Sage Journals: Discover world-class research

Abstract

Objective To comprehensively evaluate the association between Thymic Stromal Lymphopoietin (TSLP) and atopic dermatitis (AD). Methods Six databases were searched for relevant studies. For studies on TSLP levels, the standardized mean difference (SMD) was used. For studies involving gene polymorphisms, evaluation was performed using odds ratios (ORs) and 95% confidence intervals (95% CIs). Based on the between-study heterogeneity, a fixed- or random-effects model was chosen. Analyses were performed using RevMan 5.3 software and R 4.3.0 software. Trial sequential analysis was conducted to evaluate whether the number of cases was sufficient. Results A significant relationship between TSLP rs1898671 polymorphism and AD was found under homozygous (DD vs dd), and dominant contrasts (DD + Dd vs dd), with OR = 0.47 (95% CI: 0.24, 0.92) and 0.46 (95% CI: 0.24, 0.88), respectively (p < 0.05). Whereas under allele (D vs d), heterozygous (Dd vs dd) and recessive contrasts (DD vs Dd + dd), no significant relationship was found. No significant relationship was found for rs1837253 or rs11466749. Serum TSLP levels were significantly higher in patients with AD, with the SMD = 1.45 (95% CI: 0.65, 2.25) (p < 0.05). Conclusions TSLP gene rs1898671 polymorphism was associated with AD, and TSLP levels were elevated in patients with AD.

Keywords

thymic stromal lymphopoietin inflammation atopic dermatitis polymorphism biomarker meta-analysis

Introduction and aims

Atopic dermatitis (AD) is a chronic inflammatory skin disease characterized by relapse, persistent pruritus, and eczema-like lesions. Although AD typically occurs at an early age, adults can also be affected.^1,2 Currently, AD affects 20% of children and 5%–10% of adults.³ AD pathophysiology is complex and includes skin barrier dysfunction, environmental and immunological factors, and gene interactions.^2,4 Multiple cytokines and cells are involved in the pathogenesis of AD, including interleukin (IL)-4, IL-5, IL-9, IL-13, eosinophils, basophils, and mast cells.^5–7

Thymic stromal lymphopoietin (TSLP) is an IL-7-like four-helical bundle cytokine generated by keratinocytes.^8,9 TSLP mainly targets dendritic cells (DCs), and upregulates the expression of CD80, OX40L, and CD86.¹⁰ Additionally, TSLP promotes IL-4, IL-5, IL-9, and IL-13 expression through its action on mast cells, epithelial cells, macrophages, and innate lymphoid cells.¹⁰ The human TSLP gene is located on chromosome 5q22.1, which is adjacent to 5q31, a gene located in the cytokine cluster of atopic dermatitis.¹¹ TSLP is involved in the pathogenesis of various diseases including asthma, AD, inflammatory arthritis, and cancer.^11–13 The three main TSLP polymorphisms under investigation are rs1898671, rs1837253, and rs11466749.^14–18 Variants of the TSLP gene can alter TSLP protein activity, leading to inflammatory responses. For example, in patients with AD, the rs1898671 polymorphism is associated with disease persistence and risk of eczema herpeticum.^18,19

Gene polymorphisms and TSLP levels are associated with the risk of AD. However, these studies have limitations. For example, the sample sizes were relatively small, and divergent or even opposite results were observed. The statistical power was limited for individual studies. Therefore, we performed a meta-analysis and trial sequential analysis (TSA) to more comprehensively evaluate the association between TSLP and AD.

Materials and methods

Literature search

Six databases, including PubMed, Web of Science, EMBASE, Ovid, Sinomed, and China National Knowledge Infrastructure (CNKI), were searched from their establishment date to 2022.04.30. The search strategies varied for different databases and are described in the Supplemental Materials.

Inclusion and exclusion criteria

The inclusion criteria were¹: published studies on the relationships between TSLP and AD, including TSLP gene rs1898671, rs1837253, and rs11466749 polymorphisms and blood or serum protein levels²; case-control studies or cohort studies³ AD diagnosis through clinical diagnostic criteria⁴; controls were healthy individuals or individuals without related diseases⁵; sufficient information of TSLP genotype frequencies or levels was provided⁶; for studies with gene polymorphisms, p-values, odds ratios (ORs), and 95% confidence intervals (95% CIs) were provided or could be calculated from the study data⁷; for studies with levels, the form of mean ± standard deviation (SD) was provided or could be calculated.

The exclusion criteria were¹: conference publications, case reports, reviews, commentary, or animal studies²; duplicate data³; studies that failed to provide adequate information to calculate levels or genotype frequencies; and⁴ for studies with levels, the original data in the study required transformations to the form of mean ± SD.

Two investigators (Zhili Xu and Boyang Zhou) conducted the selection process. In cases of disagreement, another investigator (Tianhang Yu) checked the procedure.

Data extraction

The following information was extracted from the included studies¹: first author’s name and year of publication²; country (or region) where the study was performed³; ethnicity and gender of the case and control subjects for studies with gene polymorphisms⁴; sample size of both groups⁵; TSLP genotype frequencies or levels of both groups⁶; units and methods of detection for studies with levels⁷; results of Hardy Weinberg Equilibrium (HWE) for studies with polymorphisms. Two investigators (Zhili Xu and Suhua Wu) performed the extraction. Another investigator (Linfeng Li) reviewed the information and corrected any errors.

