Role In Allergic Inflammation Research Articles

Licochalcones suppress degranulation by decreasing the intracellular Ca 2+ level and tyrosine phosphorylation of ERK in RBL-2H3 cells

Mast cells play a key role in allergic inflammation by releasing various mediators, such as histamine, serotonin, leukotrienes and cytokines. A signaling cascade of events activated by stimulation with antigens contributes to the regulation of mast cell degranulation. While various anti-inflammatory and anti-allergic drugs have been developed that inhibit degranulation of mast cells, the inhibitory mechanism has been poorly understood. Licochalcone A (Lico A) is a retrochalcone isolated from the root of Xinjiang liquorice and has been reported to exhibit various biological activities such as anti-inflammatory activity. We examined the effects of Lico A and related chalcones on degranulation in a rat basophilic leukemia cell line, RBL-2H3. Whereas Lico A and licochalcone C (Lico C) exhibited inhibitory activity with cytotoxicity, licochalcone D (Lico D) significantly inhibited the degranulation in RBL-2H3 cells with low cytotoxicity. Moreover, Lico D significantly inhibited the Ca 2+ influx and phosphorylation of extracellular signal regulated kinase (ERK) and MEK. These results suggest that Lico D inhibits mast cell degranulation via the inhibition of both extracellular Ca 2+ influx and activation of the MEK-ERK pathway.

Signaling pathways critical for allergic airway inflammation

Activated mast cells, basophils, and CD4 helper T cells have critical roles in allergic inflammation. Therefore, devising ways to specifically inhibit these cells will likely be useful for controlling allergic inflammation. We summarize recent findings regarding the role of mast cells and basophils in allergic responses and the regulation of signaling pathways downstream of the IgE receptor, the chief inducer of mast cell and basophil activation. We also highlight studies addressing the roles of the protein tyrosine kinases Zap-70 and Itk in immune system development and in the regulation of CD4 helper T cell responses. Recent work has demonstrated that mast cell function is unexpectedly diverse and that basophils have a more prominent role in Th2-type immune responses than previously appreciated. Biochemical analysis of the IgE receptor signaling pathway has led to insights regarding the roles of phosphatases and other enzymes in this process. Studies of Zap-70 and Itk have helped to define the potential outcomes and complications of inhibiting these enzymes in order to suppress allergic inflammation. Analysis of genetically engineered mice and biochemical studies continue to help unravel the molecular pathways that drive allergic inflammatory reactions. The knowledge acquired may lead to novel approaches for suppressing allergic inflammation.

Protein kinase C-ζ is involved in the inhibition of eosinophil migration

Background The accumulation of eosinophils in lung tissue is a hallmark of asthma, and it is believed that eosinophils play a crucial pathogenic role in allergic inflammation. Therefore, eosinophils are currently considered a major therapeutic target in allergic diseases. Prostaglandin (PG) E2 exerts anti-inflammatory and broncho-protective mechanisms in asthma, but the underlying mechanisms have remained unclear. We have shown previously that PGE2 and the EP2 receptor agonist butaprost inhibit eosinophil trafficking in vitro and in vivo [1].

Inhibitory effects of prostaglandin EP4 receptors on human eosinophils

Background The accumulation of eosinophils in lung tissue is a hallmark of asthma, and it is believed that eosinophils play a crucial pathogenic role in allergic inflammation. Prostaglandin (PG) E2 exerts anti-inflammatory and bronchoprotective mechanisms in asthma, but the underlying mechanisms have remained unclear. We have shown previously that PGE2 and the EP2 receptor agonist butaprost inhibit eosinophil trafficking in vitro and in vivo.

