In the present study, we evaluated the different proinflammatory cytokines and their receptors, which could help clinicians predict the prognosis of infantile asthma. We investigated the proinflammatory cytokines IL-4, IL-13, and IL33 and their association with the pathogenesis of childhood wheezing.
ST2 plays a role in the pathogenesis of inflammatory allergic diseases, and several studies have demonstrated that serum ST2 levels are higher in patients with bronchial asthma [16, 17]. In children, there have been several reports of elevated serum ST2 concentrations during acute exacerbations of bronchial asthma . It is interesting to note that serum IL-33 did not increase despite ST2 elevations in the initial wheezing attack of participants without a diagnosis of bronchial asthma. Additionally, in the group that subsequently received a diagnosis of bronchial asthma (i.e., PW group), ST2 concentrations were high from the infancy stage. Overall, our findings provide clinical evidence that the expression of ST2 receptor levels is an appropriate predictor of infantile asthma.
IL-4 induces IgE production and Th2 cell differentiation. The IL-13 receptor is consistently expressed in the bronchial epithelial and smooth muscle cells . A recent report provided evidence that the four-locus gene model, consisting of L13 rs20541, IL4 rs2243250, ADRB2 rs1042713, and FCER1B rs569108, can determine the risk of developing asthma and atopy in Chinese Han children . Similarly, in African-American infants with a family history of atopy, the IL-4 C-589T polymorphism was associated with a 10-fold increased risk of wheezing without a cold . Another clinical report indicated a significant correlation between serum IL-13 levels in infants and the number of wheezing episodes. Moreover, an elevated serum IL-13 level and a positive history of allergy have functional significance in the recurrence of acute bronchiolitis . Severe RSV disease is linked to an increased Th2 response resulting from the overexpression of IL-4, which leads to wheezing . There was no change in IgE levels or the production of IL-4 and IL-13 in transient and recurrent wheezing. IL-4 produced by basophils activates NH cells in the lungs, and this interaction induces allergic diseases . IL-4 and IL-13 are Th2-type inflammatory cytokines that increase in response to bronchial inflammation. Cysteine protease, when acting as an antigen that presents with wheezing attacks, strongly induces allergic inflammation.
In line with the above findings, IL-4 and IL-13 might be the key cytokines that prolong symptoms, but our results showed no statistical difference between the TW and PW groups. The wheezing attacks observed in infants may not be explained by Th2-type immune responses or innate immune responses alone They may also be related to cellular damage caused by substances called pathogen-associated molecular patterns (PAMPs), including allergens and viral infections.
We hereby discuss the immune responses associated with IL-33 and ST2. IL-33 is constitutively expressed in various cells, such as endothelial, epithelial, and mast cells, of barrier tissues. It contributes to the pathogenesis of inflammatory allergic diseases. Genetic variation of the IL-33 locus is strongly associated with increased susceptibility to allergic sensitization in childhood and the development of wheezing phenotypes . A recent clinical report indicated that the interaction between IL-33 and CD4(+)CD25(+)Foxp3(+) regulatory T cells is implicated in the pathogenesis of asthma in children . Moreover, single nucleotide polymorphisms of the IL-33-IL1RL1 pathway are linked to intermediate-onset wheezing and asthma through sensitization in early childhood . ST2 is a well-replicated asthma gene associated with eosinophilia. Another clinical study indicated that ST2 has a predictive value for the development of eosinophilic airway inflammation in children with asthma . Phylogenetic analysis showed co-circulation of hMPV, and the genotype ST2 was found .
Cysteine protease, an antigen that is associated with wheezing attacks, strongly induces allergic inflammation . It damages epithelial cells, resulting in the release of IL-33 and the induction of asthmatic symptoms. IL-33 and ST2 levels were elevated during wheezing attacks, but children who developed PW did not present with differences in IL-33 levels at the initial admission. However, ST2 levels were notably elevated. It is conceivable that higher expression of ST2 in inflammatory cells is associated with increased inflammation and frequency of wheezing due to IL-33 released during acute exacerbations. The finding of elevated serum ST2 levels from infancy may be related to the phenomenon of increased susceptibility to repetitive wheezing, which may be due to epigenetic changes in ST2 expression genes and other factors that regulate these mechanisms.
IL-33 is localized in the nucleus and is upregulated in response to tissue damage . In contrast, ST2 may be expressed due to atopic diathesis. Cases of infantile asthma that progress to PW have a high latent expression of ST2 and may suffer from wheezing through IgE.
This study has several limitations. Conducting ELISA to determine serum IL-33 levels is difficult. Moreover, it might not have necessarily measured active cytokines. Thus, we could not conclude that IL-33 was not involved in children with PW and TW. It was also controversial whether serum ST2 levels measured soluble ST2 levels. In addition, it was unclear whether the ST2 measured in this study was associated with ST2 expression.
The function of ST2 has not been elucidated, although it may be important in allergic diseases, such as PW. The children who developed bronchial asthma (PW group) in our study had elevated serum ST2 when they presented with a wheezing attack for the first time compared with children with transient wheezing (TW group). Serum ST2 levels were further elevated in blood tests 12 months later. If soluble ST2 were detected, it would have bound to receptors and regulated their expression, which might have affected the prognosis of patients with infantile asthma.
ST2 levels were found to be elevated during PW attacks. However, ST2 was also notably increased in the initial measurements of children who eventually developed recurrent wheezing. Although there was no difference in the level of IL-33 in the serum between the transient and prolonged wheezing groups, the phenomenon of ST2 difference in its receptor might result in a potential predisposition to predict the future development of bronchial asthma. Patients who develop recurrent wheezing from infantile asthma have a high latent expression of ST2, which might be involved in the onset of wheezing through IgE.
Various factors should be considered in the management and prognosis of infantile asthma. For instance, biomarkers have a significant value in disease management. This study demonstrates that ST2 may be a useful index for predicting the prognosis of infantile asthma. Moreover, elucidation of the mechanism of ST2 expression in childhood allergic diseases is essential.