Newly Discovered Genetic Malfunction Causes Rare Lung Disease

In a recent study, researchers from Rockefeller University and other institutions discovered a never-before-documented genetic disease that causes macrophage dysfunction.

The macrophage is one of the most important inhabitants of the body. Meaning “big eater” in Greek, this immune cell consumes and digests problematic elements from microbes and cancer cells to dust and debris. Macrophages are particularly important in the lungs, where they fight bacterial infections and rid the lungs of excess surfactant, a protein- and lipid-rich coating that is essential for proper function but can create sticky buildup if left untreated. is not controlled.

In their study, the researchers made their discovery by establishing an unexpected link between a select group of sick children. Throughout their lives, these nine children battled serious illnesses such as pulmonary alveolar proteinosis (PAP), progressive polycystic lung disease, and recurrent bacterial and viral infections that left them gasping for air due to often compromised lungs. affected by cysts.

But as the genomic data revealed, the children shared another characteristic: the absence of a chemical receptor thought to activate alveolar macrophages. This is the first time that this missing receptor, called CCR2, has been associated with a disease. The researchers, including Jean-Laurent Casanova of Rockefeller and Anna-Lena Neehus of the Imagine Institute, recently published their results in Cell.

The study also found that children are missing half of their alveolar macrophages, located in the air sacs of the lungs.

“It was surprising to find that CCR2 is so essential for the proper functioning of alveolar macrophages,” says Casanova. “When it comes to lung defense and cleansing, people who don’t have it suffer a double loss.”

Chemical communication

More formally known as CC motif chemokine receptor 2, CCR2 is found on the surface of alveolar macrophages, a type of monocyte (or white blood cell). It responds to the presence of a chemical ligand, or binding molecule, known as CCL-2, which is also expressed by monocytes.

The receptor and ligand work together to call macrophages to the site of an infection and to maintain the appropriate level of surfactant; too little can cause lung tissue to collapse, and too much can lead to narrowing of the airways.

It was among these immune cells that first author Neehus, from Casanova’s lab at the Imagine Institute in Paris, was looking for evidence of genetic deficiencies that could alter their behavior. Looking through the genomic data of 15,000 patients in a database, she found two Algerian sisters, then aged 13 and 10, who had been diagnosed with severe PAP, a syndrome in which surfactant accumulates and gas exchanges which take place in the alveoli. is hindered.

About 90% of PAP cases are caused by antibodies that paralyze a protein that stimulates the growth of infection-fighting white blood cells. The girls, however, did not have PAP autoantibodies. Instead, they did not have CCR2, a newly identified genetic mutation. Perhaps his absence was related to their lung problems, Neehus thought.

“It looked interesting and promising,” she recalls.

She quickly found seven other children in the cohort who had the same CCR2 mutation and serious lung problems: two other sibling pairs and a sibling trio. They came from the United States and Iran.

Reduced capacity

To explore the impact the variant might have on children, researchers analyzed the children’s clinical histories, lung tissue samples and genetic data.

Several key findings emerged. “We first discovered that these patients had only half the normal number of pulmonary alveolar macrophages, which explains the different types of lesions they have in the lung tissue,” Casanova explains. With only half a crew, the reduced cleaning unit was unable to keep up with its workload, leading to tissue damage.

The macrophages were otherwise normal, as were the children’s other immune cells.

Without CCR2 signaling, monocytes have no idea where they are needed. In the study, a live imaging analysis of monocytes from the lungs of a 10-year-old girl with CCR2 deficiency showed that the cells were moving aimlessly, without knowing where to go. In contrast, live imaging of monocytes from a healthy control patient shows them migrating in the same direction, driven by the teamwork of CCR2 and CCL-2.

A troubled legacy

This lack of direction also makes people with CCR2 deficiency more susceptible to mycobacterial infections, because macrophages cannot find their way to the tissue clumps where mycobacteria take hold and thus digest the invaders.

This had disastrous effects on three of the children in the study, who developed bacterial infections after being vaccinated with a live attenuated substrain of Mycobacterium bovis, an agent of tuberculosis. Their immune systems failed to gather a legion of macrophages at the shoulder vaccination site, causing tissue destruction or hard nodes that had to be surgically removed, or infections of the lymph nodes. (All children were treated effectively with antibiotics.)

Children inherited this deficiency from their parents, and yet their parents were healthy. “Each parent carries a pathological copy of the gene, and both parents gave the affected copy to their children,” Neehus explains. “Parents are not concerned because they each only have one copy, while children have two.”

Many children are the product of consanguineous marriages, in which the parents are related. The offspring of these couples are at higher risk of inheriting the mutation that causes CCR2 to disappear.

The diagnostic examination

The absence of CCR2 leads to another effect: an excess of the chemokine CCL-2. Deprived of its receptor, CCL-2 accumulates in blood and plasma. This result may provide a diagnostic test for screening patients with unexplained pulmonary or mycobacterial disease; Detecting high levels of CCL-2 could provide some clarity on the genetic underpinnings of the disease.

In future research, Casanova and his team will leverage their database of genomes from patients with genetic mutations in CCL-2 rather than its receptor, CCR2, to understand how such errors can influence disease development.

Neehus says: “With more follow-up studies, we could potentially cure patients using gene therapy to correct the mutation. »