Impact of FOXP3 gene polymorphisms and gene-environment interactions in asthma and atopy in a Brazilian population.

BACKGROUND: Polymorphisms in genes related to the activation and development of regulatory T cells (Tregs), such as FOXP3, may be associated with asthma and atopy development. Additionally, environmental factors such as exposure to infections can modify the effect of these associations. This study evaluated the impact of polymorphisms in the FOXP3 on the risk of asthma and atopy as also gene-environment interactions in these outcomes. METHODS: This study included 1,246 children from the SCAALA program, between 4 and 11 years of age. DNA was extracted from peripheral blood and eight SNPs (rs2280883, rs11465476, rs11465472, rs2232368, rs3761549, rs3761548, rs2232365 and rs2294021) were genotyped using the 2.5 HumanOmni Beadchip from Illumina (San Diego, California, USA) or TaqMan qRT-PCR. RESULTS: The rs2232368 (Allele T) was positively associated with asthma symptoms (OR = 1.95, CI = 1.04 to 3.66, p = 0.040) and skin prick test (SPT) reactivity to aeroallergens (OR = 2.31, CI = 1.16 to 4.59, p = 0.017). The rs3761549 (Allele T) was positively associated with SPT reactivity (OR = 1.44, CI = 1.03 to 2.02, p = 0.034). The rs2280883 (Allele C) was negatively associated with specific IgE to aeroallergens (OR = 0.83, CI = 0.70 to 0.99, p = 0.040). Furthermore, the rs2280883 played a protective role in the development of atopy only in individuals seropositive to Epstein-Barr virus (EBV) infection (OR = 0.74, CI = 0.60 to 0.92, p = 0.003 and OR = 0.74; 95% CI = 0.61-0.91, p = 0.007 for SPT and slgE respectively), but not in individuals without EBV infection. CONCLUSION: Polymorphisms in the FOXP3 gene were associated with the risk of atopy and asthma development in our population. In addition, EBV infection had an effect modifier of the observed association for rs2280883 variant.

Extracellular vesicles from methicillin resistant Staphylococcus aureus stimulate proinflammatory cytokine production and trigger IgE-mediated hypersensitivity.

Extracellular vesicles (EVs) released from bacteria are enclosed particles carrying biological active molecules. They have been shown to play a role in bacterial communications and delivery of virulence factors to the host cells. Staphylococcus aureus is an opportunistic pathogen causing a variety of infections ranging from impetigo to septicaemia. The EVs released from S. aureus have a high potential to be used for vaccine development against S. aureus infections. However, it is important to clearly understand the impact of SaEVs on the host's immune response. Our study demonstrated that purified EVs from a clinical isolated methicillin-resistant S. aureus (SaEVs) significantly stimulated proinflammatory cytokine production in mouse immune cells and induced host cell death. An impairment of cytokine production in the Toll-like receptor (TLR)-silenced macrophages suggested that SaEVs stimulate proinflammatory response via TLRs 2, 4 and 9. In mouse infection model, the results demonstrated that SaEV immunization did not provide protective effect. In contrast, all SaEV-immunized mice died within Day 1 after methicillin-resistant S. aureus (MRSA) infection. After MRSA infection for 3 h, the production of IL-6, TNF-α and IL-17 in the spleen of SaEV-immunized mice was significantly higher than that of control mice. On Day 5 after the second immunization, total IgE in the serum was significantly enhanced, and a high titre of Th2-related cytokines was remarkably induced after ex vivo stimulation of the spleen cells with SaEVs. These results suggested that MRSA-derived EVs act as an immunostimulant that induces inflammatory response and IgE-mediated hypersensitivity after MRSA infection.

Shared Genetic Liability Between Major Depressive Disorder and Atopic Diseases.

