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1. Performances of two rapid LAMP-based techniques for the intrapartum detection of Group B Streptococcus vaginal colonization

Author

Rym Charfi, Cécile Guyonnet, Meiggie Untrau, Gaëlle Giacometti, Thierry Paper, Claire Poyart, Céline Plainvert, and Asmaa Tazi

Subjects
Group B Streptococcus, Intrapartum screening, NAAT, Neonatal infection, LAMP, Therapeutics. Pharmacology, RM1-950, Infectious and parasitic diseases, RC109-216, Microbiology, QR1-502
Abstract

Abstract Purpose Group B Streptococcus (GBS) is the leading cause of invasive infections in newborns. The prevention of GBS neonatal disease relies on the administration of an intrapartum antibiotic prophylaxis to GBS-colonized women. In recent years, rapid intrapartum detection of GBS vaginal colonization using real-time nucleic acid amplification tests (NAATs) emerged as an alternative to antenatal culture screening methods. Methods We compared the performances of two loop-mediated isothermal amplification (LAMP) tests, the Ampliflash® GBS and the PlusLife® GBS tests, to standard culture for GBS detection in vaginal specimens from pregnant women. The study was conducted from April to July 2023 in a French hospital of the Paris area. Results A total of 303 samples were analyzed, including 85 culture-positive samples (28.1%). The Ampliflash® GBS test and the PlusLife® GBS tests gave a result for 100% and 96.3% tests, respectively. The performances of the tests were as follows: sensitivity 87.1% (95% confidence interval (CI) 78.3–92.6) and 98.7% (95% CI 93.0-99.8), specificity 99.1% (95% CI 96.7–99.8), and 91.9% (95% CI 87.3–95.0), respectively. False negative results of the Ampliflash® GBS test correlated with low-density GBS cultures. Time-to-results correlated with GBS culture density only for the PlusLife® GBS test (p

Published
2024
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2. An unusually high substitution rate in transplant-associated BK polyomavirus in vivo is further concentrated in HLA-C-bound viral peptides.

Author

Pilar Domingo-Calap, Benjamin Schubert, Mélanie Joly, Morgane Solis, Meiggie Untrau, Raphael Carapito, Philippe Georgel, Sophie Caillard, Samira Fafi-Kremer, Nicodème Paul, Oliver Kohlbacher, Fernando González-Candelas, and Seiamak Bahram

Subjects
Immunologic diseases. Allergy, RC581-607, Biology (General), QH301-705.5
Abstract

Infection with human BK polyomavirus, a small double-stranded DNA virus, potentially results in severe complications in immunocompromised patients. Here, we describe the in vivo variability and evolution of the BK polyomavirus by deep sequencing. Our data reveal the highest genomic evolutionary rate described in double-stranded DNA viruses, i.e., 10(-3)-10(-5) substitutions per nucleotide site per year. High mutation rates in viruses allow their escape from immune surveillance and adaptation to new hosts. By combining mutational landscapes across viral genomes with in silico prediction of viral peptides, we demonstrate the presence of significantly more coding substitutions within predicted cognate HLA-C-bound viral peptides than outside. This finding suggests a role for HLA-C in antiviral immunity, perhaps through the action of killer cell immunoglobulin-like receptors. The present study provides a comprehensive view of viral evolution and immune escape in a DNA virus.

Published
2018
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3. Evaluation of human relevance of Nicofluprole-induced rat thyroid disruption

Author

Céline Parmentier, Audrey Baze, Meiggie Untrau, Andreas Kampkoetter, Dominique Lasserre, and Lysiane Richert

Subjects
Pharmacology, Insecticides, Thyroid Hormones, Symporters, Thyroid Gland, Thyrotropin, Organ Size, Endocrine Disruptors, Toxicology, Iodide Peroxidase, Rats, Liver, Species Specificity, Hepatocytes, Animals, Humans, Rats, Wistar, Cell Size
Abstract

Nicofluprole is a novel insecticide of the phenylpyrazole class conferring selective antagonistic activity on insect GABA receptors. After repeated daily dietary administration to Wistar rats for 28/90 days, Nicofluprole induced increases in thyroid (and liver) weight, associated with histopathology changes. Nicofluprole did not inhibit thyroid peroxydase nor sodium/iodide symporter, two key players in the biosynthesis of thyroid hormones, indicating the absence of a direct thyroid effect. The results seen in rats suggested a mode of action of Nicofluprole driven by the molecular initiating event of CAR/PXR nuclear receptor activation in livers, with key events of increases in liver weight and hypertrophy, decreasing circulatory thyroid hormones, a compensatory increase in TSH release and follicular cell hypertrophy. To explore the relevance of these changes to humans, well established in vitro rat and human sandwich-cultured hepatocytes were exposed to Nicofluprole up to 7 days. A concentration-dependent CYP3A induction (PXR-activation), an increase in T4-glucuronoconjugation accompanied by UGT1A/2B inductions was observed in rat but not in human hepatocytes. The inductions seen with Nicofluprole in rat (in vivo and in vitro in hepatocytes) that were absent in human hepatocytes represent another example of species-selectivity of nuclear CAR/PXR receptor activators. Importantly, the different pattern observed in rat and human models demonstrate that Nicofluprole-related thyroid effects observed in the rat are with no human relevance.

