International Journal of Molecular Sciences

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Open AccessEditorial

Editorial of Special Issue “Molecular Mechanisms of Allergy and Asthma”

by Daniel P. Potaczek

Int. J. Mol. Sci. 2021, 22(21), 11580; https://doi.org/10.3390/ijms222111580 - 27 Oct 2021

Cited by 1 | Viewed by 1859

Abstract

This Special Issue aggregates several high-quality original articles written by renowned researchers [...] Full article

(This article belongs to the Special Issue Molecular Mechanisms of Allergy and Asthma)

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17 pages, 3499 KiB

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DRP1-Mediated Mitochondrial Fission Regulates Lung Epithelial Response to Allergen

by Sierra R. Bruno, Amit Kumar, Zoe F. Mark, Ravishankar Chandrasekaran, Emily Nakada, Nicolas Chamberlain, Bethany Mihavics, Joseph Walzer, Jonathon Cahoon, Anne E. Dixon, Brian Cunniff and Vikas Anathy

Int. J. Mol. Sci. 2021, 22(20), 11125; https://doi.org/10.3390/ijms222011125 - 15 Oct 2021

Cited by 13 | Viewed by 2873

Abstract

Mitochondria regulate a myriad of cellular functions. Dysregulation of mitochondrial control within airway epithelial cells has been implicated in the pro-inflammatory response to allergens in asthma patients. Because of their multifaceted nature, mitochondrial structure must be tightly regulated through fission and fusion. Dynamin [...] Read more.

Mitochondria regulate a myriad of cellular functions. Dysregulation of mitochondrial control within airway epithelial cells has been implicated in the pro-inflammatory response to allergens in asthma patients. Because of their multifaceted nature, mitochondrial structure must be tightly regulated through fission and fusion. Dynamin Related Protein 1 (DRP1) is a key driver of mitochondrial fission. During allergic asthma, airway epithelial mitochondria appear smaller and structurally altered. The role of DRP1-mediated mitochondrial fission, however, has not been fully elucidated in epithelial response to allergens. We used a Human Bronchial Epithelial Cell line (HBECs), primary Mouse Tracheal Epithelial Cells (MTECs), and conditional DRP1 ablation in lung epithelial cells to investigate the impact of mitochondrial fission on the pro-inflammatory response to house dust mite (HDM) in vitro and in vivo. Our data suggest that, following HDM challenge, mitochondrial fission is rapidly upregulated in airway epithelial cells and precedes production of pro-inflammatory cytokines and chemokines. Further, deletion of Drp1 in lung epithelial cells leads to decreased fission and enhanced pro-inflammatory signaling in response to HDM in vitro, as well as enhanced airway hyper-responsiveness (AHR), inflammation, differential mucin transcription, and epithelial cell death in vivo. Mitochondrial fission, therefore, regulates the lung epithelial pro-inflammatory response to HDM. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Allergy and Asthma)

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15 pages, 4927 KiB

Open AccessArticle

Differential Regulation of Interferon Signaling Pathways in CD4⁺ T Cells of the Low Type-2 Obesity-Associated Asthma Phenotype

by Fahd Alhamdan, Leigh M. Marsh, Frauke Pedersen, Bilal Alashkar Alhamwe, Clemens Thölken, Petra Ina Pfefferle, Thomas Bahmer, Timm Greulich, Daniel P. Potaczek and Holger Garn

Int. J. Mol. Sci. 2021, 22(18), 10144; https://doi.org/10.3390/ijms221810144 - 20 Sep 2021

Cited by 18 | Viewed by 3621

Abstract

In the era of personalized medicine, insights into the molecular mechanisms that differentially contribute to disease phenotypes, such as asthma phenotypes including obesity-associated asthma, are urgently needed. Peripheral blood was drawn from 10 obese, non-atopic asthmatic adults with a high body mass index [...] Read more.

In the era of personalized medicine, insights into the molecular mechanisms that differentially contribute to disease phenotypes, such as asthma phenotypes including obesity-associated asthma, are urgently needed. Peripheral blood was drawn from 10 obese, non-atopic asthmatic adults with a high body mass index (BMI; 36.67 ± 6.90); 10 non-obese, non-atopic asthmatic adults with normal BMI (23.88 ± 2.73); and 10 healthy controls with normal BMI (23.62 ± 3.74). All asthmatic patients were considered to represent a low type-2 asthma phenotype according to selective clinical parameters. RNA sequencing (RNA-Seq) was conducted on peripheral blood CD4⁺ T cells. Thousands of differentially expressed genes were identified in both asthma groups compared with heathy controls. The expression of interferon (IFN)-stimulated genes associated with IFN-related signaling pathways was specifically affected in obese asthmatics, while the gap junction and G protein-coupled receptor (GPCR) ligand binding pathways were enriched in both asthma groups. Furthermore, obesity gene markers were also upregulated in CD4⁺ T cells from obese asthmatics compared with the two other groups. Additionally, the enriched genes of the three abovementioned pathways showed a unique correlation pattern with various laboratory and clinical parameters. The specific activation of IFN-related signaling and viral infection pathways might provide a novel view of the molecular mechanisms associated with the development of the low type-2 obesity-associated asthma phenotype, which is a step ahead in the development of new stratified therapeutic approaches. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Allergy and Asthma)

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16 pages, 2467 KiB

Open AccessArticle

Cord Blood T Cells Expressing High and Low PKCζ Levels Develop into Cells with a Propensity to Display Th1 and Th9 Cytokine Profiles, Respectively

by Khalida Perveen, Alex Quach, Andrew McPhee, Susan L. Prescott, Simon C. Barry, Charles S. Hii and Antonio Ferrante

Int. J. Mol. Sci. 2021, 22(9), 4907; https://doi.org/10.3390/ijms22094907 - 5 May 2021

Cited by 8 | Viewed by 2715

Abstract

Low Protein Kinase C zeta (PKCζ) levels in cord blood T cells (CBTC) have been shown to correlate with the development of allergic sensitization in childhood. However, little is known about the mechanisms responsible. We have examined the relationship between the expression of [...] Read more.