Methodological quality assessment

The Newcastle–Ottawa scale (NOS)²⁰ was used to evaluate the quality of the included studies. The NOS includes scores for selection, comparability, and exposure. The maximum score is 9; when a study attained a score of ≥6, it was considered to be of high quality. Two investigators (Zhili Xu and Boyang Zhou) completed the assessments. If any controversy was encountered, another investigator (Linfeng Li) checked the evaluation procedure and made a final decision.

Statistical analysis

For studies with TSLP levels, the standardized mean difference (SMD) was applied to eliminate the impact of different units and measurements of detection. If the data was not in the form of mean ± SD in the publication, transformation was conducted based on the methods of Luo et al. and Wan et al.^21,22 For studies with gene polymorphisms, Hardy-Weinberg Equilibrium (HWE) in the control group was calculated using STATA 16.²³ Evaluation was performed using ORs and 95% confidence intervals (CIs). The Hartung–Knapp–Sidik–Jonkman (HKSJ) method was employed as an estimator in the meta-analysis because of its greater reliability, particularly in studies with small sample sizes.²⁴ For each polymorphism in the TSLP gene, three exposure groups (DD, Dd, and dd) were defined based on two alleles (D and d). Five genetic models were applied in our study, including allele contrast (D vs d), homozygous contrast (DD vs dd), heterozygous contrast (Dd vs dd), dominant contrast (DD + Dd vs dd), and recessive contrast (DD vs Dd + dd). For each comparison, a p-value <0.05 was defined as statistically significant.

Based on the between-study heterogeneity, a fixed- or random-effects model was chosen. Q-statistics and I² tests were used to assess heterogeneity. For a p-value >0.10 and I² <50%, the heterogeneity was not significant, and the fixed-effects model was selected; otherwise, the random model was used. Sensitivity analysis was used to identify the impact of an individual study by omitting the studies in that order. Funnel plots were generated to estimate the publication bias for comparisons with five or more studies. The analysis was performed using RevMan 5.3 software and R 4.3.0 software.^20,24

Trial sequential analysis

A TSA was performed to determine whether the number of cases was sufficient for comparison. In our study, the type I error (false positive) was set at 5%, and the type II error (false negative) was set at 30%. The analysis was performed using a Java-based TSA application.^25,26

Results

Selection of the studies

A total of 4,150 publications were obtained from these six databases. Subsequently, 2,041 duplicate records were removed and 2,109 were screened for titles and abstracts. A total of 1,989 publications were excluded and the remaining 120 were screened for the whole content. On the basis of the selection criteria, 107 patients who did not meet the inclusion criteria were excluded. Thirteen studies were initially included; after the entire content and data were checked, all 13 were included. The selection flowchart is shown in Figure 1.

Figure 1.

Flowchart of selection.

Characteristics of included studies

Thirteen studies were included.^27–39 Five studies reported genetic polymorphisms.^27–31 Three gene polymorphisms, namely rs1898671, rs1837253, and rs11466749, were investigated.

For rs1898671 polymorphisms, two studies were included, which individually investigated cases from Poland and Taiwan of China.^29,31 The mean ages were 25.5 years and 5.94 ± 2.73, respectively. The diagnosis of AD was based on the International Study of Asthma and Allergies in Childhood (ISAAC) questionnaire and Hanifin and Rajka criteria. The sample sizes were 375 and 232 in the case group, and 1145 and 157 in the control group.

For rs1837253 polymorphisms, two studies were included, which individually investigated cases from Japan and Mainland China.^28,30 The mean ages were 30.7 ± 4.6 and 5.51 ± 7.93 years respectively. AD diagnosis was based on the ISAAC questionnaire and the Hanifin and Rajka criteria. The sample sizes were 188 and 2,954 in the case group and 565 and 5,347 in the control group.

For rs11466749 polymorphisms, two studies were included, which individually investigated cases from Taiwan of China and Ukraine.^27,31 The ages were 5.94 ± 2.73 years and a median of 8 years, respectively. AD diagnosis was based on the ISAAC questionnaire and multiple criteria. The sample sizes were 375 and 47 in the case group and 1,145 and 80 in the control group, respectively.

Both the alleles and detailed case numbers in the exposure groups was reported in the included studies; therefore, all five genetic models could be applied. Among the six study groups, five were compliant with the HWE, whereas one group with the rs1898671 polymorphism was not.

Eight studies reported on TSLP levels and AD (32-39). Among them, three were conducted in Korea,^33,35,39 Japan,³⁶ China,³² Denmark,³⁷ Turkey,³⁸ and Poland.³⁴ Three studies investigated the levels in children,^33,35,38 whereas the other five covered more age groups.^{32,34,36,37,39} Seven studies adopted the Hanifin and Rajka criteria to diagnose AD (33-39), whereas only one study applied the Williams criteria.³² All detection methods were ELISA, and the units were pg/mL in seven^33–39 and ng/L in one.³² The sample sizes varied from 25 to 132 in the case group and from 10 to 87 in the control group.

The basic characteristics of the included studies were in Tables 1 and 2. Descriptions of the control subjects are shown in sTable 1 in the Supplemental Material.

Table 1.

Basic characteristics of studies with TSLP gene polymorphisms and AD.