Published
2021

4. The MHC class I MICA gene is a histocompatibility antigen in kidney transplantation

Author

Raphael Carapito, Ismail Aouadi, Martin Verniquet, Meiggie Untrau, Angélique Pichot, Thomas Beaudrey, Xavier Bassand, Sébastien Meyer, Loic Faucher, Juliane Posson, Aurore Morlon, Irina Kotova, Florent Delbos, Alexandre Walencik, Alice Aarnink, Anne Kennel, Caroline Suberbielle, Jean-Luc Taupin, Benedict M. Matern, Eric Spierings, Nicolas Congy-Jolivet, Arnaud Essaydi, Peggy Perrin, Antoine Blancher, Dominique Charron, Nezih Cereb, Myriam Maumy-Bertrand, Frédéric Bertrand, Valérie Garrigue, Vincent Pernin, Laurent Weekers, Maarten Naesens, Nassim Kamar, Christophe Legendre, Denis Glotz, Sophie Caillard, Marc Ladrière, Magali Giral, Dany Anglicheau, Caner Süsal, Seiamak Bahram, Süsal, Caner, Carapito, Raphael, Aouadi, Ismail, Verniquet, Martin, Untrau, Meiggie, Pichot, Angelique, Beaudrey, Thomas, Bassand, Xavier, Meyer, Sebastien, Faucher, Loic, Posson, Juliane, Morlon, Aurore, Kotova, Irina, Delbos, Florent, Walencik, Alexandre, Aarnink, Alice, Kennel, Anne, Suberbielle, Caroline, Taupin, Jean-Luc, Matern, Benedict M., Spierings, Eric, Congy-Jolivet, Nicolas, Essaydi, Arnaud, Perrin, Peggy, Blancher, Antoine, Charron, Dominique, Cereb, Nezih, Maumy-Bertrand, Myriam, Bertrand, Frederic, Garrigue, Valerie, Pernin, Vincent, Weekers, Laurent, Naesens, Maarten, Kamar, Nassim, Legendre, Christophe, Glotz, Denis, Caillard, Sophie, Ladriere, Marc, Giral, Magali, Anglicheau, Dany, Bahram, Seiamak, and School of Medicine

Subjects
Graft Rejection, Biochemistry & Molecular Biology, Science & Technology, HLA ANTIBODIES, Biochemistry and molecular biology, Cell biology, Medicine, Graft Survival, Histocompatibility Antigens Class I, Cell Biology, General Medicine, Research & Experimental Medicine, Kidney Transplantation, General Biochemistry, Genetics and Molecular Biology, Antibodies, Kidney transplantation, Alloantibody, Medicine, Research & Experimental, REJECTION, Humans, Life Sciences & Biomedicine
Abstract

The identity of histocompatibility loci, besides human leukocyte antigen (HLA), remains elusive. The major histocompatibility complex (MHC) class I MICA gene is a candidate histocompatibility locus. Here, we investigate its role in a French multicenter cohort of 1,356 kidney transplants. MICA mismatches were associated with decreased graft survival (hazard ratio (HR), 2.12; 95% confidence interval (CI): 1.45-3.11; P < 0.001). Both before and after transplantation anti-MICA donor-specific antibodies (DSA) were strongly associated with increased antibody-mediated rejection (ABMR) (HR, 3.79; 95% CI: 1.94-7.39; P < 0.001; HR, 9.92; 95% CI: 7.43-13.20; P < 0.001, respectively). This effect was synergetic with that of anti-HLA DSA before and after transplantation (HR, 25.68; 95% CI: 3.31-199.41; P = 0.002; HR, 82.67; 95% CI: 33.67-202.97; P < 0.001, respectively). De novo-developed anti-MICA DSA were the most harmful because they were also associated with reduced graft survival (HR, 1.29; 95% CI: 1.05-1.58; P = 0.014). Finally, the damaging effect of anti-MICA DSA on graft survival was confirmed in an independent cohort of 168 patients with ABMR (HR, 1.71; 95% CI: 1.02-2.86; P = 0.041). In conclusion, assessment of MICA matching and immunization for the identification of patients at high risk for transplant rejection and loss is warranted., ‘Laboratoire d’Excellence’ (LabEx) TRANSPLANTEX; IdEx Unistra; SFRI-STRAT’US; INSERM; European Union (EU); European Regional Development Fund; INTERREG V Program; France’s National Research Agency (Agence Nationale de Recherche; ANR); Investment for the Future Program (Programme des Investissements d’Avenir; PIA); Strasbourg’s Interdisciplinary Thematic Institute (ITI) for Precision Medicine; TRANSPLANTEX NG; ITI 2021–2028 Program of the University of Strasbourg; CNRS; Institut Universitaire de France (IUF); Fédération Hospitalo-Universitaire (FHU) OMICARE; MSD Avenir ‘Autogen’

Published
2021

5. A new MHC-linked susceptibility locus for primary Sjögren’s syndrome: MICA

Author

Marius Kwemou, Seiamak Bahram, Masao Ota, Hidetoshi Inoko, Nicodème Paul, Xavier Mariette, Jean Sibilia, Jacques-Eric Gottenberg, Lydie Naegely, Corinne Micelli-Richard, Raphael Carapito, Sandra Michel, Wan-Fai Ng, Gaetane Nocturne, Irina Kotova, Simon J Bowman, Angélique Pichot, Bridget Griffiths, Ismail Aouadi, Meiggie Untrau, James Locke, and Kathy L. Sivils

