Publications by authors named "Nathalie Acevedo"

47 Publications

Multiethnic genome-wide and HLA association study of total serum IgE level.

J Allergy Clin Immunol 2021 Sep 15. Epub 2021 Sep 15.

Department of Human Genetics, University of Chicago, Chicago, Ill.

Background: Total serum IgE (tIgE) is an important intermediate phenotype of allergic disease. Whole genome genetic association studies across ancestries may identify important determinants of IgE.

Objective: We aimed to increase understanding of genetic variants affecting tIgE production across the ancestry and allergic disease spectrum by leveraging data from the National Heart, Lung and Blood Institute Trans-Omics for Precision Medicine program; the Consortium on Asthma among African-ancestry Populations in the Americas (CAAPA); and the Atopic Dermatitis Research Network (N = 21,901).

Methods: We performed genome-wide association within strata of study, disease, and ancestry groups, and we combined results via a meta-regression approach that models heterogeneity attributable to ancestry. We also tested for association between HLA alleles called from whole genome sequence data and tIgE, assessing replication of associations in HLA alleles called from genotype array data.

Results: We identified 6 loci at genome-wide significance (P < 5 × 10), including 4 loci previously reported as genome-wide significant for tIgE, as well as new regions in chr11q13.5 and chr15q22.2, which were also identified in prior genome-wide association studies of atopic dermatitis and asthma. In the HLA allele association study, HLA-A∗02:01 was associated with decreased tIgE level (P = 2 × 10; P = 5 × 10; P = 4 × 10), and HLA-DQB1∗03:02 was strongly associated with decreased tIgE level in Hispanic/Latino ancestry populations (P = 8 × 10).

Conclusion: We performed the largest genome-wide association study and HLA association study of tIgE focused on ancestrally diverse populations and found several known tIgE and allergic disease loci that are relevant in non-European ancestry populations.
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http://dx.doi.org/10.1016/j.jaci.2021.09.011DOI Listing
September 2021

Chronic Obstructive Pulmonary Disease Patients Have Increased Levels of Plasma Inflammatory Mediators Reported Upregulated in Severe COVID-19.

Front Immunol 2021 15;12:678661. Epub 2021 Jul 15.

Institute for Immunological Research, University of Cartagena, Cartagena, Colombia.

Background: Chronic obstructive pulmonary disease (COPD) is associated with increased risk of severe COVID-19, but the mechanisms are unclear. Besides, patients with severe COVID-19 have been reported to have increased levels of several immune mediators.

Methods: Ninety-two proteins were quantified in 315 plasma samples from 118 asthmatics, 99 COPD patients and 98 healthy controls (age 40-90 years), who were recruited in Colombia before the COVID-19 pandemic. Protein levels were compared between each disease group and healthy controls. Significant proteins were compared to the gene signatures of SARS-CoV-2 infection reported in the "COVID-19 Drug and Gene Set Library" and with experimentally tested protein biomarkers of severe COVID-19.

Results: Forty-one plasma proteins showed differences between patients and controls. Asthmatic patients have increased levels in IL-6 while COPD patients have a broader systemic inflammatory dysregulation driven by HGF, OPG, and several chemokines (CXCL9, CXCL10, CXCL11, CX3CL1, CXCL1, MCP-3, MCP-4, CCL3, CCL4 and CCL11). These proteins are involved in chemokine signaling pathways related with response to viral infections and some, were found up-regulated upon SARS-CoV-2 experimental infection of Calu-3 cells as reported in the COVID-19 Related Gene Sets database. An increase of HPG, CXCL9, CXCL10, IL-6, MCP-3, TNF and EN-RAGE has also been experimentally detected in patients with severe COVID-19.

Conclusions: COPD patients have altered levels of plasma proteins that have been reported increased in patients with severe COVID-19. Our study suggests that COPD patients have a systemic dysregulation in chemokine networks (including HGF and CXCL9) that could make them more susceptible to severe COVID-19. Also, that IL-6 levels are increased in some asthmatic patients (especially in females) and this may influence their response to COVID-19. The findings in this study depict a novel panel of inflammatory plasma proteins in COPD patients that may potentially associate with increased susceptibility to severe COVID-19 and might be useful as a biomarker signature after future experimental validation.
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http://dx.doi.org/10.3389/fimmu.2021.678661DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8320593PMC
August 2021

Genotyping of Ascaris spp. infecting humans and pigs in Italy, Slovakia and Colombia.

Infect Genet Evol 2021 Oct 10;94:104997. Epub 2021 Jul 10.

Department of Public Health and Infectious Diseases, Section of Parasitology, Sapienza University of Rome, Rome, Italy. Electronic address:

Background: The systematics and taxonomy of Ascaris lumbricoides and Ascaris suum, two of the world's most widespread nematodes, still represent a highly debated scientific issue. Two different transmission scenarios have been described according to endemicity: separated host-specific transmission cycles in endemic regions, and a single pool of infection shared by humans and pigs in non-endemic regions. The swine roundworm A. suum is now recognized as an important cause of human ascariasis also in endemic areas such as China, where cross-infections and hybridization have also been reported, as well as in non-endemic regions like Italy. This study aimed to investigate the molecular epidemiology of human and pig ascariasis in three countries representing different epidemiological scenarios: Italy as a non-endemic country, Colombia as an endemic country, and Slovakia as a non-endemic country, but with a poor socio-economic context linked to some focal populations of Roma settlements.

Materials And Methods: A total of 237 nematodes were analysed: 46 from Colombia (13 from humans, 33 from pigs), 114 from Slovakia (20 from humans, 94 from pigs) and 77 from Italy (17 from humans and 60 from pigs). Genotyping by PCR-RFLP of nuclear (ITS) and sequencing of mitochondrial (cox1) target regions were performed. ITS genotypes were used to estimate the Hardy-Weinberg (HW) equilibrium according to hosts and country of origin. The partial cox1 sequences were used to analyse genetic polymorphisms according to hosts and country of origin, as well as to infer the network of haplotypes, their evolutionary relationships and geographical distribution.

