Childhood asthma development and environment-mediated immunological modulation: the impact of NF-κB signaling on asthma control and clinical progression

Basse, Sarah Franziska (2026): Childhood asthma development and environment-mediated immunological modulation: the impact of NF-κB signaling on asthma control and clinical progression. Dissertation, LMU München: Faculty of Medicine

Abstract

Asthma control in children is routinely assessed based on persistent symptoms, yet some patients remain insufficiently controlled despite guideline-based treatment. This study aimed to investigate whether children with uncontrolled asthma differ in the regulation of the TLR4-dependent NF-κB signaling pathway compared to well-controlled asthmatic and healthy children, with particular focus on TNFAIP3, a negative regulator implicated in asthma protection. Furthermore, the study evaluated whether stimulation of PBMCs with LPS and farm dust modulates NF-κB–related gene expression in these groups. In addition, changes in selected NF-κB pathway genes were analyzed over a three-year period in relation to asthma control status. A total of 69 children in the TRILATERAL cohort and 63 children in the CLARA/CLAUS cohort aged 4 to 17 years were included. 21 of the study participants from the CLARA/CLAUS cohort were recruited for a three-year follow-up. The PBMCs were stimulated in vitro with antiCD3/28, LPS, LpA or farm dust extracts from Germany, Finland and China. Expression of the NF-κB signaling-related genes MALT1, MYD88, NFKBIA, RIPK1, TAB2, TICAM1, TLR4, TNFAIP3, TNIP1, TRAF6, the micro-RNAs MIR19A and MIR221 was quantified by using real-time qPCR. Uncontrolled asthmatics showed a significantly lower expression of the anti-inflammatory gene TNFAIP3 compared to healthy controls after stimulation with Chinese dust and LPS, as well as reduced expression of NFKBIA after Chinese dust stimulation compared to controlled asthmatics. These findings suggest an attenuated anti-inflammatory regulation in response to certain stimuli in uncontrolled asthmatics. Well-controlled asthmatics showed higher expression levels of the pro-inflammatory genes RIPK1, TLR4 and TRAF6 after stimulation with anti-CD3/28 antibodies or farm dust compared to healthy children, however not compared to uncontrolled asthmatics. No significant differences in gene expression were observed between the groups under unstimulated conditions. Stimulation with farm dust and LPS led to downregulation of pro-inflammatory TLR4 and upregulation of anti-inflammatory TNIP1 and NFKBIA across all groups. The stronger TLR4 downregulation in healthy children compared to uncontrolled asthmatics after anti-CD3/28 and Chinese farm dust stimulation suggests a more prominent anti-inflammatory response in healthy subjects. Over the three-year follow-up, children who achieved asthma control showed a significant decrease in expression of the pro-inflammatory gene MYD88 after stimulation. In contrast, persistently uncontrolled asthmatics exhibited higher MYD88 expression after LpA stimulation and a trend towards a higher expression following anti-CD3/28 stimulation at the three-year follow-up, indicating sustained pro-inflammatory activity in this group. Our data suggest that there are no general differences on mRNA expression of the NF-κB pathway between uncontrolled and controlled asthmatics compared to healthy children under unstimulated conditions. However, upon dust stimulation there were differences in various genes of the NF-κB pathway that point towards a weaker anti-inflammatory effect of stimulation with LPS and farm dusts from uncontrolled asthmatic versus healthy children. Increased expression of the pro-inflammatory gene MYD88 may be further evaluated as a potential biomarker for asthma symptom persistence despite treatment and could possibly be included in more specific therapy guidance of asthma in children.

• Item Type: Theses (Dissertation, LMU Munich)
• Subjects: 600 Technology, Medicine; 600 Technology, Medicine > 610 Medical sciences and medicine
• Faculties: Faculty of Medicine
• Language: English
• Date of oral examination: 31. March 2026
• 1. Referee: Schaub, Bianca
• Signature of the printed copy: 0700/UMD 22840