Subjects
Adult, Male, 0301 basic medicine, Linkage disequilibrium, Locus (genetics), Human leukocyte antigen, Biology, Major histocompatibility complex, Linkage Disequilibrium, White People, Major Histocompatibility Complex, 03 medical and health sciences, Gene Frequency, MHC class I, Genetics, HLA-B Antigens, Humans, Genetic Predisposition to Disease, Allele, Molecular Biology, Alleles, Genetics (clinical), Polymorphism, Genetic, Histocompatibility Antigens Class I, Association Studies Articles, Haplotype, General Medicine, Middle Aged, stomatognathic diseases, Sjogren's Syndrome, 030104 developmental biology, Haplotypes, Immunology, biology.protein, Female, HLA-DRB1 Chains
Abstract

The association of primary Sjögren’s syndrome (pSS) with Major Histocompatibility Complex (MHC) alleles is quintessential of MHC-disease associations. Indeed, although disease associations with classical HLA class I and II alleles/haplotypes are amply documented, further dissection is often prevented by the strong linkage disequilibrium across the entire MHC complex. Here we study the association of pSS, not with HLA genes, but with the non-conventional MHC encoded class I gene, MICA (MHC class I chain-related gene A). MICA is selectively expressed within epithelia, and is the major ligand for the activatory receptor, NKG2D, both attributes relevant to pSS’ etiology. MICA-pSS association was studied in two independent (French and UK) cohorts representing a total of 959 cases and 1,043 controls. MICA*008 allele was shown to be significantly associated with pSS (pcor=2.61 × 10−35). A multivariate logistic regression showed that this association was independent of all major known MHC-linked risk loci/alleles, as well as other relevant candidate loci that are in linkage disequilibrium with MICA*008 i.e. HLA-B*08:01, rs3131619 (T), MICB*008, TNF308A, HLA-DRB1*03:01 and HLA-DRB1*15:01 (P = 1.84 × 10−04). Furthermore, independently of the MICA*008 allele, higher levels of soluble MICA proteins were detected in sera of pSS patients compared to healthy controls. This study hence defines MICA as a new, MHC-linked, yet HLA-independent, pSS risk locus and opens a new front in our understanding of the still enigmatic pathophysiology of this disease. The fact that the soluble MICA protein is further amplified in MICA*008 carrying individuals, might also be relevant in other auto-immune diseases and cancer.

