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26 results on '"Center for Chronic Immunodeficiency (CCI), University Medical Center Freiburg, Freiburg, Germany"'

1. Dominant-negative mutations in human IL6ST underlie hyper-IgE syndrome

Author

Vivien, Béziat, Simon J, Tavernier, Yin-Huai, Chen, Cindy S, Ma, Marie, Materna, Arian, Laurence, Jens, Staal, Dominik, Aschenbrenner, Lisa, Roels, Lisa, Worley, Kathleen, Claes, Lisa, Gartner, Lisa A, Kohn, Marieke, De Bruyne, Klaus, Schmitz-Abe, Louis-Marie, Charbonnier, Sevgi, Keles, Justine, Nammour, Natasha, Vladikine, Majistor Raj Luxman, Maglorius Renkilaraj, Yoann, Seeleuthner, Mélanie, Migaud, Jérémie, Rosain, Mohamed, Jeljeli, Bertrand, Boisson, Eva, Van Braeckel, Jill A, Rosenfeld, Hongzheng, Dai, Lindsay C, Burrage, David R, Murdock, Bart N, Lambrecht, Véronique, Avettand-Fenoel, Tiphanie P, Vogel, Charles R, Esther, Sule, Haskologlu, Figen, Dogu, Peter, Ciznar, David, Boutboul, Marie, Ouachée-Chardin, Jean, Amourette, Marie-Noëlle, Lebras, Clément, Gauvain, Colas, Tcherakian, Aydan, Ikinciogullari, Rudi, Beyaert, Laurent, Abel, Joshua D, Milner, Bodo, Grimbacher, Louis-Jean, Couderc, Manish J, Butte, Alexandra F, Freeman, Émilie, Catherinot, Claire, Fieschi, Talal A, Chatila, Stuart G, Tangye, Holm H, Uhlig, Filomeen, Haerynck, Jean-Laurent, Casanova, Anne, Puel, St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller University [New York], Imagine - Institut des maladies génétiques (IHU) (Imagine - U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Paris (UP), Laboratory of Human Genetics of Infectious Diseases (Necker Branch - INSERM U1163), Institut National de la Santé et de la Recherche Médicale (INSERM)-CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Ghent University Hospital, VIB-UGent Center for Inflammation Research [Gand, Belgique] (IRC), VIB [Belgium], Center for Medical Genetics [Ghent], John Radcliffe Hospital [Oxford University Hospital], University of Oxford [Oxford], Garvan Institute of Medical Research [Darlinghurst, Australia], St. Vincent’s Clinical School, Faculty of Medicine, University of New South Wales [Sydney] (UNSW), University of California, Boston Children's Hospital, Harvard Medical School [Boston] (HMS), Necmettin Erbakan University [Konya, Turquie], Hôpital Cochin [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Baylor College of Medicine (BCM), Baylor University, Laboratoire de Virologie [CHU Necker], CHU Necker - Enfants Malades [AP-HP], University of North Carolina [Chapel Hill] (UNC), University of North Carolina System (UNC), Ankara University School of Medicine [Turkey], Comenius University in Bratislava, Service d'Immunopathologie [Hôpital Saint-Louis, Paris], Hopital Saint-Louis [AP-HP] (AP-HP), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université de Paris (UP), Unité d'Hémato-Immunologie pédiatrique [Hôpital Robert Debré, Paris], Service d'Immuno-hématologie pédiatrique [Hôpital Robert Debré, Paris], Hôpital Robert Debré-Hôpital Robert Debré, Groupe Hospitalier Artois-Ternois Centre Hospitalier d’Arras, Service de pneumologie [Hôpital Foch], Hôpital Foch [Suresnes], National Institute of Allergy and Infectious Diseases [Bethesda] (NIAID-NIH), National Institutes of Health [Bethesda] (NIH), Columbia University Irving Medical Center (CUIMC), Center for Chronic Immunodeficiency (CCI), University Medical Center Freiburg, Freiburg, Germany, Centre for Integrative Biological Signaling Studies [Freiburg, Germany], University of Freiburg [Freiburg], Hanover Medical School, Laboratoire de recherche sur les mécanismes moléculaires et pharmacologiques de l’obstruction bronchique (LOBIP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ), Université de Versailles Saint-Quentin-en-Yvelines - UFR Sciences de la santé Simone Veil (UVSQ Santé), Department of Pediatrics, Keck School of Medicine, University of Southern California, Los Angeles, Institut de Recherche Saint-Louis - Hématologie Immunologie Oncologie (Département de recherche de l’UFR de médecine, ex- Institut Universitaire Hématologie-IUH) (IRSL), Université de Paris (UP), St. Vincent’s Clinical School [Sydney, Australia], UNSW Faculty of Medicine [Sydney], and University of New South Wales [Sydney] (UNSW)-University of New South Wales [Sydney] (UNSW)

Subjects
Male, Adolescent, Models, Biological, Young Adult, Th2 Cells, Loss of Function Mutation, Cytokine Receptor gp130, Humans, Immunodeficiency, Child, Alleles, Cells, Cultured, Genes, Dominant, Human disease genetics, Cell Membrane, Correction, Fibroblasts, Middle Aged, Pedigree, Up-Regulation, Kinetics, C-Reactive Protein, Genetics, Population, HEK293 Cells, Phenotype, Mutation, Cytokines, [SDV.IMM]Life Sciences [q-bio]/Immunology, Female, Job Syndrome
Abstract

International audience; Autosomal dominant hyper-IgE syndrome (AD-HIES) is typically caused by dominant-negative (DN) STAT3 mutations. Patients suffer from cold staphylococcal lesions and mucocutaneous candidiasis, severe allergy, and skeletal abnormalities. We report 12 patients from 8 unrelated kindreds with AD-HIES due to DN IL6ST mutations. We identified seven different truncating mutations, one of which was recurrent. The mutant alleles encode GP130 receptors bearing the transmembrane domain but lacking both the recycling motif and all four STAT3-recruiting tyrosine residues. Upon overexpression, the mutant proteins accumulate at the cell surface and are loss of function and DN for cellular responses to IL-6, IL-11, LIF, and OSM. Moreover, the patients’ heterozygous leukocytes and fibroblasts respond poorly to IL-6 and IL-11. Consistently, patients with STAT3 and IL6ST mutations display infectious and allergic manifestations of IL-6R deficiency, and some of the skeletal abnormalities of IL-11R deficiency. DN STAT3 and IL6ST mutations thus appear to underlie clinical phenocopies through impairment of the IL-6 and IL-11 response pathways.

Published
2020
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2. Serum levels of hsa‐miR‐16‐5p , hsa‐miR‐29a‐3p , hsa‐miR‐150‐5p , hsa‐miR‐155‐5p and hsa‐miR ‐ 223‐3p and subsequent risk of chronic lymphocytic leukemia in the EPIC study

Author

Heiner Boeing, María Arestin, Aurelio Barricarte, Delphine Casabonne, Elio Riboli, Roel Vermeulen, Carlo La Vecchia, Alexandra Nieters, Federico Canzian, Julie A. Schmidt, Matthias B. Schulze, María Armesto, Rosario Tumino, Yolanda Benavente, Rudolf Kaaks, Salvatore Panico, María José Sánchez, Anna Karakatsani, Pilar Amiano, Caroline Besson, Marc J. Gunter, Giovanna Masala, Carlotta Sacerdote, María Dolores Chirlaque, Silvia de Sanjosé, Valeria Pala, Anne Tjønneland, Charles H. Lawrie, Antonia Trichopoulou, Elisabete Weiderpass, Eric J. Duell, Fatemeh Saberi Hosnijeh, Anja Olsen, Vittorio Perduca, Julia Seifert, Francesca Mancini, Laura Costas, CIBER de Epidemiología y Salud Pública (CIBERESP), Catalan Institute of Oncology (ICO-IDIBELL), Facultat de Medicina [Barcelona], Centre Hospitalier de Versailles André Mignot (CHV), Centre de recherche en épidémiologie et santé des populations (CESP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Institut Gustave Roussy (IGR), Épidémiologie des radiations, épidémiologie clinique des cancers et survie (U1018 (Équipe 3) ), Institut Gustave Roussy (IGR)-Centre de recherche en épidémiologie et santé des populations (CESP), Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay-Université de Versailles Saint-Quentin-en-Yvelines (UVSQ)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Paul Brousse-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris-Saclay, Unit of Nutrition, Environment, and Cancer, Catalan Institute of Oncology, Department of Community Medicine, Faculty of Health Sciences, The Arctic University of Norway (UiT), Cancer Risk Factors and LifeStyle Epidemiology Unit, Cancer Research and Prevention Institute (ISPO), Division of Cancer Epidemiology, German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg] (DKFZ), Department of Cancer Epidemiology, Mathématiques Appliquées Paris 5 (MAP5 - UMR 8145), Université Paris Descartes - Paris 5 (UPD5)-Institut National des Sciences Mathématiques et de leurs Interactions (INSMI)-Centre National de la Recherche Scientifique (CNRS), Mode de vie, génétique et santé : études intégratives et transgénérationnelles (U1018 (Équipe 9)), Epidemiology and Prevention Unit, Fondazione IRCCS Istituto Nazionale Tumori - National Cancer Institute [Milan], WHO Collaborating Center for Nutrition and Health, Unit of Nutritional Epidemiology and Nutrition in Public Health, Dept of Hygiene, Epidemiology and Medical Statistics, University of Athens Medical School [Athens]-University of Athens Medical School [Athens], Hellenic Health Foundation, Department of Clinical Sciences and Community Health [Milan, Italy], Università degli Studi di Milano [Milano] (UNIMI), Civile - M.P.Arezzo Hospital, Nutrition and Metabolism Section, International Agency for Research on Cancer, Department of Clinical and Experimental Medicine, Università degli studi di Napoli Federico II, CPO Piemonte, Department of Epidemiology, German Institute of Human Nutrition (DIfE), German Institute of Human Nutrition Potsdam-Rehbrücke (DIfE), School of Public Health [London, UK] (Faculty of Medicine), Imperial College London, Danish Cancer Society Research Center, Danish Cancer Society, Division of Environmental Epidemiology, Utrecht University [Utrecht]-Institute of Risk Assessment Sciences, Center for Chronic Immunodeficiency (CCI), University Medical Center Freiburg, Freiburg, Germany, IRAS OH Epidemiology Chemical Agents, dIRAS RA-2, and Immunology

Subjects
Oncology, Male, DOWN-REGULATION, Cancer Research, PROGNOSIS, Chronic lymphocytic leukemia, ACTIVATION, 0302 clinical medicine, mir-223, Odds Ratio, Prospective Studies, Prospective cohort study, ComputingMilieux_MISCELLANEOUS, Area under the curve, Middle Aged, MIR-155, 3. Good health, European Prospective Investigation into Cancer and Nutrition, Up-Regulation, Europe, DIFFERENTIATION, INFECTIONS, 030220 oncology & carcinogenesis, embryonic structures, Monoclonal B-cell lymphocytosis, Female, B-CELL LYMPHOCYTOSIS, Life Sciences & Biomedicine, prospective study, EXPRESSION, medicine.medical_specialty, MICRORNA SIGNATURE, miR-155, 03 medical and health sciences, Predictive Value of Tests, Internal medicine, medicine, Biomarkers, Tumor, Humans, 1112 Oncology and Carcinogenesis, Oncology & Carcinogenesis, Liquid biopsy, Science & Technology, business.industry, medicine.disease, Leukemia, Lymphocytic, Chronic, B-Cell, body regions, circulating miRNA, MicroRNAs, Case-Control Studies, chronic lymphocytic leukemia, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, business, serum, CLL
Abstract

Chronic lymphocytic leukemia (CLL) is an incurable disease accounting for almost one-third of leukemias in the Western world. Aberrant expression of microRNAs (miRNAs) is a well-established characteristic of CLL, and the robust nature of miRNAs makes them eminently suitable liquid biopsy biomarkers. Using a nested case–control study within the European Prospective Investigation into Cancer and Nutrition (EPIC), the predictive values of five promising human miRNAs (hsa-miR-16-5p, hsa-miR-29a-3p, hsa-miR-150-5p, hsa-miR-155-5p and hsa-miR-223-3p), identified in a pilot study, were examined in serum of 224 CLL cases (diagnosed 3 months to 18 years after enrollment) and 224 matched controls using Taqman based assays. Conditional logistic regressions were applied to adjust for potential confounders. The median time from blood collection to CLL diagnosis was 10 years (p25–p75: 7–13 years). Overall, the upregulation of hsa-miR-150-5p, hsa-miR-155-5p and hsa-miR-29a-3p was associated with subsequent risk of CLL [OR1∆Ct-unit increase (95%CI) = 1.42 (1.18–1.72), 1.64 (1.31–2.04) and 1.75 (1.31–2.34) for hsa-miR-150-5p, hsa-miR-155-5p and hsa-miR-29a-3p, respectively] and the strongest associations were observed within 10 years of diagnosis. However, the predictive performance of these miRNAs was modest (area under the curve

Published
2020
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3. Genetic overlap between autoimmune diseases and non-Hodgkin lymphoma subtypes