Study ID	Country or region	Ethnicity	Gender	Age	Diagnostic criteria	Case						Control						HWE
Study ID	Country or region	Ethnicity	Gender	Age	Diagnostic criteria	Sample	A	a	AA	Aa	aa	Sample	A	a	AA	Aa	aa	HWE
rs1898671
Wang 2016	Taiwan of China	Han of Chinese	Both	5.94 ± 2.73	ISAAC questionnaire	375	719	31	351	17	7	1145	2186	104	1048	90	7	<0.05
Klonowska 2021	Poland	European	Both	25.5	Hanifin & Rajka criteria	232	324	140	112	100	20	157	225	89	76	73	8	>0.05
rs1837253
Miyake 2015	Japan	Japanese	Female	30.7 ± 4.6	ISAAC questionnaire	188	230	146	68	94	26	565	749	381	250	249	66	>0.05
Jiang 2017	China	Han of Chinese	Both	5.51 ± 7.93	Hanifin & Rajka criteria	2954	3603	2305	1099	1405	450	5347	6266	4428	1826	2614	907	>0.05
rs11466749
Wang 2016	Taiwan of China	Han of Chinese	Both	5.94 ± 2.73	ISAAC questionnaire	375	689	61	320	49	6	1145	2099	191	963	173	9	>0.05
Dytiatkovskyi 2021	Ukraine	European	Both	Median 8	Multiple officially criteria	47	72	22	26	20	1	80	122	38	45	32	3	>0.05

Table 2.

Basic characteristics of studies with TSLP level and AD.

Study ID	Country or region	Gender	Age	Diagnostic criteria	Number		Detection
Study ID	Country or region	Gender	Age	Diagnostic criteria	Case	Control	Method	Unit	Case	Control
Nakamura 2008	Japan	Both	26.5	Hanifin & Rajka criteria	46	32	ELISA	pg/mL	192.2 ± 54.1	112.6 ± 52.6
Lee 2010	Korea	Both	4 ± 2.9	Hanifin & Rajka criteria	75	87	ELISA	pg/mL	31.57 ± 25.99	21.02 ± 14.58
Wu 2010	Korea	Both	15-37	Hanifin & Rajka criteria	25	10	ELISA	pg/mL	9.53 ± 3.54	9.83 ± 3.40
Li 2015	China	Both	23.8 ± 9.70	Williams criteria	40	30	ELISA	ng/L	198.24 ± 29.47	120.13 ± 19.65
Nygaard 2016	Denmark	Both	21.4 ± 11.8	Hanifin & Rajka criteria	132	31	ELISA	pg/mL	44.5 ± 245.3	10.9 ± 30.1
Uysal 2017	Turkey	Both	16 months	Hanifin & Rajka criteria	60	31	ELISA	pg/mL	158.15 ± 230.53	59.14 ± 68.00
Byeon 2020	Korea	Both	8.4 ± 2.9	Hanifin & Rajka criteria	38	10	ELISA	pg/mL	14.2 ± 5.7	9.03 ± 4.37
Jaworek 2020	Polan	Both	Median 34	Hanifin & Rajka criteria	31	20	ELISA	pg/mL	80.8 ± 12.5	14.6 ± 4.5

The NOS scores of the studies were ≥6, and the included studies were of high quality. Details of the quality assessments are presented in Table 3.

Table 3.

Results of study quality assessment through Newcastle-Ottawa scale.

	Nakamura 2008	Lee 2010	Wu 2010	Li 2015	Miyake 2015	Nygaard 2016	Wang 2016	Jiang 2017	Uysal 2017	Byeon 2020	Jaworek 2020	Klonowska 2021	Dytiatkovskyi 2021
Selection
Adequate definition of cases	★	★	★	★	★	★	★	★	★	★	★	★	★
Representativeness of cases	★	★	★	★	★	★	★	★	★	★	★	★	★
Selection of control subjects	★	★	/	★	★	/	★	★	★	/	★	★	★
Definition of control subjects	★	★	/	★	/	★	/	★	★	★	★	★	/
Comparability
Control for important factors	★	★	★	★★	★	★★	★	★★	★★	★	★★	★★	★
Exposure
Exposure assessment	★	★	★	★	★	★	★	★	★	★	★	★	★
Same method of ascertainment for all subjects	★	★	★	★	★	★	★	★	★	★	★	★	★
Non-response rate	★	★	★	★	★	★	★	★	★	★	★	★	★
Total score	8	8	6	9	7	8	7	9	9	7	9	9	7

Associations between TSLP gene polymorphisms and AD

For rs1898671 polymorphism, there were significant relationships with AD under homozygous (DD vs dd), and dominant contrasts (DD + Dd vs dd), with OR = 0.47 (95% CI: 0.24, 0.92) and 0.46 (95% CI: 0.24, 0.88), respectively (p < 0.05). Under allele (D vs d), heterozygous (Dd vs dd) and recessive contrasts (DD vs Dd + dd), no significant relationship was found, with OR = 0.95 (95% CI: 0.79, 1.15), 0.35 (95% CI: 0.00, 281.55) and 1.14 (95% CI: 0.84, 1.54), respectively (Figure 2).

Figure 2.

Forest plots of rs1898671 polymorphisms and AD.