Published
2017

6. Matching for the nonconventional MHC-I MICA gene significantly reduces the incidence of acute and chronic GVHD

Author

Christophe Picard, Cécile Macquin, Sergi Querol, Catherine Paillard, Katharina Fleischhauer, Gaëlle Giacometti, Bronno van der Holt, Ibrahim Yakoub-Agha, Wassila Ilias, Anne Cesbron, Myriam Labopin, Masao Ota, Jorge Sierra, Fabio Ciceri, Dominique Charron, Ryad Tamouza, Régis Peffault de Latour, Xavier Lafarge, Katia Gagne, Seiamak Bahram, Myriam Maumy-Bertrand, Meiggie Untrau, Pascale Loiseau, Raphael Carapito, Jürgen Kuball, Bruno Lioure, Frans H.J. Claas, Noel Milpied, Antoine Toubert, Jan J. Cornelissen, Irina Kotova, Philippe Moreau, Eric Spierings, Mauricette Michallet, Arnon Nagler, Annette Schmitt-Graeff, Angélique Pichot, Petya Apostolova, Mohamad Mohty, Aurore Morlon, Myriam Labalette, Nicolas Jung, Didier Blaise, Yoshihiko Katsuyama, Hidetoshi Inoko, A. Parissiadis, Frédéric Bertrand, Marius Kwemou, Sandra Michel, Machteld Oudshoorn, Gérard Socié, Robert Zeiser, Peter A. von dem Borne, Valérie Dubois, Luca Vago, Carapito, Raphael, Jung, Nicola, Kwemou, Mariu, Untrau, Meiggie, Michel, Sandra, Pichot, Angélique, Giacometti, Gaëlle, Macquin, Cécile, Ilias, Wassila, Morlon, Aurore, Kotova, Irina, Apostolova, Petya, Schmitt Graeff, Annette, Cesbron, Anne, Gagne, Katia, Oudshoorn, Machteld, Van Der Holt, Bronno, Labalette, Myriam, Spierings, Eric, Picard, Christophe, Loiseau, Pascale, Tamouza, Ryad, Toubert, Antoine, Parissiadis, Anne, Dubois, Valérie, Lafarge, Xavier, Maumy Bertrand, Myriam, Bertrand, Frédéric, Vago, Luca, Ciceri, Fabio, Paillard, Catherine, Querol, Sergi, Sierra, Jorge, Fleischhauer, Katharina, Nagler, Arnon, Labopin, Myriam, Inoko, Hidetoshi, Von Dem Borne, Peter A., Kuball, Jürgen, Ota, Masao, Katsuyama, Yoshihiko, Michallet, Mauricette, Lioure, Bruno, De Latour, Régis Peffault, Blaise, Didier, Cornelissen, Jan J., Yakoub Agha, Ibrahim, Claas, Fran, Moreau, Philippe, Milpied, Noël, Charron, Dominique, Mohty, Mohamad, Zeiser, Robert, Socié, Gérard, Bahram, Seiamak, inconnu, Inconnu, Institut de Recherche Mathématique Avancée (IRMA), Université de Strasbourg (UNISTRA)-Centre National de la Recherche Scientifique (CNRS), Immuno-Rhumatologie Moléculaire, Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Laboratoire de Mathématiques et Modélisation d'Evry (LaMME), Institut National de la Recherche Agronomique (INRA)-Université d'Évry-Val-d'Essonne (UEVE)-Centre National de la Recherche Scientifique (CNRS), laboratoire d'Etudes et de recherches en Statistiques et Développement (LERSTAD), Université Gaston Bergé Sénégal, Laboratoire d'Acoustique Environnementale (IFSTTAR/AME/LAE), Institut Français des Sciences et Technologies des Transports, de l'Aménagement et des Réseaux (IFSTTAR)-Université de Lyon-PRES Université Nantes Angers Le Mans (UNAM), Physique des interactions ioniques et moléculaires (PIIM), Aix Marseille Université (AMU)-Centre National de la Recherche Scientifique (CNRS), LabEx Transplantex [Strasbourg], Université de Strasbourg (UNISTRA), Etablissement Français du Sang [Nantes], Etablissement Français du Sang - Alpes-Méditerranée (EFS - Alpes-Méditerranée), Etablissement Français du Sang, Service de pneumologie [Rennes] = Pneumology [Rennes], CHU Pontchaillou [Rennes], Anthropologie bio-culturelle, Droit, Ethique et Santé (ADES), Aix Marseille Université (AMU)-EFS ALPES MEDITERRANEE-Centre National de la Recherche Scientifique (CNRS), Alloimmunité-Autoimmunité-Transplantation (A2T), Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7)-Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hématologie -Immunologie -Cibles thérapeutiques, Université Paris Diderot - Paris 7 (UPD7)-Institut National de la Santé et de la Recherche Médicale (INSERM), Hôpital Saint-Louis, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7), Sociétés, Acteurs, Gouvernement en Europe (SAGE), Politique, Religion, Institutions et Sociétés : Mutations Européennes - Groupe de Sociologie Politique Européenne (PRISME-GSPE), Centre National de la Recherche Scientifique (CNRS), Centre de Transfusion Sanguine Aquitaine-Limousin (CTS AQUITAINE-LIMOUSIN), Centre de Transfusion Sanguine, Ospedale San Raffaele, Université Pierre et Marie Curie - Paris 6 - UFR de Médecine Pierre et Marie Curie (UPMC), Université Pierre et Marie Curie - Paris 6 (UPMC), Barcelona Cord Blood Bank, Agrosystèmes tropicaux (ASTRO), Institut National de la Recherche Agronomique (INRA), Chaim Sheba Medical Center [Ramat Gan, Israel], CHU Saint-Antoine [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Hôpital Edouard Herriot [CHU - HCL], Hospices Civils de Lyon (HCL), Département d'Oncologie et Hématologie [Strasbourg], Les Hôpitaux Universitaires de Strasbourg (HUS), Université Paris Diderot - Paris 7 (UPD7), Erasmus University Medical Center [Rotterdam] (Erasmus