Variants Of Thymic Stromal Lymphopoietin Research Articles

TSLP is localized in and released from human lung macrophages activated by T2-high and T2-low stimuli: relevance in asthma and COPD

BackgroundMacrophages are the predominant immune cells in the human lung and play a central role in airway inflammation, including asthma and chronic obstructive pulmonary disease (COPD). Thymic stromal lymphopoietin (TSLP), a pleiotropic cytokine mainly expressed by bronchial epithelial cells, plays a key role in asthma and COPD pathobiology. TSLP exists in two variants: the long form (lfTSLP) and a shorter TSLP isoform (sfTSLP). We aimed to localize TSLP in human lung macrophages (HLMs) and investigate the mechanisms of its release from these cells. We also evaluated the effects of the two variants of TSLP on the release of angiogenic factor from HLMs. MethodsWe employed immunofluorescence and Western blot to localize intracellular TSLP in HLMs purified from human lung parenchyma. HLMs were activated by T2-high (IL-4, IL-13) and T2-low (lipopolysaccharide: LPS) immunological stimuli. ResultsTSLP was detected in HLMs and subcellularly localized in the cytoplasm. IL-4 and LPS induced TSLP release from HLMs. Preincubation of macrophages with brefeldin A, known to disrupt the Golgi apparatus, inhibited TSLP release induced by LPS and IL-4. lfTSLP concentration-dependently induced the release of vascular endothelial growth factor-A (VEGF-A), the most potent angiogenic factor, from HLMs. sfTSLP neither activated nor interfered with the activating property of lfTSLP on macrophages. ConclusionsOur results highlight a novel immunologic circuit between HLMs and TSLP. Given the central role of macrophages in airway inflammation, this autocrine loop holds potential translational relevance in understanding innovative aspects of the pathobiology of asthma and chronic inflammatory lung disorders.

TSLP shapes the pathogenic responses of memory CD4+ T cells in eosinophilic esophagitis.

The cytokine thymic stromal lymphopoietin (TSLP) mediates type 2 immune responses, and treatments that interfere with TSLP activity are in clinical use for asthma. Here, we investigated whether TSLP contributes to allergic inflammation by directly stimulating human CD4+ T cells and whether this process is operational in eosinophilic esophagitis (EoE), a disease linked to variants in TSLP. We showed that about 10% of esophageal-derived memory CD4+ T cells from individuals with EoE and less than 3% of cells from control individuals expressed the receptor for TSLP and directly responded to TSLP, as determined by measuring the phosphorylation of STAT5, a transcription factor activated downstream of TSLP stimulation. Accordingly, increased numbers of TSLP-responsive memory CD4+ T cells were present in the circulation of individuals with EoE. TSLP increased the proliferation of CD4+ T cells, enhanced type 2 cytokine production, induced the increased abundance of its own receptor, and modified the expression of 212 genes. The epigenetic response to TSLP was associated with an enrichment in BATF and IRF4 chromatin-binding sites, and these transcription factors were induced by TSLP, providing a feed-forward loop. The numbers of circulating and esophageal CD4+ T cells responsive to TSLP correlated with the numbers of esophageal eosinophils, supporting a potential functional role for TSLP in driving the pathogenesis of EoE and providing the basis for a blood-based diagnostic test based on the extent of TSLP-induced STAT5 phosphorylation in circulating CD4+ T cells. These findings highlight the potential therapeutic value of TSLP inhibitors for the treatment of EoE.

TSLP and IL-7R Variants Are Associated with Persistent Atopic Dermatitis

TSLP and IL-7R Variants Are Associated with Persistent Atopic Dermatitis

Tezepelumab: a novel biological therapy for the treatment of severe uncontrolled asthma