For rs1837253 polymorphism, no significant relationship was found under each contrast (p > 0.05), with OR = 0.96 (95% CI: 0.13, 7.24) for allele, 0.98 (95% CI: 0.03, 31.80) for homozygous, 1.08 (95% CI: 0.95, 1.22) for heterozygous, 1.11 (95% CI: 0.99, 1.26) for dominant, and 0.93 (95% CI: 0.05, 17.96) for recessive contrasts, respectively (Figure 3).

Figure 3.

Forest plots of rs1837253 polymorphisms and AD.

For rs11466749 polymorphism, again no significant relationship was found under each contrast (p > 0.05), with OR = 1.03 (95% CI: 0.78, 1.34) for allele, 0.61 (95% CI: 0.24, 1.59) for homozygous, 0.55 (95% CI: 0.21, 1.47) for heterozygous, 0.61 (95% CI: 0.24, 1.57) for dominant, and 1.08 (95% CI: 0.80, 1.45) for recessive contrasts, respectively (Figure 4).

Figure 4.

Forest plots of rs11466749 polymorphisms and AD.

Association between TSLP levels and AD

Overall, 447 cases and 251 control subjects from eight studies were included. The pooled data suggested that serum TSLP levels were significantly higher in patients with AD compared with control subjects, with the SMD = 1.45 (95% CI: 0.65–2.25) (p < 0.05) (Figure 5).

Figure 5.

Forest plots of TSLP levels and AD.

Sensitivity analysis and publication bias

For comparisons with polymorphisms, the significance changed when a given study was omitted under some contrast in the rs1898671 and rs1837253 polymorphisms. This indicates that the results of these gene polymorphisms were not perfectly robust. In comparisons of the rs11466749 polymorphism, the significance did not change when a given study was omitted. This indicated that the results for the rs11466749 polymorphism were robust (sTable 2 in the Supplemental Material).

For comparison with TSLP levels, the significance did not change when each study was omitted individually. Therefore, the association between TSLP levels and AD was robust.

Eight studies were included for the comparison of TSLP levels. Funnel plots were used to evaluate publication bias. The plot was asymmetric, indicating a publication bias (Supplemental Figure 1).

Subgroup analysis

In each polymorphism comparison, it was unnecessary to perform a subgroup analysis because only two study groups were included.

In the comparison of TSLP levels, eight studies were included, and the heterogeneity was significant. Subgroup analysis was performed according to location and age. In the subgroup analysis by location, significant relationships were observed in both Asia and Europe. However, heterogeneity remained significant in each subgroup. In the subgroup analysis by age group, there were significant relationships both in children and in patients with a mean or median age of >18 years. Heterogeneity was not significant in the subgroup of children, whereas it was significant in older patients (Supplemental Figure 2).

Trial sequential analysis

For rs1898671, the Z-curve failed to reach the required information size (RIS) line under heterozygous contrast (Dd vs dd), indicating an inadequate sample size. The Z-curves crossed the monitoring boundary under homozygous (DD vs dd), heterozygous (Dd vs dd), and dominant contrast (DD + Dd vs dd) conditions, indicating the significance of the meta-analysis results.

For the rs1837253 and rs11466749 polymorphisms, the Z-curves failed to reach the RIS line and the monitoring boundary under all contrasts. The sample sizes were inadequate, and there was no significant difference in the meta-analysis results.

For comparison with the TSLP levels, the Z-curve crossed the RIS line and monitoring boundary. The sample sizes were adequate and the meta-analysis results were significant. The TSA results are presented in Figures 3–6 in Supplemental Material.

Discussion

TSLP is primarily secreted by the epithelial cells, airway smooth muscle cells, keratinocytes, stromal cells, fibroblasts, mast cells, macrophages, monocytes, granulocytes, and DCs. TSLP plays various pathophysiological roles in immune-related diseases.⁴⁰ In this study, we analyzed the relationship between TSLP and AD, which is more comprehensive and specific compared with previous studies. This relationship has been diverse in previous studies. Nakamura et al.³⁶ reported that TSLP levels were not elevated in patients with AD, whereas Uysal et al.³⁸ found that serum TSLP levels could be used as a biomarker in AD to predict severity. Therefore, we conducted a meta-analysis to comprehensively evaluate this relationship. With further research on AD pathogenesis, novel topical and systemic treatments, including dupilumab, tralokinumab, nemolizumab, crisaborole, and small-molecule Janus kinase (JAK) inhibitors, are being rapidly developed.^2,41–43

Tezepelumab (AMG157/MEDI9929), an anti-TSLP monoclonal antibody, has been widely investigated for asthma treatment. Multiple studies have confirmed its efficacy in asthma.^44–47 The FDA has approved the use of TSLP-targeted antibodies for severe asthma.⁴⁸ In 2019, Simpson et al. reported an optimistic response to tezepelumab in AD patients.⁴⁹ However, only a few studies have focused on the clinical application of tezepelumab in AD. We analyzed the association between TSLP gene polymorphisms, and its level, and the risk for AD. Our study lays the foundation for future research and provides a reference for future studies evaluating anti-TSLP mAbs in patients with AD.