MC), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Department of Immunohematology and Blood Transfusion, Leiden University Medical Center (LUMC), Universiteit Leiden-Universiteit Leiden, Centre hospitalier universitaire de Nantes (CHU Nantes), Centre d'Investigations Biomédicales-Hématologie, Oncologie et Greffes (CIB-HOG), Hôpital St Louis, Assistance Publique des Hôpitaux de Paris (AP-HP), Centre d'Investigations Biomédicales-Hématologie, Institut National de la Recherche Agronomique (INRA)-Université d'Évry-Val-d'Essonne (UEVE)-ENSIIE-Centre National de la Recherche Scientifique (CNRS), Service de pneumologie, Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-CHU Pontchaillou [Rennes], Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Université Paris Diderot - Paris 7 (UPD7), Centre National de la Recherche Scientifique (CNRS)-Université de Strasbourg (UNISTRA), ALWP-EBMT & Département d'hématologie et de thérapie cellulaire [AP-HP Hôpital Saint-Antoine], AP-HP - Hôpital Saint-Antoine, Hematology, Institut de Recherche Mathématique Avancée ( IRMA ), Université de Strasbourg ( UNISTRA ) -Centre National de la Recherche Scientifique ( CNRS ), Université de Strasbourg ( UNISTRA ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Laboratoire de Mathématiques et Modélisation d'Evry ( LaMME ), Institut National de la Recherche Agronomique ( INRA ) -Université d'Évry-Val-d'Essonne ( UEVE ) -ENSIIE-Centre National de la Recherche Scientifique ( CNRS ), laboratoire d'Etudes et de recherches en Statistiques et Développement ( LERSTAD ), Laboratoire d'Acoustique Environnementale ( IFSTTAR/AME/LAE ), Institut Français des Sciences et Technologies des Transports, de l'Aménagement et des Réseaux ( IFSTTAR ) -Université de Lyon-PRES Université Nantes Angers Le Mans ( UNAM ), Laboratoire d'Histoire des Sciences et de Philosophie - Archives Henri Poincaré ( LHSP ), Université de Lorraine ( UL ) -Centre National de la Recherche Scientifique ( CNRS ), Physique des interactions ioniques et moléculaires ( PIIM ), Aix Marseille Université ( AMU ) -Centre National de la Recherche Scientifique ( CNRS ), Functional Genomics and Cancer, Etablissement Français du Sang - Alpes-Méditerranée ( EFS - Alpes-Méditerranée ), Université de Rennes 1 ( UR1 ), Université de Rennes ( UNIV-RENNES ) -Université de Rennes ( UNIV-RENNES ) -CHU Pontchaillou [Rennes], Anthropologie bio-culturelle, Droit, Ethique et Santé ( ADES ), Aix Marseille Université ( AMU ) -EFS ALPES MEDITERRANEE-Centre National de la Recherche Scientifique ( CNRS ), Alloimmunité-Autoimmunité-Transplantation ( A2T ), Université Paris Diderot - Paris 7 ( UPD7 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ), Assistance publique - Hôpitaux de Paris (AP-HP)-Université Paris Diderot - Paris 7 ( UPD7 ), Sociétés, Acteurs, Gouvernement en Europe ( SAGE ), Politique, Religion, Institutions et Sociétés : Mutations Européennes - Groupe de Sociologie Politique Européenne ( PRISME-GSPE ), Centre National de la Recherche Scientifique ( CNRS ), Centre de Transfusion Sanguine Aquitaine-Limousin ( CTS AQUITAINE-LIMOUSIN ), Géographie de l'environnement ( GEODE ), Centre National de la Recherche Scientifique ( CNRS ) -Université Toulouse - Jean Jaurès ( UT2J ), Université Pierre et Marie Curie - Paris 6 - UFR de Médecine Pierre et Marie Curie ( UPMC ), Université Pierre et Marie Curie - Paris 6 ( UPMC ), Agrosystèmes tropicaux ( ASTRO ), Institut National de la Recherche Agronomique ( INRA ), Hospices Civils de Lyon ( HCL ), IFR Saint-Louis, institut d'hématologie ( ISLIH ), Commissariat à l'énergie atomique et aux énergies alternatives ( CEA ) -Assistance publique - Hôpitaux de Paris (AP-HP)-Université Paris Diderot - Paris 7 ( UPD7 ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Centre National de la Recherche Scientifique ( CNRS ), Erasmus MC University medical Centre / Daniel den Hoed Cancer centre, Centre Hospitalier Régional Universitaire [Lille] ( CHRU Lille ), Centre hospitalier universitaire de Nantes ( CHU Nantes ), Laboratoire de Mathématiques et Modélisation d'Evry, PRES Université Nantes Angers Le Mans (UNAM)-Université de Lyon-Institut Français des Sciences et Technologies des Transports, de l'Aménagement et des Réseaux (IFSTTAR), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Strasbourg (UNISTRA), Centre National de la Recherche Scientifique (CNRS)-ENSIIE-Université d'Évry-Val-d'Essonne (UEVE)-Institut National de la Recherche Agronomique (INRA), Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Universitaire d'Hématologie (IUH), Université Paris Diderot - Paris 7 (UPD7)-Université Paris Diderot - Paris 7 (UPD7), Université Paris Diderot - Paris 7 (UPD7)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), and Université Paris Diderot - Paris 7 (UPD7)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)

