Role of IL‐17 in atopy—A systematic review

Abstract Purpose of Review Atopy is defined as the genetic predisposition to react with type I allergic diseases such as food‐, skin‐, and respiratory allergies. Distinct molecular mechanisms have been described, including the known Th2 driven immune response. IL‐17A (IL‐17) is mainly produced by Th17 cells and belongs to the IL‐17 family of cytokines, IL‐17A to F. While IL‐17 plays a major role in inflammatory and autoimmune disorders, more data was published in recent years elucidating the role of IL‐17 in allergic diseases. The present study aimed to elaborate specifically the role of IL‐17 in atopy. Methods A systematic literature search was conducted in MEDLINE, Embase, and Cochrane Central Register of Controlled Trials, regarding IL‐17 and atopy/allergic diseases. Results In total, 31 novel publications could be identified (food allergy n = 3, allergic asthma n = 7, allergic rhinitis [AR] n = 10, atopic dermatitis [AD] n = 11). In all allergic diseases, the IL‐17 pathway has been investigated. Serum IL‐17 was elevated in all allergic diseases. In AR, serum and nasal IL‐17 levels correlated with the severity of the disease. In food allergies, serum IL‐17E was also elevated in children. In AD, there is a trend for higher IL‐17 values in the serum and skin specimen, while it is more expressed in acute lesions. In allergic asthma, serum IL‐17 levels were increased. In two studies, higher serum IL‐17 levels were found in severe persistent asthmatic patients than in intermittent asthmatics or healthy controls. Only one therapeutic clinical study exists on allergic diseases (asthma patients) using a monoclonal antibody against the IL‐17 receptor A. No clinical efficacy was found in the total study population, except for a subgroup of patients with (post‐bronchodilator) high reversibility. Summary The role of IL 17 in the pathogenesis of allergic diseases is evident, but the involvement of the Th17 cytokine in the pathophysiological pathway is not conclusively defined. IL‐17 is most likely relevant and will be a clinical target in subgroups of patients. The current data indicates that IL‐17 is elevated more often in acute and severe forms of allergic diseases.

involved in the onset and progression of allergic inflammation. 6 Besides the classical Th1/Th2-concept, other pathways and cytokines have been characterized, which may play a crucial role in hypersensitivity diseases.
As a pro-inflammatory cytokine, it is of interest to identify the role of IL-17 in the pathogenesis of different allergic diseases. In All case-control studies that compared IL-17 serum levels of food allergic patients, patients with AR, allergic asthma, and atopic eczema with healthy controls were included. Additionally, case-controlled studies involving AR measuring IL-17 levels in the nasal fluid, as well as atopic eczema studies examining skin specimen were included. Studies were excluded from analysis due to multiple reasons, such as diseases (e.g., non atopic allergies), other cytokines than IL17, reviews, unclear study design, unclear study population, language other than English, conference abstract only and no full-text availability. A standardized data-collection protocol was followed to gather the data regarding publication year, number of patients, number of controls, and method of IL-17 measurement.
In total, 31 publications were selected, a summary of the main findings is shown in Table 1.

| Food allergy
In total, 103 citations were found for food allergy and IL-17. Three studies with a total of 348 patients (300 children) and 32 controls (seven children) were selected.
One study with 30 adult patients with an elevated concentration of the allergen-specific IgE showed that serum IL-17A concentrations were higher in patients with food allergic hypersensitivity (1.24 pg/ ml ± 0.63) compared to healthy volunteers (0.87 pg/ml ± 0.41). 7 Another study investigated the role of IL-17A and IL-17E also measured by ELISA in children with allergic diseases (AD, hay fever, and asthma) in patients with food allergies. They detected that increased IgE levels specific to food allergens were positively related to IL-17E serum concentrations. Median and interquartile ranges for IL-17E were 80 pg/ml (31.6-208.8) and for IL-17A 267.8 pg/ml (164.1-399.4). IL-17A showed the tendency to be negatively associated with allergic sensitization, especially in some food allergens, but specific Th17 responses were not assessed. It was stated that a dysregulation of the IL-17E/IL-17A axis might have the same impact as the dysbalance in the Th1/Th2 axis regarding the allergic outcome. 8 These findings were verified in a small study investigating the role of the Th17 response, which included 18 children with a peanut allergy and to at least one additional food allergen, and eight atopic adults without food allergies. They found an impaired Th17 response in the children but not in the atopic patients without food allergy.
They stated that the low IL-17 production could allow for an aberrant Th2 response, resulting in progression of the allergies. 9