Three gene polymorphisms, namely rs1898671, rs1837253, and rs11466749, were investigated in the present study. The rs1898671 polymorphism is an intron variant of the TSLP gene located on chr5:111072304. This polymorphism is mainly associated with allergic diseases such as AD (50), allergic rhinitis,⁵¹ and eosinophilic esophagitis.⁵² For the rs1898671 polymorphism, we found significant relationships with AD in homozygous (DD vs dd) and dominant (DD + Dd vs dd) contrasts in the present study. From our results, we conclude that the TSLP rs1898671 polymorphism is associated with AD. However, the sensitivity analysis showed that the results under these contrasts were not robust. Furthermore, in trial sequential analyses, inadequate sample sizes were included only under heterozygous contrast (Dd vs dd). Considering the overall quality of these results, further studies with a larger number of cases are required. The rs1837253 polymorphism is located on chr5:111066174, whereas the rs11466749 polymorphism is a non-coding transcript variant located on chr5:111076887. Both polymorphisms are associated with allergic diseases.^{14,15,17,51–54} In the present study, no significant relationship was found under each contrast for either polymorphism, and the TSA results indicated that the sample sizes were inadequate. Therefore, further studies with larger sample sizes should be conducted to investigate these relationships more thoroughly. Moreover, considering the diverse results of current studies, more research on both polymorphisms, focusing on their functions, is required.

Single nucleotide polymorphisms (SNPs) in different genomic regions affect gene function through various mechanisms.⁵⁵ More than 50% of SNPs are found in non-coding regions, where they primarily influence gene function by affecting the regulatory elements involved in gene expression or by altering splice-site activity, thus affecting translation. In coding regions, synonymous coding SNPs, while not altering the protein sequence, may still affect processes, such as protein folding, whereas non-synonymous SNPs directly change the amino acid composition of the encoded protein, with a functional impact depending on whether the altered amino acid plays a crucial role in the structure or function of the protein, rs1898671 is located in an intronic region, rs1837253 is located upstream of the transcription start site of TSLP, and rs11466749 is a noncoding transcript variant.^14,15,17,50 However, no studies have systematically investigated how rs1898671, rs1837253, and rs11466749 polymorphisms specifically affect TSLP protein levels, structure, or function. Further research is required to address this gap.

We also analyzed the relationship between serum TSLP levels and AD. TSLP is primarily generated by the epithelial and stromal cells of the skin, lungs, and gastrointestinal tract. In tissues and blood, TSLP acts as an alarmin. After being released from cells, TSLP participates in inflammatory and immune pathways.⁵⁶ The main targets of TSLP are DCs. Moreover, TSLP regulates neutrophils, basophils, eosinophils, group 2 innate lymphoid cells, natural killer T cells, mast cells, and smooth muscle cells.^57–59 TSLP plays an important role in the development of AD in humans. For example, Soumelis et al. found that TSLP was overexpressed in the skin lesions of patients with AD,⁶⁰ and in patients with asthma, TSLP levels were related to Th2 chemokine levels.⁶¹ In the present study, we included eight studies comprising 447 cases and 251 control subjects and found that TSLP levels were elevated in patients with AD. Previous studies have expressed different views regarding the relationship between TSLP levels and AD. For example, Nakamura et al.³⁶ suggested that serum TSLP levels are not elevated in patients with AD, whereas Jaworek et al.³⁴ suggested that serum TSLP levels are higher in patients with AD, and may play a vital role in the mechanism of this disease. Considering the limitations of the individual studies, we performed a meta-analysis. After selection based on the inclusion and exclusion criteria, our analysis included both previous and current studies of TSLP levels and AD. Moreover, adequate cases were enrolled from the TSA, indicating that the meta-analysis results were reliable. Additionally, sensitivity analysis showed that the relationship between TSLP levels and AD was robust. Therefore, it can be concluded that TSLP levels are elevated in patients with AD.

In comparison with TSLP levels, subgroup analysis was subsequently conducted based on location and age range. In each subgroup, the effect remained significant, indicating that TSLP levels remained elevated in patients with AD. However, heterogeneity remained significant, except in the subgroup of children. The genetic backgrounds of patients from different locations may differ, but the mechanism of TSLP in AD may be similar. Therefore, it could be that other factors contributed to the heterogeneity. We further analyzed the age range. AD affects children the most (20%), whereas only 5–10% of adults are affected.³ In younger patients, the immune function is still developing, which is different from that in adults; thus, the role of TSLP may differ in AD. Age may play a more important role than the region or genetic background. Consequently, the results of the studies included in the child subgroup showed high consistency and low heterogeneity. In the subgroup of patients with a mean or median age >18 years, patients with different age ranges were enrolled, which could result in significant heterogeneity. Since only two studies were included in each comparison of individual polymorphisms, subgroup analysis was unnecessary.

TSLP plays a critical role in the pathogenesis of AD and is a promising therapeutic target. A fully human IgG2λ monoclonal antibody, Tezepelumab, has been developed. Tezepelumab binds to a key part of the TSLP-binding site, preventing its interaction with TSLP receptor, thereby inhibiting various downstream inflammatory pathways.⁶² Tezepelumab has also been investigated as a treatment option for AD (49). Phase I studies have demonstrated that tezepelumab exhibits predictable linear pharmacokinetics, acceptable safety, and tolerability. Phase IIa trials have shown a higher rate of clinical improvement in the tezepelumab treatment group than in the placebo group, although this difference was not statistically significant.⁴⁹ Other drugs targeting TSLP have also been developed and are currently undergoing clinical trials (e.g. BSI-045B, CM326).⁶³ TSLP-targeted therapy shows great promise and could significantly improve AD treatment in the future.