Low Protein Kinase C zeta (PKCζ) levels in cord blood T cells (CBTC) have been shown to correlate with the development of allergic sensitization in childhood. However, little is known about the mechanisms responsible. We have examined the relationship between the expression of different levels of PKCζ in CBTC and their development into mature T cell cytokine producers that relate to allergy or anti-allergy promoting cells. Maturation of naïve CBTC was initiated with anti-CD3/-CD28 antibodies and recombinant human interleukin-2 (rhIL-2). To stimulate lymphocyte proliferation and cytokine production the cells were treated with Phytohaemagglutinin (PHA) and Phorbol myristate acetate (PMA). Irrespective of the PKCζ levels expressed, immature CBTC showed no difference in lymphocyte proliferation and the production of T helper 2 (Th2) cytokine interleukin-4 (IL-4) and Th1 cytokine, interferon-gamma (IFN-γ), and influenced neither their maturation from CD45RA⁺ to CD45RO⁺ cells nor cell viability/apoptosis. However, upon maturation the low PKCζ expressing cells produced low levels of the Th1 cytokines, IFN-γ, IL-2 and tumour necrosis factor-alpha (TNF), no changes to levels of the Th2 cytokines, IL-4, IL-5 and IL-13, and an increase in the Th9 cytokine, IL-9. Other cytokines, lymphotoxin-α (LT-α), IL-10, IL-17, IL-21, IL-22 and Transforming growth factor-beta (TGF-β) were not significantly different. The findings support the view that low CBTC PKCζ levels relate to the increased risk of developing allergic diseases. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Allergy and Asthma)

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14 pages, 1217 KiB

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Plasticity of Naturally Occurring Regulatory T Cells in Allergic Airway Disease Is Modulated by the Transcriptional Activity of Il-6

by Morgan MacBeth, Anthony Joetham, Erwin W. Gelfand and Michaela Schedel

Int. J. Mol. Sci. 2021, 22(9), 4582; https://doi.org/10.3390/ijms22094582 - 27 Apr 2021

Cited by 5 | Viewed by 2007

Abstract

The impact of naturally occurring regulatory T cells (nTregs) on the suppression or induction of lung allergic responses in mice depends on the nuclear environment and the production of the pro-inflammatory cytokine interleukin 6 (IL-6). These activities were shown to be different in [...] Read more.

The impact of naturally occurring regulatory T cells (nTregs) on the suppression or induction of lung allergic responses in mice depends on the nuclear environment and the production of the pro-inflammatory cytokine interleukin 6 (IL-6). These activities were shown to be different in nTregs derived from wild-type (WT) and CD8-deficient mice (CD8^−/−), with increased IL-6 levels in nTregs from CD8^−/− mice in comparison to WT nTregs. Thus, identification of the molecular mechanisms regulating IL-6 production is critical to understanding the phenotypic plasticity of nTregs. Electrophoretic mobility shift assays (EMSA) were performed to determine transcription factor binding to four Il-6 promoter loci using nuclear extracts from nTregs of WT and CD8^−/− mice. Increased transcription factor binding for each of the Il-6 loci was identified in CD8^−/− compared to WT nTregs. The impact of transcription factor binding and a novel short tandem repeat (STR) on Il-6 promoter activity was analyzed by luciferase reporter assays. The Il-6 promoter regions closer to the transcription start site (TSS) were more relevant to the regulation of Il-6 depending on NF-κB, c-Fos, and SP and USF family members. Two Il-6 promoter loci were most critical for the inducibility by lipopolysaccharide (LPS) and tumor necrosis factor α (TNFα). A novel STR of variable length in the Il-6 promoter was identified with diverging prevalence in nTregs from WT or CD8^−/− mice. The predominant GT repeat in CD8^−/− nTregs revealed the highest luciferase activity. These novel regulatory mechanisms controlling the transcriptional regulation of the Il-6 promoter are proposed to contribute to nTregs plasticity and may be central to disease pathogenesis. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Allergy and Asthma)

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11 pages, 3200 KiB

Open AccessArticle

Natural Killer Cells from Allergic Donors Are Defective in Their Response to CCL18 Chemokine

by Latiffa Amniai, Coline Ple, Mathieu Barrier, Patricia de Nadai, Philippe Marquillies, Han Vorng, Cécile Chenivesse, Anne Tsicopoulos and Catherine Duez

Int. J. Mol. Sci. 2021, 22(8), 3879; https://doi.org/10.3390/ijms22083879 - 9 Apr 2021

Cited by 7 | Viewed by 2278

Abstract

Natural killer (NK) cells were originally described as cytolytic effector cells, but since then have been recognized to possess regulatory functions on immune responses. Chemokines locate NK cells throughout the body in homeostatic and pathological conditions. They may also directly stimulate immune cells. [...] Read more.