Mast cells: makers and breakers of allergic inflammation

Recent findings have developed, changed, challenged and extended the established view of mast cell biology and of their role in inflammation. The purpose of this review is to present and discuss recent research in this area relating to allergic inflammation. Mast cells are traditionally viewed only as IgE-activated histamine-providing effector cells of allergic inflammation. Yet, recent findings also support a role for mast cells in the sensitization to allergens, and early released human mast cell tryptase has been shown to break down IgE, hence breaking the key maker of allergic inflammation. Furthermore, mast cells demonstrate proinflammatory action through nonhistamine and non-IgE-mediated routes. For example, the role of platelet-activating factor in contributing to allergic inflammation and anaphylaxis in mice is now starting to be shown in humans. Most surprisingly, mast cells have also emerged as modulators and downregulators of allergic inflammation. For example, the newly discovered siglec-8 receptor might act as an inhibitor of mast cell degranulation and thus of mast cell-mediated allergic inflammation. Also, mast cell-derived IL-10 is shown to be a modulator of allergic inflammation, demonstrated in a murine model of contact hypersensitivity. Understanding the mast cell's divergent phenotypes based on situation and setting is required to truly discover their role in allergic inflammation.

Human subjects are protected from mast cell tryptase deficiency despite frequent inheritance of loss-of-function mutations

Mast cell tryptases have proposed roles in allergic inflammation and host defense against infection. Tryptase gene loci TPSAB1 and TPSB2 are known to be polymorphic, but the nature and extent of diversity at these loci have not been fully explored. We sought to compare functional and nonfunctional tryptase allele frequencies and establish haplotypes in human populations. Tryptase allele frequencies were determined by means of direct sequencing in 270 individuals from HapMap populations of European, African, Chinese, and Japanese ancestry. Haplotypes were predicted, validated in parent-child trios, and compared between populations. We identify a new frame-shifted tryptase allele (betaIII(FS)) carried by 23% and 19% of individuals of European and African ancestry but 0% of Asian subjects. Homology models predict that betaIII(FS) is functionless. Our genotyping assay shows that allele and haplotype distributions in each population are unique. Strong linkage disequilibrium between TPSAB1 and TPSB2 (r(2)=0.83, D'=0.85) yields 2 major and 5 minor tryptase haplotypes. Tryptase deficiency alleles (alpha and the newly discovered betaIII(FS)) are common, causing the number of inherited active genes to range from a minimum of 2 to a maximum of 4, with major differences between populations in the proportion of individuals inheriting 2 versus 4 active alleles. African and Asian populations are especially enriched in genes encoding functional and nonfunctional tryptases, respectively. Strong linkage of TPSAB1 and TPSB2 and pairing of deficiency alleles with functional alleles in observed haplotypes protect human subjects from "knockout" genomes and indeed from inheritance of fewer than 2 active alleles.

Interleukin-13 Regulates Secretion of the Tumor Growth Factor–β Superfamily Cytokine Activin A in Allergic Airway Inflammation

Activin A is a member of the TGF-beta superfamily and plays a role in allergic inflammation and asthma pathogenesis. Recent evidence suggests that activin A regulates proinflammatory cytokine production and is regulated by inflammatory mediators. In a murine model of acute allergic airway inflammation, we observed previously that increased activin A concentrations in bronchoalveolar lavage (BAL) fluid coincide with Th2 cytokine production in lung-draining lymph nodes and pronounced mucus metaplasia in bronchial epithelium. We therefore hypothesized that IL-13, the key cytokine for mucus production, regulates activin A secretion into BAL fluid in experimental asthma. IL-13 increased BAL fluid activin A concentrations in naive mice and dose dependently induced activin A secretion from cultured human airway epithelium. A key role for IL-13 in the secretion of activin A into the BAL fluid during allergic airway inflammation was confirmed in IL-13-deficient mice. Eosinophils were not involved in this response because there was no difference in BAL fluid activin A concentrations between wild-type and eosinophil-deficient mice. Our data highlight an important role for IL-13 in the regulation of activin A intraepithelially and in BAL fluid in naive mice and during allergic airway inflammation. Given the immunomodulatory and fibrogenic effects of activin A, our findings suggest an important role for IL-13 regulation of activin A in asthma pathogenesis.