ABSTRACTIntroduction: Thymic stromal lymphopoietin (TSLP) is overexpressed in the airways of severe asthmatics and is an upstream cytokine that orchestrates inflammatory responses in asthma. TSLP exerts its effects by binding to a high affinity heteromeric receptor complex composed of TSLPR and IL-7Rα. An association of polymorphisms in TSLP with airway hyperresponsiveness, IgE, eosinophilia and asthma has been documented. TSLP has been implicated in asthma pathophysiology. Tezepelumab is a first-in-class human monoclonal antibody that binds to TSLP, thus inhibiting its interaction with TSLP receptor complex. Tezepelumab given as an add-on-therapy to patients with severe uncontrolled asthma has shown safety, tolerability and efficacy. Several trials are evaluating the long-term safety and the efficacy of tezepelumab in adults and adolescents with severe uncontrolled asthma.Areas covered: We provide an overview of the monoclonal antibody therapeutics market for severe uncontrolled asthma, examine the underlying pathophysiology that drives TSLP and discuss the use of tezepelumab for the treatment of severe uncontrolled asthma,Expert opinion: TSLP is a promising target for T2-high and perhaps some patients with T2-low asthma. The results of preliminary clinical trials are encouraging. Several unanswered questions concerning basic pathophysiological aspects of TSLP variants, the long-term safety and efficacy of tezepelumab with different phenotypes/endotypes of asthma should be addressed.

Association between fine mapping thymic stromal lymphopoietin and atopic dermatitis onset and persistence

BackgroundAtopic dermatitis (AD) is a common chronic relapsing skin disease. Genetic variants have been associated with skin barrier function and immune regulation. Thymic stromal lymphopoietin (TSLP), an immune regulator, has been previously associated with AD. ObjectiveTo fine map TSLP and evaluate associations with the onset and persistence of AD. MethodsTSLP variation was determined using targeted massively parallel sequencing in a longitudinal cohort of children with AD. Evaluations included linkage disequilibrium and the persistence of AD for as many as 10 years of follow-up. The association between the presence of AD and rs1898671 variation was evaluated in a second independent cohort. ResultsThe minor variant frequency for rs1898671 was 23.5% (95% CI, 21.4%-25.8%). This variant was not in linkage disequilibrium with other TSLP variants in the longitudinal cohort (n = 741). White children with AD were less likely to have rs1898671 variant (odds ratio [OR], 1.41; 95% CI, 1.20-1.66) than Genome Aggregation Database controls. Children with AD and the rs1898671 variant during follow-up were more likely to have remission than children who were wild type for rs1898671 (OR, 1.56; 95% CI, 1.26-1.91). In the second cohort (n = 585), the rs1898671 variant was less prevalent in those with AD than those without. The protective effect was greater in rs1898671 heterozygotes (OR, 1.91; 95% CI, 1.34-2.75) than homozygotes (OR, 1.28; 95% CI, 0.61-2.70). ConclusionTSLP and specifically rs1898671 are important in the pathogenesis of AD and could represent a potential clinical target for the development of therapies to treat individuals with AD.

TSLP Polymorphisms in Atopic Dermatitis and Atopic March in Koreans

BackgroundAtopic march (AM) is the progression from atopic dermatitis (AD) to allergic rhinitis and asthma. The development of AD is as high as 20% in children worldwide and continues to increase. AD seems to be caused by both genetic and environmental factors. Recently, polymorphisms of the thymic stromal lymphopoietin (TSLP) gene associated with allergic disorders were reported in ethnic groups from various countries.ObjectiveIdentification of TSLP polymorphisms in Koreans with AD or AM.MethodsWhole-exome sequencing was performed in 20 AD and 20 AM patients.ResultsNine single nucleotide polymorphisms (SNPs) of TSLP were detected (rs191607411, rs3806933, rs2289276, rs2289277, rs2289278, rs139817258, rs11466749, rs11466750, rs10073816). These SNPs have been correlated with susceptibility to allergic diseases in ethnic groups from China, Japan, Turkey, and Costa Rica in previous studies. Remarkably, one of 20 patients in the AD group lacked all SNPs, compared to six of 20 patients in the AM group. Odds ratios showed that Korean patients without the nine TSLP variants had an 8.14 times higher risk of moving from AD to AM. Two haplotype blocks were validated in 60 AD and 59 AM patients using Sanger sequencing. The haplotype blocks (rs3806933 and rs2289276) and (rs11466749 and rs11466750) were in high linkage disequilibrium, respectively (D′=0.97, D′=1).ConclusionThe increase of major allele frequency of respective nine TSLP variants may enhance the risk of AM. These data will contribute to improved genetic surveillance system in the early diagnosis technology of allergic disease.