Results: 110 quality cox1 sequences were obtained. Haplotype network revealed three main groups corresponding to clade A, B and C. Clade C included most of the human cases from Italy, while those from Slovakia and Colombia were grouped in clade B. Ascaris from Italian and Colombian pigs showed HW equilibrium at the ITS marker, while disequilibrium was found in A. lumbricoides from Slovak pigs, which suggest a high unexpected amount of roundworms of human origin circulating also in pigs.

Conclusions: This study updates and extends the current understanding of Ascaris species and genotypes circulating in different epidemiological scenarios, with particular attention to the inclusion of human-derived Ascaris in the phylogenetic cluster C. Despite the evidence of HW equilibrium in the ITS in pig-derived Italian samples, the amount of genetic variation seems to support the existence of two closely related species.
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http://dx.doi.org/10.1016/j.meegid.2021.104997DOI Listing
October 2021

High-resolution targeted bisulfite sequencing reveals blood cell type-specific DNA methylation patterns in IL13 and ORMDL3.

Clin Epigenetics 2021 05 10;13(1):106. Epub 2021 May 10.

Department of Biosciences and Nutrition, Karolinska Institutet, Stockholm, Sweden.

Background: Methylation of DNA at CpG sites is an epigenetic modification and a potential modifier of disease risk, possibly mediating environmental effects. Currently, DNA methylation is commonly assessed using specific microarrays that sample methylation at a few % of all methylated sites.

Methods: To understand if significant information on methylation can be added by a more comprehensive analysis of methylation, we set up a quantitative method, bisulfite oligonucleotide-selective sequencing (Bs-OS-seq), and compared the data with microarray-derived methylation data. We assessed methylation at two asthma-associated genes, IL13 and ORMDL3, in blood samples collected from children with and without asthma and fractionated white blood cell types from healthy adult controls.

Results: Our results show that Bs-OS-seq can uncover vast amounts of methylation variation not detected by commonly used array methods. We found that high-density methylation information from even one gene can delineate the main white blood cell lineages.

Conclusions: We conclude that high-resolution methylation studies can yield clinically important information at selected specific loci missed by array-based methods, with potential implications for future studies of methylation-disease associations.
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http://dx.doi.org/10.1186/s13148-021-01093-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8111952PMC
May 2021

Are the Terms Major and Minor Allergens Useful for Precision Allergology?

Front Immunol 2021 8;12:651500. Epub 2021 Mar 8.

Institute for Immunological Research, University of Cartagena, Cartagena, Colombia.

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http://dx.doi.org/10.3389/fimmu.2021.651500DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7982392PMC
September 2021

Perinatal and Early-Life Nutrition, Epigenetics, and Allergy.

Nutrients 2021 Feb 25;13(3). Epub 2021 Feb 25.

Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Science, Utrecht University, 3584 CG Utrecht, The Netherlands.

Epidemiological studies have shown a dramatic increase in the incidence and the prevalence of allergic diseases over the last several decades. Environmental triggers including risk factors (e.g., pollution), the loss of rural living conditions (e.g., farming conditions), and nutritional status (e.g., maternal, breastfeeding) are considered major contributors to this increase. The influences of these environmental factors are thought to be mediated by epigenetic mechanisms which are heritable, reversible, and biologically relevant biochemical modifications of the chromatin carrying the genetic information without changing the nucleotide sequence of the genome. An important feature characterizing epigenetically-mediated processes is the existence of a time frame where the induced effects are the strongest and therefore most crucial. This period between conception, pregnancy, and the first years of life (e.g., first 1000 days) is considered the optimal time for environmental factors, such as nutrition, to exert their beneficial epigenetic effects. In the current review, we discussed the impact of the exposure to bacteria, viruses, parasites, fungal components, microbiome metabolites, and specific nutritional components (e.g., polyunsaturated fatty acids (PUFA), vitamins, plant- and animal-derived microRNAs, breast milk) on the epigenetic patterns related to allergic manifestations. We gave insight into the epigenetic signature of bioactive milk components and the effects of specific nutrition on neonatal T cell development. Several lines of evidence suggest that atypical metabolic reprogramming induced by extrinsic factors such as allergens, viruses, pollutants, diet, or microbiome might drive cellular metabolic dysfunctions and defective immune responses in allergic disease. Therefore, we described the current knowledge on the relationship between immunometabolism and allergy mediated by epigenetic mechanisms. The knowledge as presented will give insight into epigenetic changes and the potential of maternal and post-natal nutrition on the development of allergic disease.
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http://dx.doi.org/10.3390/nu13030724DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7996340PMC
February 2021

Helminth-derived cystatins: the immunomodulatory properties of an cystatin.

Parasitology 2021 Feb 10:1-13. Epub 2021 Feb 10.

Institute for Immunological Research, University of Cartagena, Cartagena de Indias, Colombia.

Helminth infections such as ascariasis elicit a type 2 immune response resembling that involved in allergic inflammation, but differing to allergy, they are also accompanied with strong immunomodulation. This has stimulated an increasing number of investigations, not only to better understand the mechanisms of allergy and helminth immunity but to find parasite-derived anti-inflammatory products that could improve the current treatments of chronic non-communicable inflammatory diseases such as asthma. A great number of helminth-derived immunomodulators have been discovered and some of them extensively analysed, showing their potential use as anti-inflammatory drugs in clinical settings. Since Ascaris lumbricoides is one of the most successful parasites, several groups have focused on the immunomodulatory properties of this helminth. As a result, several excretory/secretory components and purified molecules have been analysed, revealing interesting anti-inflammatory activities potentially useful as therapeutic tools. One of these molecules is A. lumbricoides cystatin, whose genomic, cellular, molecular, and immunomodulatory properties are described in this review.
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http://dx.doi.org/10.1017/S0031182021000214DOI Listing
February 2021

DNA Methylation Levels in Mononuclear Leukocytes from the Mother and Her Child Are Associated with IgE Sensitization to Allergens in Early Life.

Int J Mol Sci 2021 Jan 14;22(2). Epub 2021 Jan 14.

Department of Clinical Science and Education, Karolinska Institutet, and Sachs' Children and Youth Hospital, Södersjukhuset, SE-118 83 Stockholm, Sweden.

