Shinji Toki, Masako Abney, Jian Zhang, Mark Rusznak, Christian M. Warren, Dawn C. Newcomb, Katherine N. Cahill, Daniel J. Drucker, Kevin D. Niswender, Ray Stokes Peebles Jr.
Background
Anti-inflammatory effects of incretin signaling through the glucagon-like peptide-1 receptor (GLP-1R) and the glucose-dependent insulinotropic polypeptide receptor (GIPR) in mice have been reported. Therefore, we hypothesized that signaling through the endogenous GLP-1R and the GIPR individually decreases allergic airway inflammation and that the combination of GLP-1R and GIPR signaling together additively inhibits allergen-induced lung and airway inflammation.
Methods
WT (C57BL/6J), GLP-1R knockout (KO), GIPR KO, and GLP-1R/GIPR double KO (DKO) mice were challenged intranasally with Alternaria alternata extract (Alt-Ext) or vehicle to evaluate the impact of signaling through these receptors on the innate allergen-induced inflammatory response that is primarily driven by group 2 innate lymphoid cells (ILC2).
Results
Alt-Ext-induced IL-33 release in the bronchoalveolar lavage fluid (BALF) was not different between the mouse strains, but thymic stromal lymphopoietin (TSLP) was significantly increased in GLP-1R/GIPR DKO mice challenged with Alt-Ext compared to the other strains. Furthermore, Alt-Ext-induced protein expression of IL-5, IL-13, CCL11, and CCL24 in the lung homogenates, the number of eosinophils, lymphocytes, and neutrophils in the BALF, and the number of lung GATA3+ ILC2 were significantly increased in GLP-1R/GIPR DKO mice compared to the other 3 strains. Furthermore, ICAM-1 expression on lung epithelial cells was increased in GLP-1R/GIPR DKO mice challenged with Alt-Ext compared to the other 3 strains.
Conclusions
Deficiency of both GLP-1R and GIPR signaling together increased TSLP release, ILC2 activation, and early type 2 innate immune responses to aeroallergen exposure. Combined GLP-1R and GIPR signaling should be explored for the treatment of asthma.
{"title":"Endogenous Glucagon-Like Peptide-1 Receptor and Glucose-Dependent Insulinotropic Polypeptide Receptor Signaling Inhibits Aeroallergen-Induced Innate Airway Inflammation","authors":"Shinji Toki, Masako Abney, Jian Zhang, Mark Rusznak, Christian M. Warren, Dawn C. Newcomb, Katherine N. Cahill, Daniel J. Drucker, Kevin D. Niswender, Ray Stokes Peebles Jr.","doi":"10.1111/all.16402","DOIUrl":"10.1111/all.16402","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Anti-inflammatory effects of incretin signaling through the glucagon-like peptide-1 receptor (GLP-1R) and the glucose-dependent insulinotropic polypeptide receptor (GIPR) in mice have been reported. Therefore, we hypothesized that signaling through the endogenous GLP-1R and the GIPR individually decreases allergic airway inflammation and that the combination of GLP-1R and GIPR signaling together additively inhibits allergen-induced lung and airway inflammation.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>WT (C57BL/6J), GLP-1R knockout (KO), GIPR KO, and GLP-1R/GIPR double KO (DKO) mice were challenged intranasally with <i>Alternaria alternata</i> extract (Alt-Ext) or vehicle to evaluate the impact of signaling through these receptors on the innate allergen-induced inflammatory response that is primarily driven by group 2 innate lymphoid cells (ILC2).