Distinct functions of eosinophils in severe asthma with type 2 phenotype: clinical implications

Asthma is commonly recognized as a heterogeneous condition with a complex pathophysiology. With advances in the development of multiple medications for patients with asthma, most asthma symptoms are well managed. Nevertheless, 5% to 10% of adult asthmatic patients (called severe asthma) are in uncontrolled or partially controlled status despite intensive treatment. Especially, severe eosinophilic asthma is one of the severe asthma phenotypes characterized by eosinophilia in sputum/blood driven by type 2 immune responses. Eosinophils have been widely accepted as a central effector cell in the lungs. Some evidence has demonstrated that persistent eosinophilia in upper and lower airway mucosa contributes to asthma severity by producing various mediators including cytokines, chemokines and granule proteins. Moreover, extracellular traps released from eosinophils have been revealed to enhance type 2 inflammation in patients with severe asthma. These novel molecules have the ability to induce airway inf lammation and hyperresponsiveness through enhancing innate and type 2 immune responses. In this review, we highlight recent insight into the function of eosinophil extracellular traps in patients with severe asthma. In addition, the role of eosinophil extracellular vesicles in severe asthma is also proposed. Finally, current biologics are suggested as a potential strategy for effective management of severe eosinophilic asthma.

Serum Levels of Eosinophil-Derived Neurotoxin: A Biomarker for Asthma Severity in Adult Asthmatics

PURPOSE: Eosinophilic inflammation is a key component of severe asthma (SA). However, there has been no reliable serum biomarker for the eosinophilic inflammation of SA. We hypothesized that serum eosinophil-derived neurotoxin (EDN) could predict the eosinophilic inflammation of SA in adult asthmatics. METHODS: Severe asthmatics (n = 235), nonsevere asthmatics (n = 898), and healthy controls (n = 125) were enrolled from Ajou University Hospital, South Korea. The serum levels of EDN and periostin were measured by enzyme-linked immunosorbent assay and compared between severe and nonsevere asthmatics. Their associations with total eosinophil count (TEC) and clinical parameters were evaluated; clinical validation of the K-EDN kit for the measurement of serum EDN was evaluated. RESULTS: Severe asthmatics were older and had longer disease duration with significantly lower levels of forced expiratory volume in 1 second and methacholine PC20 than nonsevere asthmatics. Significant differences were found in TEC or sputum eosinophil count (%) between the groups. The serum levels of EDN and periostin were significantly higher in severe asthmatics than in nonsevere asthmatics and in healthy controls (all P < 0.05). Although significant correlations were found between serum EDN levels measured by the 2 kits (ρ = 0.545, P < 0.0001), higher correlation coefficients between serum EDN levels measured by the K-EDN kit and TEC were higher (ρ = 0.358, P < 0.0001) than those between serum EDN levels measured by the MBL kit and TEC (ρ = 0.319, P < 0.0001) or serum periostin level (ρ = 0.222, P < 0.0001). Multivariate regression analysis demonstrated that serum EDN levels measured by the K-EDN kit predicted the phenotype of SA (P = 0.003), while 2 other biomarkers did not. CONCLUSIONS: The serum EDN level may be a useful biomarker for assessing asthma severity in adult asthmatics.

Which Factors Associated With Activated Eosinophils Contribute to the Pathogenesis of Aspirin-Exacerbated Respiratory Disease?

Eosinophils have long been recognized as a central effector cell in the lungs of asthmatic patients. They contribute to airway inflammation and remodeling through releasing several molecules such as cytokines, granule proteins, lipid mediators and extracellular traps/vesicles. Repeated evidence reveals that intense eosinophil infiltration in upper and lower airway mucosae contributes to the pathogenesis of aspirin-exacerbated respiratory disease (AERD). Persistent eosinophilia is found to be associated with type 2 immune responses, cysteinyl leukotriene overproduction and eosinophil-epithelium interactions. This review highlights recent findings about key mechanisms of eosinophil activation in the airway inflammation of AERD. In addition, current biologics (targeting type 2 immune responses) were suggested to control eosinophilic inflammation for AERD patients.

