J investing allergol clin immunol 20110

Moreover, detailed analysis of the relationship between HDM and the innate immune response have been reported [ 24 , 25 , 26 ]. Since the related PRRs vary depending on the allergen, it is also necessary to pay attention to the involvement of the innate immune response in understanding the pathology of asthma. Figure 1 Type 2 immune response via Th2 lymphocytes in asthma patients.

Dendritic cells capture inhaled antigens and present them to CD4-positive T cells via the T cell receptor. IL-4 is involved in the differentiation of B cells into IgE-producing cells. IL-5 causes eosinophil activation and tissue eosinophilia. IL-9 is involved in mast cell proliferation. IL causes goblet cell metaplasia. IL-5 and IL cause bronchial hyperreactivity. DC, dendric cell; Th2, T helper 2 cell. Figure 2 Type 2 immune response via ILC2s in asthma patients.

Allergens with protease activity, fungi, and viruses promote the production of IL, IL, and thymic stromal lymphopoietin TSLP by airway epithelial cells. IL-5 and IL have the same effect as that of the Th2 cell pathway. IL-9 prolongs ILC2 survival by autocrine actions.

Amphiregulin is involved in tissue repair. Intriguingly, some asthma patients show a neutrophil-predominant phenotype irrespective of Th2 cytokines. The non-type 2 immune response seems to involve IL, which is associated with blood and sputum neutrophils and asthma severity [ 15 ]. Moreover, in a mouse model, Thinduced inflammation and airway hyperresponsiveness showed steroid resistance [ 27 ].

Hence, Thmediated airway inflammation contributes to severe and difficult-to-treat asthma. Asthma is thought to develop due to not only environmental factors but also genetic factors. In recent years, a genome-wide association study GWAS was conducted to search for genetic factors associated with asthma, and various candidate genes have been identified [ 28 ]. Among them, IL and its receptor ST2 were identified with asthma, which suggests the importance of the IL pathway.

In addition, TSLP was found to be significantly associated with Japanese adult asthma patients [ 29 ]. Therefore, GWAS analyses also showed the importance of the ILC2 activation pathway, which is mediated by cytokines derived from airway epithelial cells.

Go to: 4. This first report also revealed a type 2 immune response independent of Th2 cells. ILC2s are present in most organs of the body but are considered to be particularly abundant in skin, lung, and adipose tissue [ 31 ]. Because ILC2s are involved in type 2 immunity, the impact on the onset of allergic immune reactions is highlighted. ILC2s can rapidly produce Th2 cytokines [ 32 ]. This allows ILC2s to initiate and amplify the immune response and affect both innate and adaptive immunity through secreted cytokines.

Hence, it is suggested that ILC2s have a crucial role in asthma pathogenesis. In fact, there have been some reports that human ILC2s are increased in the peripheral blood of patients with asthma; however, there are reports that showed opposite results [ 33 , 34 , 35 ]. This discrepancy might be due to the different methods to identify ILC2s and the different asthma populations.

In general, ILC2s in peripheral blood tend to increase in severe refractory asthma and eosinophilic asthma. Although it has been reported that ILCs in bronchoalveolar lavage fluid BALF and sputum are increased in asthma patients, it is not clear how ILC2s in peripheral blood or airway are involved in the pathology of asthma [ 36 , 37 ].

Many studies have tried to elucidate the background mechanism between asthma and ILC2s. Studies on the genetic factors in allergic diseases using GWAS have reported that IL, one of the factors that activates ILC2s, was the factor that was most highly correlated with the development of bronchial asthma [ 38 ]. IL is present in the nucleus of epithelial cells and is released from epithelial cells in response to fungi such as Alternaria, protease activity of HDMs, or viral infection.

Then, eosinophilic airway inflammation is induced by the type 2 cytokines produced by ILC2s [ 39 ]. Kondo et al. In addition, the expression of TSLP and IL is enhanced in the peripheral blood and lung tissue of patients with severe asthma [ 43 , 44 ]. In clinical settings, tezepelumab, a human monoclonal antibody specific for TSLP, reduced the rate of asthma exacerbation in patients with uncontrolled asthma [ 46 ].

SB, a DNA enzyme that is capable of cleaving and inactivating GATA3 messenger RNA, significantly attenuated the early and late phases of asthmatic responses after allergen induction in patients with allergic asthma. On the other hand, biomarker analysis showed that plasma levels of IL-5 were attenuated [ 47 ].

