Human inherited CCR2 deficiency underlies progressive polycystic lung disease

Anna-Lena Neehus; Brenna Carey; Marija Landekic; Patricia Panikulam; Gail Deutsch; Masato Ogishi; Carlos A Arango-Franco; Quentin Philippot; Mohammadreza Modaresi; Iraj Mohammadzadeh; Melissa Corcini Berndt; Darawan Rinchai; Tom Le Voyer; Jérémie Rosain; Mana Momenilandi; Marta Martin-Fernandez; Taushif Khan; Jonathan Bohlen; Ji Eun Han; Alexandre Deslys; Mathilde Bernard; Tania Gajardo-Carrasco; Camille Soudée; Corentin Le Floc'h; Mélanie Migaud; Yoann Seeleuthner; Mi-Sun Jang; Eirini Nikolouli; Simin Seyedpour; Hugues Begueret; Jean-François Emile; Pierre Le Guen; Guido Tavazzi; Costanza Natalia Julia Colombo; Federico Capra Marzani; Micol Angelini; Francesca Trespidi; Stefano Ghirardello; Nasrin Alipour; Anne Molitor; Raphael Carapito; Mohsen Mazloomrezaei; Hassan Rokni-Zadeh; Majid Changi-Ashtiani; Chantal Brouzes; Pablo Vargas; Alessandro Borghesi; Nico Lachmann; Seiamak Bahram; Bruno Crestani; Michael Fayon; François Galode; Susanta Pahari; Larry S Schlesinger; Nico Marr; Dusan Bogunovic; Stéphanie Boisson-Dupuis; Vivien Béziat; Laurent Abel; Raphael Borie; Lisa R Young; Robin Deterding; Mohammad Shahrooei; Nima Rezaei; Nima Parvaneh; Daniel Craven; Philippe Gros; Danielle Malo; Fernando E Sepulveda; Lawrence M Nogee; Nathalie Aladjidi; Bruce C Trapnell; Jean-Laurent Casanova; Jacinta Bustamante

doi:10.1016/j.cell.2023.11.036

Human inherited CCR2 deficiency underlies progressive polycystic lung disease

Cell. 2024 Jan 18;187(2):390-408.e23. doi: 10.1016/j.cell.2023.11.036. Epub 2023 Dec 28.

Authors

Anna-Lena Neehus¹, Brenna Carey², Marija Landekic³, Patricia Panikulam⁴, Gail Deutsch⁵, Masato Ogishi⁶, Carlos A Arango-Franco⁷, Quentin Philippot⁸, Mohammadreza Modaresi⁹, Iraj Mohammadzadeh¹⁰, Melissa Corcini Berndt⁸, Darawan Rinchai⁶, Tom Le Voyer⁸, Jérémie Rosain¹¹, Mana Momenilandi⁸, Marta Martin-Fernandez¹², Taushif Khan¹³, Jonathan Bohlen⁸, Ji Eun Han⁶, Alexandre Deslys¹⁴, Mathilde Bernard¹⁵, Tania Gajardo-Carrasco⁴, Camille Soudée⁸, Corentin Le Floc'h⁸, Mélanie Migaud⁸, Yoann Seeleuthner⁸, Mi-Sun Jang¹⁶, Eirini Nikolouli¹⁶, Simin Seyedpour¹⁷, Hugues Begueret¹⁸, Jean-François Emile¹⁹, Pierre Le Guen²⁰, Guido Tavazzi²¹, Costanza Natalia Julia Colombo²², Federico Capra Marzani²³, Micol Angelini²⁴, Francesca Trespidi²⁴, Stefano Ghirardello²⁴, Nasrin Alipour²⁵, Anne Molitor²⁵, Raphael Carapito²⁶, Mohsen Mazloomrezaei²⁷, Hassan Rokni-Zadeh²⁸, Majid Changi-Ashtiani²⁹, Chantal Brouzes³⁰, Pablo Vargas¹⁵, Alessandro Borghesi³¹, Nico Lachmann³², Seiamak Bahram²⁶, Bruno Crestani²⁰, Michael Fayon³³, François Galode³³, Susanta Pahari³⁴, Larry S Schlesinger³⁴, Nico Marr³⁵, Dusan Bogunovic¹², Stéphanie Boisson-Dupuis³⁶, Vivien Béziat³⁶, Laurent Abel³⁶, Raphael Borie²⁰, Lisa R Young³⁷, Robin Deterding³⁸, Mohammad Shahrooei³⁹, Nima Rezaei⁴⁰, Nima Parvaneh⁴¹, Daniel Craven⁴², Philippe Gros⁴³, Danielle Malo⁴⁴, Fernando E Sepulveda⁴, Lawrence M Nogee⁴⁵, Nathalie Aladjidi⁴⁶, Bruce C Trapnell⁴⁷, Jean-Laurent Casanova⁴⁸, Jacinta Bustamante⁴⁹