Author

Paul Brennan, M. G. Ennas, Qing Lan, Sasha Bernatsky, Alan A. Arslan, Peter Kraft, Lohith Madireddy, Roel Vermeulen, Kenan Onel, Graham G. Giles, John J. Spinelli, Eleanor Kane, Bengt Glimelius, Alexandra Nieters, David V. Conti, Christine F. Skibola, Pouya Khankhanian, Amy Moore, Ruth C. Travis, Mads Melbye, Sonja I. Berndt, Mark Liebow, Lauren R. Teras, Pierluigi Cocco, Lennox Din, Alain Monnereau, Mark P. Purdue, Lenka Foretova, Stephen J. Chanock, Stephen M. Ansell, Angela Brooks-Wilson, Wendy Cozen, Kenneth Offit, Demetrius Albanes, Anne J. Novak, Melissa C. Southey, Paolo Boffetta, Nicola J. Camp, James R. Cerhan, Rudolph Kaaks, Silvia de Sanjosé, Karen Curtin, Sophia S. Wang, James McKay, Nicole Wong Doo, Hans-Olov Adami, Tongzhang Zheng, Claire M. Vajdic, Nisha Pradhan, Giacomo Muzi, Gilles Salles, Nathaniel Rothman, Yolanda Benavente, Marc Maynadié, Brian K. Link, Delphine Casabonne, Hervé Ghesquières, Joseph Vijai, Karin E. Smedby, Paige M. Bracci, David G. Cox, Brenda M. Birmann, Lucia Miligi, Carolyn Stewart, Lucia Conde, Leonid Padyukov, Eve Roman, Richard K. Severson, Jorge R. Oksenberg, Immaculata De Vivo, Yawei Zhang, Corrado Magnani, Jacqueline Clavel, Lindsay M. Morton, Corinne Haioun, Jonathan N. Hofmann, Karen H. Costenbader, Pierre-Antoine Gourraud, Mohammad Sheikh, Stephanie J. Weinstein, Susan L. Slager, Paolo Vineis, Nikitha Kosaraju, Zachary Taub, Henrik Hjalgrim, Roger L. Milne, Morris Din, Martha Glenn, Nikolaus Becker, Timothy J. Vyse, Thomas M. Mack, Anthony Staines, Department of Medicine, Clinical Epidemiology, McGill University Health Center [Montreal] (MUHC), National Cancer Institute [Bethesda] (NCI-NIH), National Institutes of Health [Bethesda] (NIH), Emory University [Atlanta, GA], Center for Chronic Immunodeficiency (CCI), University Medical Center Freiburg, Freiburg, Germany, International Agency for Cancer Research (IACR), Department of Public Health, Vientiane Municipality, Registre des hémopathies malignes de Côte d'Or, Masaryk Memorial Cancer Institute and Medical Faculty of Masaryk University, GRAPHOS - IFROSS Recherche, Université Jean Moulin - Lyon 3 (UJML), Université de Lyon-Université de Lyon, Faculty of Medicine, Section of Rheumatology, Imperial College London, Karolinska Institutet [Stockholm], Epidémiologie environnementale des cancers, Université Paris-Sud - Paris 11 (UP11)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Santé et de la Recherche Médicale (INSERM), Department of Chemistry and Biochemistry [Boulder], University of Colorado [Boulder], Uppsala Universitet [Uppsala], Carver College of Medicine, University of Iowa, Service d'hématologie clinique, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Henri Mondor-Université Paris-Est Créteil Val-de-Marne - Paris 12 (UPEC UP12), Centre de Recherche en Cancérologie de Lyon (UNICANCER/CRCL), Centre Léon Bérard [Lyon]-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Division of Cancer Epidemiology and Genetics, National Institutes of Health [Bethesda] (NIH)-National Institutes of Health [Bethesda] (NIH), Health Sciences, University of York [York, UK], Service de Radio-Oncologie [Lyon], Hospices Civils de Lyon (HCL)-Centre Hospitalier Lyon Sud [CHU - HCL] (CHLS), Hospices Civils de Lyon (HCL), University of Melbourne, Centre Léon Bérard [Lyon], Mayo Clinic [Rochester], Occupational and Environmental Epidemiology Branch [Bethesda, Maryland], Division of Cancer Epidemiology and Genetics [Bethesda, Maryland], National Institutes of Health [Bethesda] (NIH)-National Institutes of Health [Bethesda] (NIH)-National Cancer Institute [Bethesda] (NCI-NIH), Memorial Sloane Kettering Cancer Center [New York], Huntsman Cancer Institute, Clinical Genetics Service, ISPO - Cancer Prevention and Research Institute, Unit of Environmental and Occupational Epidemiology, Dept. of Epidemiology Research, Statens Serum Institut [Copenhagen], B.B. Brodie Department of Neuroscience, Department of Pathology, Division of Cancer Epidemiology, German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg] (DKFZ), Unit of Environment Cancer Epidemiology, IARC, University of Torino and CPO-Piemonte, Università degli studi di Torino (UNITO), Department of Epidemiology, Harvard School of Public Health, Wayne State University [Detroit], Division of Environmental Epidemiology, Institute for Risk Assessment Sciences, Cancer Epidemiology Centre, Cancer Council Victoria, Cancer Epidemiology Unit, University of Oxford [Oxford], De la Molécule aux Nanos-objets : Réactivité, Interactions et Spectroscopies (MONARIS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS), Catalan Institute of Oncology (ICO), Department of Neurology [San Francisco, CA, USA], University of California [San Francisco] (UCSF), University of California-University of California, Norris Comprehensive Cancer Center, Masaryk University [Brno] (MUNI), Università degli studi di Torino = University of Turin (UNITO), University of California [San Francisco] (UC San Francisco), University of California (UC)-University of California (UC), Imperial College London, University of Oxford, Din L., Sheikh M., Kosaraju N., Smedby K.E., Bernatsky S., Berndt S.I., Skibola C.F., Nieters A., Wang S., McKay J.D., Cocco P., Maynadie M., Foretova L., Staines A., Mack T.M., de Sanjose S., Vyse T.J., Padyukov L., Monnereau A., Arslan A.A., Moore A., Brooks-Wilson A.R., Novak A.J., Glimelius B., Birmann B.M., Link B.K., Stewart C., Vajdic C.M., Haioun C., Magnani C., Conti D.V., Cox D.G., Casabonne D., Albanes D., Kane E., Roman E., Muzi G., Salles G., Giles G.G., Adami H.-O., Ghesquieres H., De Vivo I., Clavel J., Cerhan J.R., Spinelli J.J., Hofmann J., Vijai J., Curtin K., Costenbader K.H., Onel K., Offit K., Teras L.R., Morton L., Conde L., Miligi L., Melbye M., Ennas M.G., Liebow M., Purdue M.P., Glenn M., Southey M.C., Din M., Rothman N., Camp N.J., Wong Doo N., Becker N., Pradhan N., Bracci P.M., Boffetta P., Vineis P., Brennan P., Kraft P., Lan Q., Severson R.K., Vermeulen R.C.H., Milne R.L., Kaaks R., Travis R.C., Weinstein S.J., Chanock S.J., Ansell S.M., Slager S.L., Zheng T., Zhang Y., Benavente Y., Taub Z., Madireddy L., Gourraud P.-A., Oksenberg J.R., Cozen W., Hjalgrim H., Khankhanian P., and Le Bihan, Sylvie

Subjects
Oncology, Male, Multifactorial Inheritance, Lymphoma, Epidemiology, Chronic lymphocytic leukemia, Follicular lymphoma, Genome-wide association study, Disease, Neurodegenerative, meta-analysi, immune system diseases, HLA Antigens, Risk Factors, hemic and lymphatic diseases, 2.1 Biological and endogenous factors, HLA Antigen, Aetiology, Genetics (clinical), Cancer, Allele, 0303 health sciences, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Lymphoma, Non-Hodgkin, non-Hodgkin lymphoma, 030305 genetics & heredity, Single Nucleotide, Hematology, Middle Aged, 3. Good health, Public Health and Health Services, Female, Human, medicine.medical_specialty, autoimmune disease, genome-wide association study, meta-analysis, Alleles, Autoimmune Diseases, Humans, Polymorphism, Single Nucleotide, Genetic Predisposition to Disease, Non-Hodgkin, Article, 03 medical and health sciences, Rare Diseases, Internal medicine, Genetic variation, medicine, Genetics, Polymorphism, 030304 developmental biology, Autoimmune disease, business.industry, Multiple sclerosis, Risk Factor, Arthritis, Inflammatory and immune system, Human Genome, medicine.disease, Brain Disorders, business, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

International audience; Epidemiologic studies show an increased risk of non-Hodgkin lymphoma (NHL) in patients with autoimmune disease (AD), due to a combination of shared environmental factors and/or genetic factors, or a causative cascade: chronic inflammation/antigen-stimulation in one disease leads to another. Here we assess shared genetic risk in genome-wide-association-studies (GWAS). Secondary analysis of GWAS of NHL subtypes (chronic lymphocytic leukemia, diffuse large B-cell lymphoma, follicular lymphoma, and marginal zone lymphoma) and ADs (rheumatoid arthritis, systemic lupus erythematosus, and multiple sclerosis). Shared genetic risk was assessed by (a) description of regional genetic of overlap, (b) polygenic risk score (PRS), (c)"diseasome", (d)meta-analysis. Descriptive analysis revealed few shared genetic factors between each AD and each NHL subtype. The PRS of ADs were not increased in NHL patients (nor vice versa). In the diseasome, NHLs shared more genetic etiology with ADs than solid cancers (p = .0041). A meta-analysis (combing AD with NHL) implicated genes of apoptosis and telomere length. This GWAS-based analysis four NHL subtypes and three ADs revealed few weakly-associated shared loci, explaining little total risk. This suggests common genetic variation, as assessed by GWAS in these sample sizes, may not be the primary explanation for the link between these ADs and NHLs.

Published
2019
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4. Carbohydrate-dependent B cell activation by fucose-binding bacterial lectins

Author

Marco Frensch, Michael Reth, Anne Imberty, Peter Fritz Müller, Rudolf Übelhart, Johanna Jakob, Ella Levit-Zerdoun, Alessia Landi, Isabel Wilhelm, Elias Hobeika, Roland Thuenauer, Winfried Römer, Hermann Eibel, Hassan Jumaa, Sarah Villringer, Julie Claudinon, Molecular immunology, Centre de Recherches sur les Macromolécules Végétales (CERMAV ), Institut de Chimie du CNRS (INC)-Centre National de la Recherche Scientifique (CNRS)-Université Grenoble Alpes [2016-2019] (UGA [2016-2019]), Compartimentation et dynamique cellulaires (CDC), Centre National de la Recherche Scientifique (CNRS)-Institut Curie [Paris]-Université Pierre et Marie Curie - Paris 6 (UPMC), and Center for Chronic Immunodeficiency (CCI), University Medical Center Freiburg, Freiburg, Germany

Subjects
Burkholderia, [SDV]Life Sciences [q-bio], Antigens, CD19, Carbohydrates, Syk, Fucose binding, Lymphocyte Activation, Biochemistry, Fucose, CD19, 03 medical and health sciences, chemistry.chemical_compound, Mice, 0302 clinical medicine, Antigen, Bacterial Proteins, Lectins, Animals, Syk Kinase, Molecular Biology, 030304 developmental biology, CD86, Mice, Knockout, 0303 health sciences, B-Lymphocytes, biology, Cell Biology, Molecular biology, chemistry, Pseudomonas aeruginosa, biology.protein, Cytokine secretion, B7-2 Antigen, Intracellular, 030215 immunology, Signal Transduction
Abstract

International audience; Bacterial lectins are typically multivalent and bind noncovalently to specific carbohydrates on host tissues to facilitate bacterial adhesion. Here, we analyzed the effects of two fucose-binding lectins, BambL from Burkholderia ambifaria and LecB from Pseudomonas aeruginosa, on specific signaling pathways in B cells. We found that these bacterial lectins induced B cell activation, which, in vitro, was dependent on the cell surface expression of the B cell antigen receptor (BCR) and its coreceptor CD19, as well as on spleen tyrosine kinase (Syk) activity. The resulting release of intracellular Ca 2+ was followed by an increase in the cell surface abundance of the activation marker CD8, increased cytokine secretion, and subsequent cell death, replicating all of the events that are observed in vitro upon canonical and antigen-mediated B cell activation. Moreover, injection of BambL in mice resulted in a substantial, BCR-independent loss of B cells in the bone marrow with simultaneous, transient enlargement of the spleen (splenomegaly), as well as an increase in the numbers of splenic B cells and myeloid cells. Together, these data suggest that bacterial lectins can initiate polyclonal activation of B cells through their sole capacity to bind to fucose.