DNA methylation changes may predispose becoming IgE-sensitized to allergens. We analyzed whether DNA methylation in peripheral blood mononuclear cells (PBMC) is associated with IgE sensitization at 5 years of age (5Y). DNA methylation was measured in 288 PBMC samples from 74 mother/child pairs from the birth cohort ALADDIN (Assessment of Lifestyle and Allergic Disease During INfancy) using the HumanMethylation450BeadChip (Illumina). PBMCs were obtained from the mothers during pregnancy and from their children in cord blood, at 2 years and 5Y. DNA methylation levels at each time point were compared between children with and without IgE sensitization to allergens at 5Y. For replication, CpG sites associated with IgE sensitization in ALADDIN were evaluated in whole blood DNA of 256 children, 4 years old, from the BAMSE (Swedish abbreviation for Children, Allergy, Milieu, Stockholm, Epidemiology) cohort. We found 34 differentially methylated regions (DMRs) associated with IgE sensitization to airborne allergens and 38 DMRs associated with sensitization to food allergens in children at 5Y (Sidak ≤ 0.05). Genes associated with airborne sensitization were enriched in the pathway of endocytosis, while genes associated with food sensitization were enriched in focal adhesion, the bacterial invasion of epithelial cells, and leukocyte migration. Furthermore, 25 DMRs in maternal PBMCs were associated with IgE sensitization to airborne allergens in their children at 5Y, which were functionally annotated to the mTOR (mammalian Target of Rapamycin) signaling pathway. This study supports that DNA methylation is associated with IgE sensitization early in life and revealed new candidate genes for atopy. Moreover, our study provides evidence that maternal DNA methylation levels are associated with IgE sensitization in the child supporting early in utero effects on atopy predisposition.
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http://dx.doi.org/10.3390/ijms22020801DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7830007PMC
January 2021

Epigenetic alterations in skin homing CD4CLA T cells of atopic dermatitis patients.

Sci Rep 2020 10 22;10(1):18020. Epub 2020 Oct 22.

Department of Clinical Science and Education, Karolinska Institutet, and Sachs' Children and Youth Hospital, Södersjukhuset, 118 83, Stockholm, Sweden.

T cells expressing the cutaneous lymphocyte antigen (CLA) mediate pathogenic inflammation in atopic dermatitis (AD). The molecular alterations contributing to their dysregulation remain unclear. With the aim to elucidate putative altered pathways in AD we profiled DNA methylation levels and miRNA expression in sorted T cell populations (CD4, CD4CD45RA naïve, CD4CLA, and CD8) from adult AD patients and healthy controls (HC). Skin homing CD4CLA T cells from AD patients showed significant differences in DNA methylation in 40 genes compared to HC (p < 0.05). Reduced DNA methylation levels in the upstream region of the interleukin-13 gene (IL13) in CD4CLA T cells from AD patients correlated with increased IL13 mRNA expression in these cells. Sixteen miRNAs showed differential expression in CD4CLA T cells from AD patients targeting genes in 202 biological processes (p < 0.05). An integrated network analysis of miRNAs and CpG sites identified two communities of strongly interconnected regulatory elements with strong antagonistic behaviours that recapitulated the differences between AD patients and HC. Functional analysis of the genes linked to these communities revealed their association with key cytokine signaling pathways, MAP kinase signaling and protein ubiquitination. Our findings support that epigenetic mechanisms play a role in the pathogenesis of AD by affecting inflammatory signaling molecules in skin homing CD4CLA T cells and uncover putative molecules participating in AD pathways.
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http://dx.doi.org/10.1038/s41598-020-74798-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7582180PMC
October 2020

IgE Levels to and House Dust Mite Allergens Are Associated With Increased Histone Acetylation at Key Type-2 Immune Genes.

Front Immunol 2020 28;11:756. Epub 2020 Apr 28.

Institute for Immunological Research, University of Cartagena, Cartagena, Colombia.

Background: Epigenetic changes in response to allergen exposure are still not well understood. The aim of this study was to evaluate histone acetylation levels in peripheral blood leukocytes from humans naturally infected by intestinal parasites and perennially exposed to house dust mites (HDM).

Methods: Peripheral blood mononuclear cells (PBMCs) were isolated by gradient centrifugation from 20 infected and 21 non-infected individuals living in a rural/village in Colombia. Histone 3 acetylation (H3Ac) and histone 4 acetylation (H4Ac) levels were measured in six immune genes previously associated with helminth immunity by chromatin immunoprecipitation (ChIP)-quantitative PCR. Then we analyzed the association between histone acetylation levels with total parasite egg burden and IgE levels.

Results: We found an inverse correlation between H4Ac levels in the gene and egg worm burden that remained significant after adjustment by age [-0.20 (-0.32 to -0.09), < 0.0001]. Moreover, we found significant associations between H4Ac levels in [0.32 (0.05-0.60), = 0.02] and [0.29 (0.08-0.51), = 0.008] with the IgE levels to . In addition, the levels of specific IgE antibodies to HDM were associated with H4Ac levels in the gene encoding the B cell activating factor (BAFF) [0.51 (0.26-0.76), < 0.001]. All values are presented as beta (95% CI).

Conclusion: Histone acetylation levels at key type-2 immune genes in humans were modified by nematode infection and HDM allergens and are associated with the intensity of the IgE response.
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http://dx.doi.org/10.3389/fimmu.2020.00756DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7204827PMC
March 2021

The allergenic activity and clinical impact of individual IgE-antibody binding molecules from indoor allergen sources.

World Allergy Organ J 2020 May 29;13(5):100118. Epub 2020 Apr 29.

Department of Clinical Immunology and Allergy, Laboratory of Immunopathology, Sechenov First Moscow State Medical University, Moscow, Russia.