Affiliations

¹ Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, Paris 75015, France; Paris Cité University, Imagine Institute, Paris 75015, France. Electronic address: [email protected].
² Translational Pulmonary Science Center, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA; Department of Pediatrics, University of Cincinnati, College of Medicine, Cincinnati, OH 45267, USA.
³ Department of Medicine, McGill University, Montreal, QC H3G 0B1, Canada.
⁴ Molecular Basis of Altered Immune Homeostasis, INSERM U1163, Paris Cité University, Imagine Institute, Paris 75015, France.
⁵ Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA 98195, USA.
⁶ St Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University, New York, NY 10065, USA.
⁷ Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, Paris 75015, France; Paris Cité University, Imagine Institute, Paris 75015, France; Primary Immunodeficiencies Group, Department of Microbiology and Parasitology, School of Medicine, University of Antioquia, Medellín, Colombia.
⁸ Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, Paris 75015, France; Paris Cité University, Imagine Institute, Paris 75015, France.
⁹ Pediatric Pulmonary and Sleep Medicine Department, Children's Medical Center, Pediatrics Center of Excellence, Tehran University of Medical Sciences, Tehran, Iran; Pediatric Pulmonary Disease and Sleep Medicine Research Center, Children's Medical Center, Pediatric Center of Excellence, Tehran University of Medical Science, Tehran, Iran.
¹⁰ Non-communicable Pediatric Diseases Research Center, Health Research Institute, Babol University of Medical Sciences, Babol, Iran; USERN Office, Babol University of Medical Sciences, Babol, Iran.
¹¹ Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, Paris 75015, France; Paris Cité University, Imagine Institute, Paris 75015, France; Study Center for Primary Immunodeficiencies, Necker Hospital for Sick Children, AP-HP, Paris 75015, France.
¹² Center for Inborn Errors of Immunity, Icahn School, New York, NY 10029, USA; Precision Immunology Institute, Icahn School, New York, NY 10029, USA; Mindich Child Health and Development Institute, Icahn School, New York, NY 10029, USA; Department of Pediatrics, Icahn School, New York, NY 10029, USA; Department of Microbiology, Icahn School, New York, NY 10029, USA.
¹³ The Jackson Laboratory, Farmington, CT 06032, USA.
¹⁴ Leukomotion Laboratory, Paris Cité University, INSERM UMR-S1151, CNRS UMR-S8253, Necker Hospital for Sick Children, Paris 75015, France.
¹⁵ Leukomotion Laboratory, Paris Cité University, INSERM UMR-S1151, CNRS UMR-S8253, Necker Hospital for Sick Children, Paris 75015, France; Curie Institute, PSL Research University, CNRS, UMR144, Paris 75248, France; Pierre-Gilles de Gennes Institute, PSL Research University, Paris 75005, France.
¹⁶ Department of Pediatric Pneumology, Allergology and Neonatology, Hannover Medical School, Hannover 30625, Germany.
¹⁷ Research Center for Immunodeficiencies, Tehran University of Medical Sciences, Tehran, Iran; Nanomedicine Research Association (NRA), Universal Scientific Education and Research Network (USERN), Tehran, Iran.
¹⁸ Department of Pathology, Haut-Lévèque Hospital, CHU Bordeaux, Pessac 33604, France.
¹⁹ Pathology Department, Ambroise-Paré Hospital, AP-HP, Boulogne 92100, France.
²⁰ Pulmonology Service, Bichat Hospital, AP-HP and Paris Cité University, INSERM U1152, PHERE, Paris 75018, France.
²¹ Department of Surgical, Pediatric, and Diagnostic Sciences, University of Pavia, Pavia 27100, Italy; Anesthesia and Intensive Care, San Matteo Research Hospital, Pavia 27100, Italy.
²² Anesthesia and Intensive Care, San Matteo Research Hospital, Pavia 27100, Italy; Experimental Medicine, University of Pavia, Pavia 27100, Italy.
²³ Anesthesia and Intensive Care, San Matteo Research Hospital, Pavia 27100, Italy.
²⁴ Neonatal Intensive Care Unit, San Matteo Research Hospital, Pavia 27100, Italy.
²⁵ Molecular Immuno-Rheumatology Laboratory, INSERM UMR_S1109, GENOMAX Platform, Faculty of Medicine, OMICARE University Hospital Federation, Immunology and Hematology Research Center, Research Center in Biomedicine of Strasbourg (CRBS), Federation of Translational Medicine of Strasbourg (FMTS), University of Strasbourg, Strasbourg 67081, France; Interdisciplinary Thematic Institute (ITI) of Precision Medicine of Strasbourg, University of Strasbourg, Strasbourg 67081, France.
