{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T22:55:32Z","timestamp":1789685732966,"version":"4.0.1"},"reference-count":89,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,4,15]],"date-time":"2021-04-15T00:00:00Z","timestamp":1618444800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>Highly prevalent respiratory diseases such as asthma and allergy remain a pressing health challenge. Currently, there is an unmet need for precise diagnostic tools capable of predicting the great heterogeneity of these illnesses. In a previous study of 94 asthma\/respiratory allergy biomarker candidates, we defined a group of potential biomarkers to distinguish clinical phenotypes (i.e. nonallergic asthma, allergic asthma, respiratory allergy without asthma) and disease severity. Here, we analyze our experimental results using complex algorithmic approaches that establish holistic disease models (systems biology), combining these insights with information available in specialized databases developed worldwide. With this approach, we aim to prioritize the most relevant biomarkers according to their specificity and mechanistic implication with molecular motifs of the diseases. The Therapeutic Performance Mapping System (Anaxomics\u2019 TPMS technology) was used to generate one mathematical model per disease: allergic asthma (AA), non-allergic asthma (NA), and respiratory allergy (RA), defining specific molecular motifs for each. The relationship of our molecular biomarker candidates and each disease was analyzed by artificial neural networks (ANNs) scores. These analyses prioritized molecular biomarkers specific to the diseases and to particular molecular motifs. As a first step, molecular characterization of the pathophysiological processes of AA defined 16 molecular motifs: 2 specific for AA, 2 shared with RA, and 12 shared with NA. Mechanistic analysis showed 17 proteins that were strongly related to AA. Eleven proteins were associated with RA and 16 proteins with NA. Specificity analysis showed that 12 proteins were specific to AA, 7 were specific to RA, and 2 to NA. Finally, a triggering analysis revealed a relevant role for AKT1, STAT1, and MAPK13 in all three conditions and for TLR4 in asthmatic diseases (AA and NA). In conclusion, this study has enabled us to prioritize biomarkers depending on the functionality associated with each disease and with specific molecular motifs, which could improve the definition and usefulness of new molecular biomarkers.<\/jats:p>","DOI":"10.3389\/fimmu.2021.640791","type":"journal-article","created":{"date-parts":[[2021,4,15]],"date-time":"2021-04-15T05:50:34Z","timestamp":1618465834000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":15,"title":["Prioritizing Molecular Biomarkers in Asthma and Respiratory Allergy Using Systems Biology"],"prefix":"10.3389","volume":"12","author":[{"given":"Luc\u00eda","family":"Cremades-Jimeno","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mar\u00eda \u00c1ngeles","family":"de Pedro","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mar\u00eda","family":"L\u00f3pez-Ramos","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joaqu\u00edn","family":"Sastre","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pablo","family":"M\u00ednguez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ignacio Mahillo","family":"Fern\u00e1ndez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Selene","family":"Baos","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Blanca","family":"C\u00e1rdaba","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2021,4,15]]},"reference":[{"key":"B1","unstructured":"Global Initiative for Asthma. Global Strategy for Asthma Management and Prevention2019"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1007\/s40265-013-0085-4","article-title":"Omalizumab: a review of its use in patients with severe persistent allergic asthma","volume":"73","author":"McKeage","year":"2013","journal-title":"Drugs"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1016\/j.alit.2016.04.011","article-title":"Endotypes of allergic diseases and asthma: An important step in building blocks for the future of precision medicine","volume":"65","author":"Agache","year":"2016","journal-title":"Allergol Int"},{"key":"B4","doi-asserted-by":"publisher","first-page":"294","DOI":"10.1111\/all.13619","article-title":"Tight junction, mucin, and inflammasome-related molecules are differentially expressed in eosinophilic, mixed, and neutrophilic experimental asthma in