Published
2019
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5. Association of polygenic risk score with the risk of chronic lymphocytic leukemia and monoclonal B-cell lymphocytosis

Author

Kari G. Chaffee, Sonja I. Berndt, Alexandra Nieters, Lindsay M. Morton, Stephen J. Chanock, Neil E. Caporaso, Delphine Casabonne, Karin E. Smedby, Aaron D. Norman, Celine M. Vachon, James McKay, Pierluigi Cocco, Christine F. Skibola, Timothy G. Call, Nicola J. Camp, Martha Glenn, Jacqueline Clavel, Mark Liebow, Paolo Boffetta, James B. Johnston, John J. Spinelli, James R. Cerhan, Lynn R. Goldin, Hans-Olov Adami, Nathaniel Rothman, Yolanda Benavente, J. Brice Weinberg, Paul Brennan, Paige M. Bracci, Marc Maynadié, Dennis P. Robinson, Geffen Kleinstern, Silvia de Sanjosé, Susan L. Slager, Tait D. Shanafelt, Lucia Conde, Bengt Glimelius, Richard K. Severson, Jose F. Leis, Wendy Cozen, Claire M. Vajdic, Angela Brooks-Wilson, Mads Melbye, Henrik Hjalgrim, Karen Curtin, Neil E. Kay, Curtis A. Hanson, Alain Monnereau, National Cancer Institute [Bethesda] (NCI-NIH), National Institutes of Health [Bethesda] (NIH), Catalan Institute of Oncology, Department of Epidemiology, Catalan Institute of Oncology (ICO), Center for Chronic Immunodeficiency (CCI), University Medical Center Freiburg, Freiburg, Germany, Dept. of Epidemiology Research, Statens Serum Institut [Copenhagen], Uppsala Universitet [Uppsala], Department of Medical Epidemiology and Biostatistics (MEB), Karolinska Institutet [Stockholm], Icahn School of Medicine at Mount Sinai [New York] (MSSM), Centre International de Recherche contre le Cancer - International Agency for Research on Cancer (CIRC - IARC), Organisation Mondiale de la Santé / World Health Organization Office (OMS / WHO), Registre des hémopathies malignes de Côte d'Or, Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Université Bourgogne Franche-Comté [COMUE] (UBFC), International Agency for Cancer Research (IACR), Mayo Clinic [Rochester], Laboratoire Interdisciplinaire de Spectroscopie Electronique (LISE), Facultés Universitaires Notre Dame de la Paix (FUNDP), Registre des hémopathies malignes de la Gironde, Institut Bergonié [Bordeaux], UNICANCER-UNICANCER, Cancer environnement (EPICENE ), Bordeaux population health (BPH), Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), Equipe 7 : EPICEA - Epidémiologie des cancers de l'enfant et de l'adolescent (CRESS - U1153), Université Paris Descartes - Paris 5 (UPD5)-Centre de Recherche Épidémiologie et Statistique Sorbonne Paris Cité (CRESS (U1153 / UMR_A_1125 / UMR_S_1153)), Université Paris Diderot - Paris 7 (UPD7)-Université Sorbonne Paris Cité (USPC)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Recherche Agronomique (INRA)-Université Paris Diderot - Paris 7 (UPD7)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Recherche Agronomique (INRA), Huntsman Cancer Institute, Norris Comprehensive Cancer Center, Wayne State University [Detroit], Division of Cancer Epidemiology and Genetics, National Institutes of Health [Bethesda] (NIH)-National Institutes of Health [Bethesda] (NIH), Emory University [Atlanta, GA], Cancer Center Karolinska [Karolinska Institutet] (CCK), Department of Psychiatry, Facultés Universitaires Notre Dame de la Paix (FUNDP) - Namur, Institut Bergonié - CRLCC Bordeaux, Institut National de la Recherche Agronomique (INRA)-Université Paris Diderot - Paris 7 (UPD7)-Université Paris Descartes - Paris 5 (UPD5)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut National de la Recherche Agronomique (INRA)-Université Paris Diderot - Paris 7 (UPD7)-Université Sorbonne Paris Cité (USPC)-Institut National de la Santé et de la Recherche Médicale (INSERM), Kleinstern, Geffen, Camp, Nicola J., Goldin, Lynn R., Vachon, Celine M., Vajdic, Claire M., De Sanjose, Silvia, Weinberg, J. Brice, Benavente, Yolanda, Casabonne, Delphine, Liebow, Mark, Nieters, Alexandra, Hjalgrim, Henrik, Melbye, Mad, Glimelius, Bengt, Adami, Hans-Olov, Boffetta, Paolo, Brennan, Paul, Maynadie, Marc, McKay, Jame, Cocco, Pier Luigi, Shanafelt, Tait D., Call, Timothy G., Norman, Aaron D., Hanson, Curti, Robinson, Denni, Chaffee, Kari G., Brooks-Wilson, Angela R., Monnereau, Alain, Clavel, Jacqueline, Glenn, Martha, Curtin, Karen, Conde, Lucia, Bracci, Paige M., Morton, Lindsay M., Cozen, Wendy, Severson, Richard K., Chanock, Stephen J., Spinelli, John J., Johnston, James B., Rothman, Nathaniel, Skibola, Christine F., Leis, Jose F., Kay, Neil E., Smedby, Karin E., Berndt, Sonja I., Cerhan, James R., Caporaso, Neil, and Slager, Susan L.

Subjects
Adult, Male, 0301 basic medicine, Oncology, medicine.medical_specialty, Lymphocytosis, Clinical Trials and Observations, Chronic lymphocytic leukemia, Immunology, Single-nucleotide polymorphism, [SDV.CAN]Life Sciences [q-bio]/Cancer, Polymorphism, Single Nucleotide, Biochemistry, 03 medical and health sciences, 0302 clinical medicine, Risk Factors, immune system diseases, Internal medicine, hemic and lymphatic diseases, Genotype, Odds Ratio, medicine, Humans, Genetic Predisposition to Disease, 10. No inequality, Aged, Aged, 80 and over, B-Lymphocytes, business.industry, Confounding, Cell Biology, Hematology, Odds ratio, Middle Aged, medicine.disease, Leukemia, Lymphocytic, Chronic, B-Cell, 3. Good health, 030104 developmental biology, Genetic epidemiology, Genetic Loci, 030220 oncology & carcinogenesis, Monoclonal B-cell lymphocytosis, Female, medicine.symptom, business
Abstract

IF 15.132 (2017); International audience; Inherited loci have been found to be associated with risk of chronic lymphocytic leukemia (CLL). A combined polygenic risk score (PRS) of representative single nucleotide polymorphisms (SNPs) from these loci may improve risk prediction over individual SNPs. Herein, we evaluated the association of a PRS with CLL risk and its precursor, monoclonal B-cell lymphocytosis (MBL). We assessed its validity and discriminative ability in an independent sample and evaluated effect modification and confounding by family history (FH) of hematological cancers. For discovery, we pooled genotype data on 41 representative SNPs from 1499 CLL and 2459 controls from the InterLymph Consortium. For validation, we used data from 1267 controls from Mayo Clinic and 201 CLL, 95 MBL, and 144 controls with a FH of CLL from the Genetic Epidemiology of CLL Consortium. We used odds ratios (ORs) to estimate disease associations with PRS and c-statistics to assess discriminatory accuracy. In InterLymph, the continuous PRS was strongly associated with CLL risk (OR, 2.49; P = 4.4 × 10-94). We replicated these findings in the Genetic Epidemiology of CLL Consortium and Mayo controls (OR, 3.02; P = 7.8 × 10-30) and observed high discrimination (c-statistic = 0.78). When jointly modeled with FH, PRS retained its significance, along with FH status. Finally, we found a highly significant association of the continuous PRS with MBL risk (OR, 2.81; P = 9.8 × 10-16). In conclusion, our validated PRS was strongly associated with CLL risk, adding information beyond FH. The PRS provides a means of identifying those individuals at greater risk for CLL as well as those at increased risk of MBL, a condition that has potential clinical impact beyond CLL.

Published
2018
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6. 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

Author

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, Stephan Ehl, Federal Ministry of Education and Research (Germany), Novartis, GlaxoSmithKline, University of Tehran, Service de Médecine Interne, CHU Saint-Etienne-Hôpital Nord - Saint-Etienne, Département de Biothérapie [CHU Necker], CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5), Department of Medical Oncology, Regina Elena Cancer Institute, Developpement Normal et Pathologique du Système Immunitaire, Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Chaire Médecine expérimentale (A. Fischer), Collège de France (CdF (institution)), Istanbul University, Addenbrookes Hospital, Center for Chronic Immunodeficiency (CCI), University Medical Center Freiburg, Freiburg, Germany, IFR Necker-Enfants Malades (IRNEM), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), 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), Unité d'Immunologie Hématologie et Rhumatologie Pédiatrique [Necker, Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Division of Clinical Epidemiology, Deutches Krebsforschungszentrum, Faculty of Medicine, Division of Pediatric Allergy and Immunology, Marmara University, Génétique Humaine des Maladies Infectieuses (Inserm U980), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Dmitry Rogachev Federal Research and Clinical Center of Pediatric Hematology, Oncology and Immunology, Moscow, European Laboratory for Food Induced Diseases, Università degli studi di Napoli Federico II, Imagine - Institut des maladies génétiques (IMAGINE - U1163), CHU Necker - Enfants Malades [AP-HP]-Université Paris Descartes - Paris 5 (UPD5)-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Necker - Enfants Malades [AP-HP], CHU Necker - Enfants Malades [AP-HP]-Assistance publique - Hôpitaux de Paris (AP-HP) (APHP), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Paris Descartes - Paris 5 (UPD5), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Maccari, Maria Elena, Abolhassani, Hassan, Aghamohammadi, Asghar, Aiuti, Alessandro, Aleinikova, Olga, Bangs, Catherine, Baris, Safa, Barzaghi, Federica, Baxendale, Helen, Buckland, Matthew, Burns, Siobhan O., Cancrini, Caterina, Cant, Andrew, Cathebras, Pascal, Cavazzana, Marina, Chandra, Anita, Conti, Francesca, Coulter, Tanya, Devlin, Lisa A., Edgar, J. David M., Faust, Saul, Fischer, Alain, Prat, Marina Garcia, Hammarstrom, Lennart, Heeg, Maximilian, Jolles, Stephen, Karakoc-Aydiner, Elif, Kindle, Gerhard, Kiykim, Ayca, Kumararatne, Dinakantha, Grimbacher, Bodo, Longhurst, Hilary, Mahlaoui, Nizar, Milota, Tomas, Moreira, Fernando, Moshous, Despina, Mukhina, Anna, Neth, Olaf, Neven, Benedicte, Nieters, Alexandra, Olbrich, Peter, Ozen, Ahmet, Schmid, Jana Pachlopnik, Picard, Capucine, Prader, Seraina, Rae, William, Reichenbach, Janine, Rusch, Stephan, Savic, Sinisa, Scarselli, Alessia, Scheible, Raphael, Sediva, Anna, Sharapova, Svetlana O., Shcherbina, Anna, Slatter, Mary, Soler-Palacin, Pere, Stanislas, Aurelie, Suarez, Felipe, Tucci, Francesca, Uhlmann, Annette, van Montfrans, Joris, Warnatz, Klaus, Williams, Anthony Peter, Wood, Phil, Kracker, Sven, Condliffe, Alison Mary, Ehl, Stephan, Cathébras, Pascal, Hammarström, Lennart, Milota, Toma, Montfrans, Joris van, and Warnatz, Klau

Subjects
0301 basic medicine, Oncology, activated phosphoinositide 3-kinase δ syndrome, [SDV]Life Sciences [q-bio], SIROLIMUS, registry, Activated phosphoinositide 3-kinase δ syndrome, Immunology and Allergy, Registries, Young adult, Non-U.S. Gov't, Child, MUTATION, Societies, Medical, ComputingMilieux_MISCELLANEOUS, Research Support, Non-U.S. Gov't, Middle Aged, PIK3R1, 3. Good health, Europe, Settore MED/02, natural history, Child, Preschool, Perspective, Cohort, Sirolimus/therapeutic use, [SDV.IMM]Life Sciences [q-bio]/Immunology, medicine.symptom, Immunosuppressive Agents, medicine.drug, Adult, lcsh:Immunologic diseases. Allergy, medicine.medical_specialty, Registry, activated phosphoinositide 3-kinase delta syndrome, Adolescent, Class I Phosphatidylinositol 3-Kinases, Primary Immunodeficiency Diseases, Immunology, Natural history, Research Support, Asymptomatic, 03 medical and health sciences, Young Adult, Medical, Internal medicine, Journal Article, medicine, Humans, Rapamycin, Preschool, Sirolimus, Immunologic Deficiency Syndromes/drug therapy, Cytopenia, [SDV.GEN]Life Sciences [q-bio]/Genetics, Bronchiectasis, business.industry, rapamycin, Immunologic Deficiency Syndromes, PIK3CD, medicine.disease, 030104 developmental biology, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Autoimmune lymphoproliferative syndrome, Primary immunodeficiency, Immunosuppressive Agents/therapeutic use, [SDV.SPEE]Life Sciences [q-bio]/Santé publique et épidémiologie, Societies, business, lcsh: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., This study was supported by the German Federal Ministry of Education and Research (BMBF 01E01303). The ESID-APDS registry is supported by the pharmaceutical companies Novartis, GlaxoSmithKline, and UCB UK.

Published
2018
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7. Young Adult and Usual Adult Body Mass Index and Multiple Myeloma Risk: A Pooled Analysis in the International Multiple Myeloma Consortium (IMMC)

Author

John J. Spinelli, Graham G. Giles, Parveen Bhatti, Alexandra Nieters, Dennis D. Weisenburger, Anneclaire J. De Roos, Lenka Foretova, Paolo Boffetta, Mark P. Purdue, Nikolaus Becker, Nicola J. Camp, Brian C.-H. Chiu, Marc Maynadié, Guido Tricot, Silvia de Sanjosé, Pier Luigi Cocco, Dalsu Baris, Yawei Zhang, Veronique Benhaim-Luzon, Kirsten B. Moysich, Laura Costas, Anthony Staines, Elizabeth E. Brown, Wendy Cozen, Paul Brennan, Brenda M. Birmann, Gabriella Andreotti, Brigham and Women's Hospital [Boston], National Cancer Institute [Bethesda] (NCI-NIH), National Institutes of Health [Bethesda] (NIH), German Cancer Research Center - Deutsches Krebsforschungszentrum [Heidelberg] (DKFZ), CIBER de Epidemiología y Salud Pública (CIBERESP), Facultat de Medicina [Barcelona], Catalan Institute of Oncology, Masaryk University [Brno] (MUNI), The Cancer Council Victoria, Université de Bourgogne (UB), CHU Dijon, Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Registre des hémopathies malignes de Côte d'Or, Department of Cancer Prevention and Control, Roswell Park Cancer Institute [Buffalo], Center for Chronic Immunodeficiency (CCI), University Medical Center Freiburg, Freiburg, Germany, University of Iowa [Iowa City], Department of Pathology (City of Hope, Duarte, California), City of Hope Comprehensive Cancer Center [Duarte], Yale School of Public Health (YSPH), Yale University School of Medicine, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Department of Health and Human Services, German Cancer Research Center [Heidelberg] ( DKFZ ), Helmholtz-Gemeinschaft, Masaryk University, Université de Bourgogne ( UB ), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon ), Department of Internal Medicine, University of Iowa, Iowa City, Iowa, Yale School of Public Health ( YSPH ), Yale School of Medicine, and Birmann, B.M. and Andreotti, G. and De Roos, A.J. and Camp, N.J. and Chiu, B.C.H. and Spinelli, J.J. and Becker, N. and Benhaim-Luzon, V. and Bhatti, P. and Boffetta, P. and Brennan, P. and Brown, E.E. and Cocco, P. and Costas, L. and Cozen, W. and De Sanjose, S. and Foretova, L. and Giles, G.G. and Maynadie, M. and Moysich, K. and Nieters, A. and Staines, A. and Tricot, G. and Weisenburger, D. and Zhang, Y. and Baris, D. and Purdue, M.P.