²⁶ Molecular Immuno-Rheumatology Laboratory, INSERM UMR_S1109, GENOMAX Platform, Faculty of Medicine, OMICARE University Hospital Federation, Immunology and Hematology Research Center, Research Center in Biomedicine of Strasbourg (CRBS), Federation of Translational Medicine of Strasbourg (FMTS), University of Strasbourg, Strasbourg 67081, France; Interdisciplinary Thematic Institute (ITI) of Precision Medicine of Strasbourg, University of Strasbourg, Strasbourg 67081, France; Immunology Laboratory, Biology Technical Platform, Biology Pole, New Civil Hospital, Strasbourg 67091, France.
²⁷ Dr. Shahrooei Laboratory, 22 Bahman St., Ashrafi Esfahani Blvd, Tehran, Iran.
²⁸ Department of Medical Biotechnology, Zanjan University of Medical Sciences (ZUMS), Zanjan, Iran.
²⁹ School of Mathematics, Institute for Research in Fundamental Sciences (IPM), Tehran, Iran.
³⁰ Laboratory of Onco-Hematology, Necker Hospital for Sick Children, Paris 75015, France.
³¹ Neonatal Intensive Care Unit, San Matteo Research Hospital, Pavia 27100, Italy; School of Life Sciences, Swiss Federal Institute of Technology, Lausanne 1015, Switzerland.
³² Department of Pediatric Pneumology, Allergology and Neonatology, Hannover Medical School, Hannover 30625, Germany; REBIRTH - Research Center for Translational Regenerative Medicine, Hannover 30625, Germany; Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), Hannover 30625, Germany; Cluster of Excellence RESIST (EXC 2155), Hannover Medical School, Hannover 30625, Germany.
³³ Department of Pediatrics, Bordeaux Hospital, University of Bordeaux, 33000 Bordeaux, France; Cardiothoracic Research Center, U1045 INSERM, 33000 Bordeaux, France
³⁴ Host-Pathogen Interactions and Population Health programs, Texas Biomedical Research Institute, San Antonio, TX 78227, USA.
³⁵ Department of Human Immunology, Sidra Medicine, Doha, Qatar; College of Health and Life Sciences, Hamad Bin Khalifa University, Doha, Qatar; Institute of Translational Immunology, Brandenburg Medical School, Brandenburg 14770, Germany.
³⁶ Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, Paris 75015, France; Paris Cité University, Imagine Institute, Paris 75015, France; St Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University, New York, NY 10065, USA.
³⁷ Division of Pulmonary and Sleep Medicine, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
³⁸ Pediatric Pulmonary Medicine, Children's Hospital Colorado, Aurora, CO 80045, USA.
³⁹ Dr. Shahrooei Laboratory, 22 Bahman St., Ashrafi Esfahani Blvd, Tehran, Iran; Clinical and Diagnostic Immunology, KU Leuven, Leuven 3000, Belgium.
⁴⁰ Research Center for Immunodeficiencies, Tehran University of Medical Sciences, Tehran, Iran; Network of Immunity to Infection, Malignancy and Autoimmunity (NIIMA), Universal Scientific Education and Research Network (USERN), Tehran, Iran; Department of Immunology, Tehran University of Medical Sciences, Tehran, Iran.
⁴¹ Department of Pediatrics, Tehran University of Medical Sciences, Tehran, Iran.
⁴² Division of Pediatric Pulmonology, Rainbow Babies and Children's Hospital, Cleveland, OH 44106, USA.
⁴³ Department of Microbiology and Immunology, McGill University, Montreal, QC H3A 2B4, Canada; Department of Biochemistry, McGill University, Montreal, QC H3A 2B4, Canada.
⁴⁴ Department of Medicine, McGill University, Montreal, QC H3G 0B1, Canada; Department of Human Genetics, McGill University, Montreal, QC H3G 0B1, Canada.
⁴⁵ Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
⁴⁶ Pediatric Oncology Hematology Unit, Clinical Investigation Center (CIC), Multi-theme-CIC (CICP), University Hospital Bordeaux, Bordeaux 33000, France.
⁴⁷ Translational Pulmonary Science Center, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA; Departments of Medicine and Pediatrics, University of Cincinnati, College of Medicine, Cincinnati, OH 45267, USA. Electronic address: [email protected].
⁴⁸ Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, Paris 75015, France; Paris Cité University, Imagine Institute, Paris 75015, France; St Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University, New York, NY 10065, USA; Howard Hughes Medical Institute, New York, NY 10065, USA; Department of Pediatrics, Necker Hospital for Sick Children, Paris 75015, France. Electronic address: [email protected].
⁴⁹ Laboratory of Human Genetics of Infectious Diseases, Necker Branch, INSERM U1163, Necker Hospital for Sick Children, Paris 75015, France; Paris Cité University, Imagine Institute, Paris 75015, France; St Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, Rockefeller University, New York, NY 10065, USA; Study Center for Primary Immunodeficiencies, Necker Hospital for Sick Children, AP-HP, Paris 75015, France. Electronic address: [email protected].