Association between TSLP gene polymorphism and bronchial asthma in children in Beni Suef Governorate in Egypt

Asthma is a chronic inflammatory disease of the airway that is mediated by T-helper 2 (TH2) cells. Thymic stromal lymphopoietin (TSLP) gene can exacerbate the lung inflammatory process in asthma by enhancing TH2 differentiation through dendritic cell activation. Many studies showed that TSLP polymorphisms are related to bronchial asthma susceptibility in different populations. The objectives of this study are to study the polymorphism of the two SNPs Rs2289276 and Rs2289278 in TSLP gene and to analyze any possible relation to pediatric bronchial asthma liability in Egypt using case-control study. DNA was extracted from blood samples withdrawn from 40 asthmatic patients and 20 age- and sex-matched normal controls, then the genotypes of SNPs Rs2289276 and Rs2289278 in TSLP gene were identified with polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP), and genotypes and allele frequencies were calculated and statistically analyzed. Genotypes of Rs2289276 site in the asthmatic patients were dissimilar from those of the controls (P = 0.045). The genotypes of Rs2289278 in asthmatic patients were significantly different between those of intermittent and severe asthma (P = 0.044). Bronchial asthma susceptibility and severity are related to TSLP variants. Thus, TSLP might be a new target molecule for asthma treatment.

The short form of TSLP is constitutively translated in human keratinocytes and has characteristics of an antimicrobial peptide.

Thymic stromal lymphopoietin (TSLP) has multifaceted immunological functions ranging from maintenance of tolerance to induction of disease. Two human transcript variants of TSLP are described: a long form (variant 1; lfTSLP) consisting of four exons and an alternative, short form (variant 2; sfTSLP) that lacks two exons compared with variant 1. SfTSLP has not been described at the protein level or functionally studied. Here, we demonstrate that the human sfTSLP is the predominant form of TSLP, constitutively expressed at the mRNA and protein level in keratinocytes of oral mucosa and skin and in salivary glands, is released in saliva, and is not regulated in the same manner as the long form. Compared with lfTSLP, sfTSLP exhibits a markedly stronger antibacterial activity. Synthetic sfTSLP did not activate signal transducer and activator of transcription 5 (STAT5) signaling in CD1c(+) dendritic cells nor interfered with STAT5 activation by lfTSLP. SfTSLP may, therefore, act as an antimicrobial peptide in the oral cavity and on the skin to create a defense barrier that aids in the control of both commensal and pathogenic microbes. The results show that the two translational products of the TSLP gene have a different expression and different biological properties, and emphasize the importance of analyzing the two TSLP isoforms separately.

Thymic Stromal Lymphopoietin Variation, Filaggrin Loss of Function, and the Persistence of Atopic Dermatitis

Atopic dermatitis (AD) is a common chronic illness of childhood. To evaluate the association between thymic stromal lymphopoietin (TSLP) variation and the persistence of skin symptoms of AD. A prospective cohort study was conducted in the general community. Participants included 796 children enrolled in the Pediatric Eczema Elective Registry. EXPOSURE Evaluation of TSLP variation. Self-reported outcome of whether a child's skin had no symptoms of AD and required no medications for 6 months at 6-month intervals. We evaluated 14 variants of TSLP. The variant rs1898671 was significantly associated with the outcome in white children (P = .01). As measured by overlapping CIs, similar odds ratios (ORs) were noted among whites (OR, 1.72; 95% CI, 1.11-2.66) and African Americans (1.33; 0.52-3.45). Further within the subcohort of individuals with a filaggrin protein (FLG) loss-of-function mutation, those with TSLP variation were more likely to have less-persistent disease (OR, 4.92; 95% CI, 2.04-11.86). The TSLP variation is associated with less persistent AD. Therefore, TSLP may be a potential therapeutic target for the treatment of AD, especially in individuals with diminished barrier function due to FLG mutations. This is an attractive hypothesis that can be tested in clinical trials.