Subjects
0301 basic medicine, Male, obesity, procedure, Epidemiology, groups by age, Overweight, cancer risk, Body Mass Index, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, 0302 clinical medicine, study design, Risk Factors, middle aged, Young adult, risk factor, Adult, Multiple myeloma, 2. Zero hunger, education.field_of_study, anthropometry, adult, risk assessment, 3. Good health, multiple myeloma, female, Oncology, priority journal, 030220 oncology & carcinogenesis, young adult, medicine.symptom, Case-Control Studie, medicine.medical_specialty, multivariate logistic regression analysi, Population, [SDV.CAN]Life Sciences [q-bio]/Cancer, Article, 03 medical and health sciences, Internal medicine, medicine, Humans, human, education, Aged, business.industry, Case-control study, Anthropometry, case control study, medicine.disease, Confidence interval, 030104 developmental biology, Endocrinology, Case-Control Studies, pathology, business, Body mass index, body ma
Abstract

Background: Multiple myeloma risk increases with higher adult body mass index (BMI). Emerging evidence also supports an association of young adult BMI with multiple myeloma. We undertook a pooled analysis of eight case–control studies to further evaluate anthropometric multiple myeloma risk factors, including young adult BMI.Methods: We conducted multivariable logistic regression analysis of usual adult anthropometric measures of 2,318 multiple myeloma cases and 9,609 controls, and of young adult BMI (age 25 or 30 years) for 1,164 cases and 3,629 controls.Results: In the pooled sample, multiple myeloma risk was positively associated with usual adult BMI; risk increased 9% per 5-kg/m2 increase in BMI [OR, 1.09; 95% confidence interval (CI), 1.04–1.14; P = 0.007]. We observed significant heterogeneity by study design (P = 0.04), noting the BMI–multiple myeloma association only for population-based studies (Ptrend = 0.0003). Young adult BMI was also positively associated with multiple myeloma (per 5-kg/m2; OR, 1.2; 95% CI, 1.1–1.3; P = 0.0002). Furthermore, we observed strong evidence of interaction between younger and usual adult BMI (Pinteraction Conclusions: BMI-associated increases in multiple myeloma risk were highest for individuals who were overweight or obese throughout adulthood.Impact: These findings provide the strongest evidence to date that earlier and later adult BMI may increase multiple myeloma risk and suggest that healthy BMI maintenance throughout life may confer an added benefit of multiple myeloma prevention. Cancer Epidemiol Biomarkers Prev; 26(6); 876–85. ©2017 AACR.

Published
2017
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8. Mycobacteria exploit nitric oxide-induced transformation of macrophages into permissive giant cells

Author

Florens Lohrmann, Magdeldin Elgizouli, Carsten J. Kirschning, Anne Kathrin Lösslein, Anna Lena Illert, Julia Senges, Manfred Fliegauf, Kourosh Gharun, Philipp Henneke, Maximilian Seidl, Martine Gilleron, Antigoni Triantafyllopoulou, Martina Vavra, Kristina Schachtrup, Marco Alber, Julia Kolter, Center for Chronic Immunodeficiency (CCI), University Medical Center Freiburg, Freiburg, Germany, Institut de pharmacologie et de biologie structurale (IPBS), Centre National de la Recherche Scientifique (CNRS)-Université Toulouse III - Paul Sabatier (UT3), and Université Fédérale Toulouse Midi-Pyrénées-Université Fédérale Toulouse Midi-Pyrénées

Subjects
0301 basic medicine, medicine.drug_class, DNA damage, Cellular differentiation, [SDV]Life Sciences [q-bio], Medizin, [SDV.BC]Life Sciences [q-bio]/Cellular Biology, [SDV.BC.BC]Life Sciences [q-bio]/Cellular Biology/Subcellular Processes [q-bio.SC], Biology, Antimycobacterial, Nitric Oxide, Biochemistry, Giant Cells, Nitric oxide, Mycobacterium, 03 medical and health sciences, chemistry.chemical_compound, Mice, 0302 clinical medicine, Genetics, medicine, Macrophage, Animals, Humans, Molecular Biology, Cells, Cultured, ComputingMilieux_MISCELLANEOUS, 030304 developmental biology, 0303 health sciences, 030306 microbiology, Effector, Macrophages, Cell Differentiation, Articles, biology.organism_classification, Genes, p53, Corrigenda, Cell biology, 030104 developmental biology, chemistry, Giant cell, Immunology, 030215 immunology, DNA Damage
Abstract

Immunity to mycobacteria involves the formation of granulomas, characterized by a unique macrophage (MΦ) species, so‐called multinucleated giant cells (MGC). It remains unresolved whether MGC are beneficial to the host, that is, by prevention of bacterial spread, or whether they promote mycobacterial persistence. Here, we show that the prototypical antimycobacterial molecule nitric oxide (NO), which is produced by MGC in excessive amounts, is a double‐edged sword. Next to its antibacterial capacity, NO propagates the transformation of MΦ into MGC, which are relatively permissive for mycobacterial persistence. The mechanism underlying MGC formation involves NO‐induced DNA damage and impairment of p53 function. Moreover, MGC have an unsurpassed potential to engulf mycobacteria‐infected apoptotic cells, which adds a further burden to their antimycobacterial capacity. Accordingly, mycobacteria take paradoxical advantage of antimicrobial cellular efforts by driving effector MΦ into a permissive MGC state.

Published
2017
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9. Streptococci Engage TLR13 on Myeloid Cells in a Site-Specific Fashion

Author

Sachin D. Deshmukh, Reinhild Feuerstein, Zhijian J. Chen, Patrick Trieu-Cuot, Tobias Goldmann, Philipp Henneke, Kourosh Gharun, Claudia Waskow, Julia Kolter, Roland Elling, Carsten J. Kirschning, Evelyne Spoeri, Center for Chronic Immunodeficiency (CCI), University Medical Center Freiburg, Freiburg, Germany, Biologie des Bactéries pathogènes à Gram-positif, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), institute of neuropathology, University of Freiburg [Freiburg], Regeneration in Hematopoiesis and Animal Models of Hematopoiesis, Faculty of Medicine, Dresden University of Technology, Southwestern Medical School, The University of Texas Health Science Center at Houston (UTHealth), Institute of Medical Microbiology, University of Duisbourg-Essen, Center for sepsis control care, Friedrich-Schiller-Universität = Friedrich Schiller University Jena [Jena, Germany], and Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)

Subjects
0301 basic medicine, Colon, Immunology, Medizin, Mice, Transgenic, Biology, Hemolysis, Streptococcus agalactiae, Mice, 03 medical and health sciences, 0302 clinical medicine, Dermis, Immunity, Streptococcal Infections, medicine, Animals, Immunology and Allergy, Progenitor cell, Receptor, Immunity, Mucosal, Skin, Mice, Knockout, Lamina propria, Innate immune system, Microglia, Macrophages, Toll-Like Receptors, Membrane Transport Proteins, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, Mice, Inbred C57BL, 030104 developmental biology, medicine.anatomical_structure, Mucosal immunology, Organ Specificity, Host-Pathogen Interactions, Cytokines, 030215 immunology
Abstract

Streptococci are common human colonizers with a species-specific mucocutaneous distribution. At the same time, they are among the most important and most virulent invasive bacterial pathogens. Thus, site-specific cellular innate immunity, which is predominantly executed by resident and invading myeloid cells, has to be adapted with respect to streptococcal sensing, handling, and response. In this article, we show that TLR13 is the critical mouse macrophage (MΦ) receptor in the response to group B Streptococcus, both in bone marrow–derived MΦs and in mature tissue MΦs, such as those residing in the lamina propria of the colon and the dermis, as well as in microglia. In contrast, TLR13 and its chaperone UNC-93B are dispensable for a potent cytokine response of blood monocytes to group B Streptococcus, although monocytes serve as the key progenitors of intestinal and dermal MΦs. Furthermore, a specific role for TLR13 with respect to MΦ function is supported by the response to staphylococci, where TLR13 and UNC-93B limit the cytokine response in bone marrow–derived MΦs and microglia, but not in dermal MΦs. In summary, TLR13 is a critical and site-specific receptor in the single MΦ response to β-hemolytic streptococci.

Published
2016
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10. A Pooled Analysis of Reproductive Factors, Exogenous Hormone Use, and Risk of Multiple Myeloma among Women in the International Multiple Myeloma Consortium

Author

Anneclaire J. De Roos, Laura Costas, Djordje Atanackovic, Lenka Foretova, Jonathan N. Hofmann, Elisabeth E. Brown, Sophia S. Wang, Pierluigi Cocco, Alexandra Nieters, Dalsu Baris, Anthony Staines, Paul Brennan, Nicola J. Camp, Guido Tricot, Brenda M. Birmann, Nikolaus Becker, Marc Maynadié, Brice H. Lambert, Kirsten B. Moysich, Silvia de Sanjosé, Paolo Boffetta, Facultat de Medicina [Barcelona], CIBER de Epidemiología y Salud Pública (CIBERESP), Catalan Institute of Oncology (ICO-IDIBELL), Department of Epidemiology, University of Alabama at Birmingham, Harvard Medical School [Boston] ( HMS ), Channing Division of Network Medicine, Brigham and Women's Hospital [Boston], Department of Cancer Prevention and Control, Roswell Park Cancer Institute [Buffalo], Department of Environmental and Occupational Health, Drexel University School of Public Health, Philadelphia, Pennsylvania, Division of Cancer Epidemiology and Genetics, National Institutes of Health ( NIH ) -National Cancer Institute ( NIH ), Division of Cancer Etiology, Department of Population Sciences, City of Hope and Beckman Research Institute, Duarte, California, Division of Hematology and Hematologic Malignancies, University of Utah School of Medicine and Huntsman Cancer Institute, Salt Lake City, Utah, Department of Internal Medicine, University of Iowa, Iowa City, Iowa, Centre International de Recherche contre le Cancer - International Agency for Research on Cancer ( CIRC - IARC ), Organisation mondiale de la santé (OMS/WHO), Universita degli Studi di Cagliari [Cagliari], Center for Chronic Immunodeficiency (CCI), University Medical Center Freiburg, Freiburg, Germany, Deutsches Krebsforschungszentrum, Centre de ressources biologiques Ferdinand Cabanne [Dijon] ( CRB Ferdinand Cabanne ), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon ), Centre d'épidémiologie des populations ( CEP ), Université de Bourgogne ( UB ) -Centre Régional de Lutte contre le cancer - Centre Georges-François Leclerc ( CRLCC - CGFL ), Masaryk Memorial Cancer Institute and Medical Faculty of Masaryk University, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai [New York], School of Public Health and Population Science, University College Dublin, Department of Pathology, University of Alabama at Birmingham, University of Alabama at Birmingham Comprehensive Cancer Center, Birmingham, Alabama, Costas, L., Lambert, B.H., Birmann, B.M., Moysich, K.B., De Roos, A.J., Hofmann, J.N., Baris, D., Wang, S.S., Camp, N.J., Tricot, G., Atanackovic, D., Brennan, P., Cocco, P., Nieters, A., Becker, N., Maynadié, M., Foretová, L., Boffetta, P., Staines, A., Brown, E.E., De Sanjosé, S., University of Alabama at Birmingham [ Birmingham] (UAB), Harvard Medical School [Boston] (HMS), Drexel University, National Cancer Institute [Bethesda] (NCI-NIH), National Institutes of Health [Bethesda] (NIH), City of Hope National Medical Center, University of Iowa [Iowa City], Centre International de Recherche contre le Cancer - International Agency for Research on Cancer (CIRC - IARC), Organisation Mondiale de la Santé / World Health Organization Office (OMS / WHO), Centre de ressources biologiques Ferdinand Cabanne [Dijon] (CRB Ferdinand Cabanne), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Centre d'épidémiologie des populations (CEP), Université de Bourgogne (UB)-Centre Régional de Lutte contre le cancer Georges-François Leclerc [Dijon] (UNICANCER/CRLCC-CGFL), UNICANCER-UNICANCER, Icahn School of Medicine at Mount Sinai [New York] (MSSM), and University College Dublin [Dublin] (UCD)

