Exotoxin A As a Novel Allergen Induced Non-T2 Inflammation in a Murine Model of Steroid-insensitive Asthma

Overview

Journal Heliyon

Specialty Social Sciences

Date 2024 Sep 24

PMID 39315215

Authors

Huancheng Xie

Linmei Li

Yuhe Guo

Linghui Zhou

Linyi Ma

Andong He

He Lai

Ying He

Yongping Liu

Huifang Chen

Liping Luo

Yuyi Huang

Xiangyin Sha

Huanping Zhang

Jie Yan

Qingling Zhang

Ailin Tao

Affiliations

Soon will be listed here.

Abstract

Background: Despite the immediate occurrence of anaphylactic and allergic reactions following treatment with exotoxin A (PEA)-based immunotoxins, the immunological role of PEA in asthma pathogenesis remains unclear.

Objective: This study investigated the allergenic potential of PEA and the specific type of asthma induced.

Methods: Recombinant PEA (rPEA) lacking domain Ia (to eliminate non-specific cytotoxicity) was expressed, purified, and employed to detect serum PEA-specific IgE levels in asthmatic patients. Competitive ELISA assays were used to assess rPEA's IgE binding capacity and allergenicity. Additionally, rPEA-challenged C57BL/6 mice were subjected to inflammatory endotyping and therapeutic assays to characterize the allergic nature of PEA.

Results: PEA-specific IgE was identified in 17 (14.2 %) of 120 asthma patients. The rPEA-sensitized and challenged mice had increased PEA-specific immunoglobulins (such as IgE, IgG1 and IgG2a) and developed asthma-like phenotypes with airway hyperresponsiveness, severe airway inflammation, and airway remodeling. Lungs from these mice displayed significant increases in neutrophils and IL-17A cells. Innate lymphoid cells (ILCs) produced type 2 cytokines (IL-4, IL-5, and IL-13), whereas Th cells did not. Nonetheless, airway inflammation, rather than hyperresponsiveness, was elicited in non-sensitized mice upon challenge with rPEA. Importantly, rPEA-induced asthmatic mice were unresponsive to dexamethasone treatment.

Conclusion: PEA is a novel allergen that sensitizes asthmatic patients. Furthermore, mice developed steroid-resistant asthma, characterized by an atypical cytokine profile associated with non-T2 inflammation, only after being sensitized and challenged with rPEA. These findings suggest a potentially significant role for PEA in asthma development, warranting consideration in clinical diagnosis and treatment strategies.

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