The receptor for advanced glycation end products is a critical mediator of type 2 cytokine signaling in the lungs
Asthma is estimated to effect more than 300 million persons worldwide, leading to nearly 250,000 deaths annually. The majority of patients with mild-to-severe asthma have what is deemed “type–2 high” asthma, which is driven by the prototypical type 2 cytokines IL-4, IL-5, and IL-13. Studies have ind...
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| Veröffentlicht in: | Journal of allergy and clinical immunology 2019-09, Vol.144 (3), p.796-808.e12 |
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| container_title | Journal of allergy and clinical immunology |
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| creator | Perkins, Timothy N. Oczypok, Elizabeth A. Dutz, Regina E. Donnell, Mason L. Myerburg, Michael M. Oury, Tim D. |
| description | Asthma is estimated to effect more than 300 million persons worldwide, leading to nearly 250,000 deaths annually. The majority of patients with mild-to-severe asthma have what is deemed “type–2 high” asthma, which is driven by the prototypical type 2 cytokines IL-4, IL-5, and IL-13. Studies have indicated that the receptor for advanced glycation end products (RAGE) is a critical molecule in the pathogenesis of experimental asthma/allergic airway inflammation. More specifically, RAGE expressed on stromal cells, rather than hematopoietic cells, is critical to induction of asthma/allergic airway inflammation by driving type 2 inflammatory responses. However, the role of RAGE in directly mediating type 2 cytokine signaling has never been investigated.
The goal of this study was to test the hypothesis that RAGE mediates type 2 cytokine–induced signal transduction, airway inflammation, and mucus metaplasia in the lungs.
Wild-type (WT) and RAGE knockout (RAGE−/−) mice, were intranasally administered rIL-5/rIL-13 or rIL-4 alone, and signal transducer and activator of transcription 6 (STAT6) signaling, airway inflammation, and mucus metaplasia were assessed. A RAGE small-molecule antagonist was used to determine the effects of pharmacologically inhibiting RAGE on type 2 cytokine–induced effects.
Administration of type 2 cytokines induced pronounced airway inflammation and mucus metaplasia in WT mice, which was nearly completely abrogated in RAGE−/− mice. In addition, treatment with a RAGE-specific antagonist diminished the effects of type 2 cytokines in WT mice and in primary human bronchial epithelial cell cultures. Genetic ablation or pharmacologic inhibition of RAGE blocks the effects of IL-13 and IL-4 by inhibiting sustained STAT6 activation and downstream target gene expression in mice and in human bronchial epithelial cells.
This study is the first to indicate that RAGE is a critical component of type 2 cytokine signal transduction mechanisms, which is a driving force behind type 2–high asthma. |
| doi_str_mv | 10.1016/j.jaci.2019.03.019 |
| format | Article |
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The goal of this study was to test the hypothesis that RAGE mediates type 2 cytokine–induced signal transduction, airway inflammation, and mucus metaplasia in the lungs.
Wild-type (WT) and RAGE knockout (RAGE−/−) mice, were intranasally administered rIL-5/rIL-13 or rIL-4 alone, and signal transducer and activator of transcription 6 (STAT6) signaling, airway inflammation, and mucus metaplasia were assessed. A RAGE small-molecule antagonist was used to determine the effects of pharmacologically inhibiting RAGE on type 2 cytokine–induced effects.
Administration of type 2 cytokines induced pronounced airway inflammation and mucus metaplasia in WT mice, which was nearly completely abrogated in RAGE−/− mice. In addition, treatment with a RAGE-specific antagonist diminished the effects of type 2 cytokines in WT mice and in primary human bronchial epithelial cell cultures. Genetic ablation or pharmacologic inhibition of RAGE blocks the effects of IL-13 and IL-4 by inhibiting sustained STAT6 activation and downstream target gene expression in mice and in human bronchial epithelial cells.
