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 Martín-Fernández, 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 Bégueret, 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, Raphaël Carapito, Mohsen Mazloomrezaei, Hassan Rokni‐Zadeh, Majid Changi‐Ashtiani, Chantal Brouzes, Pablo Vargas, A. Borghesi, Nico Lachmann, Seiamak Bahram, Bruno Crestani, Michaël Fayon, François Galodé, Susanta Pahari, Larry S. Schlesinger, Nico Marr, Dusan Bogunovic, Stéphanie Boisson‐Dupuis, Vivien Béziat, Laurent Abel, Raphaël 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, B.C. Trapnell, Jean-Laurent Casanova, Jacinta Bustamante
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 Ca 2+ 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.