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Allergy and Asthma: From Pathogenesis to Molecular Understanding of Therapies

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A special issue of Biomedicines (ISSN 2227-9059). This special issue belongs to the section "Molecular and Translational Medicine".

Deadline for manuscript submissions: closed (30 November 2023) | Viewed by 30748

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Dr. Claudia Landi

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Department of Life Sciences, University of Siena, 53100 Siena, Italy
Interests: biomarker research of lung diseases
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Asthma and allergy represent diffused chronic diseases with a possible hereditary predisposition in rapid increase around the world. In some countries, their onset can only be explained by the changes happening in the environments and way of life.

Asthma attacks, triggered by environmental factors, such as pollen or airway infections, can be scary and impair life. Treatments lead to relieving the symptoms, especially in mild asthma, leaving a preferred track with only rescue therapy. On the other hand, for severe asthma, new biological therapies have been introduced to inhibit molecular pathways leading to severe symptoms.

Allergies are becoming more and more prevalent, and allergic sensitization against environmental allergens often happens at a young age, although it is also possible to get sensitized later in life and sometimes persists throughout life. However, allergies cause a decline in quality of life on account of allergen avoidance procedures, allergy symptoms, fear of severe reactions and a need for medications or long-lasting desensitization therapies.

We invite investigators to contribute original research as well as review articles addressing recent advances on aspects regarding disease phenotyping for personalized medicine purposes and on therapies and their effects in short and longer periods. At the same time, research regarding the understanding of the molecular mechanisms on the basis of pharmacological treatments is welcome. Original, high-quality contributions that are not yet published or that are not currently under review by other journals or peer-reviewed conferences are sought.

Dr. Claudia Landi
Guest Editor

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Keywords

asthma
allergy
pharmacological treatments
molecular mechanisms
personalized medicine
phenotyping

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Published Papers (11 papers)

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Research

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17 pages, 2395 KiB

Open AccessArticle

Toward Consensus Epitopes B and T of Tropomyosin Involved in Cross-Reactivity across Diverse Allergens: An In Silico Study

by Dalgys Martínez, Luis Fang, Catherine Meza-Torres, Gloria Garavito, Guillermo López-Lluch and Eduardo Egea

Biomedicines 2024, 12(4), 884; https://doi.org/10.3390/biomedicines12040884 - 17 Apr 2024

Cited by 1 | Viewed by 1940

Abstract

Tropomyosin (TM) is a pan-allergen with cross-reactivity to arthropods, insects, and nematodes in tropical regions. While IgE epitopes of TM contribute to sensitization, T-cell (MHC-II) epitopes polarize the Th2 immune response. This study aimed to identify linear B and T consensus epitopes among house dust mites, cockroaches, Ascaris lumbricoides, shrimp, and mosquitoes, exploring the molecular basis of cross-reactivity in allergic diseases. Amino acid sequences of Der p 10, Der f 10, Blo t 10, Lit v 1, Pen a 1, Pen m 1, rAsc l 3, Per a 7, Bla g 7, and Aed a 10 were collected from Allergen Nomenclature and UniProt. B epitopes were predicted using AlgPred 2.0 and BepiPred 3.0. T epitopes were predicted with NetMHCIIpan 4.1 against 10 HLA-II alleles. Consensus epitopes were obtained through analysis and Epitope Cluster Analysis in the Immune Epitope Database. We found 7 B-cell epitopes and 28 linear T-cell epitopes binding to MHC II. A unique peptide (residues 160–174) exhibited overlap between linear B-cell and T-cell epitopes, highly conserved across tropomyosin sequences. These findings shed light on IgE cross-reactivity among the tested species. The described immuno-informatics pipeline and epitopes can inform in vitro research and guide synthetic multi-epitope proteins’ design for potential allergology immunotherapies. Further in silico studies are warranted to confirm epitope accuracy and guide future experimental protocols. Full article

