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Scientists have reached a milestone in the research of childhood asthma. For the first time, they have clarified how a certain genetic defect in children initially leads to frequent infections and later to asthma. The study, published in the American Journal of Respiratory and Critical Care Medicine, offers a novel approach to therapeutic interventions. It is the result of a close collaboration between Helmholtz Munich, the Technical University of Munich (TUM), the Center of Allergy and Environment (ZAUM), and the German Center for Lung Research (DZL).
Searching for the Causal Reason for Childhood Asthma
In their first years of life, one in three children develop an early form of asthma. Among those, 80 percent have a genetic defect on chromosome 17. These children have frequent viral-induced wheeze attacks and progress later to asthma. The mechanisms underlying the genetic defect were unknown, which is why pediatricians could only treat the symptoms, but not the cause. “We have now discovered why the genetic defect makes children more prone to viral infections which is a strong risk of progression into asthma,” says Dr. Constanze Jakwerth, first author of the study.
Screening Among Children Reveals Increased Protein Expression
Previous epidemiological studies have already suggested that the genetic defect was associated with viral infections. Therefore, the researchers investigated the nasal mucosa tissue of 261 children with wheeze using brushes to extract some cells from the nasal cavity. This method is relatively non-invasive but allows the assessment of the entire set of gene transcripts in these nasal cells (transcriptome). Thereby, it was possible to identify changes and patterns (“nasotypes”) in the gene expression that are very different in children with and without the genetic defect.
In more detail: The researchers found that the genetic defect is causing an increased expression of the protein GSDMB. This protein forms pores and is crucial for immune responses. They revealed that the genetically enhanced expression of GSDMB is in turn causing a disturbed interferon-response. Interferons are known to be critical for the cellular response to viral infections. There are three classes of interferons. The researchers observed that nasal cells of children with the genetic defect express more type 2 interferons but fewer type 1 and 3 interferons. The latter are, however, important for the viral defense. This is why the genetic defect ultimately makes children more prone to viral infections and consequently increases the risk of asthma.
Fewer Infections Might Reduce the Risk of Asthma
“We now know that the genetic defect on chromosome 17 leads to a specific gene expression pattern that we can influence or even correct. We aim to repair the defense defect of the children’s airways. We are working on novel drugs, inhalation sprays, that support the defense against the virus by stimulating the epithelial barrier for a more appropriate response,” says Prof. Carsten Schmidt-Weber who led the study at Helmholtz Munich and TUM.
“Early viral infections are likely to change the children’s immune system and break the tolerance to normally harmless allergens that in turn will promote asthma development. Thus, if the infections can be controlled more efficiently with novel drugs targeting the genetic defect, we hope that fewer children will develop asthma," says Prof. Erika von Mutius, co-lead author of the study.
About the scientists
Prof. Dr. Carsten Schmidt-Weber, Director of the Institute of Allergy Research at Helmholtz Munich, Chair of Molecular Allergology and Environment at TUM, and Chair of the Center of Allergy and Environment (ZAUM)
Prof. Dr. med. Erika von Mutius, Director of the Institute of Asthma and Allergy Prevention and Head of the Environmental Health Center at Helmholtz Munich, Head of the Department of Asthma and Allergy at the Dr. von Hauner Children’s Hospital
Dr. Constanze Jakwerth, Deputy Group Leader of the Airway Immunology Research Group at the Institute of Allergy Research at Helmholtz Munich
About ZAUM
The Center of Allergy and Environment (ZAUM) is conducting basic to applied research to discover the origins of allergies to identify novel preventive strategies as well as targets for innovative therapies. Research at ZAUM is essentially financed through third parties, whereas the basic funds come in equal parts from Helmholtz Munich and TUM. It is a member of the German Center for Lung Research (DZL), where it plays a critical role in supporting the translation between basic and clinical research efforts. https://www.zaum-online.de/
About Helmholtz Munich
Helmholtz Munich is a leading biomedical research center. Its mission is to develop breakthrough solutions for better health in a rapidly changing world. Interdisciplinary research teams focus on environmentally triggered diseases, especially the therapy and prevention of diabetes, obesity, allergies, and chronic lung diseases. With the power of artificial intelligence and bioengineering, researchers accelerate the translation to patients. Helmholtz Munich has more than 2,500 employees and is headquartered in Munich/Neuherberg. It is a member of the Helmholtz Association, with more than 43,000 employees and 18 research centers the largest scientific organization in Germany. More about Helmholtz Munich (Helmholtz Zentrum München Deutsches Forschungszentrum für Gesundheit und Umwelt GmbH): www.helmholtz-munich.de/en
Prof. Dr. Carsten Schmidt-Weber
Email: carsten.schmidtweber@helmholtz-munich.de
Jakwerth et al., 2024: 17q21 Variants Disturb Mucosal Host Defense in Childhood Asthma. American Journal of Respiratory and Critical Care Medicine. DOI: 10.1164/rccm.202305-0934OC
https://www.atsjournals.org/doi/abs/10.1164/rccm.202305-0934OC
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