Autoimmune Mechanisms and Extracellular Traps in Non-eosinophilic Asthma

Asthma is a chronic inflammatory disease of the airways, categorized into 2 major endotypes: T2-high (eosinophilic) and T2-low (non-eosinophilic). The former has been extensively studied in severe asthma classification.1 In typical T2-high asthma, type 2 T helper (Th2) cells play an important role in eosinophilic airway inflammation by secreting distinct type 2 cytokines, including interleukin (IL)-4, IL-5, and IL-13. Additionally, Group 2 innate lymphoid cells significantly contribute as another source of Th2 cytokines.2 Currently used biologic therapies target this Th2-mediated airway inflammation, observed in only half of asthma patients. The remaining half, characterized by the T2-low endotype, remains relatively underexplored.

Extracellular DNA traps are part of the innate immune response implicated in various infectious, allergic, and autoimmune diseases. These traps are formed by different leukocytes including neutrophils, eosinophils, monocytes, and mast cells.3 Neutrophil extracellular traps (NETs) are extracellular DNA filaments formed during neutrophil activation, contributing to inflammasome activation, IL-1β secretion from monocytes and airway epithelial cell (AEC) injury. High concentrations of extracellular DNA in sputum indicate a subset of severe asthma patients with NETs and markers of inflammasome activation in their airways.4 Human blood monocytes can also release extracellular traps (ETs) in response to several stimuli. These monocyte ETs resemble NETs in morphology and are dependent on oxidative burst rather than myeloperoxidase (MPO) activity, unlike neutrophils.5 Recent studies have suggested that autoimmune responses against AECs and immune cells may contribute to asthma pathogenesis. Localized autoantibodies may target structural or immune cells, leading to tissue damage and remodeling. Elevated levels of autoantibodies in the airways activate immune cells, induce degranulation, and promote ET formation, correlating with asthma severity and resistance to therapy.6, 7 Higher titers of immunoglobulin G (IgG) and polyclonal IgE antibodies against eosinophil peroxidase and/or anti-nuclear antibody have been observed in severe asthma patients compared to healthy controls.8 Previous studies have demonstrated associations between activated immune cells (eosinophils, neutrophils, macrophages) and ETs, as well as autoimmune mechanisms in adults with severe asthma.9 Levels of ETs from eosinophils and neutrophils are higher in patients with severe asthma compared to those non-severe asthma, contributing to AEC damage, immune cell activation, and autoimmune responses. These ETs may induce the release of autoantigens from AECs, particularly cytokeratin (CK)18, CK19, α-enolase, and tissue transglutaminase, and the production of corresponding autoantibodies by activated B lymphocytes.10 This underscores the potential for ETs in enhancing autoimmune responses induced by epithelial autoantigens (e.g., CK18), further stimulating ET production and type 2 airway responses as a novel therapeutic target for severe asthma.9

In this issue of Allergy, Asthma & Immunology Research, Quoc et al. 11 demonstrate that monocyte-derived ETs (MoETs) can induce the production of CK19 and CK19-specific IgG in AECs of a mouse model, with clinical implications shown by elevated levels of CK19-specific IgG in the sera of asthma patients. Levels of CK19-specific IgG, NET-specific IgG, and MPO were significantly higher in the non-eosinophilic asthma group than in the eosinophilic asthma group and healthy controls. Moreover, CK19 and CK19-specific IgG complexes were found to enhance the NET formation in peripheral neutrophils. This study highlights how released autoantigens and their specific IgGs from AECs may activate neutrophils to form NETs, providing evidence for autoimmune involvement in severe asthma pathogenesis, that is resistant to steroid treatment.

Neutrophil and MoETs contribute to airway inflammation and tissue damage in severe asthma, indicating their potential as therapeutic targets. Therefore, targeting ET formation and autoimmune pathways could provide novel therapeutic options for managing severe asthma, especially in patients with non-eosinophilic phenotypes. Elevated levels of autoantigens such as CK19 and corresponding specific IgG antibodies in asthma patients highlight their potential as biomarkers for disease severity and therapeutic response. Further investigation is necessary to elucidate the complex interplay between ETs, autoimmune responses, and asthma pathogenesis, thereby informing the development of personalized medicine strategies tailored to distinct asthma endotypes.