mice","volume":"74","author":"Tan","year":"2019","journal-title":"Allergy"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1007\/s12016-018-8712-1","article-title":"Understanding Asthma Phenotypes, Endotypes, and Mechanisms of Disease","volume":"56","author":"Kuruvilla","year":"2019","journal-title":"Clin Rev Allergy Immunol"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaip.2014.09.006","article-title":"Asthma phenotypes: nonallergic (intrinsic) asthma","volume":"2","author":"Peters","year":"2014","journal-title":"J Allergy Clin Immunol Pract"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaci.2013.07.036","article-title":"Measures of gene expression in sputum cells can identify TH2-high and TH2-low subtypes of asthma","volume":"133","author":"Peters","year":"2014","journal-title":"J Allergy Clin Immunol"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1136\/thorax.57.10.875","article-title":"Analysis of induced sputum in adults with asthma: identification of subgroup with isolated sputum neutrophilia and poor response to inhaled corticosteroids","volume":"57","author":"Green","year":"2002","journal-title":"Thorax"},{"key":"B9","doi-asserted-by":"publisher","first-page":"135","DOI":"10.1186\/1465-9921-7-135","article-title":"IL-17 mRNA in sputum of asthmatic patients: linking T cell driven inflammation and granulocytic influx","volume":"7","author":"Bullens","year":"2006","journal-title":"Respir Res"},{"key":"B10","doi-asserted-by":"publisher","first-page":"29","DOI":"10.1111\/j.1365-2222.2012.04075.x","article-title":"AMAZES Study Research Group. Impaired macrophage phagocytosis in non-eosinophilic asthma","volume":"43","author":"Simpson","year":"2013","journal-title":"Clin Exp Allergy"},{"key":"B11","doi-asserted-by":"publisher","first-page":"81","DOI":"10.1016\/j.jaci.2014.07.046","article-title":"Identification of novel immune phenotypes for allergic and nonallergic childhood asthma","volume":"135","author":"Raedler","year":"2015","journal-title":"J Allergy Clin Immunol"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1016\/j.smim.2019.101333","article-title":"Immunologic mechanisms in asthma","volume":"46","author":"Boonpiyathad","year":"2019","journal-title":"Semin Immunol"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1016\/j.smim.2019.101294","article-title":"Asthma from immune pathogenesis to precision medicine","volume":"46","author":"Khalaf","year":"2019","journal-title":"Semin Immunol"},{"key":"B14","doi-asserted-by":"publisher","first-page":"53","DOI":"10.1097\/ACI.0000000000000497","article-title":"Innate lymphoid cells in asthma: pathophysiological insights from murine models to human asthma phenotypes","volume":"19","author":"Jonckheere","year":"2019","journal-title":"Curr Opin Allergy Clin Immunol"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1172\/JCI124606","article-title":"Epithelial cell-derived cytokines: more than just signaling the alarm","volume":"129","author":"Roan","year":"2019","journal-title":"J Clin Invest"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1055\/s-0037-1606218","article-title":"Biologic Therapy and Asthma","volume":"39","author":"Viswanathan","year":"2018","journal-title":"Semin Respir Crit Care Med"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.201807-1291OC","article-title":"A Transcriptomic Method to Determine Airway Immune Dysfunction in T2-High and T2-Low Asthma","volume":"199","author":"Peters","year":"2019","journal-title":"Am J Respir Crit Care Med"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1111\/all.13258","article-title":"Asthma in the elderly and late-onset adult asthma","volume":"73","author":"Dunn","year":"2018","journal-title":"Allergy"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1111\/all.13422","article-title":"Asthma- and IgE-associated polymorphisms affect expression of TH\u00a017 genes","volume":"73","author":"Worth","year":"2018","journal-title":"Allergy"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1016\/j.smim.2019.101332","article-title":"Immunological biomarkers in severe asthma","volume":"46","author":"Narendra","year":"2019","journal-title":"Semin Immunol"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaip.2017.07.008","article-title":"New and Anticipated Therapies for Severe Asthma","volume":"5","author":"Peters","year":"2017","journal-title":"J\u00a0Allergy Clin Immunol Pract"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaci.2016.03.010","article-title":"Precision medicine in patients with allergic diseases: Airway diseases and atopic