A large number of allergens have been discovered but we know little about their potential to induce inflammation (allergenic activity) and symptoms. Nowadays, the clinical importance of allergens is determined by the frequency and intensity of their IgE antibody binding (allergenicity). This is a rather limited parameter considering the development of experimental allergology in the last 20 years and the criteria that support personalized medicine. Now it is known that some allergens, in addition to their IgE antibody binding properties, can induce inflammation through non IgE mediated pathways, which can increase their allergenic activity. There are several ways to evaluate the allergenic activity, among them the provocation tests, the demonstration of non-IgE mediated pathways of inflammation, case control studies of IgE-binding frequencies, and animal models of respiratory allergy. In this review we have explored the current status of basic and clinical research on allergenic activity of indoor allergens and confirm that, for most of them, this important property has not been investigated. However, during recent years important advances have been made in the field, and we conclude that for at least the following, allergenic activity has been demonstrated: Der p 1, Der p 2, Der p 5 and Blo t 5 from HDMs; Per a 10 from ; Asp f 1, Asp f 2, Asp f 3, Asp f 4 and Asp f 6 from ; Mala s 8 and Mala s 13 from ; Alt a 1 from ; Pen c 13 from ; Fel d 1 from cats; Can f 1, Can f 2, Can f 3, Can f 4 and Can f 5 from dogs; Mus m 1 from mice and Bos d 2 from cows. Defining the allergenic activity of other indoor IgE antibody binding molecules is necessary for a precision-medicine-oriented management of allergic diseases.
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http://dx.doi.org/10.1016/j.waojou.2020.100118DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7195550PMC
May 2020

Personalized medicine for asthma in tropical regions.

Curr Opin Allergy Clin Immunol 2020 06;20(3):268-273

Institute for Immunological Research, University of Cartagena, Cartagena, Colombia.

Purpose Of Review: Precision medicine could help to improve diagnosis and treatment of asthma; however, in the tropics there are special conditions to be considered for applying this strategy. In this review, we analyze recent advances of precision allergology in tropical regions, highlighting its limitations and needs in high-admixed populations living under environments with high exposure to house dust mites and helminth infections.

Recent Findings: Advances have been made regarding the genetic characterization of the great diversity of populations living in the tropics. Genes involved in shared biological pathways between immune responses to nematodes and the allergic responses suggested new mechanisms of predisposition. Genome wide association studies of asthma are progressively focusing on some highly replicated genes such as those in chromosome 17q31-13, which have been also replicated in African ancestry populations. Some diagnostic difficulties, because of the endemicity of helminth infections, are now more evident in the context of phenotype definition.

Summary: The clinical impact of the advances in precision medicine for asthma in the tropics is still limited and mainly related to component resolved diagnosis. More basic and clinical research is needed to identify genetic, epigenetic, or other biologic markers that allow and accurate definition of phenotypes and endotypes of this heterogeneous disease. This will substantially improve the selection of personalized treatments.
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http://dx.doi.org/10.1097/ACI.0000000000000628DOI Listing
June 2020

House Dust Mite Allergy Under Changing Environments.

Allergy Asthma Immunol Res 2019 Jul;11(4):450-469

Institute for Immunological Research, University of Cartagena, Cartagena de Indias, Colombia.

Environmental variations induced by industrialization and climate change partially explain the increase in prevalence and severity of allergic disease. One possible mechanism is the increase in allergen production leading to more exposure and sensitization in susceptible individuals. House dust mites (HDMs) are important sources of allergens inducing asthma and rhinitis, and experimentally they have been demonstrated to be very sensitive to microenvironment modifications; therefore, global or regional changes in temperature, humidity, air pollution or other environmental conditions could modify natural HDM growth, survival and allergen production. There is evidence that sensitization to HDMs has increased in some regions of the world, especially in the subtropical and tropical areas; however, the relationship of this increase with environmental changes is not so clear as has reported for pollen allergens. In this review, we address this point and explore the effects of current and predicted environmental changes on HDM growth, survival and allergen production, which could lead to immunoglobulin E (IgE) sensitization and allergic disease prevalence. We also assess the role of adjuvants of IgE responses, such as air pollution and helminth infections, and discuss the genetic and epigenetic aspects that could influence the adaptive process of humans to drastic and relatively recent environmental changes we are experiencing.
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http://dx.doi.org/10.4168/aair.2019.11.4.450DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6557771PMC
July 2019

Epigenetic Modifications in Placenta are Associated with the Child's Sensitization to Allergens.

Biomed Res Int 2019 17;2019:1315257. Epub 2019 Apr 17.

Department of Clinical Science and Education, Karolinska Institutet, and Sachs' Children and Youth Hospital, Södersjukhuset, Stockholm, Sweden.

Prenatal environmental exposures are considered to contribute to the development of allergic sensitization by epigenetic mechanisms. The role of histone acetylation in the placenta has not been examined yet. We hypothesized that placental histone acetylation at the promoter regions of allergy-related immune regulatory genes is associated with the development of sensitization to allergens in the child. Histones H3 and H4 acetylation at the promoter regions of 6 selected allergy-related immune regulatory genes was assessed by a chromatin immunoprecipitation assay in 173 term placentas collected in the prospective birth-cohort ALADDIN. The development of IgE sensitization to allergens in the children was followed from 6 months up to 5 years of age. We discovered significant associations of histone acetylation levels with decreased risk of allergic sensitization in 3 genes. Decreased risk of sensitization to food allergens was associated with higher H3 acetylation levels in placentas at the and genes, and for H4 acetylation in . Higher H4 acetylation levels were also associated with a decreased risk of sensitization to aeroallergens. In conclusion, our results suggest that acetylation of histones in placenta has a potential to predict the development of sensitization to allergens in children.
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http://dx.doi.org/10.1155/2019/1315257DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6500694PMC
November 2019

Nocturnal asthma is affected by genetic interactions between RORA and NPSR1.

Pediatr Pulmonol 2019 06 29;54(6):847-857. Epub 2019 Mar 29.

Department of Pediatric Pneumology and Allergy, University Children's Hospital Regensburg (KUNO), Regensburg, Germany.

Background: Neuropeptide S Receptor 1 ( NPSR1) and Retinoid Acid Receptor-Related Orphan Receptor Alpha (RORA ) interact biologically, are both known candidate genes for asthma, and are involved in controlling circadian rhythm. Thus, we assessed (1) whether interactions between RORA and NPSR1 specifically affect the nocturnal asthma phenotype and (2) how this may differ from other asthma phenotypes.

