March 1, 2024

Rockefeller University » Newly discovered genetic malfunction causes rare lung disease

Instead of fighting bacterial infections or reducing sticky build-up in the lungs, these alveolar (pink) macrophages taken from a sick child’s lungs wander aimlessly, the result of a newly discovered genetic deficiency. (Anna-Lena Neehus)

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 especially important in the lungs, where they fight bacterial infections and eliminate excess surfactant, a layer rich in proteins and lipids that is essential for healthy function but can create a sticky buildup if left unchecked.

In a recent study, researchers at Rockefeller University and other institutions discovered a never-before-documented genetic disease that causes these cells to malfunction.

Researchers made the discovery by tracing an unexpected connection 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 recurring bacterial and viral infections that left them short of breath due to lungs often infested with cysts.

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

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

“It was surprising to discover 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 that are operating at a double loss.”

Chemical communication

More formally known as CC motif chemokine receptor 2, CCR2 sits 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 summon macrophages to the site of infection and to maintain the appropriate level of surfactant; too little can lead to lung tissue collapse and too much can result in narrowing of the airways.

It was among these immune cells that first author Neehus, from Casanova’s laboratory at the Institut Imagine in Paris, looked for evidence of genetic deficiencies that could alter their behavior. While combing through the genomic data of 15,000 patients in a database, she found two Algerian sisters, then ages 13 and 10, who had been diagnosed with severe PAP, a syndrome in which surfactant builds up and gas exchange occurs in the alveoli. is prevented.

About 90% of PAP cases are caused by antibodies that shut down 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 recently identified genetic mutation. Perhaps his absence was linked to his lung conditions, Neehus thought.

“It looked interesting and promising,” she recalls.

She soon found seven other children in the cohort who had the same CCR2 mutation and severe lung problems: two more pairs of siblings and a trio of siblings. They were from the United States and Iran.

Decreased capacity

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

Several important discoveries emerged. “We first discovered that these patients only have half the normal count of pulmonary alveolar macrophages, which explains the different types of lesions they present in the lung tissues,” says Casanova. With only half the crew, the skeleton cleaning unit could not keep up with the workload, causing tissue injuries.

The macrophages were 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 the cells circulating aimlessly, not knowing where to go. (See gif at top.) In contrast, live imaging of monocytes from a healthy control patient shows them migrating in the same direction, summoned by the teamwork of CCR2 and CCL-2.

A problematic legacy

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

This had dire effects for three of the children in the study, who developed bacterial infections after being vaccinated with a live attenuated sub-strain of Mycobacterium bovis, a tuberculosis agent. Their immune systems were unable to gather a legion of macrophages at the shoulder vaccination site, causing tissue destruction or hard nodules that had to be surgically removed, or lymph node infections. (All children were effectively treated with antibiotics.)

The children inherited their parents’ disabilities – and yet the parents were healthy. “Each parent carries one copy of the disease gene, and both parents gave the affected copy to their children,” says Neehus. “Parents are not affected because they each have just one copy, while children have two.”

Several children were the result of consanguineous marriages, in which the parents are related. The offspring of such pairs have a higher risk of inheriting the mutation that causes CCR2 to disappear.

The diagnostic test

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

In future research, Casanova and his team will explore their genome database for patients with genetic mutations in CCL-2 and not its receptor, CCR2, to understand how such errors can influence the development of the disease.

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

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