Subjects
Male, Epidemiology, medicine.medical_treatment, Physiology, [ SDV.CAN ] Life Sciences [q-bio]/Cancer, 0302 clinical medicine, Risk Factors, Odds Ratio, Gonadal, 030212 general & internal medicine, Reproductive History, Multiple myeloma, Incidence, Middle Aged, Statistical, Prognosis, 3. Good health, Postmenopause, Contraception, Oncology, Transgender hormone therapy, 030220 oncology & carcinogenesis, Meta-analysis, Regression Analysis, Female, Multiple Myeloma, Factor Analysis, Adult, Hormone Replacement Therapy, [SDV.CAN]Life Sciences [q-bio]/Cancer, Article, 03 medical and health sciences, Young Adult, Meta-Analysis as Topic, Reproductive factors, exogenous hormone use, and risk of multiple myeloma, medicine, Confidence Intervals, Humans, Neoplasm Staging, Steroid Hormones, business.industry, Case-control study, Odds ratio, medicine.disease, Hormones, Logistic Models, Hormonal contraception, Case-Control Studies, Sample Size, Immunology, Hormone therapy, business, Hormone, Follow-Up Studies, Meta-Analysis
Abstract

Background: Female sex hormones are known to have immunomodulatory effects. Therefore, reproductive factors and exogenous hormone use could influence the risk of multiple myeloma in women. However, the role of hormonal factors in multiple myeloma etiology remains unclear because previous investigations were underpowered to detect modest associations. Methods: We conducted a pooled analysis of seven case–control studies included in the International Multiple Myeloma Consortium, with individual data on reproductive factors and exogenous hormone use from 1,072 female cases and 3,541 female controls. Study-specific odds ratios and corresponding 95% confidence intervals (CI) were estimated using logistic regression and pooled analyses were conducted using random effects meta-analyses. Results: Multiple myeloma was not associated with reproductive factors, including ever parous [OR = 0.92; 95% confidence interval (CI), 0.68–1.25], or with hormonal contraception use (OR = 1.04; 95% CI, 0.80–1.36). Postmenopausal hormone therapy users had nonsignificantly reduced risks of multiple myeloma compared with never users, but this association differed across centers (OR = 0.65; 95% CI, 0.37–1.15, I2 = 76.0%, Pheterogeneity = 0.01). Conclusions: These data do not support a role for reproductive factors or exogenous hormones in myelomagenesis. Impact: Incidence rates of multiple myeloma are higher in men than in women, and sex hormones could influence this pattern. Associations with reproductive factors and exogenous hormone use were inconclusive despite our large sample size, suggesting that female sex hormones may not play a significant role in multiple myeloma etiology. Cancer Epidemiol Biomarkers Prev; 25(1); 217–21. ©2015 AACR.

Published
2015
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11. The Extended Clinical Phenotype Of 64 Patients With Dedicator Of Cytokinesis 8 Deficiency

Author

Tim Niehues, Karin R. Engelhardt, Mehmet Kilic, Raif S. Geha, Necil Kutukculer, Zeina Baz, Sevgi Keles, Cristina Glocker, Caner Aytekin, Ozden Sanal, Ismail Reisli, Zahra Pourpak, Ferah Genel, Mustafa Yilmaz, Alison Jones, B Gaspar, Elena C. Sigmund, Nermeen Galal, Yildiz Camcioglu, Michel J. Massaad, Amos Etzioni, Turkan Patiroglu, Laura E. Graham, Maria Cristina Pietrogrande, Majed Dasouki, Andrew R. Gennery, S Weinspach, G Dueckers, Michael E. Gertz, Monia Khemiri, M. R. Barbouche, Mehdi Yeganeh, Imen Ben-Mustapha, Shiva Saghafi, Bodo Grimbacher, Salem Al-Tamemi, Andrew J. Cant, A. Sassi, Gérard Lefranc, Ayse Metin, Vassilios Lougaris, Ayper Somer, Fethi Mellouli, Ekrem Unal, Alexandra F. Freeman, Jeannette Boutros, Ruben Ceja, Jens Thiel, André Mégarbané, Sara Sebnem Kilic, Talal A. Chatila, Mohamed Bejaoui, Alejandro A. Schäffer, Ilhan Tezcan, Waleed Al-Herz, Peter D. Arkwright, Ilka Schulze, Çocuk Sağlığı ve Hastalıkları, University College of London [London] (UCL), National Center for Biotechnology Information (NCBI), David Geffen School of Medicine [Los Angeles], University of California [Los Angeles] (UCLA), University of California-University of California, Freiburg University Medical Center, Institute of Mechanical Systems, Department of Mechanical and Process Engineering, Eidgenössische Technische Hochschule - Swiss Federal Institute of Technology [Zürich] (ETH Zürich), Tehran University of Medical Sciences (TUMS), Laboratoire d'Immunopathologie, Vaccinologie et Génétique Moléculaire (LVGM), Institut Pasteur de Tunis, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP), Laboratory for the Study of Skeletal Disorders and Rehabilitation (Boston, USA), Harvard Combined Orthopaedic Residency (USA), Department of Peadiatric Immuno-Haematology, National Bone Marrow Transplantation, Laboratoire d'immunologie clinique [Institut Pasteur de Tunis], Pediatrics Department A, Children's Hospital of Tunis, Tunis, Tunisia, National Institute of Allergy and Infectious Diseases [Bethesda] (NIAID-NIH), National Institutes of Health [Bethesda] (NIH), Center for Chronic Immunodeficiency (CCI), University Medical Center Freiburg, Freiburg, Germany, Kuwait University, the Pediatric Immunology Unit, SB Ankara Diskapi Children’s Hospital, Ankara University School of Medicine [Turkey], Tehran University of Medical Sciences, School of public health, The University of Hong Kong (HKU)-The University of Hong Kong (HKU)-Tehran University of Medical Sciences, Helios Klinikum Krefeld - Helios Klinikum Krefeld, Center of Child and Adolescent Medicine, Heinrich-Heine-University Dusseldorf, Department of Pediatrics, Division of Pediatric Hematology and Oncology, Faculty of Medicine, Erciyes University, Kayseri, Turkey, Department of Pediatrics, Division of Pediatric Immunology, Faculty of Medicine, Erciyes University, Kayseri, Turkey, Department of Oncology, Aalborg Hospital, Aarhus University [Aarhus], Behcet Uz State Hospital Division of Pediatric Immunology, Izmir, Dis Training & Res Ctr, Department of Pediatrics, Ege University, Istanbul University, Dokuz Eylül Üniversitesi = Dokuz Eylül University [Izmir] (DEÜ), Necmettin Erbakan Univ, Cerrahpasa Medical School, Université d' Istanbul, Newcastle General Hospital, the Department of Maternal and Pediatric Sciences, University of Milan, Fondazione IRCCS Policlinico Milano, the Department of Pediatrics, St George Hospital University Medical Center, Beirut, Sultan Qaboos University (SQU), Université Montpellier 2 - Sciences et Techniques (UM2), Institut de génétique humaine (IGH), Université de Montpellier (UM)-Centre National de la Recherche Scientifique (CNRS), Institut de biologie et chimie des protéines [Lyon] (IBCP), Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Primary Immunodeficiency Clinic, Cairo University Specialized Pediatric Hospital, Pediatrics Department, Bone Marrow Transplantation Center, Tunis, Tunisia., Laboratoire de Transmission, Contrôle et Immunobiologie des Infections - Laboratory of Transmission, Control and Immunobiology of Infection (LR11IPT02), and Çukurova Üniversitesi

Subjects
CD4-Positive T-Lymphocytes, Male, Allergy, Support Vector Machine, [SDV]Life Sciences [q-bio], medicine.medical_treatment, Hypereosinophilia, Hematopoietic stem cell transplantation, CD8-Positive T-Lymphocytes, autosomal recessive hyper-IgE syndrome, dedicator of cytokinesis 8, hyper-IgE syndrome, Molluscum contagiosum, Primary combined immunodeficiency, signal transducer and activator of transcription 3, Adolescent, Adult, Antigens, Bacterial, Antigens, Viral, Bacterial Infections, Child, Child, Preschool, Eosinophils, Female, Guanine Nucleotide Exchange Factors, Humans, Immunoglobulin E, Immunoglobulin M, Infant, Job Syndrome, Lymphocyte Count, Middle Aged, Mutation, STAT3 Transcription Factor, Skin Diseases, Survival Analysis, Virus Diseases, Phenotype, Immunology and Allergy, Immunology, 0302 clinical medicine, MESH: Child, MESH: Guanine Nucleotide Exchange Factors, Viral, Immunodeficiency, 0303 health sciences, MESH: Middle Aged, Respiratory tract infections, Progressive multifocal leukoencephalopathy, MESH: Immunoglobulin E, MESH: Support Vector Machine, Bacterial, MESH: STAT3 Transcription Factor, MESH: CD4-Positive T-Lymphocytes, MESH: Infant, MESH: CD8-Positive T-Lymphocytes, MESH: Immunoglobulin M, 3. Good health, MESH: Virus Diseases, MESH: Survival Analysis, Dock8, medicine.symptom, MESH: Antigens, Viral, MESH: Lymphocyte Count, MESH: Mutation, MESH: Bacterial Infections, MESH: Skin Diseases, Biology, MESH: Phenotype, 03 medical and health sciences, MESH: Eosinophils, medicine, Antigens, Preschool, 030304 developmental biology, MESH: Adolescent, MESH: Humans, MESH: Job Syndrome, MESH: Child, Preschool, MESH: Adult, medicine.disease, MESH: Male, DOCK8 Deficiency, MESH: Female, MESH: Antigens, Bacterial, 030215 immunology
Abstract

PubMedID: 25724123 Background Mutations in dedicator of cytokinesis 8 (DOCK8) cause a combined immunodeficiency (CID) also classified as autosomal recessive (AR) hyper-IgE syndrome (HIES). Recognizing patients with CID/HIES is of clinical importance because of the difference in prognosis and management. Objectives We sought to define the clinical features that distinguish DOCK8 deficiency from other forms of HIES and CIDs, study the mutational spectrum of DOCK8 deficiency, and report on the frequency of specific clinical findings. Methods Eighty-two patients from 60 families with CID and the phenotype of AR-HIES with (64 patients) and without (18 patients) DOCK8 mutations were studied. Support vector machines were used to compare clinical data from 35 patients with DOCK8 deficiency with those from 10 patients with AR-HIES without a DOCK8 mutation and 64 patients with signal transducer and activator of transcription 3 (STAT3) mutations. Results DOCK8-deficient patients had median IgE levels of 5201 IU, high eosinophil levels of usually at least 800/µL (92% of patients), and low IgM levels (62%). About 20% of patients were lymphopenic, mainly because of low CD4+ and CD8+ T-cell counts. Fewer than half of the patients tested produced normal specific antibody responses to recall antigens. Bacterial (84%), viral (78%), and fungal (70%) infections were frequently observed. Skin abscesses (60%) and allergies (73%) were common clinical problems. In contrast to STAT3 deficiency, there were few pneumatoceles, bone fractures, and teething problems. Mortality was high (34%). A combination of 5 clinical features was helpful in distinguishing patients with DOCK8 mutations from those with STAT3 mutations. Conclusions DOCK8 deficiency is likely in patients with severe viral infections, allergies, and/or low IgM levels who have a diagnosis of HIES plus hypereosinophilia and upper respiratory tract infections in the absence of parenchymal lung abnormalities, retained primary teeth, and minimal trauma fractures. © 2015 American Academy of Allergy, Asthma & Immunology. National Institutes of Health: R01AI065617 National Institutes of Health: R21AI087627

Published
2015
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12. High Levels of SOX5 Decrease Proliferative Capacity of Human B Cells, but Permit Plasmablast Differentiation

Author

Nadine Eliane Schmit, Cemil Korcan Ayata, Wolfgang Schuh, Kerstina Melkaoui, Zhibing Zhang, Beate Fischer, Luisa Moehle, Els Verhoeyen, Hermann Eibel, Sachin D. Deshmukh, Maximilian Seidl, Reinhard E. Voll, Marta Rizzi, Hans-Hartmut Peter, Mirzokhid Rakhmanov, Klaus Warnatz, Susanne Unger, Anne-Kathrin Kienzler, Heiko Sic, Ulrich Salzer, François-Loïc Cosset, Center for Chronic Immunodeficiency (CCI), University Medical Center Freiburg, Freiburg, Germany, Freiburg University Medical Center, Friedrich-Alexander Universität Erlangen-Nürnberg (FAU), Virginia Commonwealth University (VCU), Virus enveloppés, vecteurs et immunothérapie – Enveloped viruses, Vectors and Immuno-therapy (EVIR), Centre International de Recherche en Infectiologie - UMR (CIRI), Institut National de la Santé et de la Recherche Médicale (INSERM)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-École normale supérieure - Lyon (ENS Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Centre National de la Recherche Scientifique (CNRS), Centre méditerranéen de médecine moléculaire (C3M), Université Nice Sophia Antipolis (... - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Université Côte d'Azur (UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM), Universitäts Klinikum Freiburg = University Medical Center Freiburg (Uniklinik), Centre International de Recherche en Infectiologie (CIRI), École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-École normale supérieure de Lyon (ENS de Lyon)-Université Claude Bernard Lyon 1 (UCBL), Université de Lyon-Université de Lyon-Université Jean Monnet - Saint-Étienne (UJM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université Nice Sophia Antipolis (1965 - 2019) (UNS), and COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Côte d'Azur (UCA)

Subjects
B Cells, Cellular differentiation, Messenger, lcsh:Medicine, Lymphocyte Activation, Cell Fate Determination, Autoantigens, White Blood Cells, 0302 clinical medicine, Medizinische Fakultät, Animal Cells, Medicine and Health Sciences, lcsh:Science, Cells, Cultured, Regulation of gene expression, 0303 health sciences, Multidisciplinary, Tumor, Cultured, biology, Cell Differentiation, Cell biology, medicine.anatomical_structure, 030220 oncology & carcinogenesis, [SDV.MP.VIR]Life Sciences [q-bio]/Microbiology and Parasitology/Virology, [SDV.IMM]Life Sciences [q-bio]/Immunology, Cellular Types, SOXD Transcription Factors, Research Article, Cells, Immune Cells, Naive B cell, Immunology, Plasma Cells, Cell Line, 03 medical and health sciences, Cell Line, Tumor, medicine, Humans, ddc:610, RNA, Messenger, B cell, 030304 developmental biology, Cell Proliferation, CD40, Blood Cells, lcsh:R, Germinal center, Biology and Life Sciences, Cell Biology, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, B-1 cell, Gene Expression Regulation, Cell culture, biology.protein, RNA, lcsh:Q, Clinical Immunology, Developmental Biology
Abstract

International audience; Currently very little is known about the differential expression and function of the transcription factor SOX5 during B cell maturation. We identified two new splice variants of SOX5 in human B cells, encoding the known L-SOX5B isoform and a new shorter isoform L-SOX5F. The SOX5 transcripts are highly expressed during late stages of B-cell differentiation, including atypical memory B cells, activated CD21low B cells and germinal center B cells of tonsils. In tonsillar sections SOX5 expression was predominantly polarized to centrocytes within the light zone. After in vitro stimulation, SOX5 expression was down-regulated during proliferation while high expression levels were permissible for plasmablast differentiation. Overexpression of L-SOX5F in human primary B lymphocytes resulted in reduced proliferation, less survival of CD138neg B cells, but comparable numbers of CD138+CD38hi plasmablasts compared to control cells. Thus, our findings describe for the first time a functional role of SOX5 during late B cell development reducing the proliferative capacity and thus potentially affecting the differentiation of B cells during the germinal center response.

