Recent years have witnessed major advances in helminth therapy, which has led to the introduction of new strategies for the treatment of immune-mediated diseases. Most studies suggest that helminth infections can provoke symptoms of allergy and worm infestation by establishing a chronic infection, leading to reduced eosinophilia and allergic inflammation in the airways . To the best of our knowledge, this is the first report about the effect of somatic antigens of PSCs on allergic airway inflammation in a murine model. There is ample experimental evidence that the co-administration of somatic products of PSCs with OVA/alum despite the presence of laminated layer, E. granulosus antigen B (Eg AgB), and hydatid fluid can exacerbate allergic asthma [10,11,12, 14]. Moreover, some intestinal helminths such as Toxocara spp., schistosomes, and Toxoplasma gondii are parasites inversely associated with allergic disorders .
In contrast, several experimental and clinical studies have reported inconsistent findings. Researchers reported a direct association between helminth infections and helminth-derived molecules in asthma and other atopic diseases. Some reports suggest that intestinal helminths such as Ascaris lumbricoides, Strongyloides stercoralis, Toxocara cati, and Anisakis species can be directly linked to allergic-type inflammation .
In 2015, Ahumada et al. revealed that enhanced Th2-biased immune response along with IgE responses to Ascaris extract act as a risk factor for the pathogenesis of asthma . In 2020, Bakhshani et al. showed that oral administration of embryonated T. cati eggs after sensitization and OVA challenge exacerbated airway hyperresponsiveness, eosinophilia, and pulmonary inflammation while raising the IL-5 level in the lungs of mice infected with T. cati .
In our study, the administration of PSCs induced drastic histopathological changes, leading to extensive penetration of inflammatory cells into the BALF, elevated levels of IL-4, IL-5, and IL-17 in the lung homogenate, and reduced total antioxidant capacity in serum in the OVA + antigen group in comparison with the OVA and PBS groups.
Different effects can be attributed to the high allergenicity of some helminths and also species-specific disparities in the immune polarization, although the exact cause of this mechanism is unclear .
It is hypothesized that in the absence of helminth infection, allergenic proteins can influence the host immune response. According to previous studies, specific antigens from E. granulosus are capable of promoting a Th2 cytokine profile in order to induce IgE secretion, acting as the origin of allergic reactions during echinococcosis . The findings of this study demonstrate that IgE can contribute to host protection against parasitic agents, but this protective function was never documented in larval cestodes .
In particular, antigen B (AgB), antigen 5 (Ag5), cyclophilin (EA21), heat shock protein 70 (Hsp70), and elongation factor 1-beta/delta (EF-1 β/δ) have been identified as allergenic molecules in fluid cysts and PSCs. People with CE have IgE to parasite antigens AgB, a protease inhibitor, Ag5, a serine protease, and EA21 . In patients with progressive CE disease, AgB can produce IL-4 and IL-13, provoking immunopathology-associated Th2 polarization . It has been shown that AgB is able to induce an anti-inflammatory phenotype in macrophages, which is useful for the suppression of allergic airway eosinophilic inflammation . There are no details about the molecular mechanisms involved in the immunogenic and allergic features of AgB.
Ortona et al. in 2002 demonstrated that E. granulosus cyclophilin (specific antigens that exist in PSCs and fluids) plays a role in allergic symptoms associated with CE, which can compromise or protect the host .
In most patients with CE, Eg EF-1 β/δ can tilt Th1/Th2 cytokine activation towards Th2 polarization in a preferential manner . However, most proteins are not allergens, and the reason that just a minority of antigens possess allergenic properties is not clear .
Classically, asthma is treated as a Th2 disease related to enhanced IgE and eosinophilic inflammation, which is crucial to asthma pathophysiology in the airway . IL-4, as a central mediator of asthma, plays a pivotal role in the switching of the IgE isotype in B cells. IL-5 promotes the proliferation and differentiation of eosinophils . In this study, an enhanced Th2-biased immune response (IL-4, IL-5) was observed following administration of PSCs in OVA-induced mice relative to the OVA and PBS groups. These results suggest that the activation of type-2 immunity may also affect the reactivity of airways and the number of eosinophils in BALF.
Consistent with the high level of Th2 cytokines, a high concentration of IL-17 was detected in the OVA + antigen group lung homogenate compared with the OVA and PBS groups. This suggests that somatic antigens of PSCs may increase the level of Th17. Given the simultaneous surge in both Th2 and IL-17 in the OVA + antigen group, IL-17 co-transferred with Th2 cytokines can promote eosinophilic airway inflammation mediated by Th2 cells by improving the expression of eotaxin and eotaxin-1 as major chemokines for recruitment of eosinophils into the airways [26,27,28]. These findings show that IL-17 is involved in the development of allergic asthma with Th2 cytokines.
Other cell populations including Treg cells that are essential for the prevention of lung inflammation act as immunoregulatory factors . Following the measurement of its concentration in the lung homogenate, the levels of IL-10 in the OVA + antigen group were lower than those in the OVA group, but this difference was nonsignificant.
The level of type-1-specific cytokines such as IFN-γ (a representative cytokine derived from Th1 cells) increases with the exacerbation of asthma. IFN-γ prevents Th2 cell-mediated eosinophilic inflammation, airway hyperresponsiveness (AHR), and mucus production .
Following the surge in Th2 cytokines, a significant reduction was observed in IFN-γ levels in the lungs of mice in the OVA + antigen group compared with the OVA and PBS groups.
The FRAP assay was used to determine the total antioxidant power at 490 nm. Nadeem et al. in 2005 showed that in patients with acute exacerbations, the total antioxidant capacity of plasma decreased. Severe exacerbation of asthma was linked to enhanced oxidative stress. Also, reduced antioxidant power of plasma was positively correlated with inflammation, acting as a causative factor in the pathogenesis of asthma . The valuation of total antioxidant capacity in blood serum following PSC administration indicated a remarkable reduction in the OVA + antigen group in comparison with the OVA and PBS groups. Also, previous research has underlined the importance of oxidant–antioxidant balance for natural pulmonary function . However, the inflammatory response in asthma may be rooted in multiple pathways .
Histopathological findings revealed that the co-administration of somatic antigens of PSCs with OVA intensified airway inflammation. Also, abundant bronchiolar goblet cells appeared in the bronchiolar epithelium in the OVA + antigen group in comparison with the OVA and PBS groups. Hyperplasia in bronchioles and bronchi and mucus hypersecretion in bronchi were detected in the OVA + antigen group by PAS staining. Given that IL-13 is linked to goblet cell hyperplasia and mucus production in airway epithelial cells , and represents a critical pathological feature of the allergic response , its administration during OVA sensitization may raise IL-13 levels. However, IL-13 cytokine levels were not measured in the lung homogenate in the present study. Thus, it is impossible to draw any conclusions about intergroup differences in terms of lung homogenate cytokine levels.