Interleukin‐9 polymorphism in infants with respiratory syncytial virus infection: An opposite effect in boys and girls

Schuurhof, Annemieke; Bont, Louis; Siezen, Christine L. E.; Hodemaekers, Hennie M.; Houwelingen, Hans C. van; Kimman, Tjeerd G.; Hoebee, Barbara; Kimpen, Jan L. L.; Janssen, Riny

doi:10.1002/ppul.21229

Cited by 50 publications

(45 citation statements)

References 25 publications

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“…To assess whether IL-9 may contribute to allergy in CF patients, we determined the effect of the non-synonymous IL9 p.Thr117Met (c.350C>T, rs2069885) polymorphism, known to be associated with lung function and sensitization3637 on total and Aspergillus -specific IgE levels in CF patients (Supplementary Table 1). Previous association studies demonstrated the existence of sex dimorphism linked to this polymorphism3637.…”

Section: Resultsmentioning

confidence: 99%

A mast cell-ILC2-Th9 pathway promotes lung inflammation in cystic fibrosis

et al. 2017

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T helper 9 (Th9) cells contribute to lung inflammation and allergy as sources of interleukin-9 (IL-9). However, the mechanisms by which IL-9/Th9 mediate immunopathology in the lung are unknown. Here we report an IL-9-driven positive feedback loop that reinforces allergic inflammation. We show that IL-9 increases IL-2 production by mast cells, which leads to expansion of CD25+ type 2 innate lymphoid cells (ILC2) and subsequent activation of Th9 cells. Blocking IL-9 or inhibiting CD117 (c-Kit) signalling counteracts the pathogenic effect of the described IL-9-mast cell-IL-2 signalling axis. Overproduction of IL-9 is observed in expectorates from cystic fibrosis (CF) patients, and a sex-specific variant of IL-9 is predictive of allergic reactions in female patients. Our results suggest that blocking IL-9 may be a therapeutic strategy to ameliorate inflammation associated with microbial colonization in the lung, and offers a plausible explanation for gender differences in clinical outcomes of patients with CF.

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Section: Resultsmentioning

confidence: 99%

A mast cell-ILC2-Th9 pathway promotes lung inflammation in cystic fibrosis

et al. 2017

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“…Genes controlling infections that appear to be sex dependent have been observed also with other infectious agents such as viruses [69–71], bacteria [72], parasites [58], and fungi [73] and helminths [74]. Some of sex-dependent QTLs exhibit a higher or exclusive influence on susceptibility in females [58, 69, 71–73] or males [69, 71–74], phenotypic effect of other genes is present in both sexes, but with opposite direction of effect [69, 70]. All these reported loci are situated on autosomal chromosomes.…”

Section: Discussionmentioning

confidence: 99%

Gene-specific sex effects on eosinophil infiltration in leishmaniasis

et al. 2016

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BackgroundSex influences susceptibility to many infectious diseases, including some manifestations of leishmaniasis. The disease is caused by parasites that enter to the skin and can spread to the lymph nodes, spleen, liver, bone marrow, and sometimes lungs. Parasites induce host defenses including cell infiltration, leading to protective or ineffective inflammation. These responses are often influenced by host genotype and sex. We analyzed the role of sex in the impact of specific gene loci on eosinophil infiltration and its functional relevance.MethodsWe studied the genetic control of infiltration of eosinophils into the inguinal lymph nodes after 8 weeks of Leishmania major infection using mouse strains BALB/c, STS, and recombinant congenic strains CcS-1,-3,-4,-5,-7,-9,-11,-12,-15,-16,-18, and -20, each of which contains a different random set of 12.5% genes from the parental “donor” strain STS and 87.5% genes from the “background” strain BALB/c. Numbers of eosinophils were counted in hematoxylin-eosin-stained sections of the inguinal lymph nodes under a light microscope. Parasite load was determined using PCR-ELISA.ResultsThe lymph nodes of resistant STS and susceptible BALB/c mice contained very low and intermediate numbers of eosinophils, respectively. Unexpectedly, eosinophil infiltration in strain CcS-9 exceeded that in BALB/c and STS and was higher in males than in females. We searched for genes controlling high eosinophil infiltration in CcS-9 mice by linkage analysis in F2 hybrids between BALB/c and CcS-9 and detected four loci controlling eosinophil numbers. Lmr14 (chromosome 2) and Lmr25 (chromosome 5) operate independently from other genes (main effects). Lmr14 functions only in males, the effect of Lmr25 is sex independent. Lmr15 (chromosome 11) and Lmr26 (chromosome 9) operate in cooperation (non-additive interaction) with each other. This interaction was significant in males only, but sex-marker interaction was not significant. Eosinophil infiltration was positively correlated with parasite load in lymph nodes of F2 hybrids in males, but not in females.ConclusionsWe demonstrated a strong influence of sex on numbers of eosinophils in the lymph nodes after L. major infection and present the first identification of sex-dependent autosomal loci controlling eosinophilic infiltration. The positive correlation between eosinophil infiltration and parasite load in males suggests that this sex-dependent eosinophilic infiltration reflects ineffective inflammation.