Methods: Interaction effects between 24 single-nucleotide polymorphisms (SNPs) in RORA and 35 SNPs in NPSR1 on asthma and nocturnal asthma symptoms were determined in 1432 subjects (763 asthmatics [192 with nocturnal asthma symptoms]; 669 controls) from the Multicenter Asthma Genetic in Childhood/International Study of Asthma and Allergies in Childhood studies. The results were validated and extended in children from the Manchester Asthma and Allergy Study (N = 723) and the Children Allergy Milieu Stockholm and Epidemiological cohort (N = 1646).

Results: RORA* NPSR1 interactions seemed to affect both asthma and nocturnal asthma. In stratified analyses, however, interactions mainly affected nocturnal asthma and less so asthma without nocturnal symptoms or asthma severity. Results were replicated in two independent cohorts and seemed to remain constant over time throughout youth.

Conclusion: RORA* NPSR1 interactions appear to be involved in mechanisms specific for nocturnal asthma. In contrast to previous studies focusing on the role of beta 2 receptor polymorphisms in nocturnal asthma as a feature of asthma control or severity in general, our data suggest that changes in circadian rhythm control are associated with nighttime asthma symptoms.
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http://dx.doi.org/10.1002/ppul.24292DOI Listing
June 2019

Histone Acetylation of Immune Regulatory Genes in Human Placenta in Association with Maternal Intake of Olive Oil and Fish Consumption.

Int J Mol Sci 2019 03 1;20(5). Epub 2019 Mar 1.

Institute of Laboratory Medicine, member of the German Center for Lung Research (DZL), Universities of Giessen and Marburg Lung Center (UGMLC), and the inVIVO Planetary Health, Group of the Worldwide Universities Network (WUN), Philipps-University Marburg, 35043 Marburg, Germany.

Maternal diet modifies epigenetic programming in offspring, a potentially critical factor in the immune dysregulation of modern societies. We previously found that prenatal fish oil supplementation affects neonatal T-cell histone acetylation of genes implicated in adaptive immunity including , , and . In this study, we measured H3 and H4 histone acetylation levels by chromatin immunoprecipitation in 173 term placentas collected in the prospective birth cohort, ALADDIN, in which information on lifestyle and diet is thoroughly recorded. In anthroposophic families, regular olive oil usage during pregnancy was associated with increased H3 acetylation at ( = 0.004), ( = 0.008), and ( = 0.007) promoters, which remained significant after adjustment by offspring gender. Furthermore, maternal fish consumption was associated with increased H4 acetylation at the gene in placentas of female offspring ( = 0.009). In conclusion, prenatal olive oil intake can affect placental histone acetylation in immune regulatory genes, confirming previously observed pro-acetylation effects of olive oil polyphenols. The association with fish consumption may implicate ω-3 polyunsaturated fatty acids present in fish oil. Altered histone acetylation in placentas from mothers who regularly include fish or olive oil in their diets could influence immune priming in the newborn.
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http://dx.doi.org/10.3390/ijms20051060DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6429118PMC
March 2019

Association study in African-admixed populations across the Americas recapitulates asthma risk loci in non-African populations.

Nat Commun 2019 02 20;10(1):880. Epub 2019 Feb 20.

National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD, 20892, USA.

Asthma is a complex disease with striking disparities across racial and ethnic groups. Despite its relatively high burden, representation of individuals of African ancestry in asthma genome-wide association studies (GWAS) has been inadequate, and true associations in these underrepresented minority groups have been inconclusive. We report the results of a genome-wide meta-analysis from the Consortium on Asthma among African Ancestry Populations (CAAPA; 7009 asthma cases, 7645 controls). We find strong evidence for association at four previously reported asthma loci whose discovery was driven largely by non-African populations, including the chromosome 17q12-q21 locus and the chr12q13 region, a novel (and not previously replicated) asthma locus recently identified by the Trans-National Asthma Genetic Consortium (TAGC). An additional seven loci reported by TAGC show marginal evidence for association in CAAPA. We also identify two novel loci (8p23 and 8q24) that may be specific to asthma risk in African ancestry populations.
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http://dx.doi.org/10.1038/s41467-019-08469-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6382865PMC
February 2019

The antimicrobial protein S100A12 identified as a potential autoantigen in a subgroup of atopic dermatitis patients.

Clin Transl Allergy 2019 31;9. Epub 2019 Jan 31.

2Department of Clinical Science and Education, Karolinska Institutet, and Sachs' Children and Youth Hospital, Södersjukhuset, Stockholm, Sweden.

Background: Atopic dermatitis (AD) is a complex heterogeneous chronic inflammatory skin disease. Specific IgE antibodies against autoantigens have been observed in a subgroup of AD patients, however, little is known about IgG-auto-reactivity in AD. To investigate the presence of autoreactive IgG antibodies, we performed autoantibody profiling of IgG in patients with AD of different severities and in healthy controls (HC).

Methods: First, we performed an untargeted screening in plasma samples from 40 severe AD (sAD) patients and 40 HC towards 1152 protein fragments on planar antigen microarrays. Next, based on the findings and addition of more fragments, a targeted antigen suspension bead array was designed to profile a cohort of 50 sAD patients, 123 patients with moderate AD (mAD), and 84 HC against 148 protein fragments representing 96 unique proteins.

Results: Forty-nine percent of the AD patients showed increased IgG-reactivity to any of the four antigens representing keratin associated protein 17-1 (KRTAP17-1), heat shock protein family A (Hsp70) member 4 (HSPA4), S100 calcium binding proteins A12 (S100A12), and Z (S100Z). The reactivity was more frequent in the sAD patients (66%) than in those with mAD (41%), whereas only present in 25% of the HC. IgG-reactivity to S100A12, a protein including an antimicrobial peptide, was only observed in AD patients (13/173).

Conclusions: Autoantibody profiling of IgG-reactivity using microarray technology revealed an autoantibody-based subgroup in patients with AD. The four identified autoantigens and especially S100A12 could, if characterized further, increase the understanding of different pathogenic mechanisms behind AD and thereby enable better treatment.
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http://dx.doi.org/10.1186/s13601-019-0240-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6354350PMC
January 2019

Hygienic conditions influence sensitization to Blomia tropicalis allergenic components: Results from the FRAAT birth cohort.