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Alt-Ext-induced IL-33 release in the bronchoalveolar lavage fluid (BALF) was not different between the mouse strains, but thymic stromal lymphopoietin (TSLP) was significantly increased in GLP-1R/GIPR DKO mice challenged with Alt-Ext compared to the other strains. Furthermore, Alt-Ext-induced protein expression of IL-5, IL-13, CCL11, and CCL24 in the lung homogenates, the number of eosinophils, lymphocytes, and neutrophils in the BALF, and the number of lung GATA3+ ILC2 were significantly increased in GLP-1R/GIPR DKO mice compared to the other 3 strains. Furthermore, ICAM-1 expression on lung epithelial cells was increased in GLP-1R/GIPR DKO mice challenged with Alt-Ext compared to the other 3 strains.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Deficiency of both GLP-1R and GIPR signaling together increased TSLP release, ILC2 activation, and early type 2 innate immune responses to aeroallergen exposure. Combined GLP-1R and GIPR signaling should be explored for the treatment of asthma.</p>\u0000 </section>\u0000 </div>","PeriodicalId":122,"journal":{"name":"Allergy","volume":"79 12","pages":"3373-3384"},"PeriodicalIF":12.6,"publicationDate":"2024-11-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142666234","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
<p>PIEZO1 is a mechanosensitive calcium-permeable ion channel that converts mechanical stimuli into biological signals [<span>1</span>]. PIEZO1 plays important roles in innate immune cells including monocytes and natural killer cells [<span>2, 3</span>]. However, the role of <i>Piezo1</i> in mast cells remains unexplored. Mast cells release histamine in response to mechanical stimuli such as pressure, which triggers itching in a subset of patients with chronic inducible urticaria [<span>4</span>]. We therefore investigated the connection between PIEZO1 and mast cells.</p><p>First, we examined <i>Piezo1</i> mRNA expression in mouse bone marrow–derived mast cells (BMMCs) in the presence or absence of various stimuli. We found that IL-33, SCF, and IgE significantly upregulated <i>Piezo1</i> mRNA expression compared with that in the control (Figure 1A). Notably, IL-33 caused an approximately 20-fold increase in Piezo1 mRNA levels. Consistent with these findings, analysis of IL-33–induced gene expression patterns in BMMCs from a Gene Expression Omnibus dataset (GSE96695) identified <i>Piezo1</i> as one of the top upregulated genes (Figure S1). <i>Piezo1</i> mRNA levels also increased in mouse connective tissue–type mast cells (CTMCs) stimulated with IL-33 (Figure S2A), and IL-33 stimulation upregulated PIEZO1 protein expression in BMMCs (Figure 1B). These findings suggest that IL-33 induces PIEZO1 expression in mouse mast cells.</p><p>We then assessed the functional role of IL-33–induced PIEZO1 in mast cells. We measured intracellular Ca<sup>2+</sup> levels in response to stimulation with Yoda1, a specific PIEZO1 activator [<span>5</span>], in IL-33–pretreated or IL-33–untreated BMMCs. Yoda1 increased intracellular Ca<sup>2+</sup> levels in IL-33–pretreated, but not in IL-33–untreated BMMCs (Figure 1C). Consistently, Yoda1 stimulation induced degranulation responses in IL-33–pretreated, but not in IL-33–untreated BMMCs, as determined by measuring β-hexosaminidase release and CD63 expression, which were reduced by siRNA-mediated <i>Piezo1</i> knockdown (Figure 1D–F and Figure S3). In addition, Yoda1 stimulation induced the release of histamine, prostaglandin D2 (PGD2), leukotrienes (LTC4/D4/E4), and cytokines (IL-4 and IL-13) in IL-33–pretreated, but not in IL-33–untreated BMMCs (Figure 1G and Figure S4). The release of