Immune changes linked to CF lung issues begin early, study shows
Current treatments fail to protect lungs from damage
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Immune abnormalities linked to lung inflammation and damage in people with cystic fibrosis (CF) may begin early in life and persist despite treatment, a study in Australia suggested.
The study, led by researchers at the Murdoch Children’s Research Institute (MCRI) and the Peter MacCallum Cancer Centre, found widespread abnormalities in alveolar macrophages (immune cells that patrol the lungs) in preschool-age children with CF. While treatment with the CFTR modulator Kalydeco (ivacaftor) helped restore some macrophage functions, the researchers found that certain abnormalities persisted despite therapy.
“The study shows there’s still a long way to go to ensure people with cystic fibrosis can live unaffected by the disease,” Shivanthan Shanthikumar, associate professor at MCRI and a study author, said in an institute news story. “It also highlights the importance of studying lung disease in preschool children, who are often overlooked in research that focuses on adults.”
The study, “Single-cell profiling of BAL in preschool cystic fibrosis reveals macrophage dysregulation and ivacaftor-modified inflammatory programs in the early life lung,” was published in Mucosal Immunology.
CF is caused by mutations in a gene that provides instructions to make CFTR, a protein that regulates the movement of salt and water in and out of cells. Without enough working CFTR, thick, sticky mucus builds up in the lungs and other organs, driving CF symptoms.
Early immune changes
Trapped mucus promotes infection in the lungs and fuels chronic inflammation that gradually damages lung tissue. Such damage can begin during early childhood and may persist despite treatment with CFTR modulators, a class of medicines designed to boost the function of the faulty CFTR protein.
Yet “the earliest immune mechanisms that initiate and shape CF lung disease remain poorly understood,” the researchers wrote, adding that studying early life disease “offers a unique opportunity to capture immune dysregulation at a stage when interventions are most likely to alter disease trajectory.”
To investigate these early changes, the researchers analyzed 45 lung fluid samples collected from 28 children with CF, ages 5 months to 6 years, and eight age-matched children without the disease. Six children with CF contributed more than one sample.
Using single-cell RNA sequencing, a technique that examines gene activity in individual cells, the scientists profiled more than 190,000 cells and identified 43 distinct populations of immune and epithelial cells lining the airways. This allowed them to build a detailed cellular map of the developing lung.
The most common cells, accounting for nearly 89% of those analyzed, were alveolar macrophages, immune cells that patrol the lungs, clearing inhaled particles and bacteria and maintaining the balance of fatty substances needed for healthy lung function.
Compared with alveolar macrophages from healthy children, those from children with CF showed widespread abnormalities. Results showed altered activity of several genes involved in controlling inflammation, processing cholesterol (a fatty substance needed for normal cell structure and function), and tissue scarring, changes that contribute to the persistent inflammation and lung damage seen in CF.
Because the study used samples from preschool-age children with CF, the researchers could not determine exactly when macrophage dysfunction begins. However, they noted that similar abnormalities have been reported in alveolar macrophages in newborn pig models of CF, suggesting that macrophage dysfunction may begin very early in life.
These abnormalities were even more pronounced in children with bronchiectasis, a form of irreversible lung damage that can lead to lifelong breathing problems, indicating macrophage dysfunction may worsen as lung damage progresses.
Treatment with Kalydeco helped restore some macrophage functions and reduce harmful inflammatory signals in the lungs. By contrast, treatment with Orkambi (ivacaftor/lumacaftor) was not associated with detectable changes in the gene activity of macrophage, although the researchers noted that only a small number of children received that treatment.
“We discovered immune dysfunction in the lungs begins in the preschool years and persists despite current breakthrough therapies,” said Melanie R. Neeland, PhD, associate professor at MCRI and senior study author. “Although these therapies have been considered highly effective treatments, our findings in children suggest their impact on lung disease may not be as good as once predicted.”
The results suggest that “early intervention strategies that combine these medications with targeted anti-inflammatory therapies could help prevent lung damage,” Neeland said. “These findings provide a powerful new resource, highlighting a critical window for intervention.”