dermatitis-PRACTALL document of the European Academy of Allergy and Clinical Immunology and the American Academy of Allergy, Asthma & Immunology","volume":"137","author":"Muraro","year":"2016","journal-title":"J Allergy Clin Immunol"},{"key":"B23","doi-asserted-by":"publisher","first-page":"96","DOI":"10.1097\/ACI.0000000000000426","article-title":"Biomarkers and asthma management: analysis and potential applications","volume":"18","author":"Richards","year":"2018","journal-title":"Curr Opin Allergy Clin Immunol"},{"key":"B24","first-page":"81","article-title":"Aspectos gen\u00e9ticos, ambientales y epigen\u00e9ticos de las enfermedades al\u00e9rgicas","volume-title":"Tratado de Alergolog\u00eda, 2da Edici\u00f3n","author":"C\u00e1rdaba","year":"2015"},{"key":"B25","doi-asserted-by":"publisher","first-page":"170110","DOI":"10.1183\/16000617.0110-2017","article-title":"From systems biology to P4 medicine: applications in respiratory medicine","volume":"27","author":"Noell","year":"2018","journal-title":"Eur Respir Rev"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1111\/all.13771","article-title":"Precision medicine for the discovery of treatable mechanisms in severe asthma","volume":"74","author":"Chung","year":"2019","journal-title":"Allergy"},{"key":"B27","doi-asserted-by":"publisher","first-page":"34","DOI":"10.1016\/j.molimm.2016.12.012","article-title":"Biomarkers associated with disease severity in allergic and nonallergic asthma","volume":"82","author":"Baos","year":"2017","journal-title":"Mol Immunol"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1016\/j.dib.2016.12.035","article-title":"Data set on a study of gene expression in peripheral samples to identify biomarkers of severity of allergic and nonallergic asthma","volume":"10","author":"Baos","year":"2016","journal-title":"Data Brief"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2018.01416","article-title":"Nonallergic Asthma and Its Severity: Biomarkers for Its Discrimination in Peripheral Samples","volume":"9","author":"Baos","year":"2018","journal-title":"Front Immunol"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2019.01051","article-title":"Discriminatory Molecular Biomarkers of Allergic and Nonallergic Asthma and Its Severity","volume":"10","author":"Baos","year":"2019","journal-title":"Front Immunol"},{"key":"B31","volume-title":"ANAXOMICS\" Methodologies -Understanding the complexity of biological processes","author":"Valls","year":"2013"},{"key":"B32","doi-asserted-by":"publisher","first-page":"22153","DOI":"10.1038\/s41598-020-78315-0","article-title":"Systems biology drug screening identifies statins as enhancers of current therapies in chronic lymphocytic leukemia","volume":"10","author":"Gimenez","year":"2020","journal-title":"Sci Rep"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/30.1.42","article-title":"The KEGG databases at GenomeNet","volume":"30","author":"Kanehisa","year":"2002","journal-title":"Nucleic Acids Res"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkt1102","article-title":"The Reactome pathway knowledgebase","volume":"42","author":"Croft","year":"2014","journal-title":"Nucleic Acids Res"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkr1088","article-title":"The IntAct molecular interaction database in 2012","volume":"40","author":"Kerrien","year":"2012","journal-title":"Nucleic Acids Res"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth1209-860","article-title":"Recurated protein interaction datasets","volume":"6","author":"Salwinski","year":"2009","journal-title":"Nat Methods"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkn892","article-title":"Human Protein Reference Database\u20132009 update","volume":"37","author":"Keshava Prasad","year":"2009","journal-title":"Nucleic Acids Res"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkr930","article-title":"MINT, the molecular interaction database: 2012 update","volume":"40","author":"Licata","year":"2012","journal-title":"Nucleic Acids Res"},{"key":"B39","volume-title":"Pattern Recognition and Machine Learning (Information Science and Statistics)","author":"Bishop","year":"2006"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/gkx1037","article-title":"DrugBank 5.0: a major update to the DrugBank database for 2018","volume":"46","author":"Wishart","year":"2018","journal-title":"Nucleic Acids Res"},{"key":"B41","doi-asserted-by":"publisher","first-page":"1879","DOI":"10.1038\/s41598-018-19767-3","article-title":"Neuroprotective Drug for Nerve Trauma Revealed Using