Natural killer (NK) cells were originally described as cytolytic effector cells, but since then have been recognized to possess regulatory functions on immune responses. Chemokines locate NK cells throughout the body in homeostatic and pathological conditions. They may also directly stimulate immune cells. CCL18 is a constitutive and inducible chemokine involved in allergic diseases. The aim of this study was to evaluate CCL18’s effect on NK cells from allergic and nonallergic donors in terms of both chemotactic and immune effects. Results showed that CCL18 was able to induce migration of NK cells from nonallergic donors in a G-protein-dependent manner, suggesting the involvement of a classical chemokine receptor from the family of seven-transmembrane domain G-protein-coupled receptors. In contrast, NK cells from allergic patients were unresponsive. Similarly, CCL18 was able to induce NK cell cytotoxicity only in nonallergic subjects. Purified NK cells did not express CCR8, one of the receptors described to be involved in CCL18 functions. Finally, the defect in CCL18 response by NK cells from allergic patients was unrelated to a defect in CCL18 binding to NK cells. Overall, our results suggest that some NK cell functions may be defective in allergic diseases. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Allergy and Asthma)

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12 pages, 8821 KiB

Open AccessArticle

Asthma-Associated Long TSLP Inhibits the Production of IgA

by Dorianne van Heerden, Robert S. van Binnendijk, Samantha A. M. Tromp, Huub F. J. Savelkoul, R. J. Joost van Neerven and Gerco den Hartog

Int. J. Mol. Sci. 2021, 22(7), 3592; https://doi.org/10.3390/ijms22073592 - 30 Mar 2021

Cited by 7 | Viewed by 2822

Abstract

Thymic stromal lymphopoietin (TSLP) contributes to asthmatic disease. The concentrations of protective IgA may be reduced in the respiratory tract of asthma patients. We investigated how homeostatic short TSLP (shTSLP) and asthma-associated long TSLP (loTSLP) regulate IgA production. B cells from healthy donors [...] Read more.

Thymic stromal lymphopoietin (TSLP) contributes to asthmatic disease. The concentrations of protective IgA may be reduced in the respiratory tract of asthma patients. We investigated how homeostatic short TSLP (shTSLP) and asthma-associated long TSLP (loTSLP) regulate IgA production. B cells from healthy donors were stimulated in the presence or absence of shTSLP or loTSLP; the concentrations of IgA, IgM, IgE, and IgG antibodies were determined in cell culture supernatants; and B cells were analyzed by flow cytometry. LoTSLP, but not shTSLP, suppressed the secretion of IgA but not of IgE. The type 2 cytokine IL-4, which in addition to loTSLP contributes to asthmatic disease, did not affect the production of IgA or the frequency of IgA+ B cells. Instead, IL-4 increased IgG production, especially of the subclasses IgG2 and IgG4. LoTSLP inhibited IgA secretion by sorted memory B cells but not by naïve B cells. Although loTSLP inhibited IgA production, the vitamin A metabolite retinoic acid promoted the secretion of IgA, also in the presence of loTSLP, suggesting that vitamin A may promote IgA production in asthma. Our data demonstrate that asthma-associated loTSLP negatively regulates the secretion of IgA, which may negatively impact the surveillance of mucosal surfaces in asthma. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Allergy and Asthma)

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18 pages, 2862 KiB

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Cytokines Stimulated by IL-33 in Human Skin Mast Cells: Involvement of NF-κB and p38 at Distinct Levels and Potent Co-Operation with FcεRI and MRGPRX2

by Kristin Franke, Zhao Wang, Torsten Zuberbier and Magda Babina

Int. J. Mol. Sci. 2021, 22(7), 3580; https://doi.org/10.3390/ijms22073580 - 30 Mar 2021

Cited by 34 | Viewed by 3926

Abstract

The IL-1 family cytokine IL-33 activates and re-shapes mast cells (MCs), but whether and by what mechanisms it elicits cytokines in MCs from human skin remains poorly understood. The current study found that IL-33 activates CCL1, CCL2, IL-5, IL-8, IL-13, and TNF-α, while [...] Read more.

The IL-1 family cytokine IL-33 activates and re-shapes mast cells (MCs), but whether and by what mechanisms it elicits cytokines in MCs from human skin remains poorly understood. The current study found that IL-33 activates CCL1, CCL2, IL-5, IL-8, IL-13, and TNF-α, while IL-1β, IL-6, IL-31, and VEGFA remain unaffected in cutaneous MCs, highlighting that each MC subset responds to IL-33 with a unique cytokine profile. Mechanistically, IL-33 induced the rapid (1–2 min) and durable (2 h) phosphorylation of p38, whereas the phosphorylation of JNK was weaker and more transient. Moreover, the NF-κB pathway was potently activated, as revealed by IκB degradation, increased nuclear abundance of p50/p65, and vigorous phosphorylation of p65. The activation of NF-κB occurred independently of p38 or JNK. The induced transcription of the cytokines selected for further study (CCL1, CCL2, IL-8, TNF-α) was abolished by interference with NF-κB, while p38/JNK had only some cytokine-selective effects. Surprisingly, at the level of the secreted protein products, p38 was nearly as effective as NF-κB for all entities, suggesting post-transcriptional involvement. IL-33 did not only instruct skin MCs to produce selected cytokines, but it also efficiently co-operated with the allergic and pseudo-allergic/neurogenic activation networks in the production of IL-8, TNF-α, CCL1, and CCL2. Synergism was more pronounced at the protein than at the mRNA level and appeared stronger for MRGPRX2 ligands than for FcεRI. Our results underscore the pro-inflammatory nature of an acute IL-33 stimulus and imply that especially in combination with allergens or MRGPRX2 agonists, IL-33 will efficiently amplify skin inflammation and thereby aggravate inflammatory dermatoses. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Allergy and Asthma)

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14 pages, 822 KiB

Open AccessArticle

Molecular and Immunological Identification of Low Allergenic Fruits among Old and New Apple Varieties

by Aleksandra Siekierzynska, Dorota Piasecka-Kwiatkowska, Wojciech Litwinczuk, Marta Burzynska, Aleksander Myszka, Pawel Karpinski, Elzbieta Zygala, Narcyz Piorecki, Ewa Springer and Tomasz Sozanski

Int. J. Mol. Sci. 2021, 22(7), 3527; https://doi.org/10.3390/ijms22073527 - 29 Mar 2021

Cited by 12 | Viewed by 3103

Abstract

About 50–70% of patients allergic to birch pollen suffer from sensitization after apple ingestion. Apple allergenicity was established in only few varieties. Studies were performed on apple fruits of 21 traditional and nine modern varieties organically, intensively, or integratively produced. The aim of [...] Read more.

