric Jeziorski, Felipe Suarez, Françoise Sarrot-Reynauld, Dalila Nouar, Dominique Debray, Florence Lacaille, Capucine Picard, Philippe Pérot, Béatrice Regnault, Nicolas Da Rocha, Camille de Cevins, Laure Delage, Brieuc P. Pérot, Angélique Vinit, Francesco Carbone, Camille Brunaud, Manon Marchais, Marie-Claude Stolzenberg, Vahid Asnafi, Thierry Molina, Frédéric Rieux-Laucat, Luigi D. Notarangelo, Stefania Pittaluga, Jean Philippe Jais, Despina Moshous, Stephane Blanche, Harry Malech, Marc Eloit, Marina Cavazzana, Alain Fischer, Mickaël M. Ménager, and Bénédicte Neven
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Immunology ,Immunology and Allergy - Published
- 2023
26. Impact of graft function on health status and quality of life in 112 very long-term survivors who received an HSCT for Inborn Errors of Immunity, a prospective study of the CEREDIH
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Audrey Françoise Petit, Bénédicte Neven, Victoria Min, Nizar Mahlaoui, Despina Moshous, Martin Castelle, Maya Allouche, Arthur Stérin, Sandrine Visentin, Mohamed Boucekine, Alaa Mustafa Shawket, Capucine Picard, Pascal Auquier, Gérard Michel, Alain FISCHER, and Vincent Barlogis
- Abstract
Hematopoietic stem cell transplantation (HSCT) for Inborn Errors of Immunity (IEI) survival outcome has improved considerably and the indications have broadened. Subsequently, the issue of long-term quality of live (HRQoL) has become crucial. Our study focuses on the health and HRQoL of post-HSCT survivors . We conducted a multicenter prospective follow-up program enrolling IEI patients included in the CEREDIH (French IEI Reference Centers) registry, transplanted during childhood, before 2009. Answers from self-reported French Childhood Immune Deficiency Long-term Cohort (F-CILC) and 36-item Short Form (SF-36) questionnaires were compiled. 112 survivors were included with a time median from HSCT of 15 years (range :5-37), 55% were transplanted for a combined immunodeficiency. We show that in patients evaluated prospectively at least 5 years after HSCT, 55% are still affected by a poor or very poor health status. Poor and very poor health status were correlated with an abnormal graft function defined as host or mixed chimerism and/or an abnormal CD3+ count and/or a diagnosis of chronic GVHD (Poor health: OR 2,6 CI 95%: 1,1-5,9 p:0,028 ; Very poor health : OR 3,6 CI 95%: 1,1-13, p:0,049 ). Poor health directly linked to a poorer HRQoL. Significant improvements made in graft procedures translated in better survival, but we show that about half of the survivors are affected by an altered health with a correlation to both abnormal graft function and impaired HRQoL. Future prospective studies will be needed to measure the impact of those improvements on long-term health status and HRQoL.
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- 2022
27. V0-ATPase downregulation induces MVID-like brush border defects independently of apical trafficking in the mammalian intestine
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Aurélien Bidaud-Meynard, Ophélie Nicolle, Anne Bourdais, Maela Duclos, Jad Saleh, Frank Ruemmele, Henner F Farin, Delphine Delacour, Despina Moshous, Grégoire Michaux, Centre National de la Recherche Scientifique (CNRS), Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Institut de recherche en santé, environnement et travail (Irset), Université d'Angers (UA)-Université de Rennes (UR)-École des Hautes Études en Santé Publique [EHESP] (EHESP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), École des Hautes Études en Santé Publique [EHESP] (EHESP), Université de Rennes (UR), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Service d'immuno-hématologie pédiatrique [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Institute for Tumor Biology and Experimental Therapy [Frankfurt, Germany], German Cancer Consortium [Heidelberg] (DKTK), and Goethe-University Frankfurt am Main
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MVI ,[SDV]Life Sciences [q-bio] ,MVID ,microvillus inclusion ,microvillus inclusion disease - Abstract
SummaryIntestinal microvillus atrophy is a major cause of enteropathies such as idiopathic or congenital diarrhea that are often associated with severe morbidity. It can be caused by genetic disorders, inflammatory diseases, toxins or pathogens. In particular, Microvillus inclusion disease (MVID) is characterized by a chronic intractable diarrhea and a severe microvillus atrophy. It is triggered by mutations inMYO5B, STX3, MUNC18.2orUNC45Awhich alter epithelial polarity by affecting apical trafficking in intestinal epithelial cells. Furthermore, we recently established that the depletion of the V0sector of the V-ATPase complex induces an MVID-like phenotype inC. elegans. In this study we investigated the function of the V0-ATPase complex in mouse intestinal organoids. We found that its depletion also triggers a very severe microvillus atrophy in this model. Furthermore, we established that the polarity of intestinal cells is affected in a patient carrying mutations inTCIRG1which encodes a V0-ATPase subunit. However, V0- ATPase depletion does not recapitulate other MVID-specific phenotypes such as subapical vesicle accumulation and Rab11+ endosomes mislocalization. Finally, we found that the apical localization of the V0-ATPase is disrupted in MVID patients. Altogether these results suggest a role for the V0-ATPase in microvillus atrophy which might be independent from apical trafficking.
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- 2022
28. Child Neurology: Familial Hemophagocytic Lymphohistiocytosis Underlying Isolated CNS Inflammation
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Giorgia, Bucciol, Nele, Willemyns, Benjamin, Verhaaren, Xavier, Bossuyt, Katrien, Lagrou, Anniek, Corveleyn, Despina, Moshous, Katrien, Jansen, Liesbeth, De Waele, and Isabelle, Meyts
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Inflammation ,Brain Diseases ,Neurology ,Encephalitis ,Humans ,Neurology (clinical) ,Child ,Lymphohistiocytosis, Hemophagocytic - Abstract
Encephalitis and encephalopathy in children represent a diagnostic challenge. We describe a patient with relapsing encephalitis in whom the differential diagnosis included acute disseminated encephalomyelitis, human herpesvirus 6 encephalitis, and hemophagocytic lymphohistiocytosis (HLH). Because of its rarity, HLH is often overlooked as a differential diagnosis in encephalitis, especially in the isolated CNS forms. As this case illustrates, inborn errors of immunity can underlie isolated encephalitis and should be included in the differential diagnosis of these presentations. ispartof: Neurology vol:99 issue:15 pages:660-664 ispartof: location:United States status: published
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- 2022
29. Fatal encephalitis caused by Newcastle disease virus in a child
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Fabrice Chrétien, Judith Chareyre, Christophe Rodriguez, Jean-Michel Pawlotsky, Despina Moshous, Sarah Winter, Thomas Blauwblomme, Melissa N‘debi, Vanessa Demontant, Fanny Fouyssac, Stéphane Blanche, Emmanuèle Lechapt, Nathalie Boddaert, Paul-Louis Woerther, Manoelle Kossorotoff, Bénédicte Neven, and G. Gricourt