| Allergic asthma
In total, 540 citations were found that explored the involvement of IL-17 in allergic asthma. Seven studies were selected in which six studies examined the serum/plasma level of IL-17 of asthmatic patients measured by ELISA technology, and one study analysed Th17 cells in the blood of asthmatic patients. Studies measuring IL-17 level in bronchial biopsies were excluded.
Serum IL-17 levels were found to be elevated in all studies involving adults and children with allergic asthma.
In one study, allergic asthmatic patients showed higher plasma IL-17 than normal controls (22.40 vs. 11.86 pg/ml), although the differences were not statistically significant. 10 Another study with asthmatic patients and AR showed significantly elevated serum IL-17 levels in patients during asthma attacks and remission, compared with healthy control subjects. 11 Chien et al. 12 found that in asthmatic patients with different severities, serum IL-17 levels were significantly higher in mild to severe persistent asthmatic patients than in intermittent asthmatics or healthy controls. Serum IL-17 levels were higher in the uncontrolled (mean 52.33 pg/ml) and partly controlled groups (12.67 pg/ml) than in the controlled group (5.46 pg/ml). In accordance with FeNO levels, a significantly higher proportion of mild to severe persistent asthmatics had higher serum IL-17 values than mild intermittent asthmatics. Also, in asthmatic children, elevated serum IL-17 could be detected (79.5 pg/ml), while for children with asthma and AR, higher serum values were measured (107.3 pg/ml). 13 In a study analyzing serum IL-17F levels, the results showed that IL-17F was significantly up-regulated in asthmatic patients. All pa-  The percentage of Th17 cells in the blood was significantly increased in patients with allergic asthma (1.53 ± 0.30%) than that of the control group (0.97 ± 0.23%). 16 Collectively, existing clinical data shows increased levels of IL-17 in severe asthma. However, attempts to block IL-17 in asthmatics as a therapeutic target have been disappointing so far. Currently, there is only one randomized, placebo-controlled study using brodalumab, a human anti-IL-17 receptor monoclonal antibody. In patients with moderate to severe asthma, there was no effect over 12 weeks on clinical symptoms, and FEV1 in the asthmatic patients was observed. 17

| Allergic rhinitis
In total, 210 articles were reviewed and were screened by title and abstract, and 15 publications were assessed for eligibility in full text, while five records were excluded (two of which were in the Chinese language, two were without a report on relevant outcomes, and one was using mice models and total IgE levels after 6 months of cluster immunotherapy. 23 A recent paper showed elevated IL-17 cytokine serum levels in 88 patients with AR compared to 88 healthy controls. The elevated Il-17 serum level was associated with elevated ECP-and IL-33 levels. 24 These markers might be useful to monitor disease activity.

| Atopic dermatitis
In total, 4133 articles were reviewed and were screened by title and abstract. We assessed 22 publications for eligibility in full text, while 11 records were excluded (four were in the Chinese language, three had no relevant outcomes reported, four were mice models). For AD, studies examining skin biopsies were also included. From the 22 publications, 11 studies could be selected. In eight studies, patients' skin specimen were analysed, and in six studies, TH17 cells in the blood or IL-17 serum levels were evaluated.
In AD, few studies dealt with the serum IL-17 level in patients.  26 In 181 children with AD, serum IL-17 levels were significantly higher compared to healthy children. Furthermore, SCORAD-levels and IL-17 showed a positive correlation. 27 In the peripheral blood of AD patients, Th17 cells, as well as IL-17 and IL-23 levels were found to be significantly higher compared to patients with allergic contact dermatitis versus healthy patients, but lower than those of psoriasis patients. 28 Regarding different stages of AD, it was reported that the percentage of IL-17 positive lymphocytes in the blood of AD patients was significantly higher in acute versus chronic atopic eczema.
Furthermore, the number of circulating Th17-cells correlated with the clinical severity of atopic eczema. 29 In a small study with AD and psoriasis patients, Nograles et al. 30 showed that Th17 cells were significantly decreased in AD skin specimens compared to psoriatic skin, but in peripheral blood there was no difference. IL-17 mRNA was reported to be 20-fold decreased in AD skin, contrasted by only a 2-fold decrease in Th17 cell levels.
A comparison of AD and psoriasis in erythrodermic patient revealed no significant difference for Th17 cells between these two diseases in histological skin specimens. 31 Another immunohistological study in patients with atopic eczema revealed that IL-17 can be expressed as a function of different disease stages. IL-17 was significantly increased in acute lesions compared to chronic lesions and healthy skin. Furthermore, they showed that IL-17-in combination with TGF-beta-could be responsible for the development of tissue fibrosis in skin lesions of atopic eczema. 32 Recently, Gamez et al. 33 reported reduced IL-17 and IL-25 in cord blood in seven infants who developed AD during the first 12 months after birth compared to 24 infants who did not develop AD. This data highlights the in-utero period as being critical for potential maternal influence for the development of AD in infants. In asthmatic patients, there seems to be an impact on IL-17.

| DISCUSSION
When considering approaches to pathophysiology, it should be emphasized that the term "asthma" is a clinical diagnosis encompassing a spectrum of airway obstructive inflammatory diseases. The selected studies showed that serum IL-17 is elevated in asthma, and especially increased in severe asthma. Indeed, there are more factors that have an impact on the IL-17 level. Increasing IL-17 levels were seen in patients with asthma and a high BMI. In the same study, IL-17 levels were found to be elevated in asthmatic patients with elevated depressive symptoms in obesity. Regarding the different subtypes of IL-17A, there was an experimental study revealing that stimulating asthmatic neutrophils with IL-21, 23, and 6, enhanced the production of IL-17A and IL-17F at significantly higher levels compared to healthy controls. 42