Our study had some limitations. First, in the comparison of levels, publication bias may exist in the evaluation of the funnel plot. Second, in our initial research, other TSLP gene polymorphisms were identified; however, for these polymorphisms, only one study was included per polymorphism; thus, we did not perform any further analysis. Additionally, in the selection procedure, we set the inclusion and exclusion criteria, and although some publications tended to meet these criteria, they were still excluded. For example, in the study by Mócsai et al., specific data were only shown in figures, but the bars of the histogram were not clearly defined as standard error (SE) or SD.⁶⁴ In a study performed by Wang et al., the mean and SE of different age groups were obtained from the figures, but more steps were needed to merge the data; therefore, errors were not readily noticeable during the procedure.⁶⁵ Due to the absence of access to the original data, we excluded such studies. Finally, previous studies confirmed that TSLP is highly expressed in human AD lesions.⁶⁶ However, we did not analyze the TSLP levels in these lesions. For different patients with AD, the manifestations of the lesions may differ; consequently, the cytokine expression profile may vary. However, when samples are collected from patients with different manifestations and severities, the results may be inconsistent. Therefore, future studies with well-designed protocols focusing on TSLP levels in the skin lesions of patients with AD are required.

Conclusion

This meta-analysis indicated that TSLP gene rs1898671 polymorphism is associated with AD and that serum TSLP levels are elevated in patients with AD. TSLP is strongly associated with the susceptibility to AD.

Supplemental Material

Supplemental Material - Thymic stromal lymphopoietin and atopic dermatitis: A systematic review and meta-analysis with trial sequential analysis

Supplemental Material for Thymic stromal lymphopoietin and atopic dermatitis: A systematic review and meta-analysis with trial sequential analysis by Zhili Xu, Boyang Zhou, Suhua Wu, Tianhang Yu and Linfeng Li in European Journal of Inflammation.

Footnotes

Author contributions

Zhili Xu: The study concept and design; review of the literature; data collection, and interpretation of data; statistical analysis; writing of the manuscript. Boyang Zhou: Review of the literature; data collection, and interpretation of data; statistical analysis; Suhua Wu: Data collection, interpretation of data, and statistical analysis; Tianhang Yu: Data collection, interpretation of data, and statistical analysis; Linfeng Li: The study concept and design, statistical analysis; data collection; effective participation in the research guidance; final approval of the final version of the manuscript.

Declaration of conflicting interest

The authors declare no potential conflicts of interest with respect to research, authorship and/or publication of this article

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

ORCID iDs

Zhili Xu

Boyang Zhou

Linfeng Li

Supplemental Material

Supplemental material for this article is available online.

References

Kwatra

Misery

Clibborn

, et al. Molecular and cellular mechanisms of itch and pain in atopic dermatitis and implications for novel therapeutics. Clin Transl Immunology 2022; 11(5): e1390.

Mandlik

. Atopic dermatitis: new insight into the etiology, pathogenesis, diagnosis and novel treatment strategies. Immunopharmacol Immunotoxicol 2021; 43(2): 105–125.

Stefanovic

Flohr

Irvine

. The exposome in atopic dermatitis. Allergy 2020; 75(1): 63–74.

Sroka-Tomaszewska

Trzeciak

. Molecular mechanisms of atopic dermatitis pathogenesis. Int J Mol Sci 2021; 22(8): 4130.

Hammad

Debeuf

Aegerter

, et al. Emerging paradigms in type 2 immunity. Annu Rev Immunol 2022; 40: 443–467.

Nakajima

Tie

Nomura

, et al. Novel pathogenesis of atopic dermatitis from the view of cytokines in mice and humans. Cytokine 2021; 148: 155664.

Sugaya

. The role of Th17-related cytokines in atopic dermatitis. Int J Mol Sci 2020; 21(4): 1314.

Fitoussi

Virassamynaïk

Callejon

, et al. Inhibition of thymic stromal lymphopoietin production to improve pruritus and quality of life in infants and children with atopic dermatitis. J Cosmet Dermatol 2020; 19(8): 2061–2069.

Ziegler

. Thymic stromal lymphopoietin, skin barrier dysfunction, and the atopic march. Ann Allergy Asthma Immunol 2021; 127(3): 306–311.

10.

Kabata

Flamar

Mahlakõiv

, et al. Targeted deletion of the TSLP receptor reveals cellular mechanisms that promote type 2 airway inflammation. Mucosal Immunol 2020; 13(4): 626–636.

11.

Varricchi

Pecoraro

Marone

, et al. Thymic stromal lymphopoietin isoforms, inflammatory disorders, and cancer. Front Immunol 2018; 9: 1595.

12.

Yang

Lee

Shin

, et al. Efficient transdermal delivery of DNA nanostructures alleviates atopic dermatitis symptoms in NC/Nga mice. Adv Funct Mater 2018; 28(40): 1801918.

13.

Lee

Seok

Cho

, et al. Topical application of celastrol alleviates atopic dermatitis symptoms mediated through the regulation of thymic stromal lymphopoietin and group 2 innate lymphoid cells. J Toxicol Environ Health 2021; 84(22): 922–931.

14.

Moorehead

Hanna

Heroux

, et al. A thymic stromal lymphopoietin polymorphism may provide protection from asthma by altering gene expression. Clin Exp Allergy 2020; 50(4): 471–478.

15.

