The role of eosinophils and basophils in allergic diseases considering genetic findings

Nadif, Rachel; Zerimech, Farid; Matran, Régis

doi:10.1097/aci.0b013e328364e9c0

Cited by 35 publications

(20 citation statements)

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“…5E) (41, 42). Our findings provide key insights into the molecular regulation of basophil production, an important and nonredundant cell type in inflammation and host defense that has been challenging to study in humans due to its rarity (44,(61)(62)(63). The identification of these variants will also allow for further studies of the mechanisms by which genetic variants influencing basophil counts may impact on human diseases.…”

Section: Discussionmentioning

confidence: 99%

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Comprehensive population-based genome sequencing provides insight into hematopoietic regulatory mechanisms

Guo

Nandakumar

Ulirsch

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Genetic variants affecting hematopoiesis can influence commonly measured blood cell traits. To identify factors that affect hematopoiesis, we performed association studies for blood cell traits in the population-based Estonian Biobank using highcoverage whole-genome sequencing (WGS) in 2,284 samples and SNP genotyping in an additional 14,904 samples. Using up to 7,134 samples with available phenotype data, our analyses identified 17 associations across 14 blood cell traits. Integration of WGS-based fine-mapping and complementary epigenomic datasets provided evidence for causal mechanisms at several loci, including at a previously undiscovered basophil countassociated locus near the master hematopoietic transcription factor CEBPA. The fine-mapped variant at this basophil count association near CEBPA overlapped an enhancer active in common myeloid progenitors and influenced its activity. In situ perturbation of this enhancer by CRISPR/Cas9 mutagenesis in hematopoietic stem and progenitor cells demonstrated that it is necessary for and specifically regulates CEBPA expression during basophil differentiation. We additionally identified basophil count-associated variation at another more pleiotropic myeloid enhancer near GATA2, highlighting regulatory mechanisms for ordered expression of master hematopoietic regulators during lineage specification. Our study illustrates how population-based genetic studies can provide key insights into poorly understood cell differentiation processes of considerable physiologic relevance.genome sequencing | GWAS | basophils | hematopoiesis | CEBPA

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Section: Discussionmentioning

confidence: 99%

“…Basophils have been implicated in inflammation and host defense, but the causal role that basophils play in human disease is poorly understood (44,(61)(62)(63). To identify potential disease roles for basophils, we performed a phenome-wide association study (pheWAS) for rs78744187 and rs2465283 (64).…”

Section: Il-3-mediated Differentiation Of Human Cd34mentioning

confidence: 99%

Comprehensive population-based genome sequencing provides insight into hematopoietic regulatory mechanisms

Guo

Nandakumar

Ulirsch

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…We suggest that exposure to allergens results in uptake and proceeding by dendritic cells inducing the development of Th2 cells in sensitised individuals. Recent evidence indicates that airway epithelium also plays an important role in the allergic airway response by the release of interleukin (IL)-25, IL-33 and thymic stromal lymphopoietin (TSLP) which activate dendritic cells, basophils, eosinophils and Th2 cells [30,31]. TSLP, IL-25 and IL-33 promote eosinophilia in airway mucosa by inducing IL-5 production.…”

Section: Discussionmentioning

confidence: 99%

Exhaled nitric oxide, nitrite/nitrate levels, allergy, rhinitis and asthma in the EGEA study