Subjects
0301 basic medicine, Male, medicine.medical_treatment, [SDV]Life Sciences [q-bio], Medizin, Graft vs Host Disease, Hematopoietic stem cell transplantation, Biochemistry, Linkage Disequilibrium, immune system diseases, HLA Antigens, Cytotoxic T cell, Child, ComputingMilieux_MISCELLANEOUS, HLA-DQB1, biology, Histocompatibility Testing, Incidence, Hematopoietic Stem Cell Transplantation, Hematology, Middle Aged, Allografts, 3. Good health, surgical procedures, operative, NK Cell Lectin-Like Receptor Subfamily K, Child, Preschool, Acute Disease, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, Adult, Adolescent, Immunology, Human leukocyte antigen, 03 medical and health sciences, MHC class I, medicine, Journal Article, Humans, Aged, Retrospective Studies, Transplantation, [ SDV ] Life Sciences [q-bio], Histocompatibility Antigens Class I, Infant, Newborn, Infant, Cell Biology, medicine.disease, Histocompatibility, stomatognathic diseases, 030104 developmental biology, Graft-versus-host disease, Chronic Disease, biology.protein
Abstract

Graft-versus-host disease (GVHD) is among the most challenging complications in unrelated donor hematopoietic cell transplantation (HCT). The highly polymorphic MHC class I chain-related gene A, MICA, encodes a stress-induced glycoprotein expressed primarily on epithelia. MICA interacts with the invariant activating receptor NKG2D, expressed by cytotoxic lymphocytes, and is located in the MHC, next to HLA-B. Hence, MICA has the requisite attributes of a bona fide transplantation antigen. Using high-resolution sequence-based genotyping of MICA, we retrospectively analyzed the clinical effect of MICA mismatches in a multicenter cohort of 922 unrelated donor HLA-A, HLA-B, HLA-C, HLA-DRB1, and HLA-DQB1 10/10 allele-matched HCT pairs. Among the 922 pairs, 113 (12.3%) were mismatched in MICA. MICA mismatches were significantly associated with an increased incidence of grade III-IV acute GVHD (hazard ratio [HR], 1.83; 95% confidence interval [CI], 1.50-2.23; P < .001), chronic GVHD (HR, 1.50; 95% CI, 1.45-1.55; P < .001), and nonelapse mortality (HR, 1.35; 95% CI, 1.24-1.46; P < .001). The increased risk for GVHD was mirrored by a lower risk for relapse (HR, 0.50; 95% CI, 0.43-0.59; P < .001), indicating a possible graft-versus-leukemia effect. In conclusion, when possible, selecting a MICA-matched donor significantly influences key clinical outcomes of HCT in which a marked reduction of GVHD is paramount. The tight linkage disequilibrium between MICA and HLA-B renders identifying a MICA-matched donor readily feasible in clinical practice.

Published
2016

7. Hepatic and thyroid effects of phenobarbital in the minipig

Author

P. Ancian, Céline Parmentier, Lysiane Richert, Massimiliano Fonsi, Claudio Erratico, Meiggie Untrau, Carine Bansard, Pramila Singh, J. Boje Nielsen, Joachim Decorde, and Roy Forster

Subjects
medicine.medical_specialty, Endocrinology, business.industry, Internal medicine, Medicine, Phenobarbital, General Medicine, Toxicology, business, Thyroid effects, medicine.drug
Published
2018

8. A de novo ADCY5 mutation causes early‐onset autosomal dominant chorea and dystonia

Author

Philippe Damier, Mirjana Radosavljevic, Raphael Carapito, Ghada Alsaleh, Louise Ott, Marion Le Gentil, Meiggie Untrau, Seiamak Bahram, Bertrand Isidor, Pierre Jochem, Cédric Le Caignec, Albert David, and Nicodème Paul

Subjects
Adult, Male, congenital, hereditary, and neonatal diseases and abnormalities, Movement disorders, Adolescent, DNA Mutational Analysis, Biology, Chorea, medicine, Humans, Exome, Exome sequencing, Family Health, Genetics, Dystonia, ADCY5, medicine.disease, nervous system diseases, Neurology, Dystonic Disorders, Mutation, Female, Neurology (clinical), Myokymia, medicine.symptom, Haploinsufficiency, Adenylyl Cyclases
Abstract

Importance Apart from Huntington's disease, little is known of the genetics of autosomal dominant chorea associated with dystonia. Here we identify adenylate cyclase 5 (ADCY5) as a likely new causal gene for early-onset chorea and dystonia. Observations Whole exome sequencing in a three-generation family affected with autosomal dominant chorea associated with dystonia identified a single de novo mutation—c.2088+1G>A in a 5' donor splice-site of ADCY5—segregating with the disease. This mutation seeming leads to RNA instability and therefore ADCY5 haploinsufficiency. Conclusions and Relevance Our finding confirms the genetic/clinical heterogeneity of the disorder; corroborated by previous identification of ADCY5 mutations in one family with dyskinesia-facial myokymia and in two unrelated sporadic cases of paxoysmal choreic/dystonia-facial myokymia; ADCY5's high expression in the striatum and movement disorders in ADCY5-deficient mice. Hence ADCY5 genetic analyses may be relevant in the diagnostic workup of unexplained early-onset hyperkinetic movement disorders. © 2014 International Parkinson and Movement Disorder Society

Published
2014

9. Thyroid hormone perturbation in a minipig model

Author

Pramila Singh, Lysiane Richert, Sandrine Bentz, Roy Forster, Joachim Decorde, François Spézia, Meiggie Untrau, Céline Parmentier, Jonas Boje Nielsen, Massimiliano Fonsi, and Claudio-Alberto Erratico

Subjects
medicine.medical_specialty, Endocrinology, medicine.anatomical_structure, Chemistry, Internal medicine, Thyroid, medicine, Perturbation (astronomy), Toxicology, Hormone
Published
2018

10. A new mutation in the C-SH2 domain of PTPN11 causes Noonan syndrome with multiple giant cell lesions

Author

Nadège Corradini, Bertrand Isidor, Nicodème Paul, Elisabeth Cassagnau, Raphael Carapito, Seiamak Bahram, Louise Ott, Marie-Françoise Heymann, Meiggie Untrau, Emmanuelle Caldagues, Sylvaine Poignant, and Loïc Geffroy

Subjects
Male, Proband, Biopsy, DNA Mutational Analysis, Protein Tyrosine Phosphatase, Non-Receptor Type 11, Biology, medicine.disease_cause, Giant Cells, Short stature, src Homology Domains, Exon, Genetics, medicine, Humans, Exome, Child, Genetics (clinical), Mutation, Noonan Syndrome, Synovial Membrane, Facies, medicine.disease, PTPN11, Phenotype, Giant cell, Noonan syndrome, Webbed neck, Female, medicine.symptom
Abstract