(This article belongs to the Special Issue Allergy and Asthma: From Pathogenesis to Molecular Understanding of Therapies)

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18 pages, 3208 KiB

Open AccessArticle

Novel Serum Biomarkers for Patients with Allergic Asthma Phenotype

by Jolita Palacionyte, Andrius Januskevicius, Egle Vasyle, Airidas Rimkunas, Ieva Bajoriuniene, Astra Vitkauskiene, Skaidrius Miliauskas and Kestutis Malakauskas

Biomedicines 2024, 12(1), 232; https://doi.org/10.3390/biomedicines12010232 - 19 Jan 2024

Cited by 4 | Viewed by 1621

Abstract

In distinguishing the allergic asthma (AA) phenotype, it has been identified that specific biomarkers could assist; however, none of them are considered ideal. This study aimed to analyze three groups of biologically active substances in the serum. Twenty steroid-free AA patients, sensitized to Dermatophagoides pteronyssinus, and sixteen healthy subjects (HSs) were enrolled in this study. Blood samples were collected from all patients. Additionally, all AA patients underwent a bronchial allergen challenge (BAC) with Dermatophagoides pteronyssinus, all of which were positive, and blood samples were collected again 24 h later. The concentrations of ten biologically active substances were measured in the serum samples, using enzyme-linked immunosorbent assay (ELISA) and the Luminex^® 100/200™ System technology for bead-based multiplex and singleplex immunoassays. Descriptive and analytical statistical methods were used. A p-value of 0.05 or lower was considered statistically significant. The soluble interleukin 5 receptor subunit alpha (sIL-5Rα) and thioredoxin 1 (TRX1) concentrations were significantly increased, whereas those of tyrosine-protein kinase Met (MET), pentraxin 3 (PTX3), and I C-telopeptide of type I collagen (ICTP) were decreased in the AA group compared with the HS group. A significant positive correlation was noted for sIL-5Rα with fractional exhaled nitric oxide (Fe_NO), blood eosinophil (EOS) count, and total immunoglobulin E (IgE) levels, and a negative correlation was noted with forced expiratory volume in 1 s (FEV₁). Moreover, PTX3 showed negative correlations with blood EOS count and total IgE levels, whereas ICTP exhibited a negative correlation with the blood EOS count. In conclusion, this study demonstrated that the serum concentrations of MET, PTX3, TRX1, ICTP, and particularly sIL-5Rα could potentially serve as biomarkers of the AA phenotype. Full article

(This article belongs to the Special Issue Allergy and Asthma: From Pathogenesis to Molecular Understanding of Therapies)

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17 pages, 1623 KiB

Open AccessArticle

The Association between Vitamin D, Interleukin-4, and Interleukin-10 Levels and CD23+ Expression with Bronchial Asthma in Stunted Children

by Gartika Sapartini, Gary W. K. Wong, Agnes Rengga Indrati, Cissy B. Kartasasmita and Budi Setiabudiawan

Biomedicines 2023, 11(9), 2542; https://doi.org/10.3390/biomedicines11092542 - 15 Sep 2023

Cited by 4 | Viewed by 1504

Abstract

Children with stunted growth have an increased risk of wheezing, and studies have shown that low levels of vitamin D and interleukin (IL)-10, along with increased IL-4 levels and CD23+ expression, are present in stunted and asthmatic children. To date, it is not known whether these factors are related to the incidence of asthma in stunted children. This case-control study investigated the association between vitamin D, IL-4, and IL-10 levels and CD23+ expression with bronchial asthma in stunted children. The study included 99 children aged 24–59 months, i.e., 37 stunted-sthmatic children (cases), 38 stunted children without asthma, and 24 non-stunted children with asthma. All children were tested for their 25(OH)D levels using chemiluminescent immunoassay (CLIA), IL-4 and IL-10 levels were measured through enzyme-linked immunosorbent assay (ELISA) testing, and CD23+ expression was measured through flow cytometry bead testing. The data were analyzed using chi-squared, Kruskal-Wallis, and Mann-Whitney tests. The results showed that stunted asthmatic children had a higher incidence of atopic family members than those without asthma. Additionally, stunted asthmatic children had a higher prevalence of vitamin D deficiency (48.6%) than the control group (44.7% and 20.8%). Furthermore, stunted asthmatic children had significantly lower levels of 25(OH)D [20.55 (16.18–25.55), p = 0.042] and higher levels of IL-4 [1.41 (0.95–2.40), p = 0.038], although there were no significant differences in IL-10 levels and CD23+ expression. The study concluded that low vitamin D and high IL-4 levels are associated with bronchial asthma in stunted children, while IL-10 and CD23+ do not show a significant association. Full article