The Genetic Variants of Thymic Stromal Lymphopoietin Protein in Children with Asthma and Allergic Rhinitis

Background: Thymic stromal lymphopoietin (TSLP) is expressed by airway epithelial cells and plays a key role in immunological events in asthma. Data on the genetic variants of TSLP and its association with asthma and allergic rhinitis are scarce. We aimed to investigate the effects of the genetic variants of TSLP in children with asthma and allergic rhinitis. Methods: The genetic variants of the TSLP gene were determined by sequencing 25 asthmatic and 25 healthy children. In an association study, a population of 506 asthmatics and 157 healthy controls was screened for the following single-nucleotide polymorphisms (SNPs): rs3806933 and rs2289276 in the promoter region; rs11466741, rs11466742, and rs2289278 in intron 2; rs10073816, rs11466749, and rs11466750 in exon 4, and rs11466754 in 3′-UTR. Results: In Multifactor Dimensionality Reduction analysis, presence of the rs11466749 AA genotype with atopy was significantly associated with a diagnosis of asthma (testing set accuracy: 0.720 and cross validation: 9/10). Two functional SNPs showed a gender-specific association with allergy, i.e. the rs3806933 CC genotype with asthma in boys (p = 0.032, nonsignificant after multiple testing) and the rs2289276 CC genotype with higher eosinophil numbers in asthmatic girls (p = 0.003). The presence of allergic rhinitis in asthmatic children strengthened the association of the rs11466749 GG genotype with asthma (p = 0.001), and rs2289276 was significantly associated with lower FEV₁ levels in asthmatics without allergic rhinitis (p = 0.003). Conclusion: Variants in the gene encoding the TSLP protein may have differential effects on asthma phenotypes depending on gender, atopy, and the presence of allergic rhinitis.

Association Study of Functional Polymorphisms in Genes Involved in Histamine Homeostasis and Multiple NSAID–Triggered Urticaria and/or Angioedema and Anaphylaxis in Patients without Pre-Existing Chronic Urticaria (MNSAID-UA)

M O N D A Y 599 Association of Thymic Stromal Lymphopoietin Genetic Variants in Urticaria/Angioedema Induced by Multiple Nsaids Maria del Carmen Plaza-Ser on, Bsc, Pedro Ayuso Parejo, PhD, Natalia Blanca-L opez, MD, PhD, Inmaculada Do~na, MD, PhD, Mar ia Jos e Torres, MD, PhD, Javier Fern andez, Jose Julio Laguna, Veronique Goidenau, Luisa Galindo, RN, Rocio Herrera, NR, Gabriela Canto, MD, PhD, Miguel Blanca, MD, PhD, Jose Antonio Cornejo-Garc ia; Allergy Service, Infanta Leonor Hospital, Malaga, Spain, Allergy Service, Infanta Leonor Hospital, Madrid, Spain, IMABIS Foundation, Malaga, Spain, Imabis Foundation, Alicante Hospital, Hospital De La Cruz Roja, Madrid, Spain, Carlos Haya Hospital, Malaga, Spain, Alergy Service Carlos Haya Hospital, Malaga, Spain, Allergy Service, Infanta Leonor Hospital, Allergy Service, Carlos Haya Hospital, M alaga, Spain. RATIONALE: NSAIDs are the most frequent agents involved in hypersensitivity reactions to drugs (HDR), being urticaria/angioedema (MNSAID-UA) the most relevant clinical entity. A significant proportion of MNSAID-UA patients show a high prevalence of atopic status. The thymic stromal lymphopoietin (TSLP) is involved in the inflammatory skin response mediated by mast cells. These are key players in MNSAID-UA. An association of SNPs in the TSLP gene and its receptor (IL7Ra and TSLPR) has been reported in other inflammatory diseases. In this work, we analyzed the potential association between SNPs in TSLP, IL7Ra and TSLPR, and MNSAID-UA. METHODS: A total of 394 patients with MNSAID-UA and 257 controls who tolerated NSAIDs were included. This is a part of a study carried out by the Spanish National Network for Allergy (RIRAAF). A total of 6 tSNPs inTSLP, 6 tSNPs in IL7Ra and 3 tSNPs inTSLPRwere genotyped by using TaqMan O probes. Statistical analysis was done using SPSS 11.5 program and Haploview. RESULTS: Statistically significant differences were found only for SNPs rs1545169 and rs764917 in TSLP gene (p< 0.0001, and p< 0.014; respectively). After atopic status adjustment, these differences were not observed. CONCLUSIONS: Although genetic variants in TSLP and related genes appear not be associated with MNSAID-UA, these SNPs could play a role in atopy. Further studies are needed to unveil the interaction between these two entities.