Noonan syndrome (NS), an autosomal dominant multisystem disorder, is caused by the dysregulation of the RAS-MAPK pathway and is characterized by short stature, heart defects, pectus excavatum, webbed neck, learning problems, cryptorchidism and facial dysmorphism. We here present the clinical and molecular characterization of a family with NS and multiple giant cell lesions (MGCLs). The proband is a 12-year-old girl with NS and MGCL. Her mother shows typical NS without MGCL. Whole-exome sequencing of the girl, her mother and her healthy maternal grand parents revealed a previously unobserved mutation in exon 5 of the PTPN11 gene (c.598 A>T; p.N200Y), transmitted from the mother to the proband. As no other modification in the RAS-MAPK pathway genes as related to Rasopathies was detected in the proband, this report demonstrates for the first time that a unique mutation affecting this, otherwise unaffected signaling route, can cause both NS and NS/MGCL in the same family. This observation further confirms that NS/MGCL is not a distinct entity but rather that MGCL represents a rare complication of NS. Moreover, the localization of the p.N200Y mutation suggests an alternative molecular mechanism for the excessive phosphatase activity of the PTPN11-encoded protein.

Published
2013

12. Polymorphisms in EGFR and IL28B are associated with spontaneous clearance in an HCV-infected Iranian population

Author

Seiamak Bahram, Reza Malekzadeh, J Toussaint, M Le Gentil, Shahin Merat, Amir-Houshang Sharifi, Saeed Esmaili, Meiggie Untrau, Alireza Ansari-Moghaddam, Philippe Georgel, Arghavan Haj-Sheykholeslami, Mirjana Radosavljevic, Arash Etemadi, Raphael Carapito, Marius Kwemou, Hosein Poustchi, Sandra Michel, and Hossain Jabbari

Subjects
Genetic Markers, medicine.medical_specialty, Hepatitis C virus, Hepacivirus, Immunology, Population, Remission, Spontaneous, Spontaneous remission, Single-nucleotide polymorphism, Iran, medicine.disease_cause, Gastroenterology, Polymorphism, Single Nucleotide, Internal medicine, Genotype, Genetics, medicine, Humans, education, Genetics (clinical), education.field_of_study, biology, Interleukins, Hepatitis C, Odds ratio, medicine.disease, biology.organism_classification, ErbB Receptors, Multivariate Analysis, Interferons
Abstract

Although most hepatitis C virus (HCV)-infected individuals develop chronic infection, about 25% of them are able to clear the virus spontaneously without any therapeutic intervention. The aim of the present study was to identify genes associated with spontaneous HCV clearance in a population of Iranian patients. We genotyped 110 single-nucleotide polymorphisms (SNPs) in 59 selected--candidate--genes in a cohort of 107 HCV-infected participants who spontaneously cleared the infection and 176 participants whose infection persisted. Three out of the 110 SNPs were found to be associated with HCV outcome (P-values

Published
2015

13. Homozygous IL36RN mutation and NSD1 duplication in a patient with severe pustular psoriasis and symptoms unrelated to deficiency of interleukin-36 receptor antagonist

Author

C. Frenard, C. Le Caignec, Bertrand Isidor, Nicodème Paul, Louise Ott, Elisabeth Cassagnau, Seiamak Bahram, Sébastien Barbarot, Mirjana Radosavljevic, Hélène Aubert, Raphael Carapito, B. Romefort, Meiggie Untrau, Elise Launay, and N. Guerouaz

Subjects
Male, Dermatology, Histone-Lysine N-Methyltransferase, Psoriasis, Gene duplication, Medicine, Humans, Nuclear protein, Genetics, business.industry, Interleukins, Homozygote, Intracellular Signaling Peptides and Proteins, Interleukin, Infant, Nuclear Proteins, medicine.disease, Interleukin 36 receptor antagonist, Histone methyltransferase, Mutation (genetic algorithm), Mutation, Cancer research, Histone Methyltransferases, business
Published
2014

14. Matching of MHC Class I Chain-Related Genes a and B Is Associated with Reduced Incidence of Severe Acute Graft-Versus-Host Disease after Unrelated Hematopoietic Stem Cell Transplantation

Author

Myriam Labopin, Nicole Raus, Régis Peffault de Latour, Mohamad Mohty, Katharina Fleischhauer, Gérard Socié, Daniel Hanau, Nicolas Jung, Ibrahim Yakoub-Agha, Xavier Lafarge, Miriam Hoffmann, Raphael Carapito, Jordi Sierra, Philippe Moreau, Anne Cesbron, Masao Ota, Seiamak Bahram, Arnon Nagler, A. Parissiadis, Mauricette Michallet, Ryad Tamouza, Franz Claas, Gaëlle Giacometti, Myriam Labalette, Ronnie van der Holt, Pascale Loiseau, Fabio Ciceri, Didier Blaise, Eric Spierings, Meiggie Untrau, Valérie Dubois, Catherine Paillard, Luca Vago, Noel Milpied, Antoine Toubert, Hidetoshi Inoko, Sergio Querol, Christophe Picard, Angélique Pichot, Dominique Charron, Sandra Michel, Katia Gagne, Bruno Lioure, Machteld Oudshoorn, Carapito, R, Jung, N, Untrau, M, Michel, S, Pichot, A, Giacometti, G, Cesbron, A, Gagne, K, Oudshoorn, M, Van der Holt, R, Labalette, M, Spierings, E, Picard, C, Loiseau, P, Tamouza, R, Toubert, A, Hanau, D, Parissiadis, A, Dubois, V, Raus, N, Lafarge, X, Vago, L, Ciceri, F, Paillard, C, Querol, S, Sierra, J, Fleischhauer, K, Nagler, A, Hoffmann, M, Milpied, N, Michallet, M, Lioure, B, de Latour, Rp, Labopin, M, Inoko, H, Claas, F, Blaise, D, Yakoub-Agha, I, Moreau, P, Charron, D, Ota, M, Mohty, M, Socie, G, Bahram, S, Immuno-Rhumatologie Moléculaire, Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Strasbourg (UNISTRA), and Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)