(This article belongs to the Special Issue Allergy and Asthma: From Pathogenesis to Molecular Understanding of Therapies)

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13 pages, 1098 KiB

Open AccessArticle

Association of Severe Bronchiolitis during Infancy with Childhood Asthma Development: An Analysis of the ECHO Consortium

by Makiko Nanishi, Aruna Chandran, Xiuhong Li, Joseph B. Stanford, Akram N. Alshawabkeh, Judy L. Aschner, Dana Dabelea, Anne L. Dunlop, Amy J. Elliott, James E. Gern, Tina Hartert, Julie Herbstman, Gurjit K. Khurana Hershey, Alison E. Hipwell, Margaret R. Karagas, Catherine J. Karr, Leslie D. Leve, Augusto A. Litonjua, Cindy T. McEvoy, Rachel L. Miller, Emily Oken, T. Michael O’Shea, Nigel Paneth, Scott T. Weiss, Robert O. Wright, Rosalind J. Wright, Kecia N. Carroll, Xueying Zhang, Qi Zhao, Edward Zoratti, Carlos A. Camargo, Jr. and Kohei Hasegawa Show full author list Hide full author list

Biomedicines 2023, 11(1), 23; https://doi.org/10.3390/biomedicines11010023 - 22 Dec 2022

Cited by 4 | Viewed by 2847

Abstract

Objective: Many studies have shown that severe (hospitalized) bronchiolitis during infancy is a risk factor for developing childhood asthma. However, the population subgroups at the highest risk remain unclear. Using large nationwide pediatric cohort data, namely the NIH Environmental influences on Child Health Outcomes (ECHO) Program, we aimed to quantify the longitudinal relationship of bronchiolitis hospitalization during infancy with asthma in a generalizable dataset and to examine potential heterogeneity in terms of major demographics and clinical factors. Methods: We analyzed data from infants (age <12 months) enrolled in one of the 53 prospective cohort studies in the ECHO Program during 2001–2021. The exposure was bronchiolitis hospitalization during infancy. The outcome was a diagnosis of asthma by a physician by age 12 years. We examined their longitudinal association and determined the potential effect modifications of major demographic factors. Results: The analytic cohort consisted of 11,762 infants, 10% of whom had bronchiolitis hospitalization. Overall, 15% subsequently developed asthma. In the Cox proportional hazards model adjusting for 10 patient-level factors, compared with the no-bronchiolitis hospitalization group, the bronchiolitis hospitalization group had a significantly higher rate of asthma (14% vs. 24%, HR = 2.77, 95%CI = 2.24–3.43, p < 0.001). There was significant heterogeneity by race and ethnicity (P_interaction = 0.02). The magnitude of the association was greater in non-Hispanic White (HR = 3.77, 95%CI = 2.74–5.18, p < 0.001) and non-Hispanic Black (HR = 2.39, 95%CI = 1.60–3.56; p < 0.001) infants, compared with Hispanic infants (HR = 1.51, 95%CI = 0.77–2.95, p = 0.23). Conclusions: According to the nationwide cohort data, infants hospitalized with bronchiolitis are at a higher risk for asthma, with quantitative heterogeneity in different racial and ethnic groups. Full article