et al. 2014

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Although interest in biomarkers in the nitrate-nitrite-NO pathway has recently increased, associations between nitrite (NO 2 -) and nitrate (NO 3 -), and asthma, allergic sensitisation and rhinitis remain unclear. The study aimed to evaluate the associations between NO 2 -/NO 3 -and exhaled fraction of nitric oxide (FeNO) levels with asthma, allergic sensitisation and rhinitis.Plasma and exhaled breath condensate (EBC) NO 2 -/NO 3 -and FeNO levels were measured in 523 adults of the French Epidemiological study on Genetics and Environment of Asthma. Allergic sensitisation was defined by a positive skin prick test for at least one aeroallergen. Subjects were classified as non-sensitised, sensitised and as having allergic rhinitis.Plasma NO 2 -/NO 3 -level was unrelated to any disease phenotypes. EBC NO 2 -/NO 3 -level was unrelated to any asthma phenotypes. EBC NO 2 -/NO 3 -and FeNO levels were correlated in sensitised subjects only (r50.21¡0.10, p50.01). EBC NO 2 -/NO 3 -and FeNO levels were higher in sensitised than in non-sensitised subjects (adjusted geometric mean (95% CI): 2.36 (1.96-2.84) versus 1.72 (1.38-2.14) mmol per mg proteins, p50.008; and 18.3 (16.7-20.0) versus 14.8 (13.3-16.5) ppb, p50.0006, respectively), with gradual relationships from sensitised subjects to those with allergic rhinitis (p,0.0001).Results suggest that EBC NO 2 -/NO 3 -and FeNO levels may be considered as biological markers of intensity of allergic sensitisation and rhinitis. @ERSpublications The EGEA study: exhaled nitrate/nitrite/NO levels may be considered markers for intensity of allergy and rhinitis

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“…Modification of cell-mediated immunity is characterized by migration of basophils, neutrophils and eosinophils to the tick bite site with migration facilitated by T cells and antibodies specific for tick salivary components 8,11 . Recent insights into the biology of basophils suggest their role as regulators of Th2 cell responses, through IL-4 expression or the differentiation of monocytes to macrophages 12 . Th2 polarization of the cytokine response to tick feeding has been observed both in vitro and in vivo 13 .…”

Section: Introductionmentioning

confidence: 99%

Partial pathogen protection by tick-bite sensitization and epitope recognition in peptide-immunized HLA DR3 transgenic mice

Shattuck

Dyer

Desrosiers

et al. 2014

Human Vaccines & Immunotherapeutics

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Ticks are notorious vectors of disease for humans, and many species of ticks transmit multiple pathogens, sometimes in the same tick bite. Accordingly, a broad-spectrum vaccine that targets vector ticks and pathogen transmission at the tick/host interface, rather than multiple vaccines against every possible tickborne pathogen, could become an important tool for resolving an emerging public health crisis. The concept for such a tick protective vaccine comes from observations of an acquired tick resistance (ATR) that can develop in non-natural hosts of ticks following sensitization to tick salivary components. Mice are commonly used as models to study immune responses to human pathogens but normal mice are natural hosts for many species of ticks and fail to develop ATR. We evaluated HLA DR3 transgenic (tg) “humanized” mice as a potential model of ATR and assessed the possibility of using this animal model for tick protective vaccine discovery studies. Serial tick infestations with pathogen-free Ixodes scapularis ticks were used to tick-bite sensitize HLA DR3 tg mice. Sensitization resulted in a cytokine skew favoring a Th2 bias as well as partial (57%) protection to infection with Lyme disease spirochetes (Borrelia burgdorferi) following infected tick challenge when compared to tick naïve counterparts. I. scapularis salivary gland homogenate (SGH) and a group of immunoinformatic-predicted T cell epitopes identified from the I. scapularis salivary transcriptome were used separately to vaccinate HLA DR3 tg mice, and these mice also were assessed for both pathogen protection and epitope recognition. Reduced pathogen transmission along with a Th2 skew resulted from SGH vaccination, while no significant protection and a possible T regulatory bias was seen in epitope-vaccinated mice. This study provides the first proof-of-concept for using HLA DR tg “humanized” mice for studying the potential tick protective effects of immunoinformatic- or otherwise-derived tick salivary components as tickborne disease vaccines.

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The role of eosinophils and basophils in allergic diseases considering genetic findings

Cited by 35 publications

References 35 publications

Comprehensive population-based genome sequencing provides insight into hematopoietic regulatory mechanisms

Comprehensive population-based genome sequencing provides insight into hematopoietic regulatory mechanisms

Exhaled nitric oxide, nitrite/nitrate levels, allergy, rhinitis and asthma in the EGEA study

Partial pathogen protection by tick-bite sensitization and epitope recognition in peptide-immunized HLA DR3 transgenic mice

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