GPR34 is not required for mast cell degranulation induced by IgE or lysophosphatidyl-L-serine (36.1)

Abstract Mast cells play an important role in allergic inflammation. Upon activation by cross-linking of FcεRI, they rapidly release granule-associated chemical mediators and secrete cytokines, fatty acids and lipids which mediate allergic inflammation. GPR34 is a GPCR expressed on mast cells and has been proposed to be a receptor for lysophosphatidylserine (lysoPS), a phospholipid derivative which can potentiate antigen-induced mast cell degranulation (BBRC 341: 1078, 2006). To determine if GPR34 is involved in mast cell response, we generated GPR34-/- mice and evaluated mast cell function in vitro and in vivo. Bone marrow-derived mast cells from GPR34+/+ and GPR34-/- mice exhibited similar responses, as measured by beta-hexosaminidase release, to IgE cross-linking or lysoPS stimulation. We evaluated the role of GPR34 in vivo using a passive cutaneous anaphylaxis model induced by crosslinking of FcεRI on mast cells. Mast cells in GPR34+/+ and GPR34-/- mice were activated by SC injection of anti-DNP IgE mAb followed by IV administration of DNP-BSA and Evans blue dye 24 hours later. Activation resulted in vascular permeability which was measured as the amount of dye influx. In this model, the mast cell response was unaffected by GPR34 gene deficiency. Together, our results indicate that GPR34 is not required for the mast cell response to IgE crosslinking in vitro or in vivo and that GPR34 is not a receptor for lysoPS.

The role of eosinophil major basic protein in angiogenesis

Eosinophil-derived major basic protein (MBP) plays an active role in allergic inflammation and tissue remodelling. However, its role in angiogenesis has not been established as yet. Therefore our objective was to investigate whether MBP exhibits any direct pro-angiogenic effects. Rat aortic endothelial cells and human umbilical vascular endothelial cells were cultured with different concentrations of MBP and their viability (Trypan blue exclusion test), proliferation (thymidine incorporation) and capillary-like structure formation (matrigel assay) were investigated in vitro. The angiogenic activity of MBP was then tested in vivo using the chick chorio allantoic membrane (CAM) assay. Subcytotoxic concentrations of MBP induce endothelial cell proliferation and enhance the pro-mitogenic effect of vascular endothelial growth factor (VEGF), but do not affect their VEGF release. MBP promotes capillarogenesis by endothelial cells seeded on matrigel and sprouting formation in the CAM assay. Furthermore, we have shown that the pro-angiogenic effect of MBP is not due to its cationic charge since stimulation of the CAMs with the synthetic polycation, poly-L-arginine does not induce any angiogenic effects. These data demonstrate that MBP has pro-angiogenic effects in vitro and in vivo, providing a novel mechanism whereby MBP can participate in tissue inflammation and remodelling in atopic diseases.

Histamine N‐methyltransferase 939A>G polymorphism affects mRNA stability in patients with acetylsalicylic acid‐intolerant chronic urticaria

Histamine plays an important role in allergic inflammation. Histamine levels are regulated by histamine N-methyltransferase (HNMT). To investigate the functional variability of HNMT gene in relation to genetic polymorphisms in patients with aspirin intolerant chronic urticaria (AICU). Two single-nucleotide polymorphisms of the HNMT gene (314C>T, 939A>G) were genotyped in chronic urticaria patients. The functional variability of 3'-untranslated region polymorphism (3'-UTR) was assessed using the pEGFP-HNMT 3'-UTR reporter construct to examine mRNA stability and fluorescence-tagged protein expression. The HNMT enzymatic activities related to the 939A>G polymorphism were examined both in the human mast cells (HMC-1) transfected with the pHNMT CDS-3'-UTR construct and in the patients' red blood cells (RBCs). Histamine release from the basophils of AICU patients was examined. The 939A>G polymorphism was significantly associated with the AICU phenotype, while no association was found with the 314C>T polymorphism. An in vitro functional study using HMC-1 cells demonstrated that the 939A allele gave lower levels of HNMT mRNA stability, HNMT protein expression, and HNMT enzymatic activity and higher histamine release than the 939G allele. The in vivo functional study demonstrated that the AICU patients with the 939A allele had lower HNMT activity in RBC lysates and higher histamine release from their basophils. The HNMT 939A>G polymorphism lowers HNMT enzymatic activity by decreasing HNMT mRNA stability, which leads to an increase in the histamine level and contributes to the development of AICU.

