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One of the most important cells in the body is the macrophage. This immune cell, called “big eater” in Greek, eats and breaks down dangerous substances such as dust, debris, bacteria and cancer cells. Macrophages play a particularly important role in the lungs, where they fight bacterial infections and remove excess surfactant, a lipid- and protein-rich coating that is essential for lung health but can lead to sticky substance deposits if left unchecked. It is possible
Researchers at Rockefeller University and other institutions have discovered a hereditary disease that causes faulty cell function that was previously unknown.
Researchers were able to make their breakthrough by looking at an unexpected connection among a particular subgroup of sick children. These nine young men had fought lifelong battles with life-threatening conditions such as progressive polycystic lung disease, pulmonary alveolar proteinosis (PAP), and recurring viral and bacterial infections that left their lungs often filled with cysts and leaving them gasping for air. Was.
But as genomic data revealed, the children shared another characteristic: the absence of a chemical receptor that calls alveolar macrophages into action. This is the first time that this missing receptor, called CCR2, has been linked to disease. The researchers, including Jean-Laurent Casanova of Rockefeller and Anna-Lena Niehus of the Institute Imagine, recently published their results in Cell.
The study also found that the children were missing half of their alveolar macrophages, which are located in the air sacs of the lungs.
“It was surprising to find that CCR2 is essential for alveolar macrophages to function properly,” Casanova said. “When it comes to lung protection and cleanliness, without it people are operating at a double disadvantage.”
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 recruit macrophages to the site of infection and maintain appropriate levels of surfactant; Too little can destroy lung tissue and too much can narrow the airways.
It was among these immune cells that first author Niehus, from Casanova’s laboratory at the Institut Imagin in Paris, looked for evidence of genetic deficiencies that could alter their behavior. While examining genomic data on 15,000 patients in a database, they found two Algerian sisters, ages 13 and 10, who were diagnosed with severe PAP, a syndrome in which surfactant builds up and impairs gas exchange in the alveoli. . Is interrupted.
About 90 percent of PAP cases are caused by antibodies that inactivate a protein that stimulates the growth of infection-fighting white blood cells. However, the girls did not have PAP autoantibodies. Instead, they had no CCR2 – a newly identified genetic mutation. Perhaps its deficiency was related to his pulmonary conditions, Niehus thought. “It looked interesting and promising,” she recalled.
She soon found seven other children in the group who had the same CCR2 mutation and severe lung condition: two more pairs of brothers, and a trio of brothers-sisters. They were from the United States and Iran.
To explore this type of impact on children, researchers analyzed the children’s clinical histories, lung tissue samples and genetic data.
Several major findings emerged. “First we found that these patients have only half the normal number of pulmonary alveolar macrophages, which explains the variety of lesions in their pulmonary tissues,” says Casanova. With only half the crew, the reduced cleaning unit could not handle its workload, causing tissue damage.
Macrophages were otherwise normal, as were the children’s other immune cells. Without CCR2 signaling, monocytes do not know where they are needed. In the study, live-imaging analysis of monocytes from the lungs of a 10-year-old girl with CCR2 deficiency showed that the cells were wandering around aimlessly, unsure 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, called upon by the teamwork of CCR2 and CCL-2.
This misdirection makes people lacking CCR2 more susceptible to mycobacterial infections, as macrophages are unable to find their way to tissue clusters where mycobacteria reside, and thus digest the invaders.
This had a serious impact on three children included 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 assemble large numbers of macrophages at the vaccination site in the shoulder, leading to tissue destruction or hardened nodes that had to be surgically removed, or lymph node infection. (All the children were treated effectively with antibiotics.)
The children inherited this deficiency from their parents – and yet their parents were healthy. “Each parent has one disease copy of the gene, and both parents passed the affected copy to their children,” Niehus said. “The parents are not affected because each of them only has one copy, while the children have two.”
Many children were the result of consanguineous marriages, in which the parents are related. The offspring of such couples have a higher risk of inheriting the mutation that causes CCR2 to disappear.
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