(This article belongs to the Special Issue Allergy and Asthma: From Pathogenesis to Molecular Understanding of Therapies)

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14 pages, 1259 KiB

Open AccessArticle

Real-Life Performance of Mepolizumab in T2-High Severe Refractory Asthma with the Overlapping Eosinophilic-Allergic Phenotype

by Ruperto González-Pérez, Paloma Poza-Guedes, Elena Mederos-Luis and Inmaculada Sánchez-Machín

Biomedicines 2022, 10(10), 2635; https://doi.org/10.3390/biomedicines10102635 - 19 Oct 2022

Cited by 6 | Viewed by 2648

Abstract

Severe asthma (SA) is categorized into multiple overlapping phenotypes and clinical characteristics driven by complex mechanistic inflammatory pathways. Mepolizumab is a human monoclonal antibody effectively targeting interleukin-5 in severe eosinophilic asthma. However, the eligibility of biologics in coincident SA phenotypes is still unclear. We assessed the efficacy and safety of mepolizumab in real-life patients with the overlapping T2-high SA endotype. This was a phase IV, single-centre observational cohort study including patients with severe refractory T2-high asthma in treatment with mepolizumab. After 12 months of treatment with mepolizumab, significant improvements (p < 0.0001) in asthma control and lung function were recorded. Rates of clinically significant annual asthma exacerbation were also decreased by 71.22% after 52-week therapy with mepolizumab (p < 0.001) associated with a reduction in the mean daily dose of oral corticosteroids. Two patients (3.27%) had to discontinue mepolizumab due to musculoskeletal disorders with no severe safety issues reported. The use of mepolizumab as an add-on therapy in routine clinical practice was safely associated with significant clinical and functional in the overlapping eosinophilic-and-allergic SA phenotype. The current data should support clinical and therapeutic decision-making in this T2-high SA endotype. Full article

(This article belongs to the Special Issue Allergy and Asthma: From Pathogenesis to Molecular Understanding of Therapies)

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10 pages, 1690 KiB

Open AccessArticle

Identification of Hub Genes and Potential Biomarkers for Childhood Asthma by Utilizing an Established Bioinformatic Analysis Approach

by Ichtiarini Nurullita Santri, Lalu Muhammad Irham, Gina Noor Djalilah, Dyah Aryani Perwitasari, Yuniar Wardani, Yohane Vincent Abero Phiri and Wirawan Adikusuma

Biomedicines 2022, 10(9), 2311; https://doi.org/10.3390/biomedicines10092311 - 16 Sep 2022

Cited by 9 | Viewed by 2916

Abstract

Childhood asthma represents a heterogeneous disease resulting from the interaction between genetic factors and environmental exposures. Currently, finding reliable biomarkers is necessary for the clinical management of childhood asthma. However, only a few biomarkers are being used in clinical practice in the pediatric population. In the long run, new biomarkers for asthma in children are required and would help direct therapy approaches. This study aims to identify potential childhood asthma biomarkers using a genetic-driven biomarkers approach. Herein, childhood asthma-associated Single Nucleotide Polymorphisms (SNPs) were utilized from the GWAS database to drive and facilitate the biomarker of childhood asthma. We uncovered 466 childhood asthma-associated loci by extending to proximal SNPs based on r² > 0.8 in Asian populations and utilizing HaploReg version 4.1 to determine 393 childhood asthma risk genes. Next, the functional roles of these genes were subsequently investigated using Gene Ontology (GO) term enrichment analysis, a Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway, and a protein–protein interaction (PPI) network. MCODE and CytoHubba are two Cytoscape plugins utilized to find biomarker genes from functional networks created using childhood asthma risk genes. Intriguingly, 10 hub genes (IL6, IL4, IL2, IL13, PTPRC, IL5, IL33, TBX21, IL2RA, and STAT6) were successfully identified and may have been identified to play a potential role in the pathogenesis of childhood asthma. Among 10 hub genes, we strongly suggest IL6 and IL4 as prospective childhood asthma biomarkers since both of these biomarkers achieved a high systemic score in Cytohubba’s MCC algorithm. In summary, this study offers a valuable genetic-driven biomarker approach to facilitate the potential biomarkers for asthma in children. Full article