Objectives: Deciphering the genetic relationships between major depressive disorder (MDD) and atopic diseases (asthma, hay fever, and eczema) may facilitate understanding of their biological mechanisms as well as the development of novel treatment regimens. Here we tested the genetic correlation between MDD and atopic diseases by linkage disequilibrium score regression. Methods: A polygenic overlap analysis was performed to estimate shared genetic variations between the two diseases. Causal relationships between MDD and atopic diseases were investigated using two-sample bidirectional Mendelian randomization analysis. Genomic loci shared between MDD and atopic diseases were identified using cross-trait meta-analysis. Putative functional genes were evaluated by fine-mapping of transcriptome-wide associations. Results: The polygenic analysis revealed approximately 15.8 thousand variants causally influencing MDD and 0.9 thousand variants influencing atopic diseases. Among these variants, approximately 0.8 thousand were shared between the two diseases. Mendelian randomization analysis indicates that genetic liability to MDD has a causal effect on atopic diseases (b = 0.22, p = 1.76 × 10-6), while genetic liability to atopic diseases confers a weak causal effect on MDD (b = 0.05, p = 7.57 × 10-3). Cross-trait meta-analyses of MDD and atopic diseases identified 18 shared genomic loci. Both fine-mapping of transcriptome-wide associations and analysis of existing literature suggest the estrogen receptor ß-encoding gene ESR2 as one of the potential risk factors for both MDD and atopic diseases. Conclusion: Our findings reveal shared genetic liability and causal links between MDD and atopic diseases, which shed light on the phenotypic relationship between MDD and atopic diseases.

The MEFV gene and its association with familial Mediterranean fever, severe atopy, and recurrent respiratory tract infections.

BACKGROUND: Familial Mediterranean fever (FMF) is the most common auto-inflammatory disease and is characterized by self-limiting episodes of fever and polyserositis. The aim of this study was to determine the atopic clinical findings associated with the MEFV gene. METHODS: A retrospective chart review was conducted of pediatric patients who had received a diagnosis of familial Mediterranean fever between August 2015 and November 2018. RESULTS: A total of 454 patients with familial Mediterranean fever were evaluated. The median age of diagnosis was 60 months (min-max: 6-228) and the percentage of patients who were male was 57.5%. A MEFV gene mutation was determined in 310 (68.3%) children. The most frequent genetic mutation was a R202Q heterozygote mutation, which was found in 95 patients (20.9%). When compared with MEFV-negative patients, elevation of serum amyloid A and fibrinogen levels during an episode of FMF was found to occur more frequently in MEFV-positive patients (p=0.019 and 0.027, respectively). Male gender, cigarette exposure, and a younger diagnosis age were seen more frequently in patients who had episodes with fever (p=0.039, 0.022, and 0.001, respectively). Chronic cough with sputum and persistent purulent rhinitis were more frequent in the group which did not experience fever episodes (p=0.003 and 0.002, respectively). CONCLUSIONS: While being a periodic fever syndrome, familial Mediterranean fever also presents as a multisystemic disease with heterogeneous clinical symptoms. Severe atopic diseases and recurrent respiratory tract infections are characteristic features of this disease.

Long Noncoding RNA Linc00632 Inhibits Interleukin-13-Induced Inflammatory Cytokine and Mucus Production in Nasal Epithelial Cells.

Allergic rhinitis (AR) is an allergic disease characterized as (immunoglobulin E)-mediated type I hypersensitivity disorder. The interleukin-13 (IL-13) signaling pathway has been implicated in the pathogenesis of AR. In the present study, we investigated the regulatory role and mechanism of long noncoding RNA Linc00632 in IL-13-induced inflammatory cytokine and mucus production in nasal epithelial cells (NECs) from AR patients. We evaluated the expression of Linc00632 in nasal tissues from AR patients and in IL-13-treated NECs. We explored the role of Linc00632 in granulocyte-macrophage colony-stimulating factor (GM-CSF), eotaxin, and MUAC5AC production in IL-13-treated NECs. We searched for the potential target of Linc00632. Downregulation of Linc00632 was identified in nasal tissues of AR patients and in IL-13-treated NECs. Linc00632 inhibited IL-13-induced GM-CSF, eotaxin, and MUAC5AC production. Linc00632 targeted miR-498 and negatively regulated its expression. MiR-498 targeted IL1RN and inhibition of miR-498 suppressed IL-13-induced GM-CSF, eotaxin, and MUC5AC expression. The regulation of IL-13-induced dysfunction of NECs by Linc00632 depended on miR-498. Linc00632 inhibited IL-13-induced GM-CSF, eotaxin, and MUAC5AC production in IL-13-treated NECs by targeting miR-498.