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Cellular and Molecular Neuroscience ,medicine ,Neurology (clinical) ,Biology ,medicine.disease ,biology.organism_classification ,Virology ,Newcastle disease ,Encephalitis ,Virus ,Pathology and Forensic Medicine - Published
- 2021
30. Allogeneic stem cell transplantation compared to conservative management in adults with inborn errors of immunity
- Author
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Morgane Cheminant, Thomas A. Fox, Mickael Alligon, Olivier Bouaziz, Bénédicte Neven, Despina Moshous, Stéphane Blanche, Aurélien Guffroy, Claire Fieschi, Marion Malphettes, Nicolas Schleinitz, Antoinette Perlat, Jean-François Viallard, Nathalie Dhedin, Françoise Sarrot-Reynauld, Isabelle Durieu, Sébastien Humbert, Fanny Fouyssac, Vincent Barlogis, Benjamin Carpenter, Rachael Hough, Arian Laurence, Ambroise Marçais, Ronjon Chakraverty, Olivier Hermine, Alain Fischer, Siobhan O. Burns, Nizar Mahlaoui, Emma C. Morris, and Felipe Suarez
- Subjects
Adult ,Transplantation Conditioning ,Immunology ,Hematopoietic Stem Cell Transplantation ,Graft vs Host Disease ,Cell Biology ,Hematology ,Granulomatous Disease, Chronic ,Conservative Treatment ,Biochemistry ,Young Adult ,Humans ,Transplantation, Homologous ,Retrospective Studies ,Stem Cell Transplantation - Abstract
Allogeneic hematopoietic stem cell transplantation (alloSCT) is curative for severe inborn errors of immunity (IEIs), with recent data suggesting alloSCT in adulthood is safe and effective in selected patients. However, questions remain regarding the indications for and optimal timing of transplant. We retrospectively compared outcomes of transplanted vs matched nontransplanted adults with severe IEIs. Seventy-nine patients (aged ≥ 15 years) underwent alloSCT between 2008 and 2018 for IEIs such as chronic granulomatous disease (n = 20) and various combined immune deficiencies (n = 59). A cohort of nontransplanted patients from the French Centre de Référence Déficits Immunitaires Héréditaires registry was identified blindly for case-control analysis, with ≤3 matched controls per index patient, without replacement. The nontransplanted patients were matched for birth decade, age at last review greater than index patient age at alloSCT, chronic granulomatous disease or combined immune deficiencies, and autoimmune/lymphoproliferative complications. A total of 281 patients were included (79 transplanted, 202 nontransplanted). Median age at transplant was 21 years. Transplant indications were mainly lymphoproliferative disease (n = 23) or colitis (n = 15). Median follow-up was 4.8 years (interquartile range, 2.5-7.2). One-year transplant-related mortality rate was 13%. Estimated disease-free survival at 5 years was higher in transplanted patients (58% vs 33%; P = .007). Nontransplanted patients had an ongoing risk of severe events, with an increased mean cumulative number of recurrent events compared with transplanted patients. Sensitivity analyses removing patients with common variable immune deficiency and their matched transplanted patients confirm these results. AlloSCT prevents progressive morbidity associated with IEIs in adults, which may outweigh the negative impact of transplant-related mortality.
- Published
- 2022
31. Inherited TNFSF9 deficiency causes broad Epstein–Barr virus infection with EBV+ smooth muscle tumors
- Author
-
Benjamin Fournier, Akihiro Hoshino, Julie Bruneau, Camille Bachelet, Mathieu Fusaro, Roman Klifa, Romain Lévy, Christelle Lenoir, Claire Soudais, Capucine Picard, Stéphane Blanche, Martin Castelle, Despina Moshous, Thierry Molina, Anne-Sophie Defachelles, Bénédicte Neven, Sylvain Latour, Activation lymphocytaire et susceptibilité au virus d’Epstein-Barr = Lymphocyte activation and susceptibility to EBV, Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité), Centre Régional de Lutte contre le Cancer Oscar Lambret [Lille] (UNICANCER/Lille), Université de Lille-UNICANCER, ANR-18-CE15-0025,ImmunoBioCTPS1,Comprendre la biologie et la physiopathologie de CTPS1, une nouvelle cible pour le développement d'immunosuppresseurs.(2018), Lymphocyte activation and susceptibility to EBV (Equpie Inserm U1163), and LATOUR, Sylvain
- Subjects
[SDV] Life Sciences [q-bio] ,B-Lymphocytes ,Epstein-Barr Virus Infections ,Herpesvirus 4, Human ,4-1BB Ligand ,T-Lymphocytes ,[SDV]Life Sciences [q-bio] ,Immunology ,Humans ,Immunology and Allergy ,Smooth Muscle Tumor - Abstract
International audience; Epstein–Barr virus (EBV) can infect smooth muscle cells causing smooth muscle tumors (SMTs) or leiomyoma. Here, we report a patient with a heterozygous 22q11.2 deletion/DiGeorge syndrome who developed a unique, broad, and lethal susceptibility to EBV characterized by EBV-infected T and B cells and disseminated EBV+SMT. The patient also harbored a homozygous missense mutation (p.V140G) in TNFSF9 coding for CD137L/4-1BBL, the ligand of the T cell co-stimulatory molecule CD137/4-1BB, whose deficiency predisposes to EBV infection. We show that wild-type CD137L was up-regulated on activated monocytes and dendritic cells, EBV-infected B cells, and SMT. The CD137LV140G mutant was weakly expressed on patient cells or when ectopically expressed in HEK and P815 cells. Importantly, patient EBV-infected B cells failed to trigger the expansion of EBV-specific T cells, resulting in decreased T cell effector responses. T cell expansion was recovered when CD137L expression was restored on B cells. Therefore, these results highlight the critical role of the CD137–CD137L pathway in anti-EBV immunity, in particular in the control of EBV+SMT.
- Published
- 2022
32. Current Spectrum of Infections in Patients with X-Linked Agammaglobulinemia
- Author
-
Olivier Hermine, Felipe Suarez, Bénédicte Neven, Olivier Lortholary, Capucine Picard, Olivier Paccoud, Alain Fischer, Stéphane Blanche, Marc Lecuit, Claire Aguilar, Nizar Mahlaoui, Despina Moshous, and Fanny Lanternier
- Subjects
Current spectrum ,medicine.medical_specialty ,biology ,business.industry ,Immunology ,X-linked agammaglobulinemia ,medicine.disease ,Medical microbiology ,hemic and lymphatic diseases ,Internal medicine ,medicine ,biology.protein ,Immunology and Allergy ,Trough level ,In patient ,Antibody ,Antibiotic prophylaxis ,business ,Image-guided radiation therapy - Abstract
Outcome of patients with X-linked agammaglobulinemia (XLA) has improved with the widespread use of immunoglobulin replacement therapy (IgRT). There are few data on the spectrum of infections experienced by patients undergoing IgRT. We carried out a retrospective cross-sectional analysis of the records of XLA patients seen at Necker-Enfants Malades Hospital, Paris. For each infection, we evaluated infection site, microbial etiology, antibiotic prophylaxis, immunosuppressive treatment, IgRT route, and last known IgG trough level. Sixty patients were included, who cumulated a follow-up of 1470 patient-years. We recorded 188 infections, including 97 after initiation of IgRT. The rate of infection was highest before IgRT (0.66 vs. 0.06 per person-year (ppy), p 8 g/L, and 16/97 (16.7%) in patients with trough levels > 10 g/L. Infection remains a significant issue in patients with XLA undergoing IgRT despite adequate IgG trough levels. Chronic inflammatory manifestations of X-linked agammaglobulinemia and immunosuppressive therapies may be significant drivers of infection during adulthood.