(This article belongs to the Special Issue Allergy and Asthma: From Pathogenesis to Molecular Understanding of Therapies)

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9 pages, 2291 KiB

Open AccessArticle

CCL4 Functions as a Biomarker of Type 2 Airway Inflammation

by Yoshiki Kobayashi, Hanh Hong Chu, Akira Kanda, Yasutaka Yun, Masami Shimono, Linh Manh Nguyen, Akitoshi Mitani, Kensuke Suzuki, Mikiya Asako and Hiroshi Iwai

Biomedicines 2022, 10(8), 1779; https://doi.org/10.3390/biomedicines10081779 - 23 Jul 2022

Cited by 11 | Viewed by 3164

Abstract

Eosinophilic airway inflammatory disease is associated with bronchial asthma, with eosinophilic chronic rhinosinusitis (ECRS) typical of refractory type 2 airway inflammation. CCL4 produced at local inflammatory sites is involved in them via the accumulation and activation of type 2 inflammatory cells, including eosinophils. The detailed mechanism of CCL4 production remains unclear, and also the possibility it could function as a biomarker of type 2 airway inflammation remains unresolved. In this study, we evaluated CCL4 mRNA expression and production via the TSLP receptor (TSLPR) and toll-like receptors (TLRs) or proteinase-activated receptor-2 (PAR2) in BEAS-2B bronchial epithelial cells co-incubated with purified eosinophils or eosinophil peroxidase (EPX). We examined serum chemokine (CCL4, CCL11, CCL26, and CCL17) and total IgE serum levels, fractionated exhaled nitrogen oxide (FENO), and CCL4 expression in nasal polyps in patients with severe ECRS and asthma. CCL4 was induced by TSLP under eosinophilic inflammation. Furthermore, CCL4 was released via TLR3 signaling, which was enhanced by TSLP. CCL4 was mainly located in nasal polyp epithelial cells, while serum CCL4 levels were reduced after dupilumab treatment. Serum CCL4 levels were positively correlated with FENO, serum IgE, and CCL17 levels. Thus, CCL4 released from epithelial cells via the innate immune system during type 2 airway inflammation may function as a useful biomarker for the condition. Full article

(This article belongs to the Special Issue Allergy and Asthma: From Pathogenesis to Molecular Understanding of Therapies)

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20 pages, 3539 KiB

Open AccessArticle

Serum Proteomic Profile of Asthmatic Patients after Six Months of Benralizumab and Mepolizumab Treatment

by Lorenza Vantaggiato, Paolo Cameli, Laura Bergantini, Miriana d’Alessandro, Enxhi Shaba, Alfonso Carleo, Fabrizio Di Giuseppe, Stefania Angelucci, Guido Sebastiani, Francesco Dotta, Luca Bini, Elena Bargagli and Claudia Landi

Biomedicines 2022, 10(4), 761; https://doi.org/10.3390/biomedicines10040761 - 24 Mar 2022