Germline CBM-opathies: From immunodeficiency to atopy.

Caspase recruitment domain (CARD) protein-B cell CLL/lymphoma 10 (BCL10)-MALT1 paracaspase (MALT1) [CBM] complexes are critical signaling adaptors that facilitate immune and inflammatory responses downstream of both cell surface and intracellular receptors. Germline mutations that alter the function of members of this complex (termed CBM-opathies) cause a broad array of clinical phenotypes, ranging from profound combined immunodeficiency to B-cell lymphocytosis. With an increasing number of patients being described in recent years, the clinical spectrum of diseases associated with CBM-opathies is rapidly expanding and becoming unexpectedly heterogeneous. Here we review major discoveries that have shaped our understanding of CBM complex biology, and we provide an overview of the clinical presentation, diagnostic approach, and treatment options for those carrying germline mutations affecting CARD9, CARD11, CARD14, BCL10, and MALT1.

Variants in the CYSLTR2 are associated with asthma, atopy markers and helminths infections in the Brazilian population.

BACKGROUND: Asthma is a chronic disease of the airways and its most common phenotype is characterized by a T2 type response with IgE production and inflammatory mediators in response to common allergens. Cysteinyl leukotrienes (CysLTs), LTC4, LTD4 and LTE4, are mediators known to possess important proinflammatory action. CysLTs can bind to the Cysteinyl leukotriene receptor type 2 (CysLTR2) and activate an inflammatory. Polymorphisms in CysLTR2 have been associated with asthma and atopy, although the mechanism is not clear. OBJECTIVE: To evaluate the association between genetic polymorphisms in CYSLTR2 with asthma phenotypes, atopy markers and helminth infection. METHODS: Genotyping was performed using a panel Illumina and carried out in 1245 participants of SCAALA program (Social Change, Asthma, Allergy in Latin American). Logistic regressions for asthma, helminth infections (Trichuris trichiura and Ascaris lumbricoides) and allergy markers (skin tests and IgE production) were performed using PLINK 1.9 software adjusted for sex, age, helminth infection and ancestry markers. RESULTS: The G allele of rs1323556 was negatively associated with asthma in the additive model (OR 0.74, 95% CI 0.59-0.93) and in the dominant model (OR 0.71, 95% CI 0.53-0.74). The G allele of rs1575464 was also negatively associated with asthma in two genetic models, additive (OR 0.77, 95% CI 0.62-0.96) and dominant (OR 0.73, 95% CI 0.55-0.97). The G allele of rs61735175 was positively associated with asthma severity in the additive model (OR 1.72, 95% CI 1.07-2.77) and in the dominant model (OR 1.77, 95% CI 1.09-2.85). Five SNVs were associated with atopy markers and four SNVs were associated with helminth infections. CONCLUSION: Polymorphisms in the CYSLTR2 gene are associated with asthma, atopy markers and helminth infection in Brazilian individuals, which may lead to protection or risk for such conditions, however, more studies are needed to evaluate the functional of this variants here in described.

Epigenetic age acceleration is associated with allergy and asthma in children in Project Viva.

BACKGROUND: Epigenetic clocks have been suggested to capture one feature of the complexity between aging and the epigenome. However, little is known about the epigenetic clock in childhood allergy and asthma. OBJECTIVE: We sought to examine associations of DNA methylation age (DNAmAge) and epigenetic age acceleration with childhood allergy and asthma. METHODS: We calculated DNAmAge and age acceleration at birth, early childhood, and midchildhood based on the IlluminaHumanMethylation450BeadChip in Project Viva. We evaluated epigenetic clock associations with allergy and asthma using covariate-adjusted linear and logistic regressions. We attempted to replicate our findings in the Genetics of Asthma in Costa Rica Study. RESULTS: At midchildhood (mean age, 7.8 years) in Project Viva, DNAmAge and age acceleration were cross-sectionally associated with greater total serum IgE levels and greater odds of atopic sensitization. Every 1-year increase in intrinsic epigenetic age acceleration was associated with a 1.22 (95% CI, 1.07-1.39), 1.17 (95% CI, 1.03-1.34), and 1.29 (95% CI, 1.12-1.49) greater odds of atopic sensitization and environmental and food allergen sensitization. DNAmAge and extrinsic epigenetic age acceleration were also cross-sectionally associated with current asthma at midchildhood. DNAmAge and age acceleration at birth and early childhood were not associated with midchildhood allergy or asthma. The midchildhood association between age acceleration and atopic sensitization were replicated in an independent data set. CONCLUSIONS: Because the epigenetic clock might reflect immune and developmental components of biological aging, our study suggests pathways through which molecular epigenetic mechanisms of immunity, development, and maturation can interact along the age axis and associate with childhood allergy and asthma by midchildhood.

