Pseudomonas aeruginosa exotoxin A as a novel allergen induced Non-TH2 inflammation in a murine model of steroid-insensitive asthma
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
Huancheng Xie
, The Second Affiliated Hospital, Guangdong Provincial Key Laboratory of Allergy & Immunology, The State Key Laboratory of Respiratory Disease, Guangzhou Medical University, 250 Changgang Road East, Guangzhou, 510260, China
Linmei Li
, The Second Affiliated Hospital, Guangdong Provincial Key Laboratory of Allergy & Immunology, The State Key Laboratory of Respiratory Disease, Guangzhou Medical University, 250 Changgang Road East, Guangzhou, 510260, China
Yuhe Guo
, The Second Affiliated Hospital, Guangdong Provincial Key Laboratory of Allergy & Immunology, The State Key Laboratory of Respiratory Disease, Guangzhou Medical University, 250 Changgang Road East, Guangzhou, 510260, China
Linghui Zhou
, The Second Affiliated Hospital, Guangdong Provincial Key Laboratory of Allergy & Immunology, The State Key Laboratory of Respiratory Disease, Guangzhou Medical University, 250 Changgang Road East, Guangzhou, 510260, China
Linyi Ma
, The Second Affiliated Hospital, Guangdong Provincial Key Laboratory of Allergy & Immunology, The State Key Laboratory of Respiratory Disease, Guangzhou Medical University, 250 Changgang Road East, Guangzhou, 510260, China
Andong He
, The Second Affiliated Hospital, Guangdong Provincial Key Laboratory of Allergy & Immunology, The State Key Laboratory of Respiratory Disease, Guangzhou Medical University, 250 Changgang Road East, Guangzhou, 510260, China
He Lai
, The Second Affiliated Hospital, Guangdong Provincial Key Laboratory of Allergy & Immunology, The State Key Laboratory of Respiratory Disease, Guangzhou Medical University, 250 Changgang Road East, Guangzhou, 510260, China
Ying He
, The Second Affiliated Hospital, Guangdong Provincial Key Laboratory of Allergy & Immunology, The State Key Laboratory of Respiratory Disease, Guangzhou Medical University, 250 Changgang Road East, Guangzhou, 510260, China
Yongping Liu
, The Second Affiliated Hospital, Guangdong Provincial Key Laboratory of Allergy & Immunology, The State Key Laboratory of Respiratory Disease, Guangzhou Medical University, 250 Changgang Road East, Guangzhou, 510260, China
Huifang Chen
, The Second Affiliated Hospital, Guangdong Provincial Key Laboratory of Allergy & Immunology, The State Key Laboratory of Respiratory Disease, Guangzhou Medical University, 250 Changgang Road East, Guangzhou, 510260, China
Liping Luo
, The Second Affiliated Hospital, Guangdong Provincial Key Laboratory of Allergy & Immunology, The State Key Laboratory of Respiratory Disease, Guangzhou Medical University, 250 Changgang Road East, Guangzhou, 510260, China
Yuyi Huang
, The Second Affiliated Hospital, Guangdong Provincial Key Laboratory of Allergy & Immunology, The State Key Laboratory of Respiratory Disease, Guangzhou Medical University, 250 Changgang Road East, Guangzhou, 510260, China
Xiangyin Sha
, The Second Affiliated Hospital, Guangdong Provincial Key Laboratory of Allergy & Immunology, The State Key Laboratory of Respiratory Disease, Guangzhou Medical University, 250 Changgang Road East, Guangzhou, 510260, China
Huanping Zhang
, Shanxi Bethune Hospital, Shanxi Academy of Medical Sciences, Tongji Shanxi Hospital, Third Hospital of Shanxi Medical University, Taiyuan, 030032, China
Jie Yan
, The Second Affiliated Hospital, Guangdong Provincial Key Laboratory of Allergy & Immunology, The State Key Laboratory of Respiratory Disease, Guangzhou Medical University, 250 Changgang Road East, Guangzhou, 510260, China
Qingling Zhang
, Guangdong Provincial Key Laboratory of Allergy & Immunology, Guangzhou Institute of Respiratory Health, National Clinical Research Center for Respiratory Disease, National Center for Respiratory Medicine, State Key Laboratory of Respiratory Diseases, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510120, China; Corresponding author.
Ailin Tao
, The Second Affiliated Hospital, Guangdong Provincial Key Laboratory of Allergy & Immunology, The State Key Laboratory of Respiratory Disease, Guangzhou Medical University, 250 Changgang Road East, Guangzhou, 510260, China; Corresponding author.
Background: Despite the immediate in vivo occurrence of anaphylactic and allergic reactions following treatment with Pseudomonas aeruginosa 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-TH2 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.