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“…One of these studies showed a sex-specific protective effect for wheeze in girls with a particular haplotype in the IL-9 receptor gene (28) , and another identified associations (in male subjects only) between the IL-9 polymorphisms rs2069885 and rs2069882 and phenotypes for lung function and multiple-allergen sensitization, respectively (29) . Lastly, a study in infants showed effect modification by sex for the association between the IL-9 polymorphism rs2069885 and susceptibility to severe RSV bronchiolitis, where the variant appeared protective in girls, but was linked with increased risk in boys (30) . In the present study, tests for the interaction between sex and the IL-9 polymorphism rs2069885 in the CAMP cohort were not significant for lung function phenotypes (percent predicted FEV1, airway hyper-responsiveness) or for the severe asthma exacerbation outcome (p>0.5 for interaction terms).…”

Section: Discussionmentioning

confidence: 99%

Genome-wide expression profiles identify potential targets for gene-environment interactions in asthma severity

Sordillo

Kelly

Bunyavanich

et al. 2015

Journal of Allergy and Clinical Immunology

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Background Gene by environment interaction (G × E) studies utilizing GWAS data are often underpowered after adjustment for multiple comparisons. Differential gene expression, in response to the exposure of interest, may capture the most biologically relevant genes at the genome-wide level. Methods We used differential genome-wide expression profiles from the Home Allergens and Asthma Birth cohort in response to Der f 1 allergen (sensitized vs. non-sensitized) to inform a G × E study of dust mite exposure and asthma severity. Polymorphisms in differentially expressed genes were identified in GWAS data from CAMP, a clinical trial in childhood asthmatics. Home dust mite allergen (< or ≥ 10µg/g dust) was assessed at baseline, and (≥ 1) severe asthma exacerbation (emergency room (ER) visit or hospitalization for asthma in the first trial year) served as the disease severity outcome. The Genetics of Asthma in Costa Rica (GACRS) study, and a Puerto Rico/Connecticut asthma cohortwere used for replication. Results IL-9, IL-5 and PRG2 expression was up-regulated in Der f 1 stimulated PBMCs from dust mite sensitized individuals (adj. p value <0.04). IL-9 polymorphisms (rs11741137, rs2069885, rs1859430) showed evidence for interaction with dust mite in CAMP (p=0.02 to 0.03), with replication in GACRS (p=0.04). Subjects with the dominant genotype for these IL-9 polymorphisms were more likely to report a severe asthma exacerbation if exposed to elevated dust mite. Conclusions Genome-wide differential gene expression in response to dust mite allergen identified IL-9, a biologically plausible gene target that may interact with environmental dust mite to increase severe asthma exacerbations in children.

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Interleukin‐9 polymorphism in infants with respiratory syncytial virus infection: An opposite effect in boys and girls

Cited by 50 publications

References 25 publications

A mast cell-ILC2-Th9 pathway promotes lung inflammation in cystic fibrosis

A mast cell-ILC2-Th9 pathway promotes lung inflammation in cystic fibrosis

Gene-specific sex effects on eosinophil infiltration in leishmaniasis

Genome-wide expression profiles identify potential targets for gene-environment interactions in asthma severity

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