Pinellia ternata,Citrus reticulata, and Their Combinational Prescription Inhibit Eosinophil Infiltration and Airway Hyperresponsiveness by Suppressing CCR3+ and Th2 Cytokines Production in the Ovalbumin-Induced Asthma Model

Background and Objective. This study was aimed to analyse the curative effects of Pinellia ternata, Citrus reticulata, and their combination on airway hyperresponsiveness (AHR) to inhaled methacholine, pulmonary eosinophilic infiltration, Th2 cytokine production, and IgE and histamine production in a murine model of asthma. Methods. For this purpose, BALB/c mice were systemically sensitized to ovalbumin (OVA) followed intratracheally, intraperitoneally, and by aerosol allergen challenges for 12 weeks. We examined the development of pulmonary eosinophilic accumulation, control of Th2 cytokine, immunoglobulin E (IgE), and histamine productions in a murine model of asthma. Results. Our data suggest that the therapeutic mechanism by which Pinellia ternata, Citrus reticulata, and their combinational prescription effectively treats asthma is based on reductions of eosinophil infiltration, eotaxin receptor (CCR3), histamine, OVA-specific IgE productions in serum, and Th2 cytokines (IL-5, IL-13) by marked reductions of IL-5 and IL-13 mRNA expression in lung tissue. Conclusions. These findings provide evidence that Pinellia ternata, Citrus reticulata, and their combination play a regulatory role in allergic inflammation and offer therapeutic approaches as novel CCR3 antagonists for treatment asthma. However, it is not clear whether pharmacological activities of prescription composed of two herbs are potentiated due to synergistic effect or additive effect.

Increased mast cell density during the infection with velogenic Newcastle disease virus in chickens

In addition to their well-characterized role in allergic inflammation, recent data confirm that mast cells play a more extensive role in a variety of viral infections. The contribution of mast cells to Newcastle disease pathogenesis has not been investigated. We evaluated mast cell activity after Newcastle disease virus (NDV) infection in specific pathogen free chickens using cytochemical and immunocytochemical analyses. The results were as follows. Severe tissue damage was observed in the proventriculus, duodenum, jejunum and caecal tonsil, and NDV antigens were detected and presented extensively in these tissues. Second, in the NDV-infected group, the mast cell population was increased markedly in the proventriculus, duodenum, jejunum and caecal tonsil at 24, 48, 72 and 96 h after infection (P<0.01). However, very few mast cells were observed in those same tissues in the control. More intriguingly, the greatest number of mast cells was found in the proventriculus, which also showed the greatest level of NDV antigens. Third, the content of tryptase was significantly higher (P<0.01) in the NDV-infected group compared with the control from 24 to 96 h post infection). Furthermore, as an important protease released by mast cells, tryptase had a positive correlation with mast cell distribution. These data indicated that mast cells were involved in the response to NDV. Our results also suggested that the broad range of mast cell mediators might have a role in the pathology of Newcastle disease.