About 50–70% of patients allergic to birch pollen suffer from sensitization after apple ingestion. Apple allergenicity was established in only few varieties. Studies were performed on apple fruits of 21 traditional and nine modern varieties organically, intensively, or integratively produced. The aim of the study was to assess whether the factors like cultivation method, maturity stage, genotype, or type of tissue place an impact on the allergenic potential of apples. To answer these questions, we used semiquantitative real-time PCR, ELISA, and immunoblotting. Apple allergen genes present divergent expression across apple cultivars. Expression of the Mal d 1.06A correlates with the Mal d 1 level and is affected by the cultivation method and maturity of the fruit. The content of the main allergen Mal d 1 varied widely across cultivars. Interestingly, in our study, the Gala variety presented a low Mal d 1 concentration regardless of the cultivation method. Based on the Mal d 1.06A expression, the Mal d 1 protein content, and the immunoreactivity assay, the Kandil Sinap, Kosztela, Rumianka from Alma-Ata, Kantówka Gdańska, Reinette Coulon, and Gala cultivars emerged as potentially hypoallergenic apple cultivars. Our study allowed distinguishing between potentially low, medium, and highly allergenic varieties. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Allergy and Asthma)

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17 pages, 1228 KiB

Open AccessArticle

Raw Milk-Induced Protection against Food Allergic Symptoms in Mice Is Accompanied by Shifts in Microbial Community Structure

by Suzanne Abbring, Phillip A. Engen, Ankur Naqib, Stefan J. Green, Johan Garssen, Ali Keshavarzian and Betty C. A. M. van Esch

Int. J. Mol. Sci. 2021, 22(7), 3417; https://doi.org/10.3390/ijms22073417 - 26 Mar 2021

Cited by 12 | Viewed by 3476

Abstract

The mechanism underlying the allergy-protective effects of raw cow’s milk is still unknown, but the modulation of the gut microbiome may play a role. The effects of consuming raw cow’s milk or processed milk on fecal microbial communities were therefore characterized in an [...] Read more.

The mechanism underlying the allergy-protective effects of raw cow’s milk is still unknown, but the modulation of the gut microbiome may play a role. The effects of consuming raw cow’s milk or processed milk on fecal microbial communities were therefore characterized in an experimental murine model. C3H/HeOuJ mice were treated with raw milk, pasteurized milk, skimmed raw milk, pasteurized milk supplemented with alkaline phosphatase (ALP), or phosphate-buffered saline (PBS) for eight days prior to sensitization and challenge with ovalbumin (OVA). Fecal samples were collected after milk exposure and after OVA sensitization, and microbiomes were characterized using 16S ribosomal RNA gene amplicon sequencing. Treatment with raw milk prior to OVA sensitization increased the relative abundance of putative butyrate-producing bacteria from the taxa Lachnospiraceae UCG-001, Lachnospiraceae UCG-008, and Ruminiclostridium 5 (Clostridial clusters XIVa and IV), while it decreased the relative abundance of Proteobacterial genera such as Parasutterella, a putative pro-inflammatory bacterial genus. This effect was observed after eight days of raw milk exposure and became more pronounced five weeks later, after allergic sensitization in the absence of milk. Similar trends were observed after treatment with skimmed raw milk. Conversely, the feeding of pasteurized milk led to a loss of allergy protection and a putative dysbiotic microbiome. The addition of ALP to pasteurized milk restored the protective effect observed with raw milk and mitigated some of the microbial community alterations associated with milk pasteurization. Raw milk-induced protection against food allergic symptoms in mice is accompanied by an increased relative abundance of putative butyrate-producing Clostridiales and a decreased relative abundance of putative pro-inflammatory Proteobacteria. Given the safety concerns regarding raw milk consumption, this knowledge is key for the development of new, microbiologically safe, preventive strategies to reduce the incidence of allergic diseases. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Allergy and Asthma)

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18 pages, 2013 KiB

Open AccessArticle

T and B Lymphocyte Transcriptional States Differentiate between Sensitized and Unsensitized Individuals in Alpha-Gal Syndrome

by Onyinye I. Iweala, Shailesh K. Choudhary, Claire T. Addison and Scott P. Commins

Int. J. Mol. Sci. 2021, 22(6), 3185; https://doi.org/10.3390/ijms22063185 - 20 Mar 2021

Cited by 9 | Viewed by 4703

Abstract

The mechanisms of pathogenesis driving alpha-gal syndrome (AGS) are not fully understood. Differences in immune gene expression between AGS individuals and non-allergic controls may illuminate molecular pathways and targets critical for AGS development. We performed immune expression profiling with RNA from the peripheral [...] Read more.