Published
2014
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13. RNA and beta-Hemolysin of Group B Streptococcus Induce Interleukin-1 beta ( IL-1 beta) by Activating NLRP3 Inflammasomes in Mouse Macrophages

Author

Katherine A. Fitzgerald, Vijay A. K. Rathinam, Bornali Bhattacharjee, Parisa Kalantari, Egil Lien, Rosane B. DeOliveira, Anubhab Nandy, Jennie Chan, Shubhendu Ghosh, Douglas T. Golenbock, Philipp Henneke, Patrick Trieu-Cuot, Shrutie Sharma, Fabianno Ferreira, Arnaud Firon, Te-Chen Tzeng, Neal S. Silverman, Brian G. Monks, Rahul Gupta, Division of Infectious Diseases and Immunology, University of Massachusetts Medical School [Worcester] (UMASS), University of Massachusetts System (UMASS)-University of Massachusetts System (UMASS), Laboratório de Inflamação e Imunidade, Universidade Federal do Rio de Janeiro (UFRJ), Biologie des Bactéries pathogènes à Gram-positif, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Center for Chronic Immunodeficiency (CCI), University Medical Center Freiburg, Freiburg, Germany, This work was supported, in whole or in part, by National Institutes of Health Grant RO1 AI52455 (to D. T. G., P. H., and P. T.-C.) and U24 AI082663 (to D. T. G., N. S., E. L., and S. G.) and by the German Research Council (DFG HE 3127/5-1 to P. H.)., and Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Inflammasomes, medicine.medical_treatment, Interleukin-1beta, Immunology, Biology, medicine.disease_cause, Hemolysin Proteins, Biochemistry, Microbiology, Streptococcus agalactiae, 03 medical and health sciences, Mice, 0302 clinical medicine, Bacterial Proteins, Cell Signaling, Phagosomes, NLR Family, Pyrin Domain-Containing 3 Protein, medicine, Animals, Humans, Molecular Biology, reproductive and urinary physiology, 030304 developmental biology, Phagosome, 0303 health sciences, Innate immune system, integumentary system, Macrophages, RNA, Interleukin, Inflammasome, Cell Biology, bacterial infections and mycoses, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, Innate Immunity, RNA, Bacterial, Cytokine, bacteria, Carrier Proteins, Lysosomes, 030215 immunology, medicine.drug, Reports
Abstract

International audience; The inflammatory cytokine IL-1β is critical for host responses against many human pathogens. Here, we define Group B Streptococcus (GBS)-mediated activation of the Nod-like receptor-P3 (NLRP3) inflammasome in macrophages. NLRP3 activation requires GBS expression of the cytolytic toxin, β-hemolysin, lysosomal acidification, and leakage. These processes allow the interaction of GBS RNA with cytosolic NLRP3. The present study supports a model in which GBS RNA, along with lysosomal components including cathepsins, leaks out of lysosomes and interacts with NLRP3 to induce IL-1β production.

Published
2014
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14. Activation of the NLRP3 inflammasome by group B streptococci

Author

Francesco Cardile, Giuseppe Mancuso, Giuseppe Teti, Giacomo Signorino, Patrick Trieu-Cuot, Antonio Malara, Angelina Midiri, Rahul Gupta, Douglas T. Golenbock, Carmelo Biondo, Roberta Galbo, Philipp Henneke, Concetta Beninati, Alessandro Costa, Salvatore Papasergi, Elie Metchnikoff Laboratory, University of Messina, Division of Infectious Diseases and Immunology, University of Massachusetts Medical School [Worcester] (UMASS), University of Massachusetts System (UMASS)-University of Massachusetts System (UMASS), Biologie des Bactéries pathogènes à Gram-positif, Institut Pasteur [Paris]-Centre National de la Recherche Scientifique (CNRS), Center for Chronic Immunodeficiency (CCI), University Medical Center Freiburg, Freiburg, Germany, This work was supported by a PRIN grant from MIUR of Italy, a PRA grant from the University of Messina, Bundesministerium fur Bildung und Forschung Grant BMBF 01 EO 0803, Deutsche Forschungsgemeinschaft Grants HE 3127/3-1 and 5-1, and National Institutes of Health Grant ROI AI052455-06A1 (to D.T.G.)., and Institut Pasteur [Paris] (IP)-Centre National de la Recherche Scientifique (CNRS)

Subjects
Inflammasomes, Interleukin-1beta, Immunology, Caspase 1, Biology, medicine.disease_cause, Pyrin domain, Article, Virulence factor, Streptococcus agalactiae, Microbiology, GBS, Inflammasome, cytokines, Hemolysin Proteins, Mice, 03 medical and health sciences, 0302 clinical medicine, Bacterial Proteins, Streptococcal Infections, NLR Family, Pyrin Domain-Containing 3 Protein, medicine, Animals, Immunology and Allergy, RNA, Messenger, 030304 developmental biology, Mice, Knockout, 0303 health sciences, Macrophages, Interleukin-18, Dendritic Cells, [SDV.MP.BAC]Life Sciences [q-bio]/Microbiology and Parasitology/Bacteriology, Toll-Like Receptor 2, 3. Good health, CARD Signaling Adaptor Proteins, Mice, Inbred C57BL, Cytoskeletal Proteins, TLR2, Myeloid Differentiation Factor 88, Female, Signal transduction, Apoptosis Regulatory Proteins, Carrier Proteins, Signal Transduction, 030215 immunology, medicine.drug
Abstract

Group B Streptococcus (GBS) is a frequent agent of life-threatening sepsis and meningitis in neonates and adults with predisposing conditions. We tested the hypothesis that activation of the inflammasome, an inflammatory signaling complex, is involved in host defenses against this pathogen. We show in this study that murine bone marrow-derived conventional dendritic cells responded to GBS by secreting IL-1β and IL-18. IL-1β release required both pro–IL-1β transcription and caspase-1–dependent proteolytic cleavage of intracellular pro–IL-1β. Dendritic cells lacking the TLR adaptor MyD88, but not those lacking TLR2, were unable to produce pro–IL-1β mRNA in response to GBS. Pro–IL-1β cleavage and secretion of the mature IL-1β form depended on the NOD-like receptor family, pyrin domain containing 3 (NLRP3) sensor and the apoptosis-associated speck-like protein containing a caspase activation and recruitment domain adaptor. Moreover, activation of the NLRP3 inflammasome required GBS expression of β-hemolysin, an important virulence factor. We further found that mice lacking NLRP3, apoptosis-associated speck-like protein, or caspase-1 were considerably more susceptible to infection than wild-type mice. Our data link the production of a major virulence factor by GBS with the activation of a highly effective anti-GBS response triggered by the NLRP3 inflammasome.

Published
2012
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15. Hypomorphic homozygous mutations in phosphoglucomutase 3 (PGM3) impair immunity and increase serum IgE levels

Author

Karin R. Engelhardt, Bernhard Fleckenstein, Ekrem Unal, C. I. Edvard Smith, Dietmar Pfeifer, Mohamed-Ridha Barbouche, Meriem Ben-Ali, Hans J. Stauss, Mohamed Bejaoui, Mirzokhid Rakhmanov, Lamia Borchani, Monia Khemiri, Stuart M. Haslam, Zineb Jouhadi, Khadija Khadir, Imen Ben-Mustapha, Bodo Grimbacher, Karin E. Lundin, A. Charlotta Asplund, Manfred Fliegauf, Uwe Kölsch, Gang Wu, A. Sassi, Sandra Lazaroski, Turkan Patiroglu, Magdalena Dziadzio, Anne Dell, Mats Nilsson, Sellama Nadifi, Khairunnadiya Prayitno, Mehmet Akif Ozdemir, Fethi Mellouli, Andrea Maul-Pavicic, Manuela O. Gustafsson, Helene Kraus, Hermann Eibel, Lotte Moens, Hatice Eke Gungor, Thilo Jakob, Elin Falk-Sörqvist, Alejandro A. Schäffer, Sandra Schaffer, Rebecca Meier, Leila Ben-Khemis, Philipp Henneke, Laboratoire d'Immunopathologie, Vaccinologie et Génétique Moléculaire (LVGM), Institut Pasteur de Tunis, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP), Center for Chronic Immunodeficiency (CCI), University Medical Center Freiburg, Freiburg, Germany, Department of Life Sciences, Imperial College London, London, United Kingdom, Pediatrics Department, Bone Marrow Transplantation Center, Tunis,Tunisia, Pediatrics Department, Bone Marrow Transplantation Center, Tunis, Tunisia, Department of Pediatrics, Division of Pediatric Hematology and Oncology, Faculty of Medicine, Erciyes University, Kayseri, Turkey, Department of Pediatrics, Division of Pediatric Immunology, Faculty of Medicine, Erciyes University, Kayseri, Turkey, Department of Pediatric Infectious Diseases, CHU IBN ROCHD, Hassan II University, Casablanca, Morocco, Laboratoire des Venins et Biomolécules Thérapeutiques - Laboratory of Venoms and Therapeutic Biomolecules (LR11IPT08), Department of Medicine I, Specialties: Hematology, Oncology, and Stem-Cell Transplantation, University Medical Center Freiburg, Freiburg, Germany, Pediatrics Department A, Children's Hospital of Tunis, Tunis, Tunisia, Clinical Research Center, Department of Laboratory Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, Huddinge, Sweden, Karolinska Institutet [Stockholm]-Karolinska University Hospital [Stockholm], Royal Free Hospital, Institute of Immunity & Transplantation, University College London, London, United Kingdom, Department of Immunology, Genetics and Pathology, Uppsala University, Rudbeck Laboratory, Uppsala, Sweden, Institute of Virology, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany, Division of Immunology, Labor Berlin and Institute of Medical Immunology, Charité, Campus Virchow Klinikum, Berlin, Germany, Department of Genetics, Hassan II University, Casablanca, Morocco, Pediatrics Department, Bone Marrow Transplantation Center, Tunis, Tunisia., National Center for Biotechnology Information, National Institutes of Health, Department of Health and Human Services, Bethesda, Md, National Institutes of Health [Bethesda] (NIH), and Supported by the German Federal Ministry of Education and Research (BMBF 01 EO 0803). The research was supported in part by the Intramural Research Program of the National Library of Medicine–National Institutes of Health. Parts of the study were supported by the Tunisian Ministry for Higher Education and Research, the Swedish Medical Research Council, the Swedish Cancer Society and the Stockholm County Council (research grant ALF), and the European Community’s 6th and 7th Framework Programs FP7/2007-2013 under grant agreement Health-F5-2008-223292 (Euro-Gene-Scan). This work was also supported by the Biotechnology and Biological Sciences Research Council (BBF0083091 and BB/ K016164/1 to A.D. and S.M.H).