- Published
- 2021
33. Inborn errors of immunity caused by defects in the DNA damage response pathways: Importance of minimizing treatment-related genotoxicity
- Author
-
Benjamin Fournier, Nizar Mahlaoui, Despina Moshous, and Jean‐Pierre de Villartay
- Subjects
DNA Repair ,Immunology ,Pediatrics, Perinatology and Child Health ,Immunologic Deficiency Syndromes ,Immunology and Allergy ,Humans ,V(D)J Recombination ,DNA Damage - Abstract
Several primary immunodeficiencies are caused by defects in the general DNA repair machinery as exemplified by the T-B- radiosensitive SCID condition owing to impaired resolution of programmed DNA double-strand breaks introduced by RAG1/2 during V(D)J recombination. The genome instability generally associated with these conditions results in an increased propensity to develop malignancies requiring genotoxic-based anti-cancer treatments. Moreover, the extent of immune deficiency often calls for hematopoietic stem cell transplantation as a definitive treatment, also requiring genotoxic-based conditioning regimen prior to transplantation. In both cases, the underlying general DNA repair defect may result in catastrophic iatrogenic consequences. It is, therefore, of paramount importance to assess the functionality of the DNA repair apparatus prior to any genotoxic treatment when the exact molecular cause of the disease is unknown. For this purpose, two simple assays can be used on patients derived peripheral blood lymphocytes: (1) the PROMIDISα biomarker, based on the next-generation sequencing analysis of the TCRα repertoire, will highlight specific signatures of DNA repair deficiencies; (2) direct analysis of the sensitivity of peripheral lymphocytes to ionizing radiation will formally identify patients at risk to develop toxicity toward genotoxic-based treatments.
- Published
- 2022
34. Author response for 'Inborn errors of immunity caused by defects in the DNA damage response pathways: Importance of minimizing treatment‐related genotoxicity'
- Author
-
null Benjamin Fournier, null Nizar Mahlaoui, null Despina Moshous, and null Jean‐Pierre de Villartay
- Published
- 2022
35. Correction to: Hematopoietic cell transplantation cures adenosine deaminase 2 deficiency: report on 30 patients
- Author
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Hasan Hashem, Giorgia Bucciol, Seza Ozen, Sule Unal, Ikbal Ok Bozkaya, Nurten Akarsu, Mervi Taskinen, Minna Koskenvuo, Janna Saarela, Dimana Dimitrova, Dennis D. Hickstein, Amy P. Hsu, Steven M. Holland, Robert Krance, Ghadir Sasa, Ashish R. Kumar, Ingo Müller, Monica Abreu de Sousa, Selket Delafontaine, Leen Moens, Florian Babor, Federica Barzaghi, Maria Pia Cicalese, Robbert Bredius, Joris van Montfrans, Valentina Baretta, Simone Cesaro, Polina Stepensky, Neven Benedicte, Despina Moshous, Guillaume Le Guenno, David Boutboul, Jignesh Dalal, Joel P. Brooks, Elif Dokmeci, Jasmeen Dara, Carrie L. Lucas, Sophie Hambleton, Keith Wilson, Stephen Jolles, Yener Koc, Tayfun Güngör, Caroline Schnider, Fabio Candotti, Sandra Steinmann, Ansgar Schulz, Chip Chambers, Michael Hershfield, Amanda Ombrello, Jennifer A. Kanakry, and Isabelle Meyts
- Subjects
Immunology ,Immunology and Allergy - Abstract
Correction to: Journal of Clinical Immunology (2021) 41:1633–1647
- Published
- 2022
36. Two Novel Homozygous Mutations in Phosphoglucomutase 3 Leading to Severe Combined Immunodeficiency, Skeletal Dysplasia, and Malformations
- Author
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Maria Veiga-da-Cunha, Aline Vincent, Jérémie Rosain, Martin Castelle, Jill Serre, Laurent Renesme, Valérie Cormier-Daire, Takfarinas Kentache, Benjamin Fournier, Sophie Blesson, Nathalie Aladjidi, Despina Moshous, Mathieu Fusaro, Eulalie Lasseaux, Capucine Picard, Fanny Morice Picard, Nathalie Seta, Bénédicte Neven, Anne-Lise Delezoide, Catherine Fallet-Bianco, Emile Van Schaftingen, and UCL - SSS/DDUV/BCHM - Biochimie-Recherche métabolique
- Subjects
Male ,0301 basic medicine ,Immunology ,Limb Deformities, Congenital ,macromolecular substances ,Disease ,Virus ,N-Acetylphosphoglucosamine ,03 medical and health sciences ,0302 clinical medicine ,medicine ,Humans ,Immunology and Allergy ,Missense mutation ,Congenital disorders of glycosylation ,Abnormalities, Multiple ,Bone Diseases, Developmental ,Severe combined immunodeficiency ,Primary immunodeficiency ,business.industry ,Infant, Newborn ,Infant ,Phosphoglucomutase 3 ,medicine.disease ,PGM3 ,030104 developmental biology ,Phosphoglucomutase ,Dysplasia ,Child, Preschool ,Face ,Skeletal dysplasia ,Female ,Severe Combined Immunodeficiency ,Nervous System Diseases ,business ,Congenital disorder of glycosylation ,030215 immunology - Abstract
Phosphoglucomutase 3 (PGM3) deficiency is a rare congenital disorder of glycosylation. Most of patients with autosomal recessive hypomorphic mutations in PGM3 encoding for phosphoglucomutase 3 present with eczema, skin and lung infections, elevated serum IgE, as well as neurological and skeletal features. A few PGM3-deficient patients suffer from a more severe disease with nearly absent T cells and severe skeletal dysplasia. We performed targeted next-generation sequencing on two kindred to identify the underlying genetic etiology of a severe combined immunodeficiency with developmental defect. We report here two novel homozygous missense variants (p.Gly359Asp and p.Met423Thr) in PGM3 identified in three patients from two unrelated kindreds with severe combined immunodeficiency, neurological impairment, and skeletal dysplasia. Both variants segregated with the disease in the two families. They were predicted to be deleterious by in silico analysis. PGM3 enzymatic activity was found to be severely impaired in primary fibroblasts and Epstein-Barr virus immortalized B cells from the kindred carrying the p.Met423Thr variant. Our findings support the pathogenicity of these two novel variants in severe PGM3 deficiency.
- Published
- 2021
37. Hematopoietic stem cell transplantation, a curative approach in infantile osteopetrosis
- Author
-
Ansgar, Schulz and Despina, Moshous
- Subjects
Histology ,Physiology ,Endocrinology, Diabetes and Metabolism - Abstract
Most patients with osteopetrosis (OPT) can be causally and curatively treated with allogeneic hematopoietic stem cell transplantation (HSCT) because osteoclasts are derived from the HSC. However, HSCT is contraindicated in some forms of OPT, namely OPT with neurodegeneration (in all patients with OSTM1 and about half of patients with CLCN7 mutations) and OPT caused by an osteoblast defect (patients with RANKL mutations). HSCT for OPT risks serious side effects, such as transplant failure, venous occlusive disease, pulmonary hypertension, and hypercalcemic crises. Nevertheless, the success rate of HSCT has improved significantly in recent decades. This applies, in particular, to HSCT from non-HLA compatible (haploidentical) donors. Therefore, nowadays an HSCT can be discussed for intermediate OPT forms. After a successful HSCT, most patients have very good quality of life, but about two-thirds are visually impaired, and in rarer cases show motor and neurological disabilities. Early diagnosis, further improvements in transplantation procedures, and advances to improve quality-of-life after transplantation are challenges for the future.