The mechanisms of pathogenesis driving alpha-gal syndrome (AGS) are not fully understood. Differences in immune gene expression between AGS individuals and non-allergic controls may illuminate molecular pathways and targets critical for AGS development. We performed immune expression profiling with RNA from the peripheral blood mononuclear cells (PBMCs) of seven controls, 15 AGS participants, and two participants sensitized but not allergic to alpha-gal using the NanoString nCounter PanCancer immune profiling panel, which includes 770 genes from 14 different cell types. The top differentially expressed genes (DEG) between AGS subjects and controls included transcription factors regulating immune gene expression, such as the NFκB pathway (NFKBIA, NFKB2, REL), antigen presentation molecules, type 2/allergic immune responses, itch, and allergic dermatitis. The differential expression of genes linked to T and B cell function was also identified, including transcription factor BCL-6, markers of antigen experience (CD44) and memory (CD27), chemokine receptors (CXCR3, CXCR6), and regulators of B-cell proliferation, cell cycle entry and immunoglobulin production (CD70). The PBMCs from AGS subjects also had increased TNF and IFN-gamma mRNA expression compared to controls. AGS is associated with a distinct gene expression profile in circulating PBMCs. DEGs related to antigen presentation, antigen-experienced T-cells, and type 2 immune responses may promote the development of alpha-gal specific IgE and the maintenance of AGS. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Allergy and Asthma)

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21 pages, 2350 KiB

Open AccessArticle

Reticular Basement Membrane Thickness Is Associated with Growth- and Fibrosis-Promoting Airway Transcriptome Profile-Study in Asthma Patients

by Stanislawa Bazan-Socha, Sylwia Buregwa-Czuma, Bogdan Jakiela, Lech Zareba, Izabela Zawlik, Aleksander Myszka, Jerzy Soja, Krzysztof Okon, Jacek Zarychta, Paweł Kozlik, Sylwia Dziedzina, Agnieszka Padjas, Krzysztof Wojcik, Michal Kepski and Jan G. Bazan

Int. J. Mol. Sci. 2021, 22(3), 998; https://doi.org/10.3390/ijms22030998 - 20 Jan 2021

Cited by 19 | Viewed by 4367

Abstract

Airway remodeling in asthma is characterized by reticular basement membrane (RBM) thickening, likely related to epithelial structural and functional changes. Gene expression profiling of the airway epithelium might identify genes involved in bronchial structural alterations. We analyzed bronchial wall geometry (computed tomography (CT)), [...] Read more.

Airway remodeling in asthma is characterized by reticular basement membrane (RBM) thickening, likely related to epithelial structural and functional changes. Gene expression profiling of the airway epithelium might identify genes involved in bronchial structural alterations. We analyzed bronchial wall geometry (computed tomography (CT)), RBM thickness (histology), and the bronchial epithelium transcriptome profile (gene expression array) in moderate to severe persistent (n = 21) vs. no persistent (n = 19) airflow limitation asthmatics. RBM thickness was similar in the two studied subgroups. Among the genes associated with increased RBM thickness, the most essential were those engaged in cell activation, proliferation, and growth (e.g., CDK20, TACC2, ORC5, and NEK5) and inhibiting apoptosis (e.g., higher mRNA expression of RFN34, BIRC3, NAA16, and lower of RNF13, MRPL37, CACNA1G). Additionally, RBM thickness correlated with the expression of genes encoding extracellular matrix (ECM) components (LAMA3, USH2A), involved in ECM remodeling (LTBP1), neovascularization (FGD5, HPRT1), nerve functioning (TPH1, PCDHGC4), oxidative stress adaptation (RIT1, HSP90AB1), epigenetic modifications (OLMALINC, DNMT3A), and the innate immune response (STAP1, OAS2). Cluster analysis revealed that genes linked with RBM thickness were also related to thicker bronchial walls in CT. Our study suggests that the pro-fibrotic profile in the airway epithelial cell transcriptome is associated with a thicker RBM, and thus, may contribute to asthma airway remodeling. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Allergy and Asthma)

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19 pages, 2424 KiB

Open AccessArticle

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

by Nathalie Acevedo, Giovanni Scala, Simon Kebede Merid, Paolo Frumento, Sören Bruhn, Anna Andersson, Christoph Ogris, Matteo Bottai, Göran Pershagen, Gerard H. Koppelman, Erik Melén, Erik Sonnhammer, Johan Alm, Cilla Söderhäll, Juha Kere, Dario Greco and Annika Scheynius

Int. J. Mol. Sci. 2021, 22(2), 801; https://doi.org/10.3390/ijms22020801 - 14 Jan 2021

Cited by 20 | Viewed by 3501

Abstract

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 [...] Read more.

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 p ≤ 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. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Allergy and Asthma)

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16 pages, 3324 KiB

Open AccessArticle

Butyrate and Propionate Restore the Cytokine and House Dust Mite Compromised Barrier Function of Human Bronchial Airway Epithelial Cells

by Levi B. Richards, Meng Li, Gert Folkerts, Paul A.J. Henricks, Johan Garssen and Betty C.A.M. van Esch

Int. J. Mol. Sci. 2021, 22(1), 65; https://doi.org/10.3390/ijms22010065 - 23 Dec 2020

Cited by 37 | Viewed by 3660

Abstract

Barrier dysfunction of airway epithelium contributes to the development of allergies, airway hyper-responsiveness and immunological respiratory diseases. Short-chain fatty acids (SCFA) enhance and restore the barrier function of the intestinal epithelium. This study investigated whether acetate, propionate and butyrate enhance the integrity of [...] Read more.

