CIITA promoter polymorphism impairs monocytes HLA-DR expression in patients with septic shock
Jordi Miatello,
Anne-Claire Lukaszewicz,
Michael J. Carter,
Valérie Faivre,
Stéphane Hua,
Kim Z. Martinet,
Christine Bourgeois,
Lluis Quintana-Murci,
Didier Payen,
Michele Boniotto,
Pierre Tissières
Affiliations
Jordi Miatello
Institute of Integrative Biology of the Cell, CNRS, CEA, Paris-Saclay University, Gif-sur-Yvette, France; Paediatric Intensive Care and Neonatal Medicine, AP-HP, Paris-Saclay University, Bicêtre Hospital, Le Kremlin-Bicêtre, France; FHU Sepsis, AP-HP, Paris-Saclay University, INSERM, Le Kremlin-Bicêtre, France
Anne-Claire Lukaszewicz
EA 7426 PI3 (Pathophysiology of Injury-induced Immunosuppression), Hospices Civils de Lyon/ Lyon University/bioMérieux, E. Herriot Hospital, Lyon, France; Anesthesia and Critical Care Medicine Department, Hospices Civils de Lyon, Edouard Herriot Hospital, Lyon, France
Michael J. Carter
Paediatric Intensive Care and Neonatal Medicine, AP-HP, Paris-Saclay University, Bicêtre Hospital, Le Kremlin-Bicêtre, France; Department of Women and Children’s Health, School of Life Course Sciences, King’s College London, London, UK; Paediatric Intensive Care, Evelina London Children’s Hospital, Guy’s and St Thomas’ NHS Foundation Trust, London, UK
Valérie Faivre
Saint-Louis Lariboisière Hospital, AP-HP, Denis Diderot University, Paris, France; INSERM UMR1141 Neurodiderot, Université Paris Cité, France
Stéphane Hua
CEA, INRAE, Medicines and Healthcare Technologies Department, SIMoS, Université Paris-Saclay, Gif-sur-Yvette, France
Kim Z. Martinet
Université Paris-Saclay, Inserm, CEA, Center for Immunology of Viral, Auto-Immune, Hematological and Bacterial Diseases (IMVA-HB/IDMIT), Fontenay-aux-Roses, France
Christine Bourgeois
Université Paris-Saclay, Inserm, CEA, Center for Immunology of Viral, Auto-Immune, Hematological and Bacterial Diseases (IMVA-HB/IDMIT), Fontenay-aux-Roses, France
Lluis Quintana-Murci
Institut Pasteur, Université Paris Cité, CNRS UMR2000, Human Evolutionary Genetics Unit, Paris, France; Chair Human Genomics and Evolution, Collège de France, Paris, France
Didier Payen
Denis Diderot University, Paris, Sorbonne, Cité Paris, France
Michele Boniotto
University Paris Est Créteil, INSERM, IMRB, Translational Neuropsychiatry, 94010 Créteil, France
Pierre Tissières
Institute of Integrative Biology of the Cell, CNRS, CEA, Paris-Saclay University, Gif-sur-Yvette, France; Paediatric Intensive Care and Neonatal Medicine, AP-HP, Paris-Saclay University, Bicêtre Hospital, Le Kremlin-Bicêtre, France; FHU Sepsis, AP-HP, Paris-Saclay University, INSERM, Le Kremlin-Bicêtre, France; Corresponding author
Summary: Low monocyte (m)HLA-DR expression is associated with mortality in sepsis. G-286A∗rs3087456 polymorphism in promoter III of HLA class II transactivator (CIITA), the master regulator of HLA, has been associated with autoimmune diseases but its role in sepsis has never been demonstrated. In 203 patients in septic shock, GG genotype was associated with 28-day mortality and mHLA-DR remained low whereas it increased in patients with AA or AG genotype. In ex vivo cells, mHLA-DR failed to augment in GG in comparison with AG or AA genotype on exposure to IFN-γ. Promoter III transcript levels were similar in control monocytes regardless of genotype and exposure to IFN-γ. Promoter III activity was decreased in GG genotype in monocyte cell line but restored after stimulation with IFN-γ. Hereby, we demonstrated that G-286A∗rs3087456 significantly impact mHLA-DR expression in patients with septic shock in part through CIITA promoter III activity, that can be rescued using IFN-γ.