- Published
- 2023
38. Infections in Patients with Chronic Granulomatous Disease Treated with Tumor Necrosis Factor Alpha Blockers for Inflammatory Complications
- Author
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Frank M. Ruemmele, Nizar Mahlaoui, Harry Sokol, Claire Rouzaud, Anne Conrad, Olivier Lortholary, Felipe Suarez, Bénédicte Neven, Stéphane Blanche, Despina Moshous, and Fanny Lanternier
- Subjects
medicine.medical_specialty ,business.industry ,medicine.medical_treatment ,Immunology ,Folliculitis ,Hematopoietic stem cell transplantation ,medicine.disease ,Infliximab ,Pneumonia ,Chronic granulomatous disease ,Internal medicine ,medicine ,Adalimumab ,Immunology and Allergy ,Abscess ,business ,medicine.drug ,Cohort study - Abstract
Management of inflammatory complications of chronic granulomatous disease (CGD) is challenging. The aim of this study was to assess safety, with a focus on infections, and effectiveness of tumor necrosis factor alpha (TNF-α) blockers in CGD patients. A retrospective, single-center cohort study of CGD patients treated by anti-TNF-α agents at Necker-Enfants Malades University Hospital (Paris, France) and registered at the French National Reference Center for Primary Immunodeficiencies (CEREDIH). Between 2006 and 2019, 14 (X-linked: n = 10, 71.4%; autosomal-recessive: n = 4, 28.6%) CGD patients with gastrointestinal (n = 12, 85.7%), pulmonary (n = 10, 71.4%), cutaneous (n = 3, 21.4%), and/or genitourinary (n = 2, 14.3%) inflammatory manifestations received one or more doses of infliximab because of steroid-dependent (n = 7, 50%), refractory (n = 4, 28.6%) inflammatory disease or as first-line drug (n = 2, 14.3%; missing data, n = 1). All patients received adequate antimicrobial prophylaxis. Infliximab achieved complete (n = 2, 14.3%) or partial (n = 9, 64.3%) response in 11 (78.6%) patients. Seven (50%) patients were switched to adalimumab. During anti-TNF-α treatment, 11 infections (pneumonia, adenitis, invasive candidiasis, each n = 2; intra-abdominal abscess, bacteremic salmonellosis, Pseudomonas aeruginosa–related folliculitis, cat-scratch disease, proven pulmonary mucormycosis, each n = 1) occurred in 7 (50%) patients. All infectious complications had a favorable outcome. Anti-TNF-α treatment was definitively stopped because of infection in two patients. Nine (64.3%) patients finally underwent hematopoietic stem cell transplantation. No death occurred during follow-up. Anti-TNF-α treatment could improve the outcome of severe inflammatory complications in CGD patients, but increases their risk of infections. We suggest that anti-TNF-α treatment might be of short-term benefit in selected CGD patients with severe inflammatory complications awaiting hematopoietic stem cell transplantation.
- Published
- 2020
39. Review: Why screen for severe combined immunodeficiency disease?
- Author
-
M. Danielo, Nizar Mahlaoui, G. Hubert, A. Catteau, Despina Moshous, V.P. Riche, M. Audrain, Caroline Thomas, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), CCSD, Accord Elsevier, Centre hospitalier universitaire de Nantes (CHU Nantes), Centre de Référence Déficits Immunitaires Héréditaires (CEREDIH), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], CHU Necker - Enfants Malades [AP-HP], and Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Cité (UPCité)
- Subjects
Newborn screening ,Primary immunodeficiencies ,Pediatrics ,medicine.medical_specialty ,[SDV]Life Sciences [q-bio] ,Population ,Disease ,Sensitivity and Specificity ,03 medical and health sciences ,Quality of life ,medicine ,Humans ,TREC ,education ,Survival rate ,030304 developmental biology ,0303 health sciences ,education.field_of_study ,Severe combined immunodeficiency ,business.industry ,030305 genetics & heredity ,Infant, Newborn ,Prognosis ,medicine.disease ,Rare diseases ,3. Good health ,Dried blood spot ,[SDV] Life Sciences [q-bio] ,Early Diagnosis ,Severe combined immunodeficiency disease ,Severe lymphopenias ,Pediatrics, Perinatology and Child Health ,Neonatal screening ,business - Abstract
International audience; Newborn screening for severe combined immunodeficiency (SCID) is now routinely performed in many countries across Europe and around the world. The number of T-cell receptor excision circles (TRECs) reflects T cell levels. TREC quantification is possible using dried blood spot (DBS) samples already collected from newborns to screen for other conditions. This method is very sensitive and highly specific. Data in the literature show that the survival rate for children with SCID is much higher when the disease is detected through early screening, as opposed to a later diagnosis. Newborns diagnosed with SCID may receive the appropriate care quickly, before the onset of serious infectious complications, which raises survival rates, improves quality of life, and limits side effects and treatment costs. At the request of the French Ministry of Health, France's National Authority for Health (Haute Autorité de Santé) is expected to issue recommendations on this topic soon. The nationwide DEPISTREC study, involving 48 maternity units across France, showed that routine SCID screening is feasible and effective. Such screening offers the additional benefit of also diagnosing non-SCID lymphopenia within the infant population.
- Published
- 2020
40. Child Neurology: Familial Hemophagocytic Lymphohistiocytosis Underlying Isolated Central Nervous System Inflammation
- Author
-
Giorgia, Bucciol, Nele, Willemyns, Benjamin, Verhaaren, Xavier, Bossuyt, Katrien, Lagrou, Anniek, Corveleyn, Despina, Moshous, Katrien, Jansen, Liesbeth, De Waele, and Isabelle, Meyts
- Abstract
Encephalitis and encephalopathy in children represent a diagnostic challenge. We describe a patient with relapsing encephalitis in whom the differential diagnosis included acute disseminated encephalomyelitis (ADEM), human herpesvirus 6 (HHV-6) encephalitis, and hemophagocytic lymphohistiocytosis (HLH). Because of its rarity, HLH is often overlooked as a differential diagnosis in encephalitis, especially in the isolated central nervous system (CNS) forms. As this case illustrates, inborn errors of immunity (IEIs) can underlie isolated encephalitis and should be included in the differential diagnosis of these presentations.
- Published
- 2022
41. Inborn Errors of Immunity caused by defects of the DNA damage response pathways
- Author
-
Benjamin Fournier, Nizar Mahlaoui, Despina Moshous, and Jean-Pierre DE VILLARTAY
- Abstract
Several inborn errors of immunity are caused by defects in the general DNA repair machinery as exemplified by the T-B- RS-SCID condition owing to impaired resolution of programmed DNA double strands breaks introduced by RAG1/2 during V(D)J recombination. The genome instability generally associated with these conditions results in an increased propensity to develop malignancies requiring genotoxic based anti-cancer treatments. Moreover, the extent of immune deficiency often calls for hematopoietic stem cell transplantation as a definitive treatment, thus also demanding genotoxic based conditioning regimen prior to transplantation. In both cases, the underlying general DNA repair defects may result in catastrophic iatrogenic consequences. It is therefore of paramount importance to assess the functionality of the DNA repair apparatus prior to any genotoxic treatment when the exact molecular cause of the disease is unknown. For this purpose, two simple assays can be used on patient’s derived peripheral blood lymphocytes. 1) The PROMIDISα biomarker, based on the next generation sequencing analysis of the TCRα will highlight specific signatures of DNA repair deficiencies. 2) Direct analysis of the sensitivity of peripheral lymphocytes to ionizing radiations will formally identify patients at risk to develop toxicity towards genotoxic based treatments.