Thus, in recent years, the pathogenesis of bronchial asthma has been elucidated not only in the acquired immune system in association with Th2 cells but also in the innate immune system, such as ILC2s and cytokines, from epithelial cells. Go to: 5. Ovalbumin-Induced Asthma Mouse Model Since OVA is inexpensive and available in large quantities, it has frequently been used as a protein antigen to induce allergies in animal models.

The OVA-induced asthma mouse model generally induces airway inflammation by administration of OVA to mice to establish sensitization and then challenge by inhalation of OVA into the airways. This mouse model is suitable for analysis of the type-2 immune response. In general, sensitization is performed by intraperitoneal and subcutaneous routes.

However, it is difficult to promote the development of the Th2 phenotype by the immune response to a single administration of OVA [ 48 ]. Therefore, adjuvants such as aluminum hydroxide AlOH3 are required to induce airway inflammation [ 49 ].

The OVA-induced asthma mouse model is a traditional method, and there are many reports to date. This is because intraperitoneal and subcutaneous routes to sensitize animals are not similar to human sensitization. Moreover, intraperitoneal routes might induce immune tolerance. Therefore, there is a trend to use intranasal administration of antigens, which has the advantage of not requiring adjuvants and is similar to human sensitization [ 50 ].

Go to: 6. Af extracts contain not only protein antigen but also proteases or ligands for innate immune cells [ 51 ]. This model is not clearly divided between sensitization and exposure period like the OVA model, but is established by continuous intranasal administration twice a week for 8 weeks or three times a week for 3 weeks [ 52 , 53 ]. This mouse model is also suitable for analysis of the type-2 immune response. Go to: 7. House Dust Mites and Asthma Although only 4 from more than 30 of HDM allergens are proteases, HDMs are characterized by protease activity, immunogenicity, and induction of the innate immune system [ 24 ].

In general, actions to prevent asthma can be divided into three stages. Primary prevention involves preventing the development of asthma and should be performed in children before allergen sensitization. Secondary prevention involves preventing the onset of asthma after sensitization mainly by allergen exposure. Tertiary prevention involves preventing exacerbation after the onset of asthma, which prevents respiratory function decline and asthma death.

Allergens, including HDMs, are considered risk factors at all stages of prevention. Sensitization to indoor allergens is more important than outdoor allergens for the development of asthma [ 1 ]. Among children, exposure to HDMs are associated with increased risks of asthma [ 54 ].

Moreover, HDMs are a risk factor for asthma exacerbation [ 55 ]. Thus, there is a close relationship between asthma and HDMs. HDMs are a major risk factor for allergic diseases, such as atopic dermatitis AD , allergic rhinitis AR , and asthma [ 56 ]. They are found in dust, mattresses, pillows, and bedding [ 57 ]. The life cycle of HDMs from egg to adult takes 3 to 4 weeks, and they live for approximately 2 months.

Females lay approximately 80 eggs during this time. Mite allergens have been classified into more than 30 groups [ 24 ]. In particular, Dermatophagoides pteronyssinus Der p and Dermatophagoides farinae Der f are the most common sources of indoor allergens. The prevalence of HDM allergen sensitization varies from 65 to million persons in the general population [ 20 ]. The allergenic potential of HDMs is due to their dead bodies and their fecal pellets, which have protease activity.

Based on the above, it seems that various components of HDMs activate the immune system. With recent technological advances, the allergenic effects of HDMs have been identified. In Korea, Der f 2 is the most potent allergen, followed by Der f 1. Immune responses are modulated by the properties of the allergen itself and by the adjuvant-like substances that are concomitantly administered with the antigens.

Characterization of allergenic molecules and elucidation of mechanisms by which adjuvant-like molecules modulate allergic reactions, not only in Korea but also worldwide, will provide valuable information on allergic diseases, and are necessary for the development of diagnostic tools and therapeutic strategies. In Korea, the rate of sensitization to HDM has been reported to be HDM produces various proteins that could elicit IgE-mediated immune responses, and some molecules may modulate the allergic reactions by their adjuvant-like characteristics or their affinity to adjuvant.

However, it is not clear which allergenic substances of HDM are responsible for the increase in allergic disorders in Korea. Molecular characterization of these substances will provide new insight and new strategies for the development of immunotherapeutic tools to modulate the immune response.

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