Association of Thymic Stromal Lymphopoietin Genetic Variants in Urticaria/Angioedema Induced by Multiple Nsaids

M O N D A Y 599 Association of Thymic Stromal Lymphopoietin Genetic Variants in Urticaria/Angioedema Induced by Multiple Nsaids Maria del Carmen Plaza-Ser on, Bsc, Pedro Ayuso Parejo, PhD, Natalia Blanca-L opez, MD, PhD, Inmaculada Do~na, MD, PhD, Mar ia Jos e Torres, MD, PhD, Javier Fern andez, Jose Julio Laguna, Veronique Goidenau, Luisa Galindo, RN, Rocio Herrera, NR, Gabriela Canto, MD, PhD, Miguel Blanca, MD, PhD, Jose Antonio Cornejo-Garc ia; Allergy Service, Infanta Leonor Hospital, Malaga, Spain, Allergy Service, Infanta Leonor Hospital, Madrid, Spain, IMABIS Foundation, Malaga, Spain, Imabis Foundation, Alicante Hospital, Hospital De La Cruz Roja, Madrid, Spain, Carlos Haya Hospital, Malaga, Spain, Alergy Service Carlos Haya Hospital, Malaga, Spain, Allergy Service, Infanta Leonor Hospital, Allergy Service, Carlos Haya Hospital, M alaga, Spain. RATIONALE: NSAIDs are the most frequent agents involved in hypersensitivity reactions to drugs (HDR), being urticaria/angioedema (MNSAID-UA) the most relevant clinical entity. A significant proportion of MNSAID-UA patients show a high prevalence of atopic status. The thymic stromal lymphopoietin (TSLP) is involved in the inflammatory skin response mediated by mast cells. These are key players in MNSAID-UA. An association of SNPs in the TSLP gene and its receptor (IL7Ra and TSLPR) has been reported in other inflammatory diseases. In this work, we analyzed the potential association between SNPs in TSLP, IL7Ra and TSLPR, and MNSAID-UA. METHODS: A total of 394 patients with MNSAID-UA and 257 controls who tolerated NSAIDs were included. This is a part of a study carried out by the Spanish National Network for Allergy (RIRAAF). A total of 6 tSNPs inTSLP, 6 tSNPs in IL7Ra and 3 tSNPs inTSLPRwere genotyped by using TaqMan O probes. Statistical analysis was done using SPSS 11.5 program and Haploview. RESULTS: Statistically significant differences were found only for SNPs rs1545169 and rs764917 in TSLP gene (p< 0.0001, and p< 0.014; respectively). After atopic status adjustment, these differences were not observed. CONCLUSIONS: Although genetic variants in TSLP and related genes appear not be associated with MNSAID-UA, these SNPs could play a role in atopy. Further studies are needed to unveil the interaction between these two entities.

Two single nucleotide polymorphisms in TSLP gene are associated with asthma susceptibility in Chinese Han population

ABSTRACTBackground: Asthma is a chronic inflammatory disease of the airway that is mediated by T-helper 2(TH2) cells. Thymic stromal lymphopoietin (TSLP) can aggravate asthmatic lung inflammation by activating dendritic cells (DCs) to promote TH2 differentiation. TSLP promoter polymorphisms are associated with susceptibility to bronchial asthma in Japanese population. We sought to determine whether single nucleotide polymorphisms (SNPs) in TSLP gene are associated with asthma in Chinese Han population. Objective: To analyze the polymorphism of the two SNPs Rs2289276 and Rs2289278 in TSLP gene and to evaluate the association between the two SNPs and asthma susceptibility in Chinese Han population by using case-control study. Methods: five hundred and thirty one asthmatic patients and 540 age–sex matched normal controls were collected and DNA were extracted from peripheral blood, then the genotypes of SNPs Rs2289276 and Rs2289278 in TSLP gene were detected with polymerase chain reaction and restriction fragment length polymorphism (PCR-RFLP), genotype and allele frequencies were calculated and analyzed with Chi-square test. Results: Frequencies of CC/CT/TT genotypes at Rs2289276 site were 0.4706/0.4392/0.0902 in the asthmatic patients and 0.5604/0.3800/0.0595 in the healthy controls. Frequencies of CC/CG/GG genotypes at Rs2289278 site were 0.6502/0.2966/0.0532 in the asthmatic patients and 0.5795/0.3428/0.0777 in the healthy controls. The genotype and allele frequencies of the two SNPs in asthma patients were significantly different from those in the healthy controls. Rs2289278 C allele was correlated with decreased FEV1: FVC (P ≤ .05). Conclusions: TSLP variants are significantly associated with bronchial asthma. TSLP might be a new therapeutic target molecule for asthma.