- Published
- 2022
42. Curative allogeneic hematopoietic stem cell transplantation following reduced toxicity conditioning in adults with primary immunodeficiency
- Author
-
Ambroise Marçais, Nizar Mahlaoui, Bénédicte Neven, Fanny Lanternier, Émilie Catherinot, Hélène Salvator, Morgane Cheminant, Maxime Jeljeli, Vahid Asnafi, Peter van Endert, Louis-Jean Couderc, Olivier Lortholary, Capucine Picard, Despina Moshous, Olivier Hermine, Alain Fischer, and Felipe Suarez
- Subjects
Adult ,Transplantation ,Young Adult ,Transplantation Conditioning ,Adolescent ,Hematopoietic Stem Cell Transplantation ,Graft vs Host Disease ,Humans ,Hematology ,Child ,Granulomatous Disease, Chronic ,Busulfan - Abstract
Primary immunodeficiencies (PID) are heterogeneous inborn errors of the immune system. Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is curative and safe at the pediatric age but remains underperformed in adults. We report our experience on 32 consecutive adult patients with various PID including 17 (53%) with a combined immune deficiency, six (19%) with a disease of immune dysregulation and nine (28%) with a chronic granulomatous disease (CGD) who underwent an allo-HSCT between 2011 and 2020. The median age at transplant was 27 years (17-41). All assessable patients engrafted. The majority of patients received a fludarabine-Busulfan (FB) based regimen (FB2-3 in 16, FB4 in 12). Overall survival (OS) was 80.4% (100% for CGD and 74% for other PID patients) at 9 months and beyond (median follow-up 51.6 months). Six patients died, all in the first-year post-transplant. Cumulative incidences of grade II-IV acute GVHD/chronic GVHD were 18%/22%. Stem cell source, GVHD prophylaxis and conditioning intensity had no impact on OS. All surviving patients had over 90% donor chimerism, immune reconstitution, no sign of active PID related complications and were clinically improved. Allo-HSCT is effective in young adults PID patients with an acceptable toxicity and should be discussed in case of life-threatening PID.
- Published
- 2022
43. An evolutionarily conserved coronin-dependent pathway defines cell population size
- Author
-
Tohnyui Ndinyanka Fabrice, Christelle Bianda, Haiyan Zhang, Rajesh Jayachandran, Julie Ruer-Laventie, Mayumi Mori, Despina Moshous, Geoffrey Fucile, Alexander Schmidt, and Jean Pieters
- Subjects
Population Density ,4-Butyrolactone ,Microfilament Proteins ,Humans ,Cell Biology ,Molecular Biology ,Biochemistry ,Signal Transduction - Abstract
Maintenance of cell population size is fundamental to the proper functioning of multicellular organisms. Here, we describe a cell-intrinsic cell density–sensing pathway that enabled T cells to reach and maintain an appropriate population size. This pathway operated “kin-to-kin” or between identical or similar T cell populations occupying a niche within a tissue or organ, such as the lymph nodes, spleen, and blood. We showed that this pathway depended on the cell density–dependent abundance of the evolutionarily conserved protein coronin 1, which coordinated prosurvival signaling with the inhibition of cell death until the cell population reached threshold densities. At or above threshold densities, coronin 1 expression peaked and remained stable, thereby resulting in the initiation of apoptosis through kin-to-kin intercellular signaling to return the cell population to the appropriate cell density. This cell population size-controlling pathway was conserved from amoeba to humans, thus providing evidence for the existence of a coronin-regulated, evolutionarily conserved mechanism by which cells are informed of and coordinate their relative population size.
- Published
- 2022
44. International retrospective study of allogeneic hematopoietic cell transplantation for activated PI3K-delta syndrome
- Author
-
Klaus Warnatz, Kohsuke Imai, Bénédicte Neven, Mette Holm, Ulrich Duffner, B Carpenter, Musa Karakukcu, Hassan Abolhassani, Robert Wynn, Neena Kapoor, Jennifer A. Kanakry, Marina Garcia-Prat, Mariacristina Menconi, Anna Mukhina, Pere Soler-Palacín, Takahiro Tomoda, Claudia Wehr, Diana K. Bayer, Eleonora Gambineri, Gulbu Uzel, Austen Worth, Arunkumar Modi, Mary Slatter, Tania Nicole Masmas, Dimana Dimitrova, Carsten Speckmann, J.J. Bleesing, Shankara Paneesha, Kanchan Rao, Sylwia Kołtan, Carmem Bonfim, Jasmeen Dara, Colin G. Steward, Winnie Ip, Emma C. Morris, Asghar Aghamohammadi, Andrew R. Gennery, Gašper Markelj, Luigi D. Notarangelo, Stephen M. Hughes, Sujal Ghosh, Tsubasa Okano, Ansgar Schulz, Arjan C. Lankester, Stephen Jolles, Ebru Yilmaz, Alexandra Laberko, Maria Elena Maccari, Stephan Ehl, Christopher C. Dvorak, Despina Moshous, Hyoung Jin Kang, Carolina Prando, Zohreh Nademi, Institut Català de la Salut, [Dimitrova D] Experimental Transplantation and Immunotherapy Branch, National Cancer Institute, National Institutes of Health, Bethesda, Md. [Nademi Z] Children’s Bone Marrow Transplant Unit, Great North Children’s Hospital, Newcastle upon Tyne, United Kingdom. The Translational and Clinical Research Institute, Newcastle University, Newcastle upon Tyne, United Kingdom. [Maccari ME, Ehl S] Department of Pediatric Hematology and Oncology, Center for Pediatrics, Medical Center—University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany. Center for Chronic Immunodeficiency, Medical Center—University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany. [Uzel G] Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Md. [Tomoda T] Department of Pediatrics and Developmental Biology, Tokyo Medical and Dental University, Tokyo, Japan. [Garcia-Prat M, Soler-Palacín P] Unitat de Patologia Infecciosa i Immunodeficiències de Pediatria, Vall d’Hebron Hospital Universitari, Barcelona, Spain, and Vall d'Hebron Barcelona Hospital Campus
- Subjects
Graft Rejection ,Male ,0301 basic medicine ,Oncology ,Allergy ,lymphoproliferation ,mTOR inhibitor ,Kaplan-Meier Estimate ,Regenerative Medicine ,Phosphatidylinositol 3-Kinases ,0302 clinical medicine ,hemic and lymphatic diseases ,Immunology and Allergy ,Cumulative incidence ,Child ,Otros calificadores::/terapia [Otros calificadores] ,Immunodeficiency ,Cancer ,Primary immunodeficiency ,Hematopoietic Stem Cell Transplantation ,MTOR Inhibitors ,Hematology ,Middle Aged ,Síndromes de deficiència immunitària - Tractament ,enfermedades del sistema inmune::síndromes de inmunodeficiencia [ENFERMEDADES] ,Treatment Outcome ,surgical procedures, operative ,Child, Preschool ,Immune System Diseases::Immunologic Deficiency Syndromes [DISEASES] ,Female ,terapéutica::terapia biológica::tratamientos basados en células y tejidos::trasplante de células::trasplante de células madre::trasplante de células madre hematopoyéticas [TÉCNICAS Y EQUIPOS ANALÍTICOS, DIAGNÓSTICOS Y TERAPÉUTICOS] ,Homologous ,Adult ,medicine.medical_specialty ,activated phosphoinositide 3-kinase delta syndrome ,Adolescent ,Class I Phosphatidylinositol 3-Kinases ,Primary Immunodeficiency Diseases ,graft failure ,Immunology ,serotherapy ,Activated PI3K-delta syndrome ,Context (language use) ,Article ,Young Adult ,03 medical and health sciences ,Rare Diseases ,Internal medicine ,medicine ,Transplantation, Homologous ,Humans ,Preschool ,Retrospective Studies ,Aged ,Transplantation ,allogeneic hematopoietic cell transplantation ,Cèl·lules mare hematopoètiques - Trasplantació ,business.industry ,diagnóstico::pronóstico::resultado del tratamiento [TÉCNICAS Y EQUIPOS ANALÍTICOS, DIAGNÓSTICOS Y TERAPÉUTICOS] ,Retrospective cohort study ,Other subheadings::/therapy [Other subheadings] ,Diagnosis::Prognosis::Treatment Outcome [ANALYTICAL, DIAGNOSTIC AND THERAPEUTIC TECHNIQUES, AND EQUIPMENT] ,medicine.disease ,030104 developmental biology ,Graft-versus-host disease ,allogeneic hemato-poietic cell transplantation ,Avaluació de resultats (Assistència sanitària) ,Therapeutics::Biological Therapy::Cell- and Tissue-Based Therapy::Cell Transplantation::Stem Cell Transplantation::Hematopoietic Stem Cell Transplantation [ANALYTICAL, DIAGNOSTIC AND THERAPEUTIC TECHNIQUES, AND EQUIPMENT] ,business ,030215 immunology - Abstract