This study is the first to indicate that RAGE is a critical component of type 2 cytokine signal transduction mechanisms, which is a driving force behind type 2–high asthma.</description><identifier>ISSN: 0091-6749</identifier><identifier>EISSN: 1097-6825</identifier><identifier>DOI: 10.1016/j.jaci.2019.03.019</identifier><identifier>PMID: 30940519</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>Ablation ; Advanced glycosylation end products ; Allergies ; allergy ; Animals ; Asthma ; Asthma - immunology ; Biotechnology ; Bronchoalveolar Lavage Fluid - immunology ; Cells, Cultured ; Chemokines ; Cytokines ; Cytokines - immunology ; Dehydrogenases ; Epithelial cells ; Epithelial Cells - immunology ; Gene expression ; Glycosylation ; Humans ; Inflammation ; Interleukin 13 ; Interleukin 4 ; Interleukin 5 ; Laboratory animals ; Lung - immunology ; Lungs ; Metaplasia ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Mucus ; Mucus - immunology ; Proteins ; Receptor for advanced glycation end products ; Receptor for Advanced Glycation End Products - genetics ; Receptor for Advanced Glycation End Products - immunology ; Respiratory tract ; Respiratory tract diseases ; Signal Transduction ; Stat6 protein ; Statistical analysis ; Stromal cells ; TH2 ; Transcription ; Transcription factors</subject><ispartof>Journal of allergy and clinical immunology, 2019-09, Vol.144 (3), p.796-808.e12</ispartof><rights>2019 American Academy of Allergy, Asthma & Immunology</rights><rights>Copyright © 2019 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.</rights><rights>2019. American Academy of Allergy, Asthma & Immunology</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c477t-d0ac8a9bf1836aeb93b632ee9e949428401061efdef238ed92e185484ceb0df13</citedby><cites>FETCH-LOGICAL-c477t-d0ac8a9bf1836aeb93b632ee9e949428401061efdef238ed92e185484ceb0df13</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/j.jaci.2019.03.019$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,777,781,3537,27905,27906,45976</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/30940519$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Perkins, Timothy N.</creatorcontrib><creatorcontrib>Oczypok, Elizabeth A.</creatorcontrib><creatorcontrib>Dutz, Regina E.</creatorcontrib><creatorcontrib>Donnell, Mason L.</creatorcontrib><creatorcontrib>Myerburg, Michael M.</creatorcontrib><creatorcontrib>Oury, Tim D.</creatorcontrib><title>The receptor for advanced glycation end products is a critical mediator of type 2 cytokine signaling in the lungs</title><title>Journal of allergy and clinical immunology</title><addtitle>J Allergy Clin Immunol</addtitle><description>Asthma is estimated to effect more than 300 million persons worldwide, leading to nearly 250,000 deaths annually. The majority of patients with mild-to-severe asthma have what is deemed “type–2 high” asthma, which is driven by the prototypical type 2 cytokines IL-4, IL-5, and IL-13. Studies have indicated that the receptor for advanced glycation end products (RAGE) is a critical molecule in the pathogenesis of experimental asthma/allergic airway inflammation. More specifically, RAGE expressed on stromal cells, rather than hematopoietic cells, is critical to induction of asthma/allergic airway inflammation by driving type 2 inflammatory responses. However, the role of RAGE in directly mediating type 2 cytokine signaling has never been investigated.
The goal of this study was to test the hypothesis that RAGE mediates type 2 cytokine–induced signal transduction, airway inflammation, and mucus metaplasia in the lungs.
Wild-type (WT) and RAGE knockout (RAGE−/−) mice, were intranasally administered rIL-5/rIL-13 or rIL-4 alone, and signal transducer and activator of transcription 6 (STAT6) signaling, airway inflammation, and mucus metaplasia were assessed. A RAGE small-molecule antagonist was used to determine the effects of pharmacologically inhibiting RAGE on type 2 cytokine–induced effects.
Administration of type 2 cytokines induced pronounced airway inflammation and mucus metaplasia in WT mice, which was nearly completely abrogated in RAGE−/− mice. In addition, treatment with a RAGE-specific antagonist diminished the effects of type 2 cytokines in WT mice and in primary human bronchial epithelial cell cultures. Genetic ablation or pharmacologic inhibition of RAGE blocks the effects of IL-13 and IL-4 by inhibiting sustained STAT6 activation and downstream target gene expression in mice and in human bronchial epithelial cells.