Barrier dysfunction of airway epithelium contributes to the development of allergies, airway hyper-responsiveness and immunological respiratory diseases. Short-chain fatty acids (SCFA) enhance and restore the barrier function of the intestinal epithelium. This study investigated whether acetate, propionate and butyrate enhance the integrity of bronchial epithelial cells. Differentiating human bronchial epithelial cells (16HBE) grown on transwells were exposed to butyrate, propionate and acetate while trans-epithelial electrical resistance was monitored over time. Restorative effects of SCFA were investigated by subsequent incubation of cells with IL-4, IL-13 or house dust mite extract and SCFA. SCFA effects on IL-4-induced cytokine production and the expression of zonula occludens-1 (ZO-1) and Mitogen-activated protein kinases (MAPK) signalling pathways were investigated by ELISA and Western blot assays. Propionate and butyrate enhanced the barrier function of differentiating 16HBE cells and induced complete recovery of the barrier function after exposure to the above-mentioned stimuli. Butyrate decreased IL-4-induced IL-6 production. IL-4 decreased ZO-1 protein expression and induced phosphorylation of extracellular signal-regulated protein kinases 1/2 (ERK1/2) and c-Jun N-terminal kinases (JNK) in 16HBE cells, both of which could be restored by SCFA. SCFA showed prophylactic and restorative effects on airway epithelial barrier function, which might be induced by increased ZO-1 expression. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Allergy and Asthma)

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17 pages, 1747 KiB

Open AccessArticle

Eosinophil microRNAs Play a Regulatory Role in Allergic Diseases Included in the Atopic March

by Émile Bélanger, Anne-Marie Madore, Anne-Marie Boucher-Lafleur, Marie-Michelle Simon, Tony Kwan, Tomi Pastinen and Catherine Laprise

Int. J. Mol. Sci. 2020, 21(23), 9011; https://doi.org/10.3390/ijms21239011 - 27 Nov 2020

Cited by 19 | Viewed by 3295

Abstract

(1) Background: The atopic march is defined by the increased prevalence of allergic diseases after atopic dermatitis onset. In fact, atopic dermatitis is believed to play an important role in allergen sensitization via the damaged skin barrier, leading to allergic diseases such as [...] Read more.

(1) Background: The atopic march is defined by the increased prevalence of allergic diseases after atopic dermatitis onset. In fact, atopic dermatitis is believed to play an important role in allergen sensitization via the damaged skin barrier, leading to allergic diseases such as allergic asthma and allergic rhinitis. The eosinophil, a pro-inflammatory cell that contributes to epithelial damage, is one of the various cells recruited in the inflammatory reactions characterizing these diseases. Few studies were conducted on the transcriptome of this cell type and even less on their specific microRNA (miRNA) profile, which could modulate pathogenesis of allergic diseases and clinical manifestations post-transcriptionally. Actually, their implication in allergic diseases is not fully understood, but they are believed to play a role in inflammation-related patterns and epithelial cell proliferation. (2) Methods: Next-generation sequencing was performed on RNA samples from eosinophils of individuals with atopic dermatitis, atopy, allergic rhinitis and asthma to obtain differential counts of primary miRNA (pri-miRNA); these were also analyzed for asthma-related phenotypes such as forced expiratory volume in one second (FEV₁), immunoglobulin E (IgE) and provocative concentration of methacholine inducing a 20% fall in forced expiratory volume in 1 s (PC₂₀) levels, as well as FEV₁ to forced vital capacity (FEV₁/FVC) ratio. (3) Results: Eighteen miRNAs from eosinophils were identified to be significantly different between affected individuals and unaffected ones. Based on counts from these miRNAs, individuals were then clustered into groups using Ward’s method on Euclidian distances. Groups were found to be explained by asthma diagnosis, familial history of respiratory diseases and allergic rhinitis as well as neutrophil counts. (4) Conclusions: The 18 differential miRNA counts for the studying phenotypes allow a better understanding of the epigenetic mechanisms underlying the development of the allergic diseases included in the atopic march. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Allergy and Asthma)

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14 pages, 857 KiB

Open AccessArticle

Microbiological, Physicochemical, and Immunological Analysis of a Commercial Cashew Nut-Based Yogurt

by Christopher P. Mattison, Kayanush J. Aryana, Kristen Clermont, Eric Prestenburg, Steven W. Lloyd, Casey C. Grimm and Richard L. Wasserman

Int. J. Mol. Sci. 2020, 21(21), 8267; https://doi.org/10.3390/ijms21218267 - 4 Nov 2020

Cited by 20 | Viewed by 4016

Abstract

Nut-based milks and yogurts are gaining popularity, but may not offer the same benefits as dairy yogurts to consumers. Cashew nuts often cause severe allergic reactions, and cashew nut allergens are stable to several types of processing. To compare its characteristics to [...] Read more.

Nut-based milks and yogurts are gaining popularity, but may not offer the same benefits as dairy yogurts to consumers. Cashew nuts often cause severe allergic reactions, and cashew nut allergens are stable to several types of processing. To compare its characteristics to dairy yogurt and characterize the effects of fermentation on the Ana o 1–3 cashew nut allergens, a commercial yogurt made from cashew nuts (Cashewgurt) was evaluated for microbiological, physiochemical, and immunological properties. Average counts for lactobacilli and Streptococcus thermophilus were greater than 10 million colony forming units per milliliter, indicating the capacity to provide a health benefit. Cashewgurt pH and viscosity values were comparable to cow milk yogurts, and it was off white in color. SDS-PAGE analysis indicated a clear reduction in Ana o 1 and 2, and immuno-assay with polyclonal anti-cashew IgG antibody and cashew-allergic IgE indicated an overall reduction in allergen content. In contrast, SDS-PAGE, mass spectrometry, immunoblot, and ELISA all revealed that Ana o 3 was relatively unaffected by the fermentation process. In conclusion, Ana o 1 and Ana o 2 are sensitive to degradation, while Ana o 3 survives lactic acid bacterial fermentation during yogurt production. The analysis presented here indicates that cashew nut yogurt is not suitable for those with cashew nut allergy. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Allergy and Asthma)