Immunodeficiència primària; Limfoproliferació; Inhibidor de mTOR Inmunodeficiencia primaria; Linfoproliferación; Inhibidor de mTOR Primary immunodeficiency; Lymphoproliferation; MTOR inhibitor Background Activated phosphoinositide 3-kinase delta syndrome (APDS) is a combined immunodeficiency with a heterogeneous phenotype considered reversible by allogeneic hematopoietic cell transplantation (HCT). Objectives This study sought to characterize HCT outcomes in APDS. Methods Retrospective data were collected on 57 patients with APDS1/2 (median age, 13 years; range, 2-66 years) who underwent HCT. Results Pre-HCT comorbidities such as lung, gastrointestinal, and liver pathology were common, with hematologic malignancy in 26%. With median follow-up of 2.3 years, 2-year overall and graft failure–free survival probabilities were 86% and 68%, respectively, and did not differ significantly by APDS1 versus APDS2, donor type, or conditioning intensity. The 2-year cumulative incidence of graft failure following first HCT was 17% overall but 42% if mammalian target of rapamycin inhibitor(s) (mTORi) were used in the first year post-HCT, compared with 9% without mTORi. Similarly, 2-year cumulative incidence of unplanned donor cell infusion was overall 28%, but 65% in the context of mTORi receipt and 23% without. Phenotype reversal occurred in 96% of evaluable patients, of whom 17% had mixed chimerism. Vulnerability to renal complications continued post-HCT, adding new insights into potential nonimmunologic roles of phosphoinositide 3-kinase not correctable through HCT. Conclusions Graft failure, graft instability, and poor graft function requiring unplanned donor cell infusion were major barriers to successful HCT. Post-HCT mTORi use may confer an advantage to residual host cells, promoting graft instability. Longer-term post-HCT follow-up of more patients is needed to elucidate the kinetics of immune reconstitution and donor chimerism, establish approaches that reduce graft instability, and assess the completeness of phenotype reversal over time. This research was funded in part from the Intramural Program of the National Cancer Institute, National Institutes of Health. The funding source had no involvement in study design; collection, analysis, and interpretation of data; writing of the report; or in the decision to submit the article for publication.
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- 2022
45. Childhood Langerhans cell histiocytosis with severe lung involvement: a nationwide cohort study
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Ralph Epaud, Chiara Sileo, Mohamed Barkaoui, Kamila Kebaili, Aurélie Portefaix, Jean-François Emile, Jean Eudes Piloquet, Jean-François Chateil, Solenne Le Louet, Abdellatif Tazi, Sébastien Héritier, Nathalie Aladjidi, Valeria Della Valle, Corinne Armari-Alla, Philippe B. Chastagner, Claire Galambrun, Gwenaël Lorillon, Jean Miron, Despina Moshous, Sylvain Renolleau, Julien Lejeune, Hubert Ducou Le Pointe, Emmanuelle Bugnet, Raphael Chiron, J. Donadieu, Anne Lambilliotte, CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Service de pédiatrie, d'hématologie et d'oncologie [Hôpital de La Timone - APHM], Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE), CHU Bordeaux [Bordeaux], Centre Hospitalier Régional Universitaire de Nancy (CHRU Nancy), Institut d'hématologie et d'oncologie pédiatrique [CHU - HCL] (IHOPe), Hospices Civils de Lyon (HCL), Hôpital la Tronche, Service d'endocrinologie pédiatrique [CHU Lille], Hôpital Jeanne de Flandre [Lille]-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), CHU Trousseau [Tours], Centre Hospitalier Régional Universitaire de Tours (CHRU Tours), Service d'immuno-hématologie pédiatrique [CHU Necker], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Hôpital Haut-Lévêque [CHU Bordeaux], Service de Transplantation Rénale et de Soins Intensifs [Hôpital Necker - APHP], Université Paris Descartes - Paris 5 (UPD5)-PRES Sorbonne Paris Cité-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Centre Hospitalier Intercommunal de Créteil (CHIC), Hôpital Arnaud de Villeneuve [CHRU Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Hopital Saint-Louis [AP-HP] (AP-HP), Biomarqueurs et essais cliniques en Cancérologie et Onco-Hématologie (BECCOH), and Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Université Paris-Saclay
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Pediatrics ,medicine.medical_specialty ,medicine.medical_treatment ,lcsh:Medicine ,Vinblastine ,Asymptomatic ,law.invention ,Cohort Studies ,Targeted therapy ,03 medical and health sciences ,0302 clinical medicine ,Langerhans cell histiocytosis ,law ,Intensive care ,Medicine ,Lung transplantation ,Humans ,Pharmacology (medical) ,Child ,Lung ,Genetics (clinical) ,Retrospective Studies ,Childhood Langerhans Cell Histiocytosis ,[SDV.GEN]Life Sciences [q-bio]/Genetics ,Severe ,business.industry ,Research ,lcsh:R ,Infant ,Retrospective cohort study ,General Medicine ,Pulmonary ,medicine.disease ,Intensive care unit ,Childhood ,3. Good health ,Histiocytosis, Langerhans-Cell ,030228 respiratory system ,Pneumothorax ,030220 oncology & carcinogenesis ,medicine.symptom ,business - Abstract
BackgroundLung involvement in childhood Langerhans cell histiocytosis (LCH) is infrequent and rarely life threatening, but occasionally, severe presentations are observed.MethodsAmong 1482 children (ResultsThe median age was 1.3 years at the first ICU hospitalization. Of the 17 patients, 14 presented with lung involvement at the LCH diagnosis, and 7 patients (41%) had concomitant involvement of risk-organ (hematologic, spleen, or liver). Thirty-five ICU hospitalizations were analysed. Among these, 22 (63%) were secondary to a pneumothorax, 5 (14%) were associated with important cystic lesions without pneumothorax, and 8 (23%) included a diffuse micronodular lung infiltration in the context of multisystem disease.First-line vinblastine–corticosteroid combination therapy was administered to 16 patients; 12 patients required a second-line therapy (cladribine:n = 7; etoposide-aracytine:n = 3; targeted therapyn = 2). A total of 6 children (35%) died (repeated pneumothorax:n = 3; diffuse micronodular lung infiltration in the context of multisystem disease:n = 2; following lung transplantation:n = 1). For survivors, the median follow-up after ICU was 11.2 years. Among these, 9 patients remain asymptomatic despite abnormal chest imaging.ConclusionsSevere lung involvement is unusual in childhood LCH, but it is associated with high mortality. Treatment guidelines should be improved for this group of patients: viral infection prophylaxis and early administration of a new LCH therapy, such as targeted therapy.