Thymic stromal lymphopoietin (TSLP) is associated with allergic rhinitis in children with asthma

BackgroundAllergic rhinitis (AR) affects up to 80% of children with asthma and increases asthma severity. Thymic stromal lymphopoietin (TSLP) is a key mediator of allergic inflammation. The role of the TSLP gene (TSLP) in the pathogenesis of AR has not been studied.ObjectiveTo test for associations between variants in TSLP, TSLP-related genes, and AR in children with asthma.MethodsWe genotyped 15 single nucleotide polymorphisms (SNPs) in TSLP, OX40L, IL7R, and RXRα in three independent cohorts: 592 asthmatic Costa Rican children and their parents, 422 nuclear families of North American children with asthma, and 239 Swedish children with asthma. We tested for associations between these SNPs and AR. As we previously reported sex-specific effects for TSLP, we performed overall and sex-stratified analyses. We additionally performed secondary analyses for gene-by-gene interactions.ResultsAcross the three cohorts, the T allele of TSLP SNP rs1837253 was undertransmitted in boys with AR and asthma as compared to boys with asthma alone. The SNP was associated with reduced odds for AR (odds ratios ranging from 0.56 to 0.63, with corresponding Fisher's combined P value of 1.2 × 10-4). Our findings were significant after accounting for multiple comparisons. SNPs in OX40L, IL7R, and RXRα were not consistently associated with AR in children with asthma. There were nominally significant interactions between gene pairs.ConclusionsTSLP SNP rs1837253 is associated with reduced odds for AR in boys with asthma. Our findings support a role for TSLP in the pathogenesis of AR in children with asthma.

TSLP polymorphisms are associated with asthma in a sex‐specific fashion

Single nucleotide polymorphisms (SNPs) in thymic stromal lymphopoietin (TSLP) have been associated with IgE (in girls) and asthma (in general). We sought to determine whether TSLP SNPs are associated with asthma in a sex-specific fashion. We conducted regular and sex-stratified analyses of association between SNPs in TSLP and asthma in families of children with asthma in Costa Rica. Significant findings were replicated in whites and African-American participants in the Childhood Asthma Management Program, in African-Americans in the Genomic Research on Asthma in the African Diaspora study, in whites and Hispanics in the Children's Health Study, and in whites in the Framingham Heart Study (FHS). Two SNPs in TSLP (rs1837253 and rs2289276) were significantly associated with a reduced risk of asthma in combined analyses of all cohorts (P values of 2 × 10(-5) and 1 × 10(-5) , respectively). In a sex-stratified analysis, the T allele of rs1837253 was significantly associated with a reduced risk of asthma in males only (P = 3 × 10(-6) ). Alternately, the T allele of rs2289276 was significantly associated with a reduced risk of asthma in females only (P = 2 × 10(-4) ). Findings for rs2289276 were consistent in all cohorts except the FHS. TSLP variants are associated with asthma in a sex-specific fashion.

Thymic Stromal Lymphopoietin Gene Promoter Polymorphisms Are Associated with Susceptibility to Bronchial Asthma