Pediatr Allergy Immunol 2019 03 4;30(2):172-178. Epub 2018 Dec 4.

Institute for Immunological Research, University of Cartagena, Cartagena, Colombia.

Background: In tropical zones, perennial exposure to house dust mite (HDM) allergens and helminth infections is present. Studying the impact of these conditions on the inception and evolution of allergic diseases is necessary to have an accurate view of their natural history. We aimed to evaluate the dynamics of genuine sensitization to Blomia tropicalis and Ascaris in children from the FRAAT birth cohort and the effects of helminth infection, environmental HDM allergen levels, and sociodemographic factors.

Methods: Children were followed up to 6 years old. Specific IgE to recombinant allergens from B. tropicalis (Blo t 5 and Blo t 12) and Ascaris spp (Asc l 3, Asc l 13 and Asc s 1) was measured by ELISA at different time points. Allergen levels were measured in dust when children were 6 months old.

Results: IgE sensitization increased over time up to 3 years old. Correlation among the specific IgE levels to B. tropicalis and Ascaris components is poor at year 1, but coefficients are high and significant (Spearman's rho coefficients >0.70) at year 6. Unhygienic conditions increased the odds of sensitization to B. tropicalis allergenic components. Blo t 5 levels were lower in the poorest. IgE response to Blo t 5 and Blo t 12 was less intense in children with high exposure to Blo t 5 (levels >80th percentile).

Conclusion: In this tropical community, the pattern of childhood IgE sensitization is different from that in developing countries and is influenced by the hygienic conditions.
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http://dx.doi.org/10.1111/pai.13004DOI Listing
March 2019

Ascariasis as a model to study the helminth/allergy relationships.

Parasite Immunol 2019 06 6;41(6):e12595. Epub 2018 Nov 6.

Institute for Immunological Research, University of Cartagena, Cartagena, Colombia.

Ascariasis is the most frequent soil transmitted helminthiasis and, as well as other helminth infections, is expected to influence the clinical presentation of allergic diseases such as asthma. Indeed, several clinical and experimental works have shown an important impact either increasing or suppressing symptoms, and the same effects have been detected on the underlying immune responses. In this review we analyze the work on this field performed in Colombia, a Latin American tropical country, including aspects such as the molecular genetics of the IgE response to Ascaris; the allergenic activity of Ascaris IgE-binding molecular components and the immunological and clinical influences of ascariasis on asthma. The analysis allows us to conclude that the impact of ascariasis on the inception and evolution of allergic diseases such as asthma deserves more investigation, but advances have been made during the last years. The concurrent parasite-induced immunostimulatory and immunosuppressive effects during this helminthiasis do modify the natural history of asthma and some aspects of the practice of allergology in the tropics. Theoretically it can also influence the epidemiological trends of allergic diseases either by its absence or presence in different regions and countries.
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http://dx.doi.org/10.1111/pim.12595DOI Listing
June 2019

Ascaris Suum Infection Downregulates Inflammatory Pathways in the Pig Intestine In Vivo and in Human Dendritic Cells In Vitro.

J Infect Dis 2018 01;217(2):310-319

Department of Veterinary and Animal Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Frederiksberg, Denmark.

Ascaris suum is a helminth parasite of pigs closely related to its human counterpart, A. lumbricoides, which infects almost 1 billion people. Ascaris is thought to modulate host immune and inflammatory responses, which may drive immune hyporesponsiveness during chronic infections. Using transcriptomic analysis, we show here that pigs with a chronic A. suum infection have a substantial suppression of inflammatory pathways in the intestinal mucosa, with a broad downregulation of genes encoding cytokines and antigen-processing and costimulatory molecules. A. suum body fluid (ABF) suppressed similar transcriptional pathways in human dendritic cells (DCs) in vitro. DCs exposed to ABF secreted minimal amounts of cytokines and had impaired production of cyclooxygengase-2, altered glucose metabolism, and reduced capacity to induce interferon-gamma production in T cells. Our in vivo and in vitro data provide an insight into mucosal immune modulation during Ascaris infection, and show that A. suum profoundly suppresses immune and inflammatory pathways.
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http://dx.doi.org/10.1093/infdis/jix585DOI Listing
January 2018

Neuropeptide S (NPS) variants modify the signaling and risk effects of NPS Receptor 1 (NPSR1) variants in asthma.

PLoS One 2017 2;12(5):e0176568. Epub 2017 May 2.

Heart and Lung Center, Division of Pulmonary Medicine, University of Helsinki and Helsinki University Hospital, 00014 University of Helsinki, Helsinki, Finland.

Single nucleotide polymorphisms (SNPs) close to the gain-of-function substitution, Asn(107)Ile (rs324981, A>T), in Neuropeptide S Receptor 1 (NPSR1) have been associated with asthma. Furthermore, a functional SNP (rs4751440, G>C) in Neuropeptide S (NPS) encodes a Val(6)Leu substitution on the mature peptide that results in reduced bioactivity. We sought to examine the effects of different combinations of these NPS and NPSR1 variants on downstream signaling and genetic risk of asthma. In transfected cells, the magnitude of NPSR1-induced activation of cAMP/PKA signal transduction pathways and downstream gene expression was dependent on the combination of the NPS and NPSR1 variants with NPS-Val(6)/NPSR1-Ile(107) resulting in strongest and NPS-Leu(6)/NPSR1-Asn(107) in weakest effects, respectively. One or two copies of the NPS-Leu(6) (rs4751440) were associated with physician-diagnosed childhood asthma (OR: 0.67, 95%CI 0.49-0.92, p = 0.01) and together with two other linked NPS variants (rs1931704 and rs10830123) formed a protective haplotype (p = 0.008) in the Swedish birth cohort BAMSE (2033 children). NPS rs10830123 showed epistasis with NPSR1 rs324981 encoding Asn(107)Ile (p = 0.009) in BAMSE and with the linked NPSR1 rs17199659 (p = 0.005) in the German MAGIC/ISAAC II cohort (1454 children). In conclusion, NPS variants modify asthma risk and should be considered in genetic association studies of NPSR1 with asthma and other complex diseases.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0176568PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5413018PMC
September 2017

International consensus (ICON) on: clinical consequences of mite hypersensitivity, a global problem.