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- 2020
46. Chronic Granulomatous Disease with the McLeod Phenotype: a French National Retrospective Case Series
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Pierre-Simon Rohrlich, Souha Albinni, Wadih Abou-Chahla, Benedicte Neven, Jérôme Babinet, Christophe Marguet, Felipe Suarez, Olivier Hermine, Faustine Lhomme, Sébastien Héritier, Olivier Lortholary, Isabelle Durieu, Nizar Mahlaoui, Alain Fischer, Marie-Dominique Dumont, Stéphane Blanche, Despina Moshous, Denise Amiranoff, and Thierry Peyrard
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Adult ,Male ,Pediatrics ,medicine.medical_specialty ,Adolescent ,Duchenne muscular dystrophy ,medicine.medical_treatment ,Immunology ,Disease ,Hematopoietic stem cell transplantation ,Granulomatous Disease, Chronic ,Young Adult ,Chronic granulomatous disease ,Isoantibodies ,Retinitis pigmentosa ,Epidemiology ,medicine ,Humans ,Immunology and Allergy ,CYBB ,Child ,Retrospective Studies ,business.industry ,Infant ,medicine.disease ,Survival Analysis ,Abetalipoproteinemia ,Child, Preschool ,NADPH Oxidase 2 ,Primary immunodeficiency ,Female ,France ,business ,Neuroacanthocytosis ,Follow-Up Studies - Abstract
X-linked chronic granulomatous disease (CGD) is a primary immunodeficiency caused by mutations in the CYBB gene (located on Xp21.1). Patients with large deletions on chromosome Xp21.1 can present with the McLeod phenotype and also Duchenne muscular dystrophy or retinitis pigmentosa. The objective of the present study was to describe a series of French patients with CGD and the McLeod phenotype. We retrospectively collected data from the medical records of 8 patients with CGD and the McLeod phenotype registered at the French National Reference Center for blood types. The median age at diagnosis of CGD was 1.2 years, the median age at diagnosis of the McLeod phenotype was 4.5 years, and the median length of follow-up was 15.2 years. Four patients displayed allo-immunization, with anti-KEL20 and anti-XK1 (formerly known as anti-KL) antibodies. Five of the 6 patients with available blood smears had acanthocytosis. Neuropsychiatric, muscle-related, and ocular manifestations were present in 4, 2, and 1 of the patients, respectively. Three of the 4 patients having undergone allogeneic hematopoietic stem cell transplantation (HSCT) are alive. Overall, 5 patients are alive, and 3 are alive and well. This is the largest yet descriptive study of a series of patients with X-linked CGD and the McLeod phenotype. Although this disease combination is rare, the timely, accurate diagnosis of the McLeod phenotype is critical because of the serious post-transfusion complications. However, HSCT can be considered in these patients.
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- 2020
47. Neutropénie en dehors d’un contexte de chimiothérapie : bilan et prise en charge-recommandations du centre de référence
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M. Biosse Duplan, J. Donadieu, F. Bou Mitri, Marlène Pasquet, S. Cohen Beaussant, Despina Moshous, Laure Croisille, C. Bellanné Chantelot, F. Sicre de Fontbrune, Blandine Beaupain, Claire Fieschi, and Marie Audrain
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03 medical and health sciences ,0302 clinical medicine ,030220 oncology & carcinogenesis ,030215 immunology - Abstract
Resume La decouverte d’une neutropenie est une circonstance relativement frequente en pediatrie. La tres grande majorite des neutropenies sont transitoires, le plus souvent secondaires a une infection virale ou bacterienne, ou encore liees a la prematurite, et exceptionnellement inaugurales d’une hemopathie maligne. La neutropenie peut egalement etre chronique, persistant au-dela de 3 mois, et peut faire discuter plusieurs etiologies comme la neutropenie dite « ethnique », la neutropenie auto-immune, et les neutropenies genetiques. Parmi les neutropenies chroniques, la neutropenie auto-immune primitive constitue une cause frequente. Son evolution est habituellement marquee par une bonne tolerance et une recuperation dans un delai de 12 a 36 mois. Les neutropenies « congenitales » sont une famille de pathologies monogeniques, tres rares (environ 20 nouveaux cas/an en France) et tres diverses (environ 30 sous-types differents). On les evoque devant une presentation clinique severe, des pathologies d’autres organes associes ou d’une neutropenie profonde et persistante sans signe d’auto-immunite. Les enfants atteints de neutropenies genetiques sont exposes a des infections bacteriennes majeures et a des infections buccodentaires. Ils presentent un risque leucemique et souvent des anomalies de plusieurs organes en plus de l’atteinte hematologique. La prevention des infections chez les enfants atteints de neutropenie chronique repose d’abord sur une evaluation individuelle de chaque enfant concerne. Elle peut faire appel a l’antibiotherapie prophylactique qui repose avant tout sur l’association sulfamethoxazole-trimethoprime quotidienne, et d’autre part, sur les facteurs de croissance hematopoietique, principalement le granulocyte-colony stimulating factor (G-CSF).
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- 2020
48. High rates of antiretroviral coverage and virological suppression in HIV-1-infected children and adolescents
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Stéphane Blanche, Florence Veber, Nizar Mahlaoui, Despina Moshous, A. Soumah, Véronique Avettand-Fenoel, and Pierre Frange
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Male ,medicine.medical_specialty ,Adolescent ,Pediatric hiv ,Anti-HIV Agents ,Human immunodeficiency virus (HIV) ,Emigrants and Immigrants ,Integrase inhibitor ,HIV Infections ,medicine.disease_cause ,03 medical and health sciences ,Acquired immunodeficiency syndrome (AIDS) ,Antiretroviral Therapy, Highly Active ,Internal medicine ,Drug Resistance, Viral ,Humans ,Medicine ,Protease inhibitor (pharmacology) ,Viremia ,Child ,Africa South of the Sahara ,High rate ,0303 health sciences ,030306 microbiology ,Clinical events ,business.industry ,Infant, Newborn ,Infant ,Viral Load ,Thailand ,medicine.disease ,CD4 Lymphocyte Count ,Infectious Diseases ,Drug class ,Socioeconomic Factors ,Vietnam ,Child, Preschool ,HIV-1 ,Female ,France ,Child, Adopted ,business - Abstract
To assess the outcome of HIV-infected individuals attending one of the largest French pediatric HIV centers in 2016-2017 and to compare the rates of antiretroviral coverage and virological suppression with the UNAIDS targets.The clinical and immuno-virological status of 163 HIV-1-infected children and adolescents attending Necker Hospital in Paris, France, were investigated. Virological suppression was defined as an HIV-1 viral load50 copies/mL for at least six months. All genotypic resistance tests performed since birth were analyzed.Most patients were born in Sub-Saharan African countries (41.7%) or in France (38.0%). Their median age was 14 years [IQR 7.3-17.0]. Although 33.7% of individuals had a history of AIDS-defining clinical event(s), 86.5% of children/adolescents were free from HIV-related symptoms at their most recent evaluation. Antiretroviral coverage was high (98.2%; mainly including one integrase inhibitor [42.3%] or one protease inhibitor [23.9%]). At the last visit, most patients (82.8%) had normal CD4T lymphocytes counts (≥25%). Although 61.7% of antiretroviral-experienced children had resistance to≥1 drug class and 9.2% had triple-class resistance, 80.3% of patients receiving antiretrovirals for≥6 months (126/157) were virologically suppressed. International adoptees were more frequently virologically suppressed than other patients (96.0% versus 74.6%, P=0.02).Antiretroviral coverage exceeded the second UNAIDS 90 target aimed at ending the AIDS epidemic. The rate of virological suppression, one of the highest reported in children in high-income countries, is approaching the third UNAIDS 90 target and the rate observed in French HIV-infected adults on antiretrovirals.