Variation in the BDNF and NGFB genes in German atopic dermatitis patients

In humans, atopic dermatitis (AD) is believed to result from a complex interaction between genetic and environmental factors. Based on recent evidence, it has been proposed that neurotrophins play an important role in allergic inflammation. Levels of nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) in blood have been found to be elevated and correlated positively with disease in AD patients. Therefore, we sought to evaluate the role of nucleotide variation in the NGFB and BDNF genes in relation to the pathogenesis of AD. A functional polymorphism within the BDNF gene (Val66Met) and six selected polymorphisms in the NGFB gene were examined in 361 German AD patients and 325 non-atopic controls. In this cohort, no significant association with AD was detected, refuting the hypothesis that variation in these two neurotrophin genes contributes substantially to AD.

Prostaglandin E2 Inhibits Eosinophil Trafficking through E-Prostanoid 2 Receptors

The accumulation of eosinophils in lung tissue is a hallmark of asthma, and it is believed that eosinophils play a crucial pathogenic role in allergic inflammation. Prostaglandin (PG) E(2) exerts anti-inflammatory and bronchoprotective mechanisms in asthma, but the underlying mechanisms have remained unclear. In this study we show that PGE(2) potently inhibits the chemotaxis of purified human eosinophils toward eotaxin, PGD(2), and C5a. Activated monocytes similarly attenuated eosinophil migration, and this was reversed after pretreatment of the monocytes with a cyclooxygenase inhibitor. The selective E-prostanoid (EP) 2 receptor agonist butaprost mimicked the inhibitory effect of PGE(2) on eosinophil migration, whereas an EP2 antagonist completely prevented this effect. Butaprost, and also PGE(2), inhibited the C5a-induced degranulation of eosinophils. Moreover, selective kinase inhibitors revealed that the inhibitory effect of PGE(2) on eosinophil migration depended upon activation of PI3K and protein kinase C, but not cAMP. In animal models, the EP2 agonist butaprost inhibited the rapid mobilization of eosinophils from bone marrow of the in situ perfused guinea pig hind limb and prevented the allergen-induced bronchial accumulation of eosinophils in OVA-sensitized mice. Immunostaining showed that human eosinophils express EP2 receptors and that EP2 receptor expression in the murine lungs is prominent in airway epithelium and, after allergen challenge, in peribronchial infiltrating leukocytes. In summary, these data show that EP2 receptor agonists potently inhibit eosinophil trafficking and activation and might hence be a useful therapeutic option in eosinophilic diseases.

Heme Oxygenase-1 and Carbon Monoxide: Emerging Therapeutic Targets in Inflammation and Allergy

Cumulative evidence suggests that the induction of the antioxidant/anti-inflammatory heme oxygenase (HO)-1 may play a protective role in allergic inflammation. HO-1 suppresses mast cell degranulation and cytokine synthesis. The up-regulation of the HO-1 pathway has a significant protective effect against airway inflammation, mucus hyper-secretion, and hyper-responsiveness in a model of allergic asthma. Moreover, HO-1 inhibits T cell-dependent skin inflammation and differentiation and function of antigen-presenting cells. The precise underlying mechanisms for HO-1-based protection against allergic inflammation are not yet completely understood, but appear to involve the protective effects of HO-1 by-products, such as carbon monoxide (CO), biliverdin/bilirubin and free iron. Among the HO-1 by-products, CO has been shown to mimic some protective actions of HO-1 in allergic inflammations. This article reviews the latest knowledge, recent patent and studies on the protective roles and mechanisms of HO-1/CO in inflammation and allergy.

An IL-1 Cytokine Member, IL-33, Induces Human Basophil Activation via Its ST2 Receptor