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14 pages, 1792 KiB

Open AccessArticle

Increased Expression of TLR4 in Circulating CD4+T Cells in Patients with Allergic Conjunctivitis and In Vitro Attenuation of Th2 Inflammatory Response by Alpha-MSH

by Jane E. Nieto, Israel Casanova, Juan Carlos Serna-Ojeda, Enrique O. Graue-Hernández, Guillermo Quintana, Alberto Salazar and María C. Jiménez-Martinez

Int. J. Mol. Sci. 2020, 21(21), 7861; https://doi.org/10.3390/ijms21217861 - 23 Oct 2020

Cited by 7 | Viewed by 2510

Abstract

Ocular allergic diseases are frequently seen in ophthalmological clinical practice. Immunological damage is mediated by a local Th2 inflammatory microenvironment, accompanied by changes in circulating cell subsets, with more effector cells and fewer T regulatory cells (Tregs). This study aimed to evaluate the [...] Read more.

Ocular allergic diseases are frequently seen in ophthalmological clinical practice. Immunological damage is mediated by a local Th2 inflammatory microenvironment, accompanied by changes in circulating cell subsets, with more effector cells and fewer T regulatory cells (Tregs). This study aimed to evaluate the involvement of toll-like receptor 4 (TLR4) and α-melanocyte stimulating hormone (α-MSH) in the immune regulation associated with perennial allergic conjunctivitis (PAC). We performed an Ag-specific stimulation during 72 h of culturing with or without lipopolysaccharide (LPS) or α-MSH in peripheral blood mononuclear cells (PBMC), analyzing the cell subsets and cytokines induced by the stimuli. We also determined α-MSH in tear samples from healthy donors (HD) or PAC patients. Our findings demonstrate an immunological dysregulation characterized by an increased frequency of CD4+TLR4+ in the PBMC of patients with PAC, compared to HD. Most of these CD4+TLR4+ cells were also CD25+, and when α-MSH was added to the culture, the percentage of CD4+CD25+FoxP3+ increased significantly, while the percentage of CD69+ cells and cytokines IL-4 and IL-6 were significantly decreased. In tears, we found an increased concentration of α-MSH in PAC patients, compared with HD. These findings indicate a novel mechanism involved in controlling ocular allergic diseases, in which α-MSH diminishes the concentration of IL-6 and IL-4, restoring the frequency of Tregs and down-regulating CD4 activation. Moreover, we demonstrated the involvement of CD4+TLR4+ cells as an effector cell subset in ocular allergy. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Allergy and Asthma)

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Review

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20 pages, 1930 KiB

Open AccessReview

Extracellular Vesicles and Asthma—More Than Just a Co-Existence

by Bilal Alashkar Alhamwe, Daniel P. Potaczek, Sarah Miethe, Fahd Alhamdan, Lukas Hintz, Arslan Magomedov and Holger Garn

Int. J. Mol. Sci. 2021, 22(9), 4984; https://doi.org/10.3390/ijms22094984 - 7 May 2021

Cited by 43 | Viewed by 4861

Abstract

Extracellular vesicles (EVs) are membranous structures, which are secreted by almost every cell type analyzed so far. In addition to their importance for cell-cell communication under physiological conditions, EVs are also released during pathogenesis and mechanistically contribute to this process. Here we summarize [...] Read more.

Extracellular vesicles (EVs) are membranous structures, which are secreted by almost every cell type analyzed so far. In addition to their importance for cell-cell communication under physiological conditions, EVs are also released during pathogenesis and mechanistically contribute to this process. Here we summarize their functional relevance in asthma, one of the most common chronic non-communicable diseases. Asthma is a complex persistent inflammatory disorder of the airways characterized by reversible airflow obstruction and, from a long-term perspective, airway remodeling. Overall, mechanistic studies summarized here indicate the importance of different subtypes of EVs and their variable cargoes in the functioning of the pathways underlying asthma, and show some interesting potential for the development of future therapeutic interventions. Association studies in turn demonstrate a good diagnostic potential of EVs in asthma. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Allergy and Asthma)

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16 pages, 1513 KiB

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IL-10 in Mast Cell-Mediated Immune Responses: Anti-Inflammatory and Proinflammatory Roles

by Kazuki Nagata and Chiharu Nishiyama

Int. J. Mol. Sci. 2021, 22(9), 4972; https://doi.org/10.3390/ijms22094972 - 7 May 2021

Cited by 73 | Viewed by 7980

Abstract

Mast cells (MCs) play critical roles in Th2 immune responses, including the defense against parasitic infections and the initiation of type I allergic reactions. In addition, MCs are involved in several immune-related responses, including those in bacterial infections, autoimmune diseases, inflammatory bowel diseases, [...] Read more.

