Anna-Lena Neehus of the Imagine Institute at Paris Cité University was searching through genomic data from over 15,000 patients. She wanted to understand how and whether genetic deficiencies contributed to altered macrophage behavior. Macrophages help clear excess surfactant from the lung and fight infections. If the lung has too much surfactant, the airways in the lung become too narrow. But if you have too little surfactant, lung tissue can collapse.

Her search brought her to data from two sisters, ages 10 and 13. The sisters, who hailed from Algeria, were diagnosed with severe pulmonary arterial proteinosis (PAP), a rare lung disease that leads to clogged air ducts in the lungs. At first, Neehus didn’t realize that she had stumbled upon a scientific discovery. Then she noticed the genetic alterations. 

Unlike many people with PAP, the sisters had no PAP autoantibodies in the blood. However, they did have CCR2 gene mutations. This began Neehus’ journey and research into a never-before-documented genetic disorder called CCR2 deficiency, which catalyzed a stronger understanding of how this deficiency contributes to the development of PAP and other lung diseases. 

Identifying CCR2 Deficiency

Jean-Laurent Casanova shares in an article for The Rockefeller University that Neehus then dug further into the database and discovered seven other children with CCR2 gene mutations. These children also had lung diseases including PAP, progressive polycystic lung disease, and recurrent and severe infections such as bacillus Calmette Guérin disease. 

In a study published in Cell, Neehus, alongside other researchers, began exploring the relationship between CCR2 mutations and lung disease. Findings from the study show that:

• The CCR2 mutations were inherited in an autosomal recessive pattern. This means that each affected child inherited one deficient gene from each parent.
• The research team found that many of the children with CCR2 deficiency came from consanguineous marriages, or marriages in which the parents are related to one another.
• CCR2 mutations led to a deficiency of C-C chemokine receptor type 2 (CCR2). Normally, CCR2 helps macrophages in the lungs work correctly. 
• While people with CCR2 deficiency have normal macrophages, they only have 50% of the macrophages that healthy individuals do. 
• CCR2 normally responds to a chemical ligand called CCL-2. CCR2 and CCL-2 work together. The CCR2 mutations mean that CCR2 doesn’t signal correctly. The macrophages don’t know where to go or where to respond to, so they just move around randomly and function poorly. People also have too much CCL-2. 
• Additionally, the macrophages can’t figure out where to go to fight infections. So people with CCR2 deficiency have a higher risk of mycobacterial infections. Though these can be treated, these infections can also be dangerous or cause long-term damage. 

Moving forward, the researchers hope to launch more research into CCR2 deficiency—as well as look into potential CCL-2 mutations to see if there is any overlap. Knowing that CCR2 deficiency is also characterized by too much CCL-2 means that CCL-2 can be a diagnostic biomarker.