Subjects
Male, Candidate gene, Glycosylation, Allergy, Genetic Linkage, [SDV]Life Sciences [q-bio], T-Lymphocytes, medicine.disease_cause, chemistry.chemical_compound, MESH: Child, 2.1 Biological and endogenous factors, Immunology and Allergy, Aetiology, Child, MESH: Immunity, Genetics, Mutation, MESH: Immunoglobulin E, Homozygote, MESH: Glycosylation, Disease gene identification, MESH: Amino Acid Substitution, MESH: Infant, Phenotype, 3. Good health, Hyper-IgE syndrome, Genetic Diseases, signal transducer and activator of transcription 3, [SDV.IMM]Life Sciences [q-bio]/Immunology, Chromosomes, Human, Pair 6, Female, Pair 6, Dock8, MESH: Tunisia, MESH: Phosphoglucomutase, Job Syndrome, MESH: Homozygote, Human, Adult, MESH: Genetic Diseases, Inborn, Staphylococcus aureus, Tunisia, MESH: Chromosomes, Human, Pair 6, Immunology, Mutation, Missense, MESH: Genetic Linkage, Biology, phosphoglucomutase 3, Article, Chromosomes, Rare Diseases, Clinical Research, Genetic linkage, MESH: Cell Proliferation, medicine, Humans, Cell Proliferation, MESH: Mutation, Missense, MESH: Humans, MESH: Job Syndrome, Genetic Diseases, Inborn, Immunity, Infant, MESH: Adult, Immunoglobulin E, medicine.disease, Molecular biology, MESH: Male, MESH: T-Lymphocytes, Inborn, Emerging Infectious Diseases, Phosphoglucomutase, Amino Acid Substitution, chemistry, Missense, dedicator of cytokinesis 8, MESH: Female, Congenital disorder of glycosylation
Abstract

International audience; BACKGROUND: Recurrent bacterial and fungal infections, eczema, and increased serum IgE levels characterize patients with the hyper-IgE syndrome (HIES). Known genetic causes for HIES are mutations in signal transducer and activator of transcription 3 (STAT3) and dedicator of cytokinesis 8 (DOCK8), which are involved in signal transduction pathways. However, glycosylation defects have not been described in patients with HIES. One crucial enzyme in the glycosylation pathway is phosphoglucomutase 3 (PGM3), which catalyzes a key step in the synthesis of uridine diphosphate N-acetylglucosamine, which is required for the biosynthesis of N-glycans. OBJECTIVE: We sought to elucidate the genetic cause in patients with HIES who do not carry mutations in STAT3 or DOCK8. METHODS: After establishing a linkage interval by means of SNPchip genotyping and homozygosity mapping in 2 families with HIES from Tunisia, mutational analysis was performed with selector-based, high-throughput sequencing. Protein expression was analyzed by means of Western blotting, and glycosylation was profiled by using mass spectrometry. RESULTS: Mutational analysis of candidate genes in an 11.9-Mb linkage region on chromosome 6 shared by 2 multiplex families identified 2 homozygous mutations in PGM3 that segregated with disease status and followed recessive inheritance. The mutations predict amino acid changes in PGM3 (p.Glu340del and p.Leu83Ser). A third homozygous mutation (p.Asp502Tyr) and the p.Leu83Ser variant were identified in 2 other affected families, respectively. These hypomorphic mutations have an effect on the biosynthetic reactions involving uridine diphosphate N-acetylglucosamine. Glycomic analysis revealed an aberrant glycosylation pattern in leukocytes demonstrated by a reduced level of tri-antennary and tetra-antennary N-glycans. T-cell proliferation and differentiation were impaired in patients. Most patients had developmental delay, and many had psychomotor retardation. CONCLUSION: Impairment of PGM3 function leads to a novel primary (inborn) error of development and immunity because biallelic hypomorphic mutations are associated with impaired glycosylation and a hyper-IgE-like phenotype.

Published
2014
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16. Complement Genetics for the Practicing Allergist Immunologist: Focus on Complement Deficiencies.

Author

Szilágyi Á, Csuka D, Geier CB, and Prohászka Z

Subjects
Hereditary Complement Deficiency Diseases, Humans, Allergists, Complement System Proteins genetics
Abstract

Complement deficiencies have been considered to be rare for many decades, but this assumption is changing year by year. Recognition of these conditions significantly increases thanks to the availability of different testing approaches and due to clinical awareness. Furthermore, sequencing technologies (including Sanger sequencing, targeted gene panels, and whole exome/genome sequencing) may facilitate the identification of the underlying disease-causing genetic background. On the other hand, functional characterization of the identified possibly pathogenic variations and performing family studies, as illustrated by some of our cases, remain similarly important to establish a precise clinical diagnosis facilitating the most appropriate management. Here, we present 4 illustrative cases with complement deficiencies of diverse etiologies and also provide an educative, step-by-step description on how to identify the underlying cause of complement deficiency based on the results of complement laboratory testing., (Copyright © 2022 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Published
2022
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17. Can we identify WHIM in infancy? Opportunities with the public newborn screening process.

Author

Yilmaz M, Potts DE, Geier C, and Walter JE

Subjects
Infant, Newborn, Humans, Neonatal Screening, Receptors, Antigen, T-Cell genetics, Severe Combined Immunodeficiency diagnosis, Severe Combined Immunodeficiency genetics, Lymphopenia diagnosis
Abstract

Newborn screening (NBS) for severe combined immunodeficiency (SCID) utilizing T-cell receptor excision circles (TRECs) has been implemented in all 50 states as of December 2018 and has been transformative for the clinical care of SCID patients. Though having high sensitivity for SCID, NBS-SCID has low specificity, therefore is able to detect other causes of lymphopenia in newborns including many inborn errors of immunity (IEIs). In a recent study, three of six newborns later diagnosed with Warts, Hypogammaglobulinemia, Infections, and Myelokathexis (WHIM) syndrome were found to have a low TRECs and lymphopenia at birth. This presents an opportunity to increase the detection and diagnosis of WHIM syndrome by NBS-SCID with immunological follow-up along with a combination of flow cytometry for immune cell subsets, absolute neutrophil count, and genetic testing, extending beyond the conventional bone marrow studies. Coupled with emerging technologies such as next-generation sequencing, transcriptomics and proteomics, dried blood spots used in NBS-SCID will promote earlier detection, diagnosis, and therefore treatment of IEIs such as WHIM syndrome., (© 2022 Wiley Periodicals LLC.)

Published
2022
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18. Pembrolizumab for treatment of progressive multifocal leukoencephalopathy in primary immunodeficiency and/or hematologic malignancy: a case series of five patients.

Author

Volk T, Warnatz K, Marks R, Urbach H, Schluh G, Strohmeier V, Rojas-Restrepo J, Grimbacher B, and Rauer S

Subjects
Antibodies, Monoclonal, Humanized therapeutic use, Humans, Hematologic Neoplasms, JC Virus, Leukoencephalopathy, Progressive Multifocal drug therapy
Abstract

Progressive multifocal leukoencephalopathy is a rare opportunistic infection of the brain by John Cunningham polyomavirus in immune-compromised patients. In cases where no overt option for immune reconstitution is available [e.g., in patients with primary immunodeficiency (PID)], the disease is lethal in the majority of patients. Immune checkpoint inhibition has been applied in recent years with mixed outcomes. We present four novel patients and the follow-up of a previously published patient suffering from progressive multifocal leukoencephalopathy (PML) due to PID and/or hematologic malignancy who were treated with the immune checkpoint inhibitor pembrolizumab. In two patients with PID, symptoms improved and stabilized. One patient died because of worsening PML another of intracranial hemorrhage which was unrelated to PML or its treatment with pembrolizumab. The fifth patient suffered from PID and died of a pre-existing immune dysregulation, possibly exacerbated by pembrolizumab. The long-term follow-up of the first patient provides support for therapeutic decisions during this therapy and is the longest published clinical course of a patient with checkpoint inhibition for PML. We conclude that pembrolizumab can control PML symptoms long term in a subgroup of patients with PID, in our cases for 21 and 36 months. However, therapy must be started early because symptoms are only partially reversible. In light of severe adverse events, application of pembrolizumab is only justified if the prognosis for the individual patient is very poor., (© 2021. The Author(s).)

Published
2022
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19. 2019 update of EULAR recommendations for vaccination in adult patients with autoimmune inflammatory rheumatic diseases.

Author

Furer V, Rondaan C, Heijstek MW, Agmon-Levin N, van Assen S, Bijl M, Breedveld FC, D'Amelio R, Dougados M, Kapetanovic MC, van Laar JM, de Thurah A, Landewé RB, Molto A, Müller-Ladner U, Schreiber K, Smolar L, Walker J, Warnatz K, Wulffraat NM, and Elkayam O

Subjects
Family Characteristics, Hepatitis A prevention & control, Hepatitis A Vaccines therapeutic use, Hepatitis B prevention & control, Hepatitis B Vaccines therapeutic use, Herpes Zoster prevention & control, Herpes Zoster Vaccine therapeutic use, Humans, Influenza Vaccines therapeutic use, Influenza, Human prevention & control, Papillomavirus Infections prevention & control, Papillomavirus Vaccines therapeutic use, Pneumococcal Infections prevention & control, Pneumococcal Vaccines therapeutic use, Tetanus prevention & control, Tetanus Toxoid therapeutic use, Vaccines, Attenuated therapeutic use, Antirheumatic Agents therapeutic use, Autoimmune Diseases drug therapy, Bacterial Infections prevention & control, Rheumatic Diseases drug therapy, Vaccines therapeutic use, Virus Diseases prevention & control
Abstract

To update the European League Against Rheumatism (EULAR) recommendations for vaccination in adult patients with autoimmune inflammatory rheumatic diseases (AIIRD) published in 2011. Four systematic literature reviews were performed regarding the incidence/prevalence of vaccine-preventable infections among patients with AIIRD; efficacy, immunogenicity and safety of vaccines; effect of anti-rheumatic drugs on the response to vaccines; effect of vaccination of household of AIIRDs patients. Subsequently, recommendations were formulated based on the evidence and expert opinion. The updated recommendations comprise six overarching principles and nine recommendations. The former address the need for an annual vaccination status assessment, shared decision-making and timing of vaccination, favouring vaccination during quiescent disease, preferably prior to the initiation of immunosuppression. Non-live vaccines can be safely provided to AIIRD patients regardless of underlying therapy, whereas live-attenuated vaccines may be considered with caution. Influenza and pneumococcal vaccination should be strongly considered for the majority of patients with AIIRD. Tetanus toxoid and human papilloma virus vaccination should be provided to AIIRD patients as recommended for the general population. Hepatitis A, hepatitis B and herpes zoster vaccination should be administered to AIIRD patients at risk. Immunocompetent household members of patients with AIIRD should receive vaccines according to national guidelines, except for the oral poliomyelitis vaccine. Live-attenuated vaccines should be avoided during the first 6 months of life in newborns of mothers treated with biologics during the second half of pregnancy. These 2019 EULAR recommendations provide an up-to-date guidance on the management of vaccinations in patients with AIIRD., (© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.)

Published
2020
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20. The crossroads of autoimmunity and immunodeficiency: Lessons from polygenic traits and monogenic defects.

Author

Grimbacher B, Warnatz K, Yong PFK, Korganow AS, and Peter HH

Subjects
Animals, Autoimmunity genetics, Genetic Predisposition to Disease, Humans, Multifactorial Inheritance, Autoimmune Diseases genetics, Immunologic Deficiency Syndromes genetics
Abstract

Autoimmune and immunodeficiency diseases are outcomes of a dysfunctional immune system and represent 2 sides of the same coin. Multiple single-gene defects have been identified, resulting in rare diseases with features of both autoimmunity and immunodeficiency. On the other hand, more common autoimmune diseases, such as rheumatoid arthritis and systemic lupus erythematosus, show a polygenic inheritance pattern. Not surprisingly, the genes implicated in single-gene disorders have also been shown to be linked to polygenic disorders. In this review article, we discuss the contribution of various immune system genes to common polygenic autoimmune disorders, as well as the pathophysiologic pathways and clinical features of monogenic defects that result in autoimmune disease. We also explore the hypotheses underlying the development of autoimmune disease and the overlap between immunodeficiency and autoimmunity., (Copyright © 2015 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Published
2016
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21. The extended clinical phenotype of 64 patients with dedicator of cytokinesis 8 deficiency.

Author

Engelhardt KR, Gertz ME, Keles S, Schäffer AA, Sigmund EC, Glocker C, Saghafi S, Pourpak Z, Ceja R, Sassi A, Graham LE, Massaad MJ, Mellouli F, Ben-Mustapha I, Khemiri M, Kilic SS, Etzioni A, Freeman AF, Thiel J, Schulze I, Al-Herz W, Metin A, Sanal Ö, Tezcan I, Yeganeh M, Niehues T, Dueckers G, Weinspach S, Patiroglu T, Unal E, Dasouki M, Yilmaz M, Genel F, Aytekin C, Kutukculer N, Somer A, Kilic M, Reisli I, Camcioglu Y, Gennery AR, Cant AJ, Jones A, Gaspar BH, Arkwright PD, Pietrogrande MC, Baz Z, Al-Tamemi S, Lougaris V, Lefranc G, Megarbane A, Boutros J, Galal N, Bejaoui M, Barbouche MR, Geha RS, Chatila TA, and Grimbacher B

Subjects
Adolescent, Adult, Antigens, Bacterial blood, Antigens, Bacterial immunology, Antigens, Viral blood, Antigens, Viral immunology, Bacterial Infections genetics, Bacterial Infections immunology, Bacterial Infections mortality, CD4-Positive T-Lymphocytes immunology, CD4-Positive T-Lymphocytes pathology, CD8-Positive T-Lymphocytes immunology, CD8-Positive T-Lymphocytes pathology, Child, Child, Preschool, Eosinophils immunology, Eosinophils pathology, Female, Guanine Nucleotide Exchange Factors genetics, Guanine Nucleotide Exchange Factors immunology, Humans, Immunoglobulin E blood, Immunoglobulin E genetics, Immunoglobulin M blood, Immunoglobulin M genetics, Infant, Job Syndrome genetics, Job Syndrome immunology, Job Syndrome mortality, Lymphocyte Count, Male, Middle Aged, Mutation, STAT3 Transcription Factor genetics, STAT3 Transcription Factor immunology, Skin Diseases genetics, Skin Diseases immunology, Skin Diseases mortality, Support Vector Machine, Survival Analysis, Virus Diseases genetics, Virus Diseases immunology, Virus Diseases mortality, Bacterial Infections complications, Guanine Nucleotide Exchange Factors deficiency, Job Syndrome complications, Phenotype, Skin Diseases complications, Virus Diseases complications
Abstract

Background: Mutations in dedicator of cytokinesis 8 (DOCK8) cause a combined immunodeficiency (CID) also classified as autosomal recessive (AR) hyper-IgE syndrome (HIES). Recognizing patients with CID/HIES is of clinical importance because of the difference in prognosis and management., Objectives: We sought to define the clinical features that distinguish DOCK8 deficiency from other forms of HIES and CIDs, study the mutational spectrum of DOCK8 deficiency, and report on the frequency of specific clinical findings., Methods: Eighty-two patients from 60 families with CID and the phenotype of AR-HIES with (64 patients) and without (18 patients) DOCK8 mutations were studied. Support vector machines were used to compare clinical data from 35 patients with DOCK8 deficiency with those from 10 patients with AR-HIES without a DOCK8 mutation and 64 patients with signal transducer and activator of transcription 3 (STAT3) mutations., Results: DOCK8-deficient patients had median IgE levels of 5201 IU, high eosinophil levels of usually at least 800/μL (92% of patients), and low IgM levels (62%). About 20% of patients were lymphopenic, mainly because of low CD4(+) and CD8(+) T-cell counts. Fewer than half of the patients tested produced normal specific antibody responses to recall antigens. Bacterial (84%), viral (78%), and fungal (70%) infections were frequently observed. Skin abscesses (60%) and allergies (73%) were common clinical problems. In contrast to STAT3 deficiency, there were few pneumatoceles, bone fractures, and teething problems. Mortality was high (34%). A combination of 5 clinical features was helpful in distinguishing patients with DOCK8 mutations from those with STAT3 mutations., Conclusions: DOCK8 deficiency is likely in patients with severe viral infections, allergies, and/or low IgM levels who have a diagnosis of HIES plus hypereosinophilia and upper respiratory tract infections in the absence of parenchymal lung abnormalities, retained primary teeth, and minimal trauma fractures., (Copyright © 2015 American Academy of Allergy, Asthma & Immunology. All rights reserved.)