Basophils are thought to play pivotal roles in allergic inflammation through rapid release of chemical mediators in addition to sustained production of Th2 cytokines, including IL-4. A newly identified cytokine, IL-33, has been recognized as one of the key cytokines enhancing Th2-balanced immune regulation through its receptor, ST2. The present study was conducted to elucidate whether IL-33 acts directly on, and affects the functions of, human basophils. Real-time PCR analysis showed that basophils express transcripts for ST2. The expression levels were significantly higher compared with eosinophils and neutrophils, and treatment with IL-33 significantly up-regulated basophil ST2 mRNA expression. Expressions of IL-4 and IL-13 mRNA were also up-regulated by IL-33, and there was also enhanced secretion of IL-4 protein. IL-33 increased the surface levels of basophil CD11b expression and enhanced basophil adhesiveness. Although IL-33 failed to directly induce degranulation or attract basophils, it exerted priming effects on basophils. It enhanced degranulation in response to IgE-crosslinking stimulus and also enhanced basophil migration toward eotaxin without changing surface CCR3. Also, IL-33 synergistically enhanced IL-4 production and CD11b expression by IL-3-stimulated basophils. Neutralization using Ab specific for ST2 significantly diminished the enhancing effects of IL-33 on both basophil CD11b expression and migration toward eotaxin, indicating that IL-33 signals via ST2 expressed on basophils. This study revealed that IL-33 potently regulates migration and activation of human basophils. IL-33 may be a key cytokine in the pathogenesis of Th2-dominant inflammation by acting not only on lymphocytes but also on effector cells such as basophils.

ADAM8 in Allergy

ADAM (a disintegrin and metalloprotease) family members are membrane-anchored proteins with wide ranging functions, including proteolytic cleavage of cell surface molecules, cell fusion, cell adhesion and intracellular signaling. ADAM8, also known as CD156a, is expressed mainly in cells of the immune system, such as monocytes, neutrophils, eosinophils, dendritic cells, and B cells. It can cleave a variety of substrates and is a sheddase for CD23 and L-selectin. ADAM8 has an important role in allergic inflammation. ADAM8 mRNA expression is increased with disease progression in asthma. ADAM8 is strongly induced by allergens and Th2 cytokines in the lung in experimental asthma. Soluble ADAM8 is elevated in the bronchoalveolar lavage fluid of patients with eosinophilic pneumonia and has a physiologic role in protecting against allergic pulmonary disease in experimental murine asthma. Together, these findings support the view that ADAM8 might be a therapeutic target for allergic respiratory diseases. This review discusses novel strategies for immune intervention in allergic respiratory disease.

Interferon-γ enhances human eosinophil effector functions induced by granulocyte-macrophage colony-stimulating factor or interleukin-5

T helper (Th) 2-type cytokines play a dominant role in allergic inflammation. Accumulating evidence suggests that Th1-type cytokines antagonize Th2-type cytokine responses; however, recent studies demonstrate that Th1 cytokines might enhance Th2 immune responses. We examined whether interferon (IFN)-γ, a representative Th1 cytokine, modifies the effector functions of human eosinophils stimulated by granulocyte-macrophage colony-stimulating factor (GM-CSF) and interleukin (IL)-5. GM-CSF and IL-5 have significant functional homology, and contribute to the regulation of Th2 immunity. After the pretreatment of eosinophils with IFN-γ, GM-CSF- or IL-5-induced eosinophil functions were examined, including superoxide anion generation, degranulation, adhesion, expression of GM-CSF receptor (R), IL-5R, or CD11b, and phosphorylation of intracellular signaling molecules. Superoxide anion generation was measured using the cytochrome c reduction method. Degranulation and cell adhesion were evaluated based on eosinophil-derived neurotoxin (EDN) contents in supernatants or adherent cells. Phosphorylation of signaling molecules was analyzed using a multiplex beads array system. Preincubation with IFN-γ resulted in enhanced GM-CSF- or IL-5-induced superoxide anion generation and degranulation of human eosinophils, whereas stimulus-induced eosinophil adhesion was unaffected. In addition, IFN-γ did not influence the expression of GM-CSFR, IL-5R, and CD11b. Furthermore, IFN-γ upregulated GM-CSF- or IL-5-induced phosphorylation of extracellular signal-regulated kinase (ERK), p38 mitogen-activated protein kinase (MAPK), c-Jun N-terminal kinase (JNK), and activating transcription factor (ATF)-2. Finally, we confirmed that MAPK inhibitors blocked the enhancement of stimuli-induced superoxide anion generation of IFN-γ treated eosinophils. In conclusion, IFN-γ might upregulate ERK, p38, or JNK/ATF-2 phosphorylation induced by GM-CSF or IL-5, leading to enhanced cytokine-induced eosinophil superoxide generation and degranulation.