Early Life Origins of Asthma: A Review of Potential Effectors.

There is growing evidence that events occurring early in life, both before and after birth, are significantly associated with the risk of asthma, chronic obstructive pulmonary disease, and diminished lung function later in life. In fact, from conception to death, a series of continuous, dynamic gene-environment interactions determine 2 fundamental biological processes, namely, lung development and lung aging. Over 130 birth cohorts have been initiated in the last 30 years. Data from these cohorts have improved our understanding of the inception, progression, and persistency of asthma. In this review, we summarize the main data for the early life events proven to determine later development and persistence of asthma, such as maternal atopy and smoking, preterm birth/bronchopulmonary dysplasia, infections, nutrition, obesity, smoking, and other environmental exposures in childhood and adolescence. While some of these factors are obviously impossible to prevent or eliminate, others have been proven to have a protective role, and current research is aimed optimizing them. Available prophylactic measures are also reviewed. In the case of environmental pollution, large scale political interventions successfully managed to decrease contamination levels, leading to improved lung function and lower asthma prevalence in the respective geographical areas. Future research should focus on better understanding these complex interactions in order to develop and enhance effective preventive therapeutic measures.

MicroRNAs in type 2 immunity.

Type 2 immunity drives the pathology of allergic diseases and is necessary for expulsion of parasitic worms as well as having important implications in tumor progression. Over the last decade, a new research field has emerged describing a significant link between type 2 immunity and cancer development, called AllergoOncology. Thus, type 2 immune responses must be carefully regulated to mediate effective protection against damaging environmental factors, yet avoid excessive activation and immunopathology. Regulation of gene expression by microRNAs is required for normal behavior of most mammalian cells and has been studied extensively in the context of cancer. Although microRNA regulation of the immune system in cancer is well established and includes type 2 immune reactions in the tumor microenvironment, the involvement of microRNAs in these responses initiated by allergens, parasites or other environmental factors is just emerging. In this review, we focus on recent advances which increase the understanding of microRNA-mediated regulation of key mechanisms of type 2 immunity.

Effect of personal exposure to black carbon on changes in allergic asthma gene methylation measured 5 days later in urban children: importance of allergic sensitization.

BACKGROUND: Asthma gene DNA methylation may underlie the effects of air pollution on airway inflammation. However, the temporality and individual susceptibility to environmental epigenetic regulation of asthma has not been fully elucidated. Our objective was to determine the timeline of black carbon (BC) exposure, measured by personal sampling, on DNA methylation of allergic asthma genes 5 days later to capture usual weather variations and differences related to changes in behavior and activities. We also sought to determine how methylation may vary by seroatopy and cockroach sensitization and by elevated fractional exhaled nitric oxide (FeNO). METHODS: Personal BC levels were measured during two 24-h periods over a 6-day sampling period in 163 New York City children (age 9-14 years), repeated 6 months later. During home visits, buccal cells were collected as noninvasive surrogates for lower airway epithelial cells and FeNO measured as an indicator of airway inflammation. CpG promoter loci of allergic asthma genes (e.g., interleukin 4 (IL4), interferon gamma (IFNγ), inducible nitric oxide synthase (NOS2A)), arginase 2 (ARG2)) were pyrosequenced at the start and end of each sampling period. RESULTS: Higher levels of BC were associated with lower methylation of IL4 promoter CpG-48 5 days later. The magnitude of association between BC exposure and demethylation of IL4 CpG-48 and NOS2A CpG+5099 measured 5 days later appeared to be greater among seroatopic children, especially those sensitized to cockroach allergens (RR [95% CI] 0.55 [0.37-0.82] and 0.67 [0.45-0.98] for IL4 CpG-48 and NOS2A CpG+5099, respectively), compared to non-sensitized children (RR [95% CI] 0.87 [0.65-1.17] and 0.95 [0.69-1.33] for IL4 CpG-48 and NOS2A CpG+5099, respectively); however, the difference was not statistically different. In multivariable linear regression models, lower DNA methylation of IL4 CpG-48 and NOS2A CpG+5099 were associated with increased FeNO. CONCLUSIONS: Our results suggest that exposure to BC may exert asthma proinflammatory gene demethylation 5 days later that in turn may link to airway inflammation. Our results further suggest that seroatopic children, especially those sensitized to cockroach allergens, may be more susceptible to the effect of acute BC exposure on epigenetic changes.