This study is the first to indicate that RAGE is a critical component of type 2 cytokine signal transduction mechanisms, which is a driving force behind type 2–high asthma.</description><subject>Ablation</subject><subject>Advanced glycosylation end products</subject><subject>Allergies</subject><subject>allergy</subject><subject>Animals</subject><subject>Asthma</subject><subject>Asthma - immunology</subject><subject>Biotechnology</subject><subject>Bronchoalveolar Lavage Fluid - immunology</subject><subject>Cells, Cultured</subject><subject>Chemokines</subject><subject>Cytokines</subject><subject>Cytokines - immunology</subject><subject>Dehydrogenases</subject><subject>Epithelial cells</subject><subject>Epithelial Cells - immunology</subject><subject>Gene expression</subject><subject>Glycosylation</subject><subject>Humans</subject><subject>Inflammation</subject><subject>Interleukin 13</subject><subject>Interleukin 4</subject><subject>Interleukin 5</subject><subject>Laboratory animals</subject><subject>Lung - immunology</subject><subject>Lungs</subject><subject>Metaplasia</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>Mice, Knockout</subject><subject>Mucus</subject><subject>Mucus - immunology</subject><subject>Proteins</subject><subject>Receptor for advanced glycation end products</subject><subject>Receptor for Advanced Glycation End Products - genetics</subject><subject>Receptor for Advanced Glycation End Products - immunology</subject><subject>Respiratory tract</subject><subject>Respiratory tract diseases</subject><subject>Signal Transduction</subject><subject>Stat6 protein</subject><subject>Statistical analysis</subject><subject>Stromal cells</subject><subject>TH2</subject><subject>Transcription</subject><subject>Transcription factors</subject><issn>0091-6749</issn><issn>1097-6825</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2019</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kTtrHDEUhUWIidePP5AiCNKkmbEes1oJ0gST2AaDG7sWGunORpNZaS1pDPvvrWGdFClciIPgO_dezkHoMyUtJVRcje1orG8ZoaolvK3yAa0oUZtGSLb-iFaEKNqITadO0VnOI6l_LtUndMqJ6siaqhV6fvwNOIGFfYkJD_UZ92KCBYe308Ga4mPAEBzep-hmWzL2GRtsky_emgnvwHmzWOOAy2EPmGF7KPGPD4Cz3wYz-bDFPuBS90xz2OYLdDKYKcPlm56jp18_H69vm_uHm7vrH_eN7Tab0jhirDSqH6jkwkCveC84A1CgOtUx2RFKBIXBwcC4BKcYULnuZGehJ26g_Bx9O86tlz_PkIve-WxhmkyAOGfNGGFCCMpkRb_-h45xTvX2hZJc1Uy5qBQ7UjbFnBMMep_8zqSDpkQvhehRL4XopRBNuK5STV_eRs99zeqf5W8DFfh-BKBm8eIh6Ww9LAX4WkvRLvr35r8ChiSclw</recordid><startdate>201909</startdate><enddate>201909</enddate><creator>Perkins, Timothy N.</creator><creator>Oczypok, Elizabeth A.</creator><creator>Dutz, Regina E.</creator><creator>Donnell, Mason L.</creator><creator>Myerburg, Michael M.</creator><creator>Oury, Tim D.</creator><general>Elsevier Inc</general><general>Elsevier Limited</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7SS</scope><scope>7T5</scope><scope>H94</scope><scope>K9.</scope><scope>NAPCQ</scope><scope>7X8</scope></search><sort><creationdate>201909</creationdate><title>The receptor for advanced glycation end products is a critical mediator of type 2 cytokine signaling in the lungs</title><author>Perkins, Timothy N. ; Oczypok, Elizabeth A. ; Dutz, Regina E. ; Donnell, Mason L. ; Myerburg, Michael M. ; Oury, Tim D.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c477t-d0ac8a9bf1836aeb93b632ee9e949428401061efdef238ed92e185484ceb0df13</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2019</creationdate><topic>Ablation</topic><topic>Advanced glycosylation end products</topic><topic>Allergies</topic><topic>allergy</topic><topic>Animals</topic><topic>Asthma</topic><topic>Asthma - immunology</topic><topic>Biotechnology</topic><topic>Bronchoalveolar Lavage Fluid - immunology</topic><topic>Cells, Cultured</topic><topic>Chemokines</topic><topic>Cytokines</topic><topic>Cytokines - immunology</topic><topic>Dehydrogenases</topic><topic>Epithelial cells</topic><topic>Epithelial Cells - immunology</topic><topic>Gene expression</topic><topic>Glycosylation</topic><topic>Humans</topic><topic>Inflammation</topic><topic>Interleukin 13</topic><topic>Interleukin 4</topic><topic>Interleukin 5</topic><topic>Laboratory animals</topic><topic>Lung - immunology</topic><topic>Lungs</topic><topic>Metaplasia</topic><topic>Mice</topic><topic>Mice, Inbred C57BL</topic><topic>Mice, Knockout</topic><topic>Mucus</topic><topic>Mucus - immunology</topic><topic>Proteins</topic><topic>Receptor for advanced glycation end products</topic><topic>Receptor for Advanced Glycation End Products - genetics</topic><topic>Receptor for Advanced Glycation End Products - immunology</topic><topic>Respiratory tract</topic><topic>Respiratory tract diseases</topic><topic>Signal Transduction</topic><topic>Stat6 protein</topic><topic>Statistical analysis</topic><topic>Stromal cells</topic><topic>TH2</topic><topic>Transcription</topic><topic>Transcription factors</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Perkins, Timothy N.