Published
2015
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22. Enterococcus faecalis Glycolipids Modulate Lipoprotein-Content of the Bacterial Cell Membrane and Host Immune Response.

Author

Theilacker C, Diederich AK, Otto A, Sava IG, Wobser D, Bao Y, Hese K, Broszat M, Henneke P, Becher D, and Huebner J

Subjects
Animals, Bacterial Proteins immunology, Cell Line, Chemokine CXCL2 blood, Female, HEK293 Cells, Humans, Immunity, Innate immunology, Interleukin-6 blood, Macrophages, Membrane Lipids immunology, Membrane Proteins immunology, Mice, Mice, Inbred BALB C, Toll-Like Receptor 2 immunology, Tumor Necrosis Factor-alpha blood, Tumor Necrosis Factor-alpha immunology, Virulence immunology, Cell Membrane immunology, Enterococcus faecalis immunology, Glycolipids immunology, Host-Pathogen Interactions immunology, Lipoproteins immunology
Abstract

In this study, we investigated the impact of the cell membrane composition of E. faecalis on its recognition by the host immune system. To this end, we employed an E. faecalis deletion mutant (ΔbgsA) that does not synthesize the major cell membrane glycolipid diglycosyl-diacylglycerol (DGlcDAG). Proteomic analysis revealed that 13 of a total of 21 upregulated surface-associated proteins of E. faecalis ΔbgsA were lipoproteins. This led to a total lipoprotein content in the cell membrane of 35.8% in ΔbgsA compared to only 9.4% in wild-type bacteria. Increased lipoprotein content strongly affected the recognition of ΔbgsA by mouse macrophages in vitro with an increased stimulation of TNF-α production by heat-fixed bacteria and secreted antigens. Inactivation of the prolipoprotein diacylglycerol transferase (lgt) in ΔbgsA abrogated TNF-α induction by a ΔbgsA_lgt double mutant indicating that lipoproteins mediate increased activation of mouse macrophages by ΔbgsA. Heat-fixed ΔbgsA bacteria, culture supernatant, or cell membrane lipid extract activated transfected HEK cells in a TLR2-dependent fashion; the same was not true of wild-type bacteria. In mice infected intraperitoneally with a sublethal dose of E. faecalis we observed a 70% greater mortality in mice infected with ΔbgsA compared with wild-type-infected mice. Increased mortality due to ΔbgsA infection was associated with elevated plasma levels of the inflammatory cytokines TNF-α, IL-6 and MIP-2. In summary, our results provide evidence that an E. faecalis mutant lacking its major bilayer forming glycolipid DGlcDAG upregulates lipoprotein expression leading to increased activation of the host innate immune system and virulence in vivo.

Published
2015
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23. Reply: To PMID 24582167.

Author

Gao Y, Gadola S, Grimbacher B, and Williams AP

Subjects
Female, Humans, Male, Common Variable Immunodeficiency immunology, Natural Killer T-Cells immunology
Published
2014
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24. Medical history, lifestyle, family history, and occupational risk factors for marginal zone lymphoma: the InterLymph Non-Hodgkin Lymphoma Subtypes Project.

Author

Bracci PM, Benavente Y, Turner JJ, Paltiel O, Slager SL, Vajdic CM, Norman AD, Cerhan JR, Chiu BC, Becker N, Cocco P, Dogan A, Nieters A, Holly EA, Kane EV, Smedby KE, Maynadié M, Spinelli JJ, Roman E, Glimelius B, Wang SS, Sampson JN, Morton LM, and de Sanjosé S

Subjects
Adult, Aged, Aged, 80 and over, Australia epidemiology, Australia ethnology, Case-Control Studies, Comorbidity, Europe epidemiology, Europe ethnology, Female, Humans, Lymphoma, B-Cell, Marginal Zone diagnosis, Male, Middle Aged, North America epidemiology, North America ethnology, Odds Ratio, Risk Factors, Young Adult, Life Style, Lymphoma, B-Cell, Marginal Zone epidemiology, Lymphoma, B-Cell, Marginal Zone etiology, Occupational Exposure
Abstract

Background: Marginal zone lymphoma (MZL), comprised of nodal, extranodal, and splenic subtypes, accounts for 5%-10% of non-Hodgkin lymphoma cases. A detailed evaluation of the independent effects of risk factors for MZL and its subtypes has not been conducted., Methods: Data were pooled from 1052 MZL cases (extranodal [EMZL] = 633, nodal [NMZL] = 157, splenic [SMZL] = 140) and 13766 controls from 12 case-control studies. Adjusted unconditional logistic regression was used to compute odds ratios (ORs) and 95% confidence intervals (CIs)., Results: Novel findings for MZL subtypes include increased risk for B-cell activating autoimmune conditions (EMZL OR = 6.40, 95% CI = 4.24 to 9.68; NMZL OR = 7.80, 95% CI = 3.32 to 18.33; SMZL OR = 4.25, 95% CI = 1.49 to 12.14), hepatitis C virus seropositivity (EMZL OR = 5.29, 95% CI = 2.48 to 11.28), self-reported peptic ulcers (EMZL OR = 1.83, 95% CI = 1.35 to 2.49), asthma without other atopy (SMZL OR = 2.28, 95% CI = 1.23 to 4.23), family history of hematologic cancer (EMZL OR = 1.90, 95% CI = 1.37 to 2.62) and of non-Hodgkin lymphoma (NMZL OR = 2.82, 95% CI = 1.33 to 5.98), permanent hairdye use (SMZL OR = 6.59, 95% CI = 1.54 to 28.17), and occupation as a metalworker (NMZL OR = 3.56, 95% CI = 1.67 to 7.58). Reduced risks were observed with consumption of any alcohol (EMZL fourth quartile OR = 0.48, 95% CI = 0.28 to 0.82) and lower consumption of wine (NMZL first to third quartile ORs < 0.45) compared with nondrinkers, and occupation as a teacher (EMZL OR = 0.58, 95% CI = 0.37 to 0.88)., Conclusion: Our results provide new data suggesting etiologic heterogeneity across MZL subtypes although a common risk of MZL associated with B-cell activating autoimmune conditions was found., (Published by Oxford University Press 2014.)

Published
2014
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25. Medical history, lifestyle, family history, and occupational risk factors for chronic lymphocytic leukemia/small lymphocytic lymphoma: the InterLymph Non-Hodgkin Lymphoma Subtypes Project.

Author

Slager SL, Benavente Y, Blair A, Vermeulen R, Cerhan JR, Costantini AS, Monnereau A, Nieters A, Clavel J, Call TG, Maynadié M, Lan Q, Clarke CA, Lightfoot T, Norman AD, Sampson JN, Casabonne D, Cocco P, and de Sanjosé S

Subjects
Adult, Aged, Aged, 80 and over, Australia epidemiology, Australia ethnology, Case-Control Studies, Comorbidity, Europe epidemiology, Europe ethnology, Female, Humans, Male, Middle Aged, North America epidemiology, North America ethnology, Odds Ratio, Risk Factors, Young Adult, Leukemia, Lymphocytic, Chronic, B-Cell epidemiology, Leukemia, Lymphocytic, Chronic, B-Cell etiology, Life Style, Occupational Exposure
Abstract

Background: Chronic lymphocytic leukemia (CLL) and small lymphocytic lymphoma (SLL) are two subtypes of non-Hodgkin lymphoma. A number of studies have evaluated associations between risk factors and CLL/SLL risk. However, these associations remain inconsistent or lacked confirmation. This may be due, in part, to the inadequate sample size of CLL/SLL cases., Methods: We performed a pooled analysis of 2440 CLL/SLL cases and 15186 controls from 13 case-control studies from Europe, North America, and Australia. We evaluated associations of medical history, family history, lifestyle, and occupational risk factors with CLL/SLL risk. Multivariate logistic regression analyses were used to estimate odds ratios (ORs) and 95% confidence intervals (CIs)., Results: We confirmed prior inverse associations with any atopic condition and recreational sun exposure. We also confirmed prior elevated associations with usual adult height, hepatitis C virus seropositivity, living or working on a farm, and family history of any hematological malignancy. Novel associations were identified with hairdresser occupation (OR = 1.77, 95% CI = 1.05 to 2.98) and blood transfusion history (OR = 0.79, 95% CI = 0.66 to 0.94). We also found smoking to have modest protective effect (OR = 0.9, 95% CI = 0.81 to 0.99). All exposures showed evidence of independent effects., Conclusions: We have identified or confirmed several independent risk factors for CLL/SLL supporting a role for genetics (through family history), immune function (through allergy and sun), infection (through hepatitis C virus), and height, and other pathways of immune response. Given that CLL/SLL has more than 30 susceptibility loci identified to date, studies evaluating the interaction among genetic and nongenetic factors are warranted., (Published by Oxford University Press 2014.)

Published
2014
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26. Medical history, lifestyle, family history, and occupational risk factors for diffuse large B-cell lymphoma: the InterLymph Non-Hodgkin Lymphoma Subtypes Project.

Author

Cerhan JR, Kricker A, Paltiel O, Flowers CR, Wang SS, Monnereau A, Blair A, Dal Maso L, Kane EV, Nieters A, Foran JM, Miligi L, Clavel J, Bernstein L, Rothman N, Slager SL, Sampson JN, Morton LM, and Skibola CF

Subjects
Adult, Aged, Aged, 80 and over, Australia, Case-Control Studies, Comorbidity, Europe, Female, Humans, Male, Middle Aged, North America, Odds Ratio, Risk Factors, Young Adult, Life Style, Lymphoma, Large B-Cell, Diffuse epidemiology, Lymphoma, Large B-Cell, Diffuse etiology, Occupational Exposure
Abstract

Background: Although risk factors for diffuse large B-cell lymphoma (DLBCL) have been suggested, their independent effects, modification by sex, and association with anatomical sites are largely unknown., Methods: In a pooled analysis of 4667 cases and 22639 controls from 19 studies, we used stepwise logistic regression to identify the most parsimonious multivariate models for DLBCL overall, by sex, and for selected anatomical sites., Results: DLBCL was associated with B-cell activating autoimmune diseases (odds ratio [OR] = 2.36, 95% confidence interval [CI] = 1.80 to 3.09), hepatitis C virus seropositivity (OR = 2.02, 95% CI = 1.47 to 2.76), family history of non-Hodgkin lymphoma (OR = 1.95, 95% CI = 1.54 to 2.47), higher young adult body mass index (OR = 1.58, 95% CI = 1.12 to 2.23, for 35+ vs 18.5 to 22.4 kg/m(2)), higher recreational sun exposure (OR = 0.78, 95% CI = 0.69 to 0.89), any atopic disorder (OR = 0.82, 95% CI = 0.76 to 0.89), and higher socioeconomic status (OR = 0.86, 95% CI = 0.79 to 0.94). Additional risk factors for women were occupation as field crop/vegetable farm worker (OR = 1.78, 95% CI = 1.22 to 2.60), hairdresser (OR = 1.65, 95% CI = 1.12 to 2.41), and seamstress/embroider (OR = 1.49, 95% CI = 1.13 to 1.97), low adult body mass index (OR = 0.46, 95% CI = 0.29 to 0.74, for <18.5 vs 18.5 to 22.4 kg/m(2)), hormone replacement therapy started age at least 50 years (OR = 0.68, 95% CI = 0.52 to 0.88), and oral contraceptive use before 1970 (OR = 0.78, 95% CI = 0.62 to 1.00); and for men were occupation as material handling equipment operator (OR = 1.58, 95% CI = 1.02 to 2.44), lifetime alcohol consumption (OR = 0.57, 95% CI = 0.44 to 0.75, for >400 kg vs nondrinker), and previous blood transfusion (OR = 0.69, 95% CI = 0.57 to 0.83). Autoimmune disease, atopy, and family history of non-Hodgkin lymphoma showed similar associations across selected anatomical sites, whereas smoking was associated with central nervous system, testicular and cutaneous DLBCLs; inflammatory bowel disease was associated with gastrointestinal DLBCL; and farming and hair dye use were associated with mediastinal DLBCL., Conclusion: Our results support a complex and multifactorial etiology for DLBCL with some variation in risk observed by sex and anatomical site., (Published by Oxford University Press 2014.)

Published
2014
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