both β-hexosaminidase and histamine was suppressed by EGTA, a calcium chelator (Figure 1D,G), suggesting that Ca<sup>2+</sup> influx via PIEZO1 plays a role in these responses. Similar results were obtained in CTMCs (Figure S2B,C). IL-33 also upregulated PIEZO1 in human mast cells (huMCs) derived from CD34<sup>+</sup> stem cells isolated from human peripheral blood (Figure 1H and Figure S5A). Furthermore, IL-33–pretreated, but not IL-33–untreated huMCs increased CD63 expression upon Yoda1 stimulation (Figure 1I and Figure S5B). These findings suggest that IL-33 induction of PIEZO1 in mast cells leads to degranulation and the release of
{"title":"IL-33 Sensitizes Mast Cells to PIEZO1 Stimulation Leading to Degranulation","authors":"Yoshiaki Kobayashi, Kent Sakai, Nguyen Quoc Vuong Tran, Kayoko Ishimaru, Takuya Sato, Yuki Nakamura, Daiki Nakagomi, Satoshi Tanaka, Schuichi Koizumi, Atsuhito Nakao","doi":"10.1111/all.16397","DOIUrl":"10.1111/all.16397","url":null,"abstract":"<p>PIEZO1 is a mechanosensitive calcium-permeable ion channel that converts mechanical stimuli into biological signals [<span>1</span>]. PIEZO1 plays important roles in innate immune cells including monocytes and natural killer cells [<span>2, 3</span>]. However, the role of <i>Piezo1</i> in mast cells remains unexplored. Mast cells release histamine in response to mechanical stimuli such as pressure, which triggers itching in a subset of patients with chronic inducible urticaria [<span>4</span>]. We therefore investigated the connection between PIEZO1 and mast cells.</p><p>First, we examined <i>Piezo1</i> mRNA expression in mouse bone marrow–derived mast cells (BMMCs) in the presence or absence of various stimuli. We found that IL-33, SCF, and IgE significantly upregulated <i>Piezo1</i> mRNA expression compared with that in the control (Figure 1A). Notably, IL-33 caused an approximately 20-fold increase in Piezo1 mRNA levels. Consistent with these findings, analysis of IL-33–induced gene expression patterns in BMMCs from a Gene Expression Omnibus dataset (GSE96695) identified <i>Piezo1</i> as one of the top upregulated genes (Figure S1). <i>Piezo1</i> mRNA levels also increased in mouse connective tissue–type mast cells (CTMCs) stimulated with IL-33 (Figure S2A), and IL-33 stimulation upregulated PIEZO1 protein expression in BMMCs (Figure 1B). These findings suggest that IL-33 induces PIEZO1 expression in mouse mast cells.</p><p>We then assessed the functional role of IL-33–induced PIEZO1 in mast cells. We measured intracellular Ca<sup>2+</sup> levels in response to stimulation with Yoda1, a specific PIEZO1 activator [<span>5</span>], in IL-33–pretreated or IL-33–untreated BMMCs. Yoda1 increased intracellular Ca<sup>2+</sup> levels in IL-33–pretreated, but not in IL-33–untreated BMMCs (Figure 1C). Consistently, Yoda1 stimulation induced degranulation responses in IL-33–pretreated, but not in IL-33–untreated BMMCs, as determined by measuring β-hexosaminidase release and CD63 expression, which were reduced by siRNA-mediated <i>Piezo1</i> knockdown (Figure 1D–F and Figure S3). In addition, Yoda1 stimulation induced the release of histamine, prostaglandin D2 (PGD2), leukotrienes (LTC4/D4/E4), and cytokines (IL-4 and IL-13) in IL-33–pretreated, but not in IL-33–untreated BMMCs (Figure 1G and Figure S4). The release of both β-hexosaminidase and histamine was suppressed by EGTA, a calcium chelator (Figure 1D,G), suggesting that Ca<sup>2+</sup> influx via PIEZO1 plays a role in these responses. Similar