Abstract

We describe a human lung disease caused by autosomal recessive, complete deficiency of the monocyte chemokine receptor C-C motif chemokine receptor 2 (CCR2). Nine children from five independent kindreds have pulmonary alveolar proteinosis (PAP), progressive polycystic lung disease, and recurrent infections, including bacillus Calmette Guérin (BCG) disease. The CCR2 variants are homozygous in six patients and compound heterozygous in three, and all are loss-of-expression and loss-of-function. They abolish CCR2-agonist chemokine C-C motif ligand 2 (CCL-2)-stimulated Ca²⁺ signaling in and migration of monocytic cells. All patients have high blood CCL-2 levels, providing a diagnostic test for screening children with unexplained lung or mycobacterial disease. Blood myeloid and lymphoid subsets and interferon (IFN)-γ- and granulocyte-macrophage colony-stimulating factor (GM-CSF)-mediated immunity are unaffected. CCR2-deficient monocytes and alveolar macrophage-like cells have normal gene expression profiles and functions. By contrast, alveolar macrophage counts are about half. Human complete CCR2 deficiency is a genetic etiology of PAP, polycystic lung disease, and recurrent infections caused by impaired CCL2-dependent monocyte migration to the lungs and infected tissues.

Keywords: PAP; chemotaxis; cystic lung disease; macrophage; monocyte; recurrent infection.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Child
Humans
Lung / metabolism
Macrophages, Alveolar / metabolism
Pulmonary Alveolar Proteinosis* / diagnosis
Pulmonary Alveolar Proteinosis* / genetics
Receptors, CCR2* / deficiency
Receptors, CCR2* / genetics
Receptors, CCR2* / metabolism
Reinfection / metabolism

Substances

CCR2 protein, human
Receptors, CCR2

Abstract

Publication types

MeSH terms

Substances

Grants and funding