World Allergy Organ J 2017 18;10(1):14. Epub 2017 Apr 18.

Allergy and Clinical Immunology Department, Centro Médico Docente La Trinidad, Caracas, Venezuela.

Since mite allergens are the most relevant inducers of allergic diseases worldwide, resulting in significant morbidity and increased burden on health services, the International Collaboration in Asthma, Allergy and Immunology (iCAALL), formed by the American Academy of Allergy, Asthma and Immunology (AAAAI), the American College of Allergy, Asthma and Immunology (ACAAI), the European Academy of Allergy and Clinical Immunology (EAACI), and the World Allergy Organization (WAO), has proposed to issue an International Consensus (ICON) on the clinical consequences of mite hypersensitivity. The objectives of this document are to highlight aspects of mite biology that are clinically relevant, to update the current knowledge on mite allergens, routes of sensitization, the genetics of IgE responses to mites, the epidemiologic aspects of mite hypersensitivity, the clinical pictures induced by mites, the diagnosis, specific immunotherapeutic approaches, and prevention.
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http://dx.doi.org/10.1186/s40413-017-0145-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5394630PMC
April 2017

Increased Expression of Toll-Like Receptors 4, 5, and 9 in Small Bowel Mucosa from Patients with Irritable Bowel Syndrome.

Biomed Res Int 2017 29;2017:9624702. Epub 2017 Jan 29.

Department of Medicine, Karolinska Institutet and Center for Digestive Diseases, Karolinska University Hospital, Huddinge, Stockholm, Sweden.

The aim of our study was to compare patients with irritable bowel syndrome (IBS) and healthy controls regarding the expression of toll-like receptors 2, 4, 5, and 9 (TLR2, TLR4, TLR5, and TLR9), the primary mucosal receptors of bacterial components, in small and large bowel mucosa. We analysed biopsies from jejunum and sigmoid colon of 22 patients (17 females) with IBS aged 18-66 (median: 39) years and 14 healthy volunteers (12 females) aged 22-61 (median: 42) years. Eight patients had constipation-predominant IBS (C-IBS), 7 had diarrhoea-predominant IBS (D-IBS), and 7 had IBS without predominance of constipation or diarrhoea. We analysed mRNA levels for TLRs using quantitative PCR and distribution of TLRs in mucosa using immunohistochemistry. We found increased mRNA expression of TLR4 (mean fold change 1.85 ± 0.31 versus 1.0 ± 0.20; < 0.05), TLR5 (1.96 ± 0.36 versus 1.0 ± 0.20; < 0.05) and TLR9 (2.00 ± 0.24 versus 1.0 ± 0.25; < 0.01) but not of TLR2 in the small bowel mucosa from patients with IBS compared to the controls. There was no significant difference in mRNA levels for TLRs in colon mucosa between patients and controls. Upregulation of TLR4, TLR5, and TLR9 suggests the involvement of bacteria or dysregulation of the immune response to commensal flora in small bowel mucosa in IBS patients.
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http://dx.doi.org/10.1155/2017/9624702DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5303582PMC
March 2017

Zika Virus, Chikungunya Virus, and Dengue Virus in Cerebrospinal Fluid from Adults with Neurological Manifestations, Guayaquil, Ecuador.

Front Microbiol 2017 24;8:42. Epub 2017 Jan 24.

Laboratorio de Biología Molecular, Hospital Luis Vernaza Guayaquil, Ecuador.

Zika virus (ZIKV), chikungunya virus (CHIKV), and dengue virus (DENV) have been associated with clinical presentations that involve acute neurological complaints. In the current study, we identified ZIKV, CHIKV, and DENV in cerebrospinal fluid (CSF) samples from patients admitted to the Hospital Luis Vernaza (Guayaquil, Ecuador) to the Emergency Room or the Intensive Care Unit, with neurological symptoms and/or concern for acute arboviral infections. Viral RNA from one or more virus was detected in 12/16 patients. Six patients were diagnosed with meningitis or encephalitis, three with Guillain-Barré Syndrome, and one with CNS vasculitis. Two additional patients had a systemic febrile illness including headache that prompted testing of CSF. Two patients, who were diagnosed with encephalitis and meningoencephalitis, died during their hospitalizations. These cases demonstrate the breadth and significance of neurological manifestations associated with ZIKV, CHIKV, and DENV infections.
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http://dx.doi.org/10.3389/fmicb.2017.00042DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5258761PMC
January 2017

Genetic Variants in CHIA and CHI3L1 Are Associated with the IgE Response to the Ascaris Resistance Marker ABA-1 and the Birch Pollen Allergen Bet v 1.

PLoS One 2016 15;11(12):e0167453. Epub 2016 Dec 15.

Institute for Immunological Research, University of Cartagena, Cartagena, Colombia.

Helminth infections and allergic diseases are associated with IgE hyperresponsiveness but the genetics of this phenotype remain to be defined. Susceptibility to Ascaris lumbricoides infection and antibody levels to this helminth are associated with polymorphisms in locus 13q33-34. We aimed to explore this and other genomic regions to identify genetic variants associated with the IgE responsiveness in humans. Forty-eight subjects from Cartagena, Colombia, with extreme values of specific IgE to Ascaris and ABA-1, a resistance marker of this nematode, were selected for targeted resequencing. Burden analyses were done comparing extreme groups for IgE values. One-hundred one SNPs were genotyped in 1258 individuals of two well-characterized populations from Colombia and Sweden. Two low-frequency coding variants in the gene encoding the Acidic Mammalian Chitinase (CHIA rs79500525, rs139812869, tagged by rs10494133) were found enriched in high IgE responders to ABA-1 and confirmed by genetic association analyses. The SNP rs4950928 in the Chitinase 3 Like 1 gene (CHI3L1) was associated with high IgE to ABA-1 in Colombians and with high IgE to Bet v 1 in the Swedish population. CHIA rs10494133 and ABDH13 rs3783118 were associated with IgE responses to Ascaris. SNPs in the Tumor Necrosis Factor Superfamily Member 13b gene (TNFSF13B) encoding the cytokine B cell activating Factor were associated with high levels of total IgE in both populations. This is the first report on the association between low-frequency and common variants in the chitinases-related genes CHIA and CHI3L1 with the intensity of specific IgE to ABA-1 in a population naturally exposed to Ascaris and with Bet v 1 in a Swedish population. Our results add new information about the genetic influences of human IgE responsiveness; since the genes encode for enzymes involved in the immune response to parasitic infections, they could be helpful for understanding helminth immunity and allergic responses. We also confirmed that TNFSF13B has an important and conserved role in the regulation of total IgE levels, which supports potential evolutionary links between helminth immunity and allergic response.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0167453PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5157985PMC
June 2017