Association of Gene Polymorphisms in Interleukin 6 in Infantile Bronchial Asthma. / Asociación entre polimorfismos genéticos de la interleucina 6 y el asma bronquial en niños.

INTRODUCTION: The genetic background of bronchial asthma is complex, and it is likely that multiple genes contribute to its development both directly and through gene-gene interactions. Cytokines contribute to different aspects of asthma, as they determine the type, severity and outcomes of asthma pathogenesis. Allergic asthmatics undergoing an asthmatic attack exhibit significantly higher levels of pro-inflammatory cytokines, such as interleukins and chemokines. In recent years, cytokines and their receptors have been shown to be highly polymorphic, and this prompted us to investigate interleukin 6 promoter polymorphisms at position -174G/C (rs1800795) and at -572G/C (rs1800796) in relation to asthma in children. METHODS: Interleukin 6 promoter polymorphisms were analyzed in bronchial asthma patients and healthy children using polymerase chain reaction-restriction fragment length polymorphism analysis. RESULTS: We observed a significant association between polymorphism at -174G/C and bronchial asthma (OR=3.4, 95% CI: 2.045-5.638, P<.001). Higher associations between polymorphism at IL-6 -174G/C and bronchial asthma were observed in atopic patients (OR=4.1, 95% CI: 2.308-7.280, P<8.10-7). CONCLUSIONS: Interleukin 6 polymorphism is associated with bronchial asthma, particularly its atopic phenotype. Expression and secretion of interleukins in asthmatic patients may be affected by genetic polymorphisms, and could have a disease-modifying effect in the asthmatic airway and modify the therapeutic response.

Airway and peripheral urokinase plasminogen activator receptor is elevated in asthma, and identifies a severe, nonatopic subset of patients.

RATIONALE: Genetic polymorphisms in the asthma susceptibility gene, urokinase plasminogen activator receptor (uPAR/PLAUR) have been associated with lung function decline and uPAR blood levels in asthma subjects. Preliminary studies have identified uPAR elevation in asthma; however, a definitive study regarding which clinical features of asthma uPAR may be driving is currently lacking. OBJECTIVES: We aimed to comprehensively determine the uPAR expression profile in asthma and control subjects utilizing bronchial biopsies and serum, and to relate uPAR expression to asthma clinical features. METHODS: uPAR levels were determined in control (n = 9) and asthmatic (n = 27) bronchial biopsies using immunohistochemistry, with a semi-quantitative score defining intensity in multiple cell types. Soluble-cleaved (sc) uPAR levels were determined in serum through ELISA in UK (cases n = 129; controls n = 39) and Dutch (cases n = 514; controls n = 96) cohorts. MEASUREMENTS AND MAIN RESULTS: In bronchial tissue, uPAR was elevated in inflammatory cells in the lamina propria (P = 0.0019), bronchial epithelial (P = 0.0002) and airway smooth muscle cells (P = 0.0352) of patients with asthma, with uPAR levels correlated between the cell types. No correlation with disease severity or asthma clinical features was identified. scuPAR serum levels were elevated in patients with asthma (1.5-fold; P = 0.0008), and we identified an association between high uPAR serum levels and severe, nonatopic disease. CONCLUSIONS: This study provides novel data that elevated airway and blood uPAR is a feature of asthma and that blood uPAR is particularly related to severe, nonatopic asthma. The findings warrant further investigation and may provide a therapeutic opportunity for this refractory population.