Artificial Intelligence","volume":"8","author":"Romeo-Guitart","year":"2018","journal-title":"Sci Rep"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0147626","article-title":"Novel Neuroprotective Multicomponent Therapy for Amyotrophic Lateral Sclerosis Designed by Networked Systems","volume":"11","author":"Herrando-Grabulosa","year":"2016","journal-title":"PloS One"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1113\/JP275292","article-title":"Muscle molecular adaptations to endurance exercise training are conditioned by glycogen availability: a proteomics-based analysis in the McArdle mouse model","volume":"596","author":"Fiuza-Luces","year":"2018","journal-title":"J Physiol"},{"key":"B44","doi-asserted-by":"publisher","first-page":"80","DOI":"10.1038\/msb4100116","article-title":"Chemical combination effects predict connectivity in biological systems","volume":"3","author":"Leh\u00e1r","year":"2007","journal-title":"Mol Syst Biol"},{"key":"B45","article-title":"Citochine ed asma [Cytokines and asthma]","volume":"89","author":"Gani","year":"1998","journal-title":"Recenti Prog Med"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.1007\/s11882-996-0005-8","article-title":"Interleukin-10-secreting regulatory T cells in allergy and asthma","volume":"6","author":"Urry","year":"2006","journal-title":"Curr Allergy Asthma Rep"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.1517\/14728222.11.5.613","article-title":"The IL-6\/sIL-6R complex as a novel target for therapeutic approaches","volume":"11","author":"Rose-John","year":"2007","journal-title":"Expert Opin Ther Targets"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.2332\/allergolint.R-08-161","article-title":"Prostaglandin as a target molecule for pharmacotherapy of allergic inflammatory diseases","volume":"57","author":"Nagai","year":"2008","journal-title":"Allergol Int"},{"key":"B49","article-title":"Regulation der Zytokinproduktion humaner T-Lymphozyten in der allergischen Immunantwort [Regulation of cytokine production by human T-lymphocytes in allergic immune response]","volume":"105","author":"Schwarz","year":"1993","journal-title":"Wien Klin Wochenschr"},{"key":"B50","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(94)90356-5","article-title":"An IL-4 receptor region containing an insulin receptor motif is important for IL-4-mediated IRS-1 phosphorylation and cell growth","volume":"76","author":"Keegan","year":"1994","journal-title":"Cell"},{"key":"B51","doi-asserted-by":"publisher","DOI":"10.1128\/JVI.70.6.3599-3605.1996","article-title":"The human T-cell leukemia\/lymphotropic virus type 1 p12I proteins bind the interleukin-2 receptor beta and gammac chains and affects their expression on the cell surface","volume":"70","author":"Mulloy","year":"1996","journal-title":"J Virol"},{"key":"B52","doi-asserted-by":"publisher","DOI":"10.1513\/AnnalsATS.201407-304AW","article-title":"Epithelial barrier function and immunity in asthma","author":"Davies","year":"2014","journal-title":"Ann Am Thorac Soc"},{"key":"B53","article-title":"[IL-33\/ST2 promotes airway remodeling in asthma by activating the expression of fibronectin 1 and type 1 collagen in human lung fibroblasts]","volume":"30","author":"Guo","year":"2014","journal-title":"Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi (Chin J Cell Mol Immunol)"},{"key":"B54","doi-asserted-by":"publisher","DOI":"10.1067\/mai.2003.1557","article-title":"Airway remodeling-associated mediators in moderate to severe asthma: effect of steroids on TGF-beta, IL-11, IL-17, and type I and type III collagen expression","volume":"111","author":"Chakir","year":"2003","journal-title":"J Allergy Clin Immunol"},{"key":"B55","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.201405-0859PP","article-title":"IL-17 in severe asthma. Where do we stand","volume":"190","author":"Chesn\u00e9","year":"2014","journal-title":"Am J Respir Crit Care Med"},{"key":"B56","doi-asserted-by":"publisher","DOI":"10.1165\/rcmb.2009-0220TR","article-title":"The cytokine network in chronic obstructive pulmonary disease","volume":"41","author":"Barnes","year":"2009","journal-title":"Am J Respir Cell Mol Biol"},{"key":"B57","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.200903-0392OC","article-title":"T-helper type 2-driven inflammation defines major subphenotypes of asthma","volume":"180","author":"Woodruff","year":"2009","journal-title":"Am J Respir Crit Care Med"},{"key":"B58","doi-asserted-by":"publisher","DOI":"10.1111\/cea.12296","article-title":"Airway epithelial