</creatorcontrib><creatorcontrib>Oczypok, Elizabeth A.</creatorcontrib><creatorcontrib>Dutz, Regina E.</creatorcontrib><creatorcontrib>Donnell, Mason L.</creatorcontrib><creatorcontrib>Myerburg, Michael M.</creatorcontrib><creatorcontrib>Oury, Tim D.</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Entomology Abstracts (Full archive)</collection><collection>Immunology Abstracts</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>ProQuest Health & Medical Complete (Alumni)</collection><collection>Nursing & Allied Health Premium</collection><collection>MEDLINE - Academic</collection><jtitle>Journal of allergy and clinical immunology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Perkins, Timothy N.</au><au>Oczypok, Elizabeth A.</au><au>Dutz, Regina E.</au><au>Donnell, Mason L.</au><au>Myerburg, Michael M.</au><au>Oury, Tim D.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>The receptor for advanced glycation end products is a critical mediator of type 2 cytokine signaling in the lungs</atitle><jtitle>Journal of allergy and clinical immunology</jtitle><addtitle>J Allergy Clin Immunol</addtitle><date>2019-09</date><risdate>2019</risdate><volume>144</volume><issue>3</issue><spage>796</spage><epage>808.e12</epage><pages>796-808.e12</pages><issn>0091-6749</issn><eissn>1097-6825</eissn><abstract>Asthma is estimated to effect more than 300 million persons worldwide, leading to nearly 250,000 deaths annually. The majority of patients with mild-to-severe asthma have what is deemed “type–2 high” asthma, which is driven by the prototypical type 2 cytokines IL-4, IL-5, and IL-13. Studies have indicated that the receptor for advanced glycation end products (RAGE) is a critical molecule in the pathogenesis of experimental asthma/allergic airway inflammation. More specifically, RAGE expressed on stromal cells, rather than hematopoietic cells, is critical to induction of asthma/allergic airway inflammation by driving type 2 inflammatory responses. However, the role of RAGE in directly mediating type 2 cytokine signaling has never been investigated.
The goal of this study was to test the hypothesis that RAGE mediates type 2 cytokine–induced signal transduction, airway inflammation, and mucus metaplasia in the lungs.
Wild-type (WT) and RAGE knockout (RAGE−/−) mice, were intranasally administered rIL-5/rIL-13 or rIL-4 alone, and signal transducer and activator of transcription 6 (STAT6) signaling, airway inflammation, and mucus metaplasia were assessed. A RAGE small-molecule antagonist was used to determine the effects of pharmacologically inhibiting RAGE on type 2 cytokine–induced effects.
Administration of type 2 cytokines induced pronounced airway inflammation and mucus metaplasia in WT mice, which was nearly completely abrogated in RAGE−/− mice. In addition, treatment with a RAGE-specific antagonist diminished the effects of type 2 cytokines in WT mice and in primary human bronchial epithelial cell cultures. Genetic ablation or pharmacologic inhibition of RAGE blocks the effects of IL-13 and IL-4 by inhibiting sustained STAT6 activation and downstream target gene expression in mice and in human bronchial epithelial cells.
This study is the first to indicate that RAGE is a critical component of type 2 cytokine signal transduction mechanisms, which is a driving force behind type 2–high asthma.</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>30940519</pmid><doi>10.1016/j.jaci.2019.03.019</doi><oa>free_for_read</oa></addata></record> |
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| subjects | Ablation Advanced glycosylation end products Allergies allergy Animals Asthma Asthma - immunology Biotechnology Bronchoalveolar Lavage Fluid - immunology Cells, Cultured Chemokines Cytokines Cytokines - immunology Dehydrogenases Epithelial cells Epithelial Cells - immunology Gene expression Glycosylation Humans Inflammation Interleukin 13 Interleukin 4 Interleukin 5 Laboratory animals Lung - immunology Lungs Metaplasia Mice Mice, Inbred C57BL Mice, Knockout Mucus Mucus - immunology Proteins Receptor for advanced glycation end products Receptor for Advanced Glycation End Products - genetics Receptor for Advanced Glycation End Products - immunology Respiratory tract Respiratory tract diseases Signal Transduction Stat6 protein Statistical analysis Stromal cells TH2 Transcription Transcription factors |
| title | The receptor for advanced glycation end products is a critical mediator of type 2 cytokine signaling in the lungs |
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