Urticaria papular y sus agentes causales en Colombia / Papular urticaria: A review of causal agents in Colombia

Resumen La urticaria papular es una enfermedad alérgica causada por la picadura de insectos, la cual predomina en el trópico. El objetivo de esta revisión fue profundizar en sus aspectos epidemiológicos e inmunológicos, particularmente con base en datos publicados en Latinoamérica. Se hizo una revisión no sistemática mediante la búsqueda electrónica de artículos sobre la epidemiología de la urticaria papular, las características entomológicas de los agentes causales y los mecanismos inmunológicos asociados. Según los diversos reportes de centros médicos de Latinoamérica la urticaria papular es frecuente; el único estudio de prevalencia publicado indica que afecta a una cuarta parte de los niños escolares de Bogotá. Hay información sobre la relación causal entre la exposición domiciliaria a la pulga, la pobreza y la urticaria papular en Bogotá, una ciudad representativa de las altitudes andinas. No hay estudios que indaguen directamente sobre los insectos causales en zonas cálidas, aunque se sospecha clínicamente de los mosquitos Aedes aegypti y Culex quinquefasciatus. En cuanto a su patogenia, se destaca la participación de mecanismos celulares que involucran las células colaboradoras Th2, lo cual explica que sea una condición de hipersensibilidad retardada. El papel de la inmunoglobulina E (IgE) en la urticaria papular no está tan claro. Se desconocen los antígenos derivados de los insectos que causan la enfermedad, aunque se plantea que existen moléculas comunes de reacción cruzada entre los insectos, tales como el alérgeno Cte f 2 en la pulga, y sus homólogos en los mosquitos. La urticaria papular es una condición frecuente en Latinoamérica que debe investigarse en profundidad. La caracterización inmunológica de los componentes moleculares que causan esta condición puede resolver interrogantes sobre su etiología y su patogenia.

Abstract Papular urticaria is a chronic allergic reaction induced by insect bites, which is common in the tropics. The objective of this review was to deepen on epidemiological and immunological aspects of this disease, focused on data published in Latin American countries. We conducted a non-systematic review of the literature through electronic search on the epidemiology of papular urticaria, the entomological characteristics of the causative agents and associated immunological mechanisms. Several reports from medical centers suggest that papular urticaria is common in Latin America. Only one epidemiological survey designed to estimate prevalence of papular urticaria has been published, reporting that about a quarter of children under six years of age is affected by this condition in Bogotá. There is evidence on the causal relationship among exposure to indoor fleas, poverty and papular urticaria in Bogotá, a representative city of the Andean altitudes. Information about causal insects in tropical warmer areas is scarce, although from clinical reports Aedes aegypti and Culex quienquefasciatus appear to be the most common. Th2 cellular-mediated mechanisms are involved in its pathogenesis, which explains its delayed hypersensitivity. The role of immunoglobulin E is not clear in this disease. Insect-derived antigens directly involved in papular urticaria etiology are unknown. However, it is possible that common molecules among causal insects mediate cross-reactive reactions, such as Cte f 2 allergen, found in cat fleas, and its counterparts in mosquitoes. Papular urticaria is a frequent disease in Latin America that should be further investigated. Immunological characterization of the molecular components that cause this condition may solve questions about its pathogenesis.

Pregnancy alters the circulating B cell compartment in atopic asthmatic women, and transitional B cells are positively associated with the development of allergy manifestations in their progeny.