Mast cells (MCs) play critical roles in Th2 immune responses, including the defense against parasitic infections and the initiation of type I allergic reactions. In addition, MCs are involved in several immune-related responses, including those in bacterial infections, autoimmune diseases, inflammatory bowel diseases, cancers, allograft rejections, and lifestyle diseases. Whereas antigen-specific IgE is a well-known activator of MCs, which express FcεRI on the cell surface, other receptors for cytokines, growth factors, pathogen-associated molecular patterns, and damage-associated molecular patterns also function as triggers of MC stimulation, resulting in the release of chemical mediators, eicosanoids, and various cytokines. In this review, we focus on the role of interleukin (IL)-10, an anti-inflammatory cytokine, in MC-mediated immune responses, in which MCs play roles not only as initiators of the immune response but also as suppressors of excessive inflammation. IL-10 exhibits diverse effects on the proliferation, differentiation, survival, and activation of MCs in vivo and in vitro. Furthermore, IL-10 derived from MCs exerts beneficial and detrimental effects on the maintenance of tissue homeostasis and in several immune-related diseases including contact hypersensitivity, auto-immune diseases, and infections. This review introduces the effects of IL-10 on various events in MCs, and the roles of MCs in IL-10-related immune responses and as a source of IL-10. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Allergy and Asthma)

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21 pages, 8419 KiB

Open AccessReview

The Predictive Role of Biomarkers and Genetics in Childhood Asthma Exacerbations

by Emanuela di Palmo, Erika Cantarelli, Arianna Catelli, Giampaolo Ricci, Marcella Gallucci, Angela Miniaci and Andrea Pession

Int. J. Mol. Sci. 2021, 22(9), 4651; https://doi.org/10.3390/ijms22094651 - 28 Apr 2021

Cited by 23 | Viewed by 3805

Abstract

Asthma exacerbations are associated with significant childhood morbidity and mortality. Recurrent asthma attacks contribute to progressive loss of lung function and can sometimes be fatal or near-fatal, even in mild asthma. Exacerbation prevention becomes a primary target in the management of all asthmatic [...] Read more.

Asthma exacerbations are associated with significant childhood morbidity and mortality. Recurrent asthma attacks contribute to progressive loss of lung function and can sometimes be fatal or near-fatal, even in mild asthma. Exacerbation prevention becomes a primary target in the management of all asthmatic patients. Our work reviews current advances on exacerbation predictive factors, focusing on the role of non-invasive biomarkers and genetics in order to identify subjects at higher risk of asthma attacks. Easy-to-perform tests are necessary in children; therefore, interest has increased on samples like exhaled breath condensate, urine and saliva. The variability of biomarker levels suggests the use of seriate measurements and composite markers. Genetic predisposition to childhood asthma onset has been largely investigated. Recent studies highlighted the influence of single nucleotide polymorphisms even on exacerbation susceptibility, through involvement of both intrinsic mechanisms and gene-environment interaction. The role of molecular and genetic aspects in exacerbation prediction supports an individual-shaped approach, in which follow-up planning and therapy optimization take into account not only the severity degree, but also the risk of recurrent exacerbations. Further efforts should be made to improve and validate the application of biomarkers and genomics in clinical settings. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Allergy and Asthma)

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19 pages, 1268 KiB

Open AccessReview

Asthma in the Precision Medicine Era: Biologics and Probiotics

by Chiao-Juno Chiu and Miao-Tzu Huang

Int. J. Mol. Sci. 2021, 22(9), 4528; https://doi.org/10.3390/ijms22094528 - 26 Apr 2021

Cited by 40 | Viewed by 5466

Abstract

Asthma is a major global health issue. Over 300 million people worldwide suffer from this chronic inflammatory airway disease. Typical clinical symptoms of asthma are characterized by a recurrent wheezy cough, chest tightness, and shortness of breath. The main goals of asthma management [...] Read more.

Asthma is a major global health issue. Over 300 million people worldwide suffer from this chronic inflammatory airway disease. Typical clinical symptoms of asthma are characterized by a recurrent wheezy cough, chest tightness, and shortness of breath. The main goals of asthma management are to alleviate asthma symptoms, reduce the risk of asthma exacerbations, and minimize long-term medicinal adverse effects. However, currently available type 2 T helper cells (Th2)-directed treatments are often ineffective due to the heterogeneity of the asthma subgroups, which manifests clinically with variable and poor treatment responses. Personalized precision therapy of asthma according to individualized clinical characteristics (phenotype) and laboratory biomarkers (endotype) is the future prospect. This mini review discusses the molecular mechanisms underlying asthma pathogenesis, including the hot sought-after topic of microbiota, add-on therapies and the potential application of probiotics in the management of asthma. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Allergy and Asthma)

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16 pages, 1870 KiB

Open AccessReview

Molecular Mechanisms of Atopic Dermatitis Pathogenesis

by Jowita Sroka-Tomaszewska and Magdalena Trzeciak

Int. J. Mol. Sci. 2021, 22(8), 4130; https://doi.org/10.3390/ijms22084130 - 16 Apr 2021

Cited by 231 | Viewed by 24217

Abstract

Atopic dermatitis is a chronic, non-infectious inflammatory dermatosis. Acharacteristic feature is persistent itching of the skin. The chronic, relapsing course of the disease, economic burden, and the whole family’s involvement in the treatment process immensely reduce the quality of life of patients and [...] Read more.

Atopic dermatitis is a chronic, non-infectious inflammatory dermatosis. Acharacteristic feature is persistent itching of the skin. The chronic, relapsing course of the disease, economic burden, and the whole family’s involvement in the treatment process immensely reduce the quality of life of patients and their families. The disease emerges as a social problem by increasing indirect costs, such as visiting a doctor, absenteeism from work and school, and avoiding social interactions. Thepathophysiology of atopic dermatitis is complex and multifactorial. It includes genetic disorders, a defect in the epidermal barrier, an altered immune response, anddisruption of the skin’s microbial balance. The numerous complex changes at thegenetic level and innate and adaptive immunity provide the basis for characterizing the various phenotypes and endotypes of atopic dermatitis. Emerging therapies rely on the action of specific molecules involved in the disease’s pathogenesis. It may be the starting point for the individualization of atopic dermatitis treatment. This paper will try to present some molecular mechanisms of atopic dermatitis and their clinical implications. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Allergy and Asthma)

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