Molecular Mechanisms of Cytokine and Chemokine Release from Eosinophils Activated by IL-17A, IL-17F, and IL-23: Implication for Th17 Lymphocytes-Mediated Allergic Inflammation

IL-17A and IL-17F are members of the IL-17 family that play crucial roles in allergic inflammation. Recent studies reported that IL-17A and IL-17F production from a distinct Th lymphocyte subset, Th17, was specifically induced by IL-23, which was produced by dendritic cells and macrophages in response to microbial stimuli. The IL-23-IL-17 axis might therefore provide a link between infections and allergic diseases. In the present study, we investigated the effects of IL-17A, IL-17F, and IL-23, alone or in combination, on cytokine and chemokine release from eosinophils and the underlying intracellular mechanisms. Human eosinophils were found to constitutively express receptors for IL-17A, IL-17F, and IL-23 at the protein level. IL-17A, IL-17F, and IL-23 could induce the release of chemokines GRO-alpha/CXCL1, IL-8/CXCL8, and MIP-1beta/CCL4 from eosinophils, while IL-17F and IL-23 could also increase the production of proinflammatory cytokines IL-1beta and IL-6. Synergistic effects were observed in the combined treatment of IL-17F and IL-23 on the release of proinflammatory cytokines, and the effects were dose-dependently enhanced by IL-23, but not IL-17F. Further investigations showed that IL-17A, IL-17F, and IL-23 differentially activated the ERK, p38 MAPK, and NF-kappaB pathways. Moreover, inhibition of these pathways using selective inhibitors could significantly abolish the chemokine release induced by IL-17A, IL-17F, and IL-23 and the synergistic increases on IL-1beta and IL-6 production mediated by combined treatment of IL-17F and IL-23. Taken together, our findings provide insight for the Th17 lymphocyte-mediated activation of eosinophils via differential intracellular signaling cascades in allergic inflammation.

Comprehensive evaluation of genetic variation in S100A7 suggests an association with the occurrence of allergic rhinitis

BackgroundS100A7 is a calcium-binding protein with chemotactic and antimicrobial properties. S100A7 protein levels are decreased in nasal lavage fluid from individuals with ongoing allergic rhinitis, suggesting a role for S100A7 in allergic airway inflammation. The aims of this study were to describe genetic variation in S100A7 and search for associations between this variation and allergic rhinitis.MethodsPeripheral blood was collected from 184 atopic patients with a history of pollen-induced allergic rhinitis and 378 non-atopic individuals, all of Swedish origin. DNA was extracted and the S100A7 gene was resequenced in a subset of 47 randomly selected atopic individuals. Nine polymorphisms were genotyped in 184 atopic and 378 non-atopic individuals and subsequently investigated for associations with allergic rhinitis as well as skin prick test results. Haplotypes were estimated and compared in the two groups.ResultsThirteen polymorphisms were identified in S100A7, of which 7 were previously undescribed. rs3014837 (G/C), which gives rise to an Asp → Glu amino acid shift, had significantly increased minor allele frequency in atopic individuals. The major haplotype, containing the major allele at all sites, was more common in non-atopic individuals, while the haplotype containing the minor allele at rs3014837 was equally more common among the atopic individuals. Additionally, heterozygotes at this site had significantly higher scores in skin prick tests for 9 out of 11 tested allergens, compared to homozygotes.ConclusionThis is the first study describing genetic variation, associated with allergy, in S100A7. The results indicate that rs3014837 is linked to allergic rhinitis in our Swedish population and render S100A7 a strong candidate for further investigations regarding its role in allergic inflammation.