PROBLEM: Maternal atopy is a risk factor for allergy. B cells are poorly studied in reproduction and atopy. We aimed to assess how pregnancy affects B cells in atopic women and whether B cells relate to allergic manifestations in offspring. METHOD OF STUDY: Women with and without atopic asthma, pregnant and non-pregnant were enrolled for the study, and circulating B cells were evaluated by flow cytometry, using CD19, CD27, CD38, IgD, and IgM. RESULTS: Compared to healthy non-pregnant, atopic asthmatic non-pregnant (ANP) women presented increased B cell counts, enlarged memory subsets, less transitional cells, and plasmablasts. Atopic asthmatic pregnant (AP) and healthy pregnant (HP) women showed similarities: reduced B cell counts and percentages, fewer memory cells, especially switched, and higher plasmablast percentages. Transitional B cell percentages were increased in AP women with allergic manifestations in their progeny. CONCLUSION: Atopic asthmatic non-pregnant women have a distinctive B cell compartment. B cells change in pregnancy, similarly in AP and HP women. The recognition that AP women with allergy in their progeny have a typical immune profile may help, in the future, the adoption of preventive measures to avoid the manifestation of allergic diseases in their newborns.

Associations of TNFα -308G>A, TNFα -238G>A, IL-1α -889C>T and IL-10 -1082G>A Genetic Polymorphisms with Atopic Diseases: Asthma, Rhinitis and Dermatitis.

BACKGROUND: Polymorphisms of cytokine genes are an interesting focus for association studies involving atopic diseases due to their role in immune cell communications during inflammation. The aim of this study was to investigate associations of TNFα -308G>A, TNFα -238G>A, IL-1α -889C>T and IL-10 -1082G>A polymorphisms with atopic diseases with adjustment for confounding lifestyle and environmental factors. METHODS: This study was performed on 356 Croatian students. The diagnosis of atopic asthma, atopic rhinitis and atopic dermatitis was based on symptoms reported by the modified International Study of Asthma and Allergies in Childhood questionnaire and a positive skin prick test (SPT) to at least one common inhalatory allergen. Genetic polymorphisms were genotyped using the polymerase chain reaction-based technique. The influence of personal (gender, body mass index, parental history of atopic disease), lifestyle (cigarette smoking, pet ownership) and environmental (urban/rural residency, residency in continental/Mediterranean region) factors reported in the questionnaire was investigated by univariate and multivariate analysis. RESULTS: Compared to the control subjects, univariate analysis showed a significant negative association of the TNFα -308G>A polymorphism with atopic asthma, atopic dermatitis, asthma and skin symptoms and positive SPT. These observations were confirmed in a multivariate model only for atopic dermatitis and skin symptoms (atopic dermatitis: OR = 0.27; 95% CI 0.07-1.00; p = 0.050; skin symptoms: OR = 0.29; 95% CI 0.10-0.83; p = 0.021). CONCLUSIONS: The results indicate a protective role of TNFα -308G>A genetic polymorphisms regarding atopic dermatitis and skin symptoms even after controlling for personal, lifestyle and environmental factors. Further studies are needed to elucidate the molecular patterns of this association in atopic dermatitis and other chronic inflammatory skin disorders.

Eotaxin-Rich Proangiogenic Hematopoietic Progenitor Cells and CCR3+ Endothelium in the Atopic Asthmatic Response.

Angiogenesis is closely linked to and precedes eosinophilic infiltration in asthma. Eosinophils are recruited into the airway by chemoattractant eotaxins, which are expressed by endothelial cells, smooth muscles cells, epithelial cells, and hematopoietic cells. We hypothesized that bone marrow-derived proangiogenic progenitor cells that contain eotaxins contribute to the initiation of angiogenesis and inflammation in asthma. Whole-lung allergen challenge of atopic asthma patients revealed vascular activation occurs within hours of challenge and before airway inflammation. The eotaxin receptor CCR3 was expressed at high levels on submucosal endothelial cells in patients and a murine model of asthma. Ex vivo exposure of murine endothelial cells to eotaxins induced migration and angiogenesis. In mechanistic studies, wild-type mice transplanted with eotaxin-1/2-deficient bone marrow had markedly less angiogenesis and inflammation in an atopic asthma model, whereas adoptive transfer of proangiogenic progenitor cells from wild-type mice in an atopic asthma model into the eotaxin-1/2-deficient mice led to angiogenesis and airway inflammation. The findings indicate that Th2-promoting hematopoietic progenitor cells are rapidly recruited to the lung upon allergen exposure and release eotaxins that coordinately activate endothelial cells, angiogenesis, and airway inflammation.