Subjects
medicine.medical_treatment, Immunology, Medizin, Hematopoietic stem cell transplantation, Human leukocyte antigen, Biochemistry, 03 medical and health sciences, 0302 clinical medicine, medicine, Minor histocompatibility antigen, Cumulative incidence, 030304 developmental biology, 0303 health sciences, Univariate analysis, business.industry, Donor selection, Cell Biology, Hematology, 3. Good health, Transplantation, surgical procedures, operative, [SDV.IMM]Life Sciences [q-bio]/Immunology, business, CD8, 030215 immunology
Abstract

Background: Graft-versus-host disease (GVHD) is a major cause of mortality after unrelated hematopoietic stem cell transplantations (HSCT). Despite the development of modern immunosuppressive strategies, a nearly perfectly controlled compatibility of the classical HLA genes (HLA-A, -B, -C, -DRB1, -DQB1, and -DPB1) and availability of numerous so-called minor histocompatibility antigens (e.g. HY or HA-1), its incidence remains largely unexplained to date. MIC genes (MHC class I chain-related) - a distinct lineage of MHC class I genes – are promising candidates to explain, at least partially, the incidence of GVHD in HLA-matched transplantations. MICA and MICB are highly polymorphic (100 alleles for MICA and 40 for MICB) and encode functional cell-surface glycoproteins up-regulated by cell stress. They interact with NKG2D, an activating receptor expressed on the surface of cytotoxic αβ CD8+ and γδ T lymphocytes and natural killer cells. MIC genes are already known to have a HLA-independent effect on solid graft outcomes and may play a similar role in HSCT by triggering GVHD. Objective: The objective of the present study was to determine the impact of donor/patient matching at the MICA and MICB loci on the incidence of GVHD in patients undergoing unrelated HSCT. Methods: We retrospectively analyzed a multicenter cohort of 1072 unrelated transplantations performed between 1996 and 2013. All donor-recipient pairs were fully typed at high resolution for HLA-A, -B, -C, -DRB1, -DQB1, and -DPB1 and were matched for ten of ten HLA alleles (HLA 10/10 matched). High resolution genotyping of MICA and MICB was performed by sequenced-based typing in order to define matching grades between donors and patients. The endpoints of the study were acute and chronic GVHD. Apart from HLA-DPB1 matching, statistical models were adjusted for major clinical variables which have been shown to be associated with outcome (patient’s age, patient’s and donor’s sex, patient’s and donor’s serological status for cytomegalovirus, year of transplantation, time to transplantation, transplantation center, source of stem cells, conditioning regimen, GVHD prophylaxis, treatment with anti-thymocyte globulin, disease category and severity at transplantation). Results: Of the 1072 transplantations, 134 (12.5 %) and 380 (35.4 %) were mismatched at the MICA and MICB locus, respectively. Both MICA and MICB mismatches were significantly associated with an increased incidence of severe acute GVHD (grades III-IV) in univariate and multivariate models (multivariate model: HR = 2.32, 95 % CI = 1.84-2.92; p=0.0003 for MICA and HR = 1.49, 95 % CI = 1.24-1.79; p=0.03 for MICB). At day 100 post-HSCT severe acute GVHD incidences in mismatched vs. matched transplantations were 19.62 % vs. 15.08 % and 20.00 % vs. 14.84 % for MICA and MICB, respectively (Figure 1). Chronic GVHD was associated with MICA and MICB mismatches in univariate analysis (HR = 1.55, 95 % CI = 1.27-1.89; p=0.029 for MICA and HR=1.38, 95 % CI = 1.19-1.62; p=0.03 for MICB), but showed only a trend for association in multivariate models. Figure 1 Estimated cumulative incidence curves of grades III–IV acute GVHD according to MICA (panel A) and MICB (panel B) matching status. The solid and dashed lines represent MIC matched and mismatched grafts, respectively. The Fine and Gray model was used with relapse and death considered as competing risks. Figure 1. Estimated cumulative incidence curves of grades III–IV acute GVHD according to MICA (panel A) and MICB (panel B) matching status. The solid and dashed lines represent MIC matched and mismatched grafts, respectively. The Fine and Gray model was used with relapse and death considered as competing risks. Conclusion: To date this is the largest reported MICA and MICB sequence analysis whether in HSCT or solid organ transplantation. Inclusion of MICA and MICB typing in the donor selection process may be a practical clinical strategy for lowering the risks of severe acute GVHD after unrelated HSCT. Disclosures No relevant conflicts of interest to declare.

Published
2014

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