Sun

Wei

Deng

, et al. Association of IL1RL1 rs3771180 and TSLP rs1837253 variants with asthma in the Guangxi Zhuang population in China. J Clin Lab Anal 2019; 33(6): e22905.

16.

Heo

Park

Lee

, et al. TSLP polymorphisms in atopic dermatitis and atopic march in Koreans. Ann Dermatol 2018; 30(5): 529–535.

17.

Wang

Chen

Wang

, et al. The level of thymic stromal lymphopoietin and its gene polymorphism are associated with rheumatoid arthritis. Immunobiology 2021; 226(2): 152055.

18.

Chang

Mitra

Hoffstad

, et al. Association of filaggrin loss of function and thymic stromal lymphopoietin variation with treatment use in pediatric atopic dermatitis. JAMA Dermatol 2017; 153(3): 275–281.

19.

Margolis

Kim

Apter

, et al. Thymic stromal lymphopoietin variation, filaggrin loss of function, and the persistence of atopic dermatitis. JAMA Dermatol 2014; 150(3): 254–259.

20.

Zhou

Chen

Shang

, et al. Association of CTLA-4 gene polymorphisms and alopecia areata: a systematic review and meta-analysis. Biomarkers 2022; 27: 338–348.

21.

Luo

Wan

Liu

, et al. Optimally estimating the sample mean from the sample size, median, mid-range, and/or mid-quartile range. Stat Methods Med Res 2018; 27(6): 1785–1805.

22.

Wan

Wang

Liu

, et al. Estimating the sample mean and standard deviation from the sample size, median, range and/or interquartile range. BMC Med Res Methodol 2014; 14: 135.

23.

Ryckman

Williams

. Calculation and use of the Hardy-weinberg model in association studies. Curr Protoc Hum Genet 2008; Chapter 1: Unit1.18.

24.

Hilton

Hempel

Ewing

, et al. Mindfulness meditation for chronic pain: systematic review and meta-analysis. Ann Behav Med 2017; 51(2): 199–213.

25.

Gao

Chen

Yue

, et al. -196 to -174del, rs4696480, rs3804099 polymorphisms of Toll-like receptor 2 gene impact the susceptibility of cancers: evidence from 37053 subjects. Biosci Rep. 2019; 39(12): BSR20191698.

26.

Meng

Wang

Zhang

, et al. TP73 G4C14-A4T14 polymorphism and cancer susceptibility: evidence from 36 case-control studies. Biosci Rep. 2018; 38(6): BSR20181452.

27.

Dytiatkovskyi

Drevytska

Lapikova-Bryhinska

, et al. Genotype associations with the different phenotypes of atopic dermatitis in children. Acta Med 2021; 64(2): 96–100.

28.

Jiang

Zhao

, et al. Association analyses identify two susceptibility loci 5q31 and 5q22.1 for atopic dermatitis in Chinese Han population. Asian Pac J Allergy Immunol 2017; 35(4): 196–202.

29.

Klonowska

Gleń

Nowicki

, et al. Combination of FLG mutations and SNP of TSLP (rs1898671) influence on atopic dermatitis occurrence. Postepy Dermatol Alergol 2022; 39(1): 152–158.

30.

Miyake

Hitsumoto

Tanaka

, et al. Association between TSLP polymorphisms and eczema in Japanese women: the kyushu okinawa maternal and child health study. Inflammation 2015; 38(4): 1663–1668.

31.

Wang

Lockett

, et al. TSLP polymorphisms, allergen exposures, and the risk of atopic disorders in children. Ann Allergy Asthma Immunol 2016; 116(2): 139–145.

32.

Jiang

, et al. Effects of narrow-band ultraviolet B on the expressions of thymic stromal lymphopoietin, interleukin-25 and their receptors in peripheral blood of patients with atopic dermatitis. Chin J Dermatol 2015; 48(08): 551–553, (Article in Chinese).

33.

Byeon

Yoon

Ahn

, et al. Correlation of serum interleukin-31 with pruritus and blood eosinophil markers in children with atopic dermatitis. Allergy Asthma Proc 2020; 41(1): 59–65.

34.

Jaworek

Szafraniec

Zuber

, et al. Interleukin 25, thymic stromal lymphopoietin and house dust mites in pathogenesis of atopic dermatitis. J Physiol Pharmacol. 2020; 71(2): 291–297.

35.

Lee

Kim

Hong

, et al. Increased serum thymic stromal lymphopoietin in children with atopic dermatitis. Pediatr Allergy Immunol 2010; 21(2 Pt 2): e457–e460.

36.

Nakamura

Tsuchida

Tsunemi

, et al. Serum thymic stromal lymphopoietin levels are not elevated in patients with atopic dermatitis. J Dermatol 2008; 35(8): 546–547.

37.

Nygaard

Hvid

Johansen

, et al. TSLP, IL-31, IL-33 and sST2 are new biomarkers in endophenotypic profiling of adult and childhood atopic dermatitis. J Eur Acad Dermatol Venereol 2016; 30(11): 1930–1938.

38.

Uysal

Birtekocak

Karul

. The relationship between serum TARC, TSLP and POSTN levels and childhood atopic dermatitis. Clin Lab 2017; 63(7): 1071–1077.

39.

Park

, et al. Thymic stromal lymphopoietin-activated invariant natural killer T cells trigger an innate allergic immune response in atopic dermatitis. J Allergy Clin Immunol 2010; 126(2): 290–299.