Cited by 4 | Viewed by 2761

Abstract

Severe eosinophilic asthma is characterized by chronic airway inflammation, oxidative stress, and elevated proinflammatory cytokines, especially IL-5. Mepolizumab and benralizumab are both humanized IgG antibodies directed against IL-5 signaling, directly acting on eosinophils count. Together with the complexity of severe asthma classification and patient selection for the targeted treatment, there is also the urgency to clarify the follow-up of therapy to identify biomarkers, in addition to eosinophils, for the optimal duration of treatment, persistence of effectiveness, and safety. To this purpose, here we performed a follow-up study using differential proteomic analysis on serum samples after 1 and 6 months of both therapies and sera from healthy patients. Statistical analysis by PCA and heatmap analyses were performed, and identified proteins were used for enrichment analysis by MetaCore software. The analysis highlighted 82 differences among all considered conditions. In particular, 30 referred to benralizumab time point (T0, T1B, T6B) and 24 to mepolizumab time point (T0, T1M, T6M) analyses. t-SNE and heatmap analyses evidence that the differential serum protein profile at 6 months of both treatments is more similar to that of the healthy subjects. Among the identified proteins, APOAI, APOC-II, and APOC-III are upregulated principally after 6 months of benralizumab treatment, plasminogen is upregulated after 6 months of both treatments and ceruloplasmin, upregulated already after 1 month of benralizumab, becoming higher after 6 months of mepolizumab. Using enrichment analysis, identified proteins were related to lipid metabolism and transport, blood coagulation, and ECM remodeling. Full article

(This article belongs to the Special Issue Allergy and Asthma: From Pathogenesis to Molecular Understanding of Therapies)

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Review

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15 pages, 2190 KiB

Open AccessReview

Diagnosis of Hymenoptera Venom Allergy: State of the Art, Challenges, and Perspectives

by Joanna Matysiak, Eliza Matuszewska, Kacper Packi and Agnieszka Klupczyńska-Gabryszak

Biomedicines 2022, 10(9), 2170; https://doi.org/10.3390/biomedicines10092170 - 2 Sep 2022

Cited by 5 | Viewed by 4377 | Correction

Abstract

Hymenoptera venom allergy is the most common cause of anaphylaxis in adults and the second-most frequent in children. The proper diagnosis of this life-threatening allergy remains a challenge. This review focuses on the current knowledge regarding diagnostics of Hymenoptera venom allergy. The paper includes a brief description of the representatives of Hymenoptera order and the composition of their venoms. Then, diagnostic tests for allergy to Hymenoptera venom are described. Common diagnostic problems, especially double positivity in tests for IgE antibodies specific to honeybee and wasp venom, are also discussed. Special attention is paid to the search for new diagnostic capabilities using modern methodologies. Multidimensional molecular analysis offers an opportunity to characterize changes in body fluids associated with Hymenoptera venom allergy and yields a unique insight into the cell status. Despite recent developments in the diagnostics of Hymenoptera venom allergy, new testing methodologies are still needed to answer questions and doubts we have. Full article

(This article belongs to the Special Issue Allergy and Asthma: From Pathogenesis to Molecular Understanding of Therapies)

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18 pages, 1024 KiB

Open AccessReview

Novel Biological Therapies for Severe Asthma Endotypes

by Corrado Pelaia, Giulia Pelaia, Claudia Crimi, Angelantonio Maglio, Anna Agnese Stanziola, Cecilia Calabrese, Rosa Terracciano, Federico Longhini and Alessandro Vatrella

Biomedicines 2022, 10(5), 1064; https://doi.org/10.3390/biomedicines10051064 - 4 May 2022

Cited by 15 | Viewed by 4582

Abstract

Severe asthma comprises several heterogeneous phenotypes, underpinned by complex pathomechanisms known as endotypes. The latter are driven by intercellular networks mediated by molecular components which can be targeted by specific monoclonal antibodies. With regard to the biological treatments of either allergic or non-allergic eosinophilic type 2 asthma, currently available antibodies are directed against immunoglobulins E (IgE), interleukin-5 (IL-5) and its receptor, the receptors of interleukins-4 (IL-4) and 13 (IL-13), as well as thymic stromal lymphopoietin (TSLP) and other alarmins. Among these therapeutic strategies, the best choice should be made according to the phenotypic/endotypic features of each patient with severe asthma, who can thus respond with significant clinical and functional improvements. Conversely, very poor options so far characterize the experimental pipelines referring to the perspective biological management of non-type 2 severe asthma, which thereby needs to be the focus of future thorough research. Full article

(This article belongs to the Special Issue Allergy and Asthma: From Pathogenesis to Molecular Understanding of Therapies)

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