ORIGINAL RESEARCH article
Front. Immunol.
Sec. B Cell Biology
Low IgE and Absence of Sensitization in Non-T2 Asthma: A Transcriptomic and Cytokine Study
Provisionally accepted
- National Taiwan University Hospital, Taipei, Taiwan
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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). Ingenuity Pathway Analysis (IPA) was applied to identify canonical pathways. Database for Annotation, Visualization, and Integrated Discovery (DAVID) was used for functional annotation. We examined reactome pathways activities, focusing on differential genes related to FcεRI signaling and BCR signaling. Weighted Gene Co-expression Network Analysis (WGCNA) were conducted for specific gene module. We also quantified 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 logistic regression was performed to assess their associations with non-T2 asthma. 3 Results: Ingenuity Pathway Analysis (IPA) core analysis predicted the inhibition of key canonical pathways in non-Type 2 asthma, notably including high-affinity immunoglobulin E receptor (FcεRI) signaling and B-cell receptor (BCR) signaling, with 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, 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 positively associated with non-Type 2 asthma. Weighted Gene Co-expression Network Analysis (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 SLC7A8 and SIGLEC8, suggesting impaired Type 2 innate lymphoid cell function. Furthermore, transcripts for immunoglobulin heavy variable (IGHV), kappa variable (IGKV), and lambda variable (IGLV) gene segments were markedly downregulated. Functional annotation (DAVID) of these segments revealed enrichment for terms related to immunoglobulin production and antigen binding; their reduced function
Keywords: Asthma, Cytokines, Immunoglobulin E (IgE), Interleukin-4, RNA-Seq, sensitization, type 2 inflammation
Received: 24 Sep 2025; Accepted: 17 Dec 2025.
Copyright: © 2025 LEE, Lin, Wang, Yu, Hu, Yang and Chiang. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: JYH-HONG LEE
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