High-specificity bioinformatics framework for epigenomic profiling of discordant twins reveals specific and shared markers for ACPA and ACPA-positive rheumatoid arthritis.

Genome Med 2016 11 22;8(1):124. Epub 2016 Nov 22.

Center for Molecular Medicine at Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden.

Background: Twin studies are powerful models to elucidate epigenetic modifications resulting from gene-environment interactions. Yet, commonly a limited number of clinical twin samples are available, leading to an underpowered situation afflicted with false positives and hampered by low sensitivity. We investigated genome-wide DNA methylation data from two small sets of monozygotic twins representing different phases during the progression of rheumatoid arthritis (RA) to find novel genes for further research.

Methods: We implemented a robust statistical methodology aimed at investigating a small number of samples to identify differential methylation utilizing the comprehensive CHARM platform with whole blood cell DNA from two sets of twin pairs discordant either for ACPA (antibodies to citrullinated protein antigens)-positive RA versus ACPA-negative healthy or for ACPA-positive healthy (a pre-RA stage) versus ACPA-negative healthy. To deconvolute cell type-dependent differential methylation, we assayed the methylation patterns of sorted cells and used computational algorithms to resolve the relative contributions of different cell types and used them as covariates.

Results: To identify methylation biomarkers, five healthy twin pairs discordant for ACPAs were profiled, revealing a single differentially methylated region (DMR). Seven twin pairs discordant for ACPA-positive RA revealed six significant DMRs. After deconvolution of cell type proportions, profiling of the healthy ACPA discordant twin-set revealed 17 genome-wide significant DMRs. When methylation profiles of ACPA-positive RA twin pairs were adjusted for cell type, the analysis disclosed one significant DMR, associated with the EXOSC1 gene. Additionally, the results from our methodology suggest a temporal connection of the protocadherine beta-14 gene to ACPA-positivity with clinical RA.

Conclusions: Our biostatistical methodology, optimized for a low-sample twin design, revealed non-genetically linked genes associated with two distinct phases of RA. Functional evidence is still lacking but the results reinforce further study of epigenetic modifications influencing the progression of RA. Our study design and methodology may prove generally useful in twin studies.
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http://dx.doi.org/10.1186/s13073-016-0374-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5120506PMC
November 2016

Particularities of allergy in the Tropics.

World Allergy Organ J 2016 27;9:20. Epub 2016 Jun 27.

Allergy Section, Department of Internal Medicine, Hospital Vall d'Hebron, Barcelona, Spain.

Allergic diseases are distributed worldwide and their risk factors and triggers vary according to geographical and socioeconomic conditions. Allergies are frequent in the Tropics but aspects of their prevalence, natural history, risk factors, sensitizers and triggers are not well defined and some are expected to be different from those in temperate zone countries. The aim of this review is to investigate if allergic diseases in the Tropics have particularities that deserve special attention for research and clinical practice. Such information will help to form a better understanding of the pathogenesis, diagnosis and management of allergic diseases in the Tropics. As expected, we found particularities in the Tropics that merit further study because they strongly affect the natural history of common allergic diseases; most of them related to climate conditions that favor permanent exposure to mite allergens, helminth infections and stinging insects. In addition, we detected several unmet needs in important areas which should be investigated and solved by collaborative efforts led by the emergent research groups on allergy from tropical countries.
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http://dx.doi.org/10.1186/s40413-016-0110-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4924335PMC
July 2016

Proanthocyanidins inhibit Ascaris suum glutathione-S-transferase activity and increase susceptibility of larvae to levamisole in vitro.

Parasitol Int 2016 Aug 16;65(4):336-9. Epub 2016 Apr 16.

Department of Veterinary Disease Biology, Faculty of Health and Medical Sciences, University of Copenhagen, Frederiksberg, Denmark. Electronic address:

Proanthocyanidins (PAC) are a class of plant secondary metabolites commonly found in the diet that have shown potential to control gastrointestinal nematode infections. The anti-parasitic mechanism(s) of PAC remain obscure, however the protein-binding properties of PAC suggest that disturbance of key enzyme functions may be a potential mode of action. Glutathione-S-transferases (GSTs) are essential for parasite detoxification and have been investigated as drug and vaccine targets. Here, we show that purified PAC strongly inhibit the activity of both recombinant and native GSTs from the parasitic nematode Ascaris suum. As GSTs are involved in detoxifying xenobiotic substances within the parasite, we hypothesised that this inhibition may render parasites hyper-susceptible to anthelmintic drugs. Migration inhibition assays with A. suum larvae demonstrated that the potency of levamisole (LEV) and ivermectin (IVM) were significantly increased in the presence of PAC purified from pine bark (4.6-fold and 3.2-fold reduction in IC50 value for LEV and IVM, respectively). Synergy analysis revealed that the relationship between PAC and LEV appeared to be synergistic in nature, suggesting a specific enhancement of LEV activity, whilst the relationship between PAC and IVM was additive rather than synergistic, suggesting independent actions. Our results demonstrate that these common dietary compounds may increase the efficacy of synthetic anthelmintic drugs in vitro, and also suggest one possible mechanism for their well-known anti-parasitic activity.
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http://dx.doi.org/10.1016/j.parint.2016.04.001DOI Listing
August 2016
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