Thymic stromal lymphopoietin (TSLP) triggers dendritic cell--mediated T helper (Th) 2 inflammatory responses. A single-nucleotide polymorphism (SNP), rs3806933, in the promoter region of the TSLP gene creates a binding site for the transcription factor activating protein (AP)-1. The variant enhances AP-1 binding to the regulatory element, and increases the promoter--reporter activity of TSLP in response to polyinosinic-polycytidylic acid (poly[I:C]) stimulation in normal human bronchial epithelium (NHBE). We investigated whether polymorphisms including the SNP rs3806933 could affect the susceptibility to and clinical phenotypes of bronchial asthma. We selected three representative (i.e., Tag) SNPs and conducted association studies of the TSLP gene, using two independent populations (639 patients with childhood atopic asthma and 838 control subjects, and 641 patients with adult asthma and 376 control subjects, respectively). We further examined the effects of corticosteroids and a long-acting β(2)-agonist (salmeterol) on the expression levels of the TSLP gene in response to poly(I:C) in NHBE. We found that the promoter polymorphisms rs3806933 and rs2289276 were significantly associated with disease susceptibility in both childhood atopic and adult asthma. The functional SNP rs3806933 was associated with asthma (meta-analysis, P = 0.000056; odds ratio, 1.29; 95% confidence interval, 1.14-1.47). A genotype of rs2289278 was correlated with pulmonary function. Moreover, the induction of TSLP mRNA and protein expression induced by poly(I:C) in NHBE was synergistically impaired by a corticosteroid and salmeterol. TSLP variants are significantly associated with bronchial asthma and pulmonary function. Thus, TSLP may serve as a therapeutic target molecule for combination therapy.

Variants of thymic stromal lymphopoietin and its receptor associate with eosinophilic esophagitis

The genetic cause of eosinophilic esophagitis (EE) has been largely unexplored until a recent genome-wide association study identified a disease susceptibility locus on 5q22, a region that harbors the thymic stromal lymphopoietin (TSLP) gene. However, it is unclear whether the observed genetic associations with EE are disease-specific or confounded by the high rate of allergy in patients with EE. In addition, the genetic contributions of other allergy-associated genes to EE risk have not been explored. We aimed to delineate single nucleotide polymorphisms (SNPs) that associated with EE apart from allergy. We used a custom array containing 738 SNPs in 53 genes implicated in allergic responses, immune responses, or both to genotype 220 allergic or 246 nonallergic control subjects and a discovery cohort of 170 patients with EE. We replicated a statistically significant SNP association in an independent case-control cohort and examined the induction of the candidate gene in primary esophageal epithelial cells. A single SNP residing in the TSLP gene reached Bonferroni linkage disequilibrium-adjusted significance but only when patients with EE were compared with allergic control subjects (rs10062929; P = 4.11 x 10(-5); odds ratio, 0.35). A nonsynonymous polymorphism in the thymic stromal lymphopoietin receptor (TSLPR) gene on Xp22.3 and Yp11.3 was significantly associated with disease only in male patients with EE. Primary esophageal epithelial cells expressed TSLP mRNA after Toll-like receptor 3 stimulation. These data collectively identify TSLP as a candidate gene critically involved in EE susceptibility beyond its role in promoting T(H)2 responses.

A thymic stromal lymphopoietin gene variant is associated with asthma and airway hyperresponsiveness

The epithelial cell-derived protein thymic stromal lymphopoietin stimulates dendritic and mast cells to promote proallergic T(H)2 responses. Studies of transgenic expression of thymic stromal lymphopoietin and its receptor knockout mice have emphasized its critical role in the development of allergic inflammation. Association of genetic variation in thymic stromal lymphopoietin with IgE levels has been reported for human subjects. The aim of this study was to evaluate the relationship between variants of thymic stromal lymphopoietin and asthma and related phenotypes. We selected 6 single nucleotide polymorphisms in thymic stromal lymphopoietin and genotyped 5565 individuals from 4 independent asthma studies and tested for association with asthma, atopy, atopic asthma, and airway hyperresponsiveness by using a general allelic likelihood ratio test. P values were corrected for the effective number of independent single nucleotide polymorphisms and phenotypes. The A allele of rs1837253, which is 5.7 kb upstream of the transcription start site of the gene, was associated with protection from asthma, atopic asthma, and airway hyperresponsiveness, with the odds ratios and corrected P values for each being 0.79 and 0.0058; 0.75 and 0.0074; and 0.76 and 0.0094, respectively. Associations between thymic stromal lymphopoietin and asthma-related phenotypes were the most statistically significant observations in our study, which has to date examined 98 candidate genes. Full results are available online at http://genapha.icapture.ubc.ca/. A genetic variant in the region of the thymic stromal lymphopoietin gene is associated with the phenotypes of asthma and airway hyperresponsiveness.