results were obtained in CTMCs (Figure S2B,C). IL-33 also upregulated PIEZO1 in human mast cells (huMCs) derived from CD34<sup>+</sup> stem cells isolated from human peripheral blood (Figure 1H and Figure S5A). Furthermore, IL-33–pretreated, but not IL-33–untreated huMCs increased CD63 expression upon Yoda1 stimulation (Figure 1I and Figure S5B). These findings suggest that IL-33 induction of PIEZO1 in mast cells leads to degranulation and the release of ","PeriodicalId":122,"journal":{"name":"Allergy","volume":"79 12","pages":"3517-3520"},"PeriodicalIF":12.6,"publicationDate":"2024-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/all.16397","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142637952","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Jie Ma, Debra J. Palmer, Donna Geddes, Ching Tat Lai, Susan L. Prescott, Nina D'Vaz, Philip Vlaskovsky, Lisa F. Stinson
{"title":"Human Milk Microbiome Is Associated With Allergic Diseases in Early Childhood","authors":"Jie Ma, Debra J. Palmer, Donna Geddes, Ching Tat Lai, Susan L. Prescott, Nina D'Vaz, Philip Vlaskovsky, Lisa F. Stinson","doi":"10.1111/all.16399","DOIUrl":"10.1111/all.16399","url":null,"abstract":"","PeriodicalId":122,"journal":{"name":"Allergy","volume":"79 12","pages":"3509-3511"},"PeriodicalIF":12.6,"publicationDate":"2024-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142612909","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
M Jutel, C Vogelberg, K Duwensee, D Troyke, L Klimek
Background: Allergen immunotherapy (AIT) aims at modulating the immune response by administration of allergen preparations at regular intervals over several years (1). For subcutaneous AIT (SCIT), the treatment is initiated with a dose escalation phase followed by a maintenance dose administration. Over the last decade, there has been a trend towards shortening dose escalation regimens to increase patient adherence. This open-label, phase II trial aimed to investigate the safety and tolerability of a house dust mites (HDMs) SCIT product when used in a newly designed one-strength dose escalation scheme.
Method: Patients, aged 12-65, suffering from HDM-allergic rhinitis/rhinoconjunctivitis ± asthma were included. Patients were randomized to the one-strength (6 injections from the highest strength 3) or the Standard dose escalation regimen (14 injections from strengths 1 to 3) using the HDMs-SCIT product. All adverse events were reported. Tolerability was assessed on the Likert scale.
Results: One hundred and forty-three patients were randomized, 79 adults and 64 adolescents. In total, the one-strength regimen caused more adverse drug reactions (ADRs) than the Standard regimen (p = .0457). With both regimens most ADRs were local reactions which occurred more often in the one-strength group (p = .0393). But there was no significant difference in the number of patients affected by systemic or serious ADRs between both regimens. No relevant differences occurred between the two age groups and no other risks were observed for adolescents compared to adults.
Conclusion: The safety and tolerability of both regimens can be considered comparable, as most ADRs were local reactions, primarily rated as mild in intensity. Nevertheless, the one-strength regimen caused more ADRs. Reducing the number of injections from 14 to 6 while using only one strength offers the potential to improve patient adherence which further might increase clinical efficacy. Future trials could confirm this hypothesis.