Familial IgG3 subclass deficiency: A report of two cases

Primary immunodeficiency in adults is thought to be underestimated in Korea. IgG subclass deficiency, defined as a deficiency at least among the 4 subtypes of IgG subclass, IgG1, IgG2, IgG3, and IgG4, results in recurrent infections, in which IgG3 subclass deficiency (IgGSD) is the most commonly found in adult asthmatic patients. Herein, we report 2 cases of familial IgG3SD. In family 1, a female patient aged 17 years with allergic rhinitis (AR) had recurrent upper respiratory infections (URIs), and gastroenteritis. Her mother aged 50 with AR had recurrent URI, otitis media, urinary tract infection, gastroenteritis, and oral ulcer. A younger sister aged 9 years with AR and asthma had recurrent URI almost all the year round. The serum IgA level was found to be lower than the normal level in her mother and the patient, and IgG3 was decreased in the patient and her sister. The IgG3 level of mother showed within the lower normal limit. In family 2, the mother aged 39 years with nonallergic rhinitis had recurrent URI and oral ulcer. Her son aged 16 years and daughter aged 13 years with AR and asthma had recurrent URI, resulting in uncontrolled asthma. Family 2 was found to be IgG3 deficiency in mother and son, and IgA deficiency in son. The IgG3 level of daughter was within the lower normal level. Mother and the first daughter in family 1 as well as mother and son in family 2 was treated with intravenous immunoglobulin, and their recurrent URI reduced. We reported 2 cases of familial IgG3SD.

Serum Periostin Levels: A Potential Serologic Marker for Toluene Diisocyanate-Induced Occupational Asthma

PURPOSE: Toluene diisocyanate (TDI) is a leading cause of occupational asthma (OA). Periostin is a matricellular protein implicated in type 2 immunity-driven asthma. Its pathogenic role in TDI-OA has not been completely elucidated. The present study was performed to investigate the role of periostin in TDI-OA. MATERIALS AND METHODS: Serum periostin levels were measured in subjects with TDI-OA, asymptomatic TDI-exposure controls (AECs), non-occupational asthmatics (NAs), and unexposed normal controls (NCs). To understand the mechanism by which TDI induces periostin production, primary small airway epithelial cells (SAECs) were cultured under stimulation of TDI and neutrophils from asthmatic patients. RESULTS: Fifty-three subjects with TDI-OA, 71 AECs, 67 NAs, and 83 NCs were enrolled. Serum periostin levels were significantly higher in TDI-OA subjects than in AECs (p=0.001), NAs (p < 0.001), and NCs (p < 0.001). In TDI-exposed subjects (TDI-OA and AEC), the PC20 methacholine levels were significantly lower in subjects with a higher periostin level than in those with a lower periostin level. TDI exposure did not increase periostin production directly by SAECs; however, periostin production increased significantly after co-culture with TDI and neutrophils, which was suppressed by an antioxidant. In addition, increased release of TGF-β1 was noted from SAECs when exposed to TDI and neutrophils, which was also suppressed by an antioxidant. CONCLUSION: These results suggest that an increased periostin level may contribute to the progression of airway inflammation to remodeling in TDI-exposed workers. A high serum periostin level is a potential serologic marker of the phenotype of TDI-OA.

Akkermansia muciniphila-derived extracellular vesicles influence gut permeability through the regulation of tight junctions

The gut microbiota has an important role in the gut barrier, inflammation and metabolic functions. Studies have identified a close association between the intestinal barrier and metabolic diseases, including obesity and type 2 diabetes (T2D). Recently, Akkermansia muciniphila has been reported as a beneficial bacterium that reduces gut barrier disruption and insulin resistance. Here we evaluated the role of A. muciniphila-derived extracellular vesicles (AmEVs) in the regulation of gut permeability. We found that there are more AmEVs in the fecal samples of healthy controls compared with those of patients with T2D. In addition, AmEV administration enhanced tight junction function, reduced body weight gain and improved glucose tolerance in high-fat diet (HFD)-induced diabetic mice. To test the direct effect of AmEVs on human epithelial cells, cultured Caco-2 cells were treated with these vesicles. AmEVs decreased the gut permeability of lipopolysaccharide-treated Caco-2 cells, whereas Escherichia coli-derived EVs had no significant effect. Interestingly, the expression of occludin was increased by AmEV treatment. Overall, these results imply that AmEVs may act as a functional moiety for controlling gut permeability and that the regulation of intestinal barrier integrity can improve metabolic functions in HFD-fed mice.

Extracellular Vesicles, a Key Mediator to Link Environmental Microbiota to Airway Immunity

Asthma is considered the hallmark of chronic airway inflammation, in which several inflammatory cells of the innate and adaptive immune system act together. The disease is thought to be caused by a combination of genetic and environmental factors; however, precise mechanisms for airway inflammation remain unclear. The human microbiota provides an increasingly favored explanation for inflammatory diseases; an altered microbiota composition has been shown to regulate immune responses. However, given the complexity of the microbiota, additional research is needed to elucidate its role in the development of disease. One of the candidate molecules that link microbiota to disease is the extracellular vesicles (EVs). EVs are secreted by diverse cell types and they possess the pathophysiological function of delivering signals between bacteria and host. We discuss the role of the microbiota in the development of asthma through releasing EVs.