barrier function regulates the pathogenesis of allergic asthma","volume":"44","author":"Heijink","year":"2014","journal-title":"Clin Exp Allergy"},{"key":"B59","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM200203143461116","article-title":"Radiotherapy for breast cancer","volume":"346","author":"Whelan","year":"2002","journal-title":"N Engl J Med"},{"key":"B60","doi-asserted-by":"publisher","first-page":"4","DOI":"10.1097\/MCP.0b013e32831da8d3","article-title":"Mucus hypersecretion in asthma: causes and effects","volume":"15","author":"Evans","year":"2009","journal-title":"Curr Opin Pulm Med"},{"key":"B61","doi-asserted-by":"publisher","DOI":"10.231\/JIM.0b013e3181d88fde","article-title":"Regulation of neutrophil elastase-induced MUC5AC expression by nuclear factor erythroid-2 related factor 2 in human airway epithelial cells","volume":"58","author":"Qi","year":"2010","journal-title":"J Investig Med"},{"key":"B62","doi-asserted-by":"publisher","first-page":"895","DOI":"10.1067\/mai.2001.120194","article-title":"A report from the International Eosinophil Society: eosinophils in a tug of war","volume":"108","author":"Lacy","year":"2001","journal-title":"J Allergy Clin Immunol"},{"key":"B63","doi-asserted-by":"publisher","DOI":"10.1111\/cea.12309","article-title":"Epithelial function and dysfunction in asthma","volume":"44","author":"Loxham","year":"2014","journal-title":"Clin Exp Allergy"},{"key":"B64","doi-asserted-by":"publisher","DOI":"10.1159\/000370067","article-title":"Exacerbating factors induce different gene expression profiles in peripheral blood mononuclear cells from asthmatics, patients with chronic obstructive pulmonary disease and healthy subjects","volume":"165","author":"Pniewska","year":"2014","journal-title":"Int Arch Allergy Immunol"},{"key":"B65","doi-asserted-by":"publisher","DOI":"10.1038\/clpt.2013.181","article-title":"Network Medicine in Disease Analysis and Therapeutics","volume":"94","author":"Chen","year":"2013","journal-title":"Clin Pharmacol Ther"},{"key":"B66","doi-asserted-by":"publisher","first-page":"4212","DOI":"10.1038\/ncomms5212","article-title":"Human symptoms\u2013disease network","author":"Zhou","year":"2014","journal-title":"Nat Commun"},{"key":"B67","doi-asserted-by":"publisher","first-page":"21","DOI":"10.1038\/s41540-018-0059-y","article-title":"Systems medicine disease maps: community-driven comprehensive representation of disease mechanisms","volume":"4","author":"Mazein","year":"2018","journal-title":"NPJ Syst Biol Appl"},{"key":"B68","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pcbi.1004120","article-title":"A DiseAse MOdule Detection (DIAMOnD) algorithm derived from a systematic analysis of connectivity patterns of disease proteins in the human Interactome","volume":"11","author":"Ghiassian","year":"2015","journal-title":"PloS Comput Biol"},{"key":"B69","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddv001","article-title":"A disease module in the interactome explains disease heterogeneity, drug response and captures novel pathways and genes in asthma","volume":"24","author":"Sharma","year":"2015","journal-title":"Hum Mol Genet"},{"key":"B70","doi-asserted-by":"publisher","first-page":"7","DOI":"10.1159\/000070474","article-title":"The roles of cysteinyl leukotrienes in eosinophilic inflammation of asthmatic airways","author":"Nagata","year":"2003","journal-title":"Int Arch Allergy Immunol"},{"key":"B71","doi-asserted-by":"publisher","DOI":"10.1002\/jcla.21749","article-title":"Soluble L-Selectin as an Independent Biomarker of Bronchial Asthma","volume":"29","author":"Nadi","year":"2015","journal-title":"J Clin Lab Anal"},{"key":"B72","doi-asserted-by":"publisher","DOI":"10.1517\/14728220902889788","article-title":"ADAM8: a new therapeutic target for asthma","volume":"13","author":"Knolle","year":"2009","journal-title":"Expert Opin Ther Targets"},{"key":"B73","doi-asserted-by":"publisher","DOI":"10.1155\/2012\/720976","article-title":"IL-8, IL-10, TGF-\u03b2, and GCSF levels were increased in severe persistent allergic asthma patients with the anti-IgE treatment","volume":"2012","author":"Yalcin","year":"2012","journal-title":"Mediators Inflammation"},{"key":"B74","doi-asserted-by":"publisher","DOI":"10.1038\/mi.2012.109","article-title":"The C-C motif chemokine ligands CCL5, CCL11, and CCL24 induce the migration of circulating fibrocytes from patients with severe asthma","volume":"6","author":"Isgr\u00f2","year":"2013","journal-title":"Mucosal