Low IgE and absence of sensitization in non-T2 asthma: a transcriptomic and cytokine study.

Background: Asthma exhibits heterogeneity, including type 2 (T2-high) and non-T2 phenotypes. This study aimed to elucidate the inflammatory mechanisms that drive non-type 2 asthma, a subtype characterized by low immunoglobulin E levels and negative allergic sensitization. This context considers the complex processes of allergic sensitization. Methods: We performed gene expression analysis in non-T2 (n = 11) versus T2-high (n = 17) pediatric patients using public datasets GSE145505 for comparison (non-atopic and high-atopic datasets). We applied Ingenuity Pathway Analysis (IPA) to identify canonical pathways. We used the Database for Annotation, Visualization, and Integrated Discovery (DAVID) for functional annotation. We examined the Reactome pathway activities, focusing on differential genes related to high-affinity immunoglobulin E receptor (FcϵRI) signaling and B-cell receptor (BCR) signaling. We conducted Weighted Gene Co-expression Network Analysis (WGCNA) for a specific gene module. We also quantified the spontaneous secretion of 12 serum cytokines in an independent pediatric (non-T2, n = 50; T2-high, n = 142) and adult (non-T2, n = 111; T2-high, n = 103) asthma cohort, and we performed logistic regression to assess their associations with non-T2 asthma. Results: IPA Core Analysis predicted the inhibition of key canonical pathways in non-type 2 asthma, notably including FcϵRI signaling and BCR signaling, with the associated downregulation of calcium signaling. Gene Set Enrichment Analysis (GSEA) confirmed the significant downregulation of these and other key Reactome pathways in non-type 2 asthma, such as those related to complement activation and Fc gamma receptor-dependent phagocytosis, indicating broad suppression of pathways crucial for allergic responses. Congruently, the serum levels of interleukin-4 (IL-4) and interleukin-9 (IL-9), cytokines vital for type 2 responses, were reduced, while interleukin-2 (IL-2) levels were positively associated with non-type 2 asthma. WGCNA identified a gene module positively correlated with total immunoglobulin E that was downregulated in non-type 2 asthma; this module included interleukin-4 messenger RNA and genes like Conclusion: Non-type 2 asthma represents a distinct inflammatory endotype characterized by impaired type 2 helper cell differentiation, inhibited B-cell activation and immunoglobulin E class switching, and possibly skewed immunoglobulin variable gene usage linked to altered antibody specificity. These findings suggest a multi-faceted mechanism involving broad inhibition of key sensitization and immunoglobulin E production pathways, explaining the low serum immunoglobulin E levels and the absence of allergic sensitization in non-type 2 asthma.