Identification of a new genetic disease responsible for pulmonary alveolar proteinosis and mycobacterial infections

In a study published in the journal Cell, the Human Genetics of Infectious Diseases research team from Université Paris Cité, Inserm and AP-HP, led by Prof Jean-Laurent Casanova and Dr Laurent Abel at Institut Imagine, has identified mutations in the CCR2 gene in nine children with pulmonary alveolar proteinosis (PAP) and mycobacterial infections. In addition to their essential role in controlling these infections, the identification of these mutations has also highlighted the crucial importance of the transition from monocytes to macrophages in patients with PAP.

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Pulmonary alveolar proteinosis (PAP) is a rare disease characterised by the accumulation of surfactant, a fat- and protein-rich substance derived from the pulmonary alveoli that lines the inside of the lungs. In patients diagnosed with PAP, the elimination of this surfactant is severely disrupted, leading to poor gas exchange. Progressive breathlessness, coughing and chronic sputum production are very frequently observed in these patients.

As part of her thesis project in the Human Genetics of Infectious Diseases research laboratory, Anna-Lena Neehus analysed the genetic data of nine children suffering from PAP (a disease that begins in childhood) and infections, particularly by mycobacteria. This work led to the identification of rare pathogenic mutations in the CCR2 gene in these nine patients. This work was carried out under the supervision of Prof Bruce Trapnell, Prof Jean-Laurent Casanova* and Dr Jacinta Bustamante**.

Generally speaking, the number of monocytes, one of the populations of 'white blood cells', increases in the event of infection, inflammation, allergy or bone marrow dysfunction. The CCR2 protein, encoded by the gene of the same name, transmits the signals essential for the migration of monocytes from the blood to tissues, including the lung. During this migration, the monocytes become macrophages, cells capable of ingesting and destroying pathogens and cellular 'waste', such as surfactant.

In children with a defect in the CCR2 gene, the number of macrophages detected in the lungs (and even in the product obtained after washing the lungs, BAL) is half that observed in healthy children. The production of monocytes by the bone marrow is not altered, and the number of monocytes in the peripheral blood remains normal. The triggering of PAP is therefore dependent on the migration of monocytes to the tissues. The cytokine CCL2, a protein that binds to CCR2, was elevated in serum and BAL in all nine patients. The assay of this biomarker on a simple blood sample may be a new tool for screening for CCR2 deficiency and searching for mutations in this gene, enabling a more rapid diagnosis.

Paediatric diffuse lung diseases are heterogeneous, with no specific diagnosis or therapy; they are classified on the basis of clinical, radiographic and pathological manifestations. This work has enabled us to identify a new genetic disease that predisposes children with hereditary PAP to infections: CCR2 deficiency. These results also pave the way for therapeutic possibilities: by bone marrow transplantation, it is possible to correct the CCR2 deficiency in patients, thereby restoring the migration of monocytes to the lungs and lymph nodes in particular.


Reference : Human inherited CCR2 deficiency underlies progressive polycystic lung disease 

doi: 10.1016/j.cell.2023.11.036


Corresponding authors :

*Pr Jean-Laurent Casanova : PU-PH, Université Paris Cité et Université Rockefeller, Institut Imagine, Hôpital Necker Enfants Malades, AP-HP, co-fondateur du Laboratoire de Génétique Humaine des Maladies Infectieuses

** Dr Jacinta Bustamante : MCU-PH, team leader-Institut Imagine, Centre d’Etudes de Déficits Immunitaires, DMU BioPhyGen, Hôpital Necker Enfants Malades, AP-HP.Centre-Université Paris Cité


Press release available on the AP-HP website