Interferon-swap explains asthma risk in children with genetic defect

Key takeaways:

• The expression of GSDMB was high in children with a 17q21 genetic variant.
• These children did not have sufficient type 1 and 3 interferons, which negatively impacts viral defense.

Discovery of higher GSDMB expression in children with a genetic defect linked to asthma explains why they commonly experience viral infections and face an elevated risk for asthma, according to study results.

Researchers of this study, published in American Journal of Respiratory and Critical Care Medicine, noted that the 17q21 locus is the strongest genetic risk factor for childhood asthma and makes individuals more susceptible to viral infections and viral-induced wheeze attacks.

“With this knowledge, interventions can be developed to support the epithelium of these children to raise the correct host defense against these viruses,” Carsten Schmidt-Weber, PhD, director of the Center for Allergy and Environmental research (ZAUM), Technical University and Helmholtz Munich, and member of the German Center of Lung Research (DZL), told Healio.

“We hope that early interventions in these early years of life may also help to prevent unfavorable asthma development of these children,” he continued.

In a genome-wide transcriptome analysis, Schmidt-Weber and colleagues evaluated nasal brush samples from 104 children with asthma (median age, 12.5 years; 67.3% boys), 79 children with preschool wheezing (median age, 4.29 years; 67.1% boys) and 78 healthy children (median age, 11.6 years; 41% boys) to find out what mechanisms are behind the 17q21 risk allele.

When analyzing the samples from children with the genetic defect vs. healthy children, researchers observed a higher expression of GSDMB, a protein important for immune responses, among those with the defect.

Further, having more of this protein was found to disturb interferons, which play a major role in cellular response to viral infections, according to a press release from Helmholtz Munich.

Of the three types of interferons, type 2 interferons were found more frequently than type 1 and 3 interferons in those with the 17q21 risk allele.

Researchers noted that this interferon-swap is significant in showing why these children have a higher susceptibility for viral infections and risk for asthma because type 1 and 3 interferons aid in viral defense. Lower expressions of these interferons mean less defense against viral infections.

“The findings are surprising as children carrying this risk allele are suffering initially from recurrent respiratory infections,” Schmidt-Weber said. “The genetic mutation, however, is shown to clearly trigger an immune response, but we observe that it is the ‘wrong’ response, which inadequately triggers an epithelial response that is inefficient in defense against these viruses.”

Looking toward the future, Schmidt-Weber and his team plan to use what they found in this study to develop drugs and sprays that restore the defense defect.

“Novel intervention will hopefully promote the epithelial response selectively while the use of broadly acting immunosuppressants can be avoided,” Schmidt-Weber said.

Reference:

• Asthma in children: Researchers envision novel drug to reduce the risk of the disease. https://www.helmholtz-munich.de/en/newsroom/news-all/artikel/asthma-in-children-researchers-envision-novel-drug-to-reduce-the-risk-of-the-disease. Published April 15, 2024. Accessed April 15, 2024.