Even with the advent of new treatments, cystic fibrosis frequently results in lasting lung damage. Collaborating with a global team, researchers at the Technical University of Munich (TUM) have found that the disease triggers changes in the immune system early in life, potentially even in newborns. These alterations contribute to recurring inflammation and are not influenced by medications that target the abnormal mucus production.
Cystic fibrosis arises from inherited genetic mutations that disrupt or completely stop the production of the CFTR protein, predominantly affecting the respiratory system. In this region, the mucus becomes thick and sticky, hindering the elimination of bacteria through coughing. This leads to a vicious cycle of infections and inflammation.
In recent years, the medical community has begun to use CFTR modulator therapies aimed at enhancing the function of the CFTR protein. These treatments help reduce mucus buildup and greatly enhance the quality of life for patients. Nevertheless, clinical research indicates that inflammation in the airways remains a prevalent issue, and lung function in older patients continues to deteriorate relentlessly.
Ongoing studies are focused on discovering additional mechanisms involved in cystic fibrosis. “We specifically examined how the immune system responds in cystic fibrosis prior to the onset of the infection-inflammation cycle,” stated Prof. Nikolai Klymiuk from TUM, a contributor to a recent study published in Science Translational Medicine.
Immature immune cells in pediatric blood samples
Researchers observed that blood samples from children diagnosed with cystic fibrosis, along with biological samples from pigs with the same genetic defect, contained immune cells that were not fully developed. This immaturity compromises their ability to effectively combat bacterial infections. Additionally, the lungs of cystic fibrosis-affected pigs displayed an increased quantity and significantly altered types of immune cells at birth. Given the close similarity between porcine and human immune systems, it is likely that these findings are relevant to human cystic fibrosis patients as well.
Could an emergency program be to blame?
The authors propose that the immune system alterations may be due to a form of “emergency program.” This program prompts the body to swiftly generate a large number of immune cells over an extended duration. One outcome is the production of immature immune cells, which could perpetuate the detrimental cycle of infections and inflammation in cystic fibrosis: although immune cells are present in the lungs, they lack effectiveness, resulting in lung damage without controlling long-term infections.
As immune cells typically produce very limited amounts of CFTR, the research team believes that the immune system’s response to cystic fibrosis is indirect. This insight may elucidate why new CFTR modulator therapies struggle to adequately address impaired immune reactions.
Changes not due to frequent infections
“We do not yet fully understand why immune cells in cystic fibrosis display such alterations,” remarks Nikolai Klymiuk, Professor of Cardiovascular Translation in Large Animal Models. “However, we can demonstrate that these modifications occur early in life and persist as individuals grow older.” Klymiuk notes that although modified immune cells were previously documented in blood samples of adults with cystic fibrosis, they were typically considered a result of chronic infections.
“To enable individuals with cystic fibrosis to live symptom-free lives, we likely need to address the condition from multiple angles,” Klymiuk asserts. “We hope our research will lead to a deeper understanding of the underlying causes of the faulty immune system and pave the way for future corrections.”