40.

Takai

. TSLP expression: cellular sources, triggers, and regulatory mechanisms. Allergol Int 2012; 61(1): 3–17.

41.

Newsom

Bashyam

Balogh

, et al. New and emerging systemic treatments for atopic dermatitis. Drugs 2020; 80(11): 1041–1052.

42.

Puar

Chovatiya

Paller

. New treatments in atopic dermatitis. Ann Allergy Asthma Immunol 2021; 126(1): 21–31.

43.

Bissonnette

Pavel

Diaz

, et al. Crisaborole and atopic dermatitis skin biomarkers: an intrapatient randomized trial. J Allergy Clin Immunol 2019; 144(5): 1274–1289.

44.

Gauvreau

O'Byrne

Boulet

, et al. Effects of an anti-TSLP antibody on allergen-induced asthmatic responses. N Engl J Med 2014; 370(22): 2102–2110.

45.

Matera

Rogliani

Calzetta

, et al. TSLP inhibitors for asthma: current status and future prospects. Drugs 2020; 80(5): 449–458.

46.

Pelaia

Crimi

, et al. Tezepelumab: a potential new biological therapy for severe refractory asthma. Int J Mol Sci 2021; 22(9): 4369.

47.

Corren

Parnes

Wang

, et al. Tezepelumab in adults with uncontrolled asthma. N Engl J Med 2017; 377(10): 936–946.

48.

Mullard

. FDA approves first-in-class TSLP-targeted antibody for severe asthma. Nat Rev Drug Discov 2022; 21(2): 89.

49.

Simpson

Parnes

She

, et al. Tezepelumab, an anti-thymic stromal lymphopoietin monoclonal antibody, in the treatment of moderate to severe atopic dermatitis: a randomized phase 2a clinical trial. J Am Acad Dermatol 2019; 80(4): 1013–1021.

50.

Lou

Mitra

Wubbenhorst

, et al. Association between fine mapping thymic stromal lymphopoietin and atopic dermatitis onset and persistence. Ann Allergy Asthma Immunol 2019; 123(6): 595–601.

51.

Šaulienė

Greičiuvienė

Šukienė

, et al. Genetic loci associated with allergic sensitization in Lithuanians. PLoS One 2015; 10(7): e0134188.

52.

Sherrill

Gao

Stucke

, et al. Variants of thymic stromal lymphopoietin and its receptor associate with eosinophilic esophagitis. J Allergy Clin Immunol 2010; 126(1): 160–165.

53.

Moheimani

Hsu

Reid

, et al. The genetic and epigenetic landscapes of the epithelium in asthma. Respir Res 2016; 17(1): 119.

54.

Robinson

Baumann

Gilman

, et al. The Peru Urban versus Rural Asthma (PURA) Study: methods and baseline quality control data from a cross-sectional investigation into the prevalence, severity, genetics, immunology and environmental factors affecting asthma in adolescence in Peru. BMJ Open 2012; 2(1): e000421.

55.

Shastry

. SNPs: impact on gene function and phenotype. Methods Mol Biol 2009; 578: 3–22.

56.

Ebina-Shibuya

Leonard

. Role of thymic stromal lymphopoietin in allergy and beyond. Nat Rev Immunol 2022; 23: 24–37.

57.

West

Spolski

Kazemian

, et al. A TSLP-complement axis mediates neutrophil killing of methicillin-resistant Staphylococcus aureus. Sci Immunol 2016; 1(5): eaaf8471.

58.

Corren

Ziegler

. TSLP: from allergy to cancer. Nat Immunol 2019; 20(12): 1603–1609.

59.

Kobayashi

Voisin

Kim

, et al. Homeostatic control of sebaceous glands by innate lymphoid cells regulates commensal bacteria Equilibrium. Cell 2019; 176(5): 982–997.

60.

Soumelis

Reche

Kanzler

, et al. Human epithelial cells trigger dendritic cell mediated allergic inflammation by producing TSLP. Nat Immunol 2002; 3(7): 673–680.

61.

Ying

O'Connor

Ratoff

, et al. Thymic stromal lymphopoietin expression is increased in asthmatic airways and correlates with expression of Th2-attracting chemokines and disease severity. J Immunol 2005; 174(12): 8183–8190.

62.

Verstraete

Peelman

Braun

, et al. Structure and antagonism of the receptor complex mediated by human TSLP in allergy and asthma. Nat Commun 2017; 8: 14937.

63.

Eggel

Pennington

Jardetzky

. Therapeutic monoclonal antibodies in allergy: targeting IgE, cytokine, and alarmin pathways. Immunol Rev. 2024; 1–25.

64.

Mócsai

Gáspár

Nagy

, et al. Severe skin inflammation and filaggrin mutation similarly alter the skin barrier in patients with atopic dermatitis. Br J Dermatol 2014; 170(3): 617–624.

65.

Wang

Zhu

, et al. Distinct clinical features and serum cytokine pattern of elderly atopic dermatitis in China. J Eur Acad Dermatol Venereol 2020; 34(10): 2346–2352.

66.

Clausen

Kezic

Olesen

, et al. Cytokine concentration across the stratum corneum in atopic dermatitis and healthy controls. Sci Rep 2020; 10(1): 21895.

Supplementary Material

Please find the following supplemental material available below.

For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.

For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.

0.00 MB

0.37 MB