Immunol"},{"key":"B75","doi-asserted-by":"publisher","DOI":"10.1038\/nrm2312","article-title":"Apoptosis: controlled demolition at the cellular level","volume":"9","author":"Taylor","year":"2008","journal-title":"Nat Rev Mol Cell Biol"},{"key":"B76","article-title":"Severity of asthma: the role of CD25+, CD30+, NF-\u03baB, and apoptotic markers","volume":"19","author":"Abdulamir","year":"2009","journal-title":"J Investig Allergol Clin Immunol"},{"key":"B77","article-title":"Evaluating the activity of the apoptosis-regulating genes from Bcl-2, Bax expression, and caspase-3 activity in bronchial epithelial cells in patients with asthma","volume":"73","author":"Mineev","year":"2011","journal-title":"Arkh Patol"},{"key":"B78","doi-asserted-by":"publisher","first-page":"75","DOI":"10.1016\/j.jdermsci.2006.06.002","article-title":"Thymus and activation regulated chemokine (TARC)\/CCL17 and skin diseases","volume":"43","author":"Saeki","year":"2006","journal-title":"J Dermatol Sci"},{"key":"B79","doi-asserted-by":"crossref","DOI":"10.1016\/S0161-5890(02)00013-5","article-title":"Cytokines and chemoattractants in allergic inflammation","volume":"38","author":"Romagnani","year":"2002","journal-title":"Mol Immunol"},{"key":"B80","doi-asserted-by":"publisher","first-page":"e316","DOI":"10.1038\/mtna.2016.29","article-title":"Targeting TSLP with shRNA alleviates airway inflammation and decreases epithelial CCL17 in a murine model of asthma","volume":"5","author":"Chen","year":"2016","journal-title":"Mol Ther Nucleic Acids"},{"key":"B81","doi-asserted-by":"publisher","first-page":"201","DOI":"10.1038\/s41392-020-00303-7","article-title":"Chitinase-3 like-protein-1 function and its role in diseases","volume":"5","author":"Zhao","year":"2020","journal-title":"Signal Transduct Target Ther"},{"key":"B82","doi-asserted-by":"publisher","first-page":"136","DOI":"10.1186\/1465-9921-14-136","article-title":"Galectin-3: its role in asthma and potential as an anti-inflammatory target","volume":"14","author":"Gao","year":"2013","journal-title":"Respir Res"},{"key":"B83","doi-asserted-by":"publisher","first-page":"5","DOI":"10.1186\/s12931-014-0163-5","article-title":"Anti-inflammatory deficiencies in neutrophilic asthma: reduced galectin-3 and IL-1RA\/IL-1\u03b2","volume":"16","author":"Gao","year":"2015","journal-title":"Respir Res"},{"key":"B84","doi-asserted-by":"publisher","DOI":"10.1097\/MD.0000000000020953","article-title":"Association of RANTES gene polymorphisms with susceptibility to childhood asthma: A meta-analysis","volume":"99","author":"Zhang","year":"2020","journal-title":"Med (Baltimore)"},{"key":"B85","article-title":"MicroRNA-223 inhibits deposition of the extracellular matrix by airway smooth muscle cells through targeting IGF-1R in the PI3K\/Akt pathway","volume":"10","author":"Liu","year":"2018","journal-title":"Am J Transl Res"},{"key":"B86","doi-asserted-by":"publisher","DOI":"10.1152\/ajplung.00119.2009","article-title":"Akt activation induces hypertrophy without contractile phenotypic maturation in airway smooth muscle","volume":"300","author":"Ma","year":"2011","journal-title":"Am J Physiol Lung Cell Mol Physiol"},{"key":"B87","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaci.2014.08.023","article-title":"IL-27 and type 2 immunity in asthmatic patients: association with severity, CXCL9, and signal transducer and activator of transcription signaling","volume":"135","author":"Xie","year":"2015","journal-title":"J Allergy Clin Immunol"},{"key":"B88","doi-asserted-by":"publisher","DOI":"10.1172\/JCI64896","article-title":"IL-13-induced airway mucus production is attenuated by\u00a0MAPK13\u00a0inhibition","volume":"122","author":"Alevy","year":"2012","journal-title":"J Clin Invest"},{"key":"B89","doi-asserted-by":"publisher","first-page":"15","DOI":"10.1186\/s12920-018-0331-4","article-title":"Novel candidate genes important for\u00a0asthma\u00a0and hypertension comorbidity revealed from associative gene networks","volume":"11","author":"Saik","year":"2018","journal-title":"BMC Med Genomics"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2021.640791\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,4,15]],"date-time":"2021-04-15T05:50:57Z","timestamp":1618465857000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2021.640791\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,4,15]]},"references-count":89,"alternative-id":["10.3389\/fimmu.2021.640791"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2021.640791","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,4,15]]},"article-number":"640791"}}