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- 2020
49. Bone Marrow Transplantation in Congenital Erythropoietic Porphyria: Sustained Efficacy but Unexpected Liver Dysfunction
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Cécile Ged, Stéphane Blanche, Dominique Debray, Marina Cavazzana, Louise Galmiche-Rolland, Caroline Schmitt, Elisa Magrin, Caroline Besnard, Thierry Jo Molina, Martin Castelle, Bénédicte Neven, Despina Moshous, Laurent Gouya, Monique Fabre, and Marie-Louise Frémond
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medicine.medical_specialty ,Porphyria, Erythropoietic ,medicine.medical_treatment ,Congenital erythropoietic porphyria ,Hematopoietic stem cell transplantation ,Gastroenterology ,03 medical and health sciences ,0302 clinical medicine ,Fibrosis ,Internal medicine ,Biopsy ,medicine ,Humans ,Child ,Bone Marrow Transplantation ,Retrospective Studies ,Transplantation ,medicine.diagnostic_test ,business.industry ,Liver Diseases ,Hematopoietic Stem Cell Transplantation ,Hematology ,medicine.disease ,Uroporphyrinogen III Synthetase ,Pathophysiology ,surgical procedures, operative ,Porphyria ,030220 oncology & carcinogenesis ,Liver function ,business ,030215 immunology ,Rare disease - Abstract
Congenital erythropoietic porphyria (CEP) is a rare disease characterized by erosive photosensitivity and chronic hemolysis due to a defect of the enzyme uroporphyrinogen-III-synthase (UROS). To date, hematopoietic stem cell transplantation (HSCT) is the only curative therapy for the devastating early and severe form of the disease. We describe 6 patients with CEP treated with HSCT (3 of them twice after failure of a first graft) between 1994 and 2016 in our center, including 2 of the very first living patients treated more than 20 years ago. Four patients are doing well at 6 to 25 years post-HSCT, with near-normal biochemical parameters of porphyrin metabolism without the cutaneous or hematologic features of CEP. One patient died within the first year after HSCT from severe graft-versus-host disease (GVHD), and 1 child died of unexplained acute hepatic failure at 1 year after HSCT, despite full donor chimerism. Retrospectively, it appears that all but 1 child had increased transaminase activity with onset from the early postnatal period, which was significantly more marked in the child who died of liver failure. In contrast, liver function values progressively normalized after engraftment in all other children. Liver pathology before HSCT for 3 patients revealed varying degrees of portal, centrilobular, and perisinusoidal fibrosis; clarification of hepatocytes; and cytosolic porphyrin deposits. The liver porphyrin content in biopsy specimens was >60 times the normal values. Despite difficult engraftment, the long-term efficacy of HSCT in CEP appears to be favorable and reinforces its benefits for the severe form of CEP. Hepatic involvement requires careful evaluation before and after HSCT and further investigation into its pathophysiology and care.
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- 2020
50. Expanded circulating hematopoietic stem/progenitor cells as novel cell source for the treatment of TCIRG1 osteopetrosis
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Lucia Sergi Sergi, Polina Stepensky, Roberto Cusano, Serena Scala, Alper Gezdirici, Paolo Uva, Cristina Sobacchi, Bernhard Gentner, Eleonora Palagano, Ekrem Unal, Valentina Capo, Elena Draghici, Alessandro Aiuti, Ivan Merelli, Silvia L. Locatelli, Zühre Kaya, Carmelo Carlo-Stella, Ansgar Schulz, Laura Crisafulli, Luca Basso-Ricci, Francesca Ficara, Marta Serafini, Giacomo Desantis, Despina Moshous, Erika Zonari, Sara Penna, Giuseppe Menna, Matteo Barcella, Katarzyna Drabko, Anna Villa, Capo, V, Penna, S, Merelli, I, Barcella, M, Scala, S, Basso-Ricci, L, Draghici, E, Palagano, E, Zonari, E, Desantis, G, Uva, P, Cusano, R, Sergi Sergi, L, Crisafulli, L, Moshous, D, Stepensky, P, Drabko, K, Kaya, Z, Unal, E, Gezdirici, A, Menna, G, Serafini, M, Aiuti, A, Locatelli, S, Carlo-Stella, C, Schulz, A, Ficara, F, Sobacchi, C, Gentner, B, Villa, A, Capo, Valentina, Penna, Sara, Merelli, Ivan, Barcella, Matteo, Scala, Serena, Basso-Ricci, Luca, Draghici, Elena, Palagano, Eleonora, Zonari, Erika, Desantis, Giacomo, Uva, Paolo, Cusano, Roberto, Sergi Sergi, Lucia, Crisafulli, Laura, Moshous, Despina, Stepensky, Polina, Drabko, Katarzyna, Kaya, Zühre, Unal, Ekrem, Gezdirici, Alper, Menna, Giuseppe, Serafini, Marta, Aiuti, Alessandro, Locatelli, Silvia Laura, Carlo-Stella, Carmelo, Schulz, Ansgar S, Ficara, Francesca, Sobacchi, Cristina, Gentner, Bernhard, and Villa, Anna
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Vacuolar Proton-Translocating ATPases ,Genetic enhancement ,medicine.medical_treatment ,CD34 ,Osteoclasts ,Antigens, CD34 ,Hematopoietic stem cell transplantation ,Biology ,Article ,03 medical and health sciences ,0302 clinical medicine ,medicine ,Humans ,Progenitor cell ,030304 developmental biology ,0303 health sciences ,hematopoietic stem cell bone marrow failure stem cell transplantation Gene Therapy and Transfer HSPC expansion ,Hematopoietic Stem Cell Transplantation ,Hematopoietic stem cell ,Hematopoietic Stem Cell ,Genetic Therapy ,Hematology ,Hematopoietic Stem Cells ,Bone Marrow Failure ,HSPC expansion ,Haematopoiesis ,medicine.anatomical_structure ,Gene Therapy and Transfer ,Osteopetrosis ,030220 oncology & carcinogenesis ,Cancer research ,Bone marrow ,Stem cell ,Stem Cell Transplantation - Abstract
Allogeneic hematopoietic stem cell transplantation is the treatment of choice for autosomal recessive osteopetrosis caused by defects in the TCIRG1 gene. Despite recent progress in conditioning, an important number of patients are not eligible for allogeneic stem cell transplantation because of the severity of the disease and significant transplant-related morbidity. We exploited peripheral CD34(+) cells, known to circulate at high frequency in the peripheral blood of TCIRG1-deficient patients, as a novel cell source for autologous transplantation of gene corrected cells. Detailed phenotypical analysis showed that circulating CD34(+). cells have a cellular composition that resembles bone marrow (BM), supporting their use in gene therapy protocols. Transcriptomic profile revealed enrichment in genes expressed by hematopoietic stem and progenitor cells (HSPC). To overcome the limit of BM harvest/HSPC mobilization and serial blood drawings in TCIRG1 patients, we applied UM171-based ex vivo expansion of HSPC coupled with lentiviral gene transfer. Circulating CD34(+). cells from TCIRG1-defective patients were transduced with a clinically-optimized lentiviral vector expressing TCIRG1 under the control of phosphoglycerate promoter and expanded ex vivo. Expanded cells maintained long-term engraftment capacity and multi-lineage repopulating potential when transplanted in vivo both in primary and secondary NOD scid gamma common chain (NSG) recipients. Moreover, when CD34(+) cells were differentiated in vitro, genetically corrected osteoclasts resorbed the bone efficiently. Overall, we provide evidence that expansion of circulating HSPC coupled to gene therapy can overcome the limit of stem cell harvest in osteopetrotic patients, thus opening the way to future gene-based treatment of skeletal diseases caused by BM fibrosis.
- Published
- 2020
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