{"title":"One-strength dose escalation of house dust mite depot product for subcutaneous immunotherapy is safe and tolerable.","authors":"M Jutel, C Vogelberg, K Duwensee, D Troyke, L Klimek","doi":"10.1111/all.16370","DOIUrl":"https://doi.org/10.1111/all.16370","url":null,"abstract":"<p><strong>Background: </strong>Allergen immunotherapy (AIT) aims at modulating the immune response by administration of allergen preparations at regular intervals over several years (1). For subcutaneous AIT (SCIT), the treatment is initiated with a dose escalation phase followed by a maintenance dose administration. Over the last decade, there has been a trend towards shortening dose escalation regimens to increase patient adherence. This open-label, phase II trial aimed to investigate the safety and tolerability of a house dust mites (HDMs) SCIT product when used in a newly designed one-strength dose escalation scheme.</p><p><strong>Method: </strong>Patients, aged 12-65, suffering from HDM-allergic rhinitis/rhinoconjunctivitis ± asthma were included. Patients were randomized to the one-strength (6 injections from the highest strength 3) or the Standard dose escalation regimen (14 injections from strengths 1 to 3) using the HDMs-SCIT product. All adverse events were reported. Tolerability was assessed on the Likert scale.</p><p><strong>Results: </strong>One hundred and forty-three patients were randomized, 79 adults and 64 adolescents. In total, the one-strength regimen caused more adverse drug reactions (ADRs) than the Standard regimen (p = .0457). With both regimens most ADRs were local reactions which occurred more often in the one-strength group (p = .0393). But there was no significant difference in the number of patients affected by systemic or serious ADRs between both regimens. No relevant differences occurred between the two age groups and no other risks were observed for adolescents compared to adults.</p><p><strong>Conclusion: </strong>The safety and tolerability of both regimens can be considered comparable, as most ADRs were local reactions, primarily rated as mild in intensity. Nevertheless, the one-strength regimen caused more ADRs. Reducing the number of injections from 14 to 6 while using only one strength offers the potential to improve patient adherence which further might increase clinical efficacy. Future trials could confirm this hypothesis.</p>","PeriodicalId":122,"journal":{"name":"Allergy","volume":" ","pages":""},"PeriodicalIF":12.6,"publicationDate":"2024-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142612921","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Bing Zhong, Jing Liu, Hsiao Hui Ong, Jintao Du, Feng Liu, Yafeng Liu, Luo Ba, Silu Sun, De Yun Wang
BackgroundChronic rhinosinusitis with nasal polyps (CRSwNP) is an upper respiratory disease characterized by persistent inflammation of the nasal mucosa. However, the mechanism of abnormal Mucin5AC expression by CRSwNP epithelial cells is not fully understood.ObjectiveWe investigated the potential role of yes‐associated protein (YAP) underlying the mechanism of excessive epithelial Mucin5AC expression in CRSwNP in a hypoxic model.MethodsTissue biopsies of CRSwNP (n = 60), chronic rhinosinusitis without nasal polyps (CRSsNP) (n = 9) and healthy controls (n = 30) were investigated together with a well‐established hypoxic model of primary human nasal epithelial cells (hNECs). The expression levels of hypoxia inducible factor (HIF)‐1α and YAP, and the effect of the signaling axis on mucus secretion in hNECs were analyzed.ResultsWe observed a significant elevated expression levels of YAP in patients with CRSwNP and CRSsNP compared to controls. In addition, HIF‐1α expression of CRSwNP was higher than that of control group. Under hypoxic conditions, HIF‐1α was found to regulate the upregulation of YAP in hNECs. Further investigations revealed that HIF‐1α facilitated the activation and nuclear localization of active‐YAP by reducing the phosphorylation of YAP. This mechanism appeared to be linked to HIF‐1α‐mediated inhibition of LATS 1 phosphorylation and subsequent YAP degradation. HIF‐1α was shown to promote the expression of P63 and the levels of Mucin5AC in hNECs by enhancing YAP activation.ConclusionOur findings indicated that hypoxia enhances YAP activation by decreasing p‐LATS 1 and YAP phosphorylation. This has the potential to impact on the proliferation of basal cells and the differentiation of goblet cells in CRSwNP, ultimately leading to a pathological condition characterized by excessive Mucin5AC expression.
{"title":"Hypoxia‐reduced YAP phosphorylation enhances expression of Mucin5AC in nasal epithelial cells of chronic rhinosinusitis with nasal polyps","authors":"Bing Zhong, Jing Liu, Hsiao Hui Ong, Jintao Du, Feng Liu, Yafeng Liu, Luo Ba, Silu Sun, De Yun Wang","doi":"10.1111/all.16394","DOIUrl":"https://doi.org/10.1111/all.16394","url":null,"abstract":"BackgroundChronic rhinosinusitis with nasal polyps (CRSwNP) is an upper respiratory disease characterized by persistent inflammation of the nasal mucosa. However, the mechanism of abnormal Mucin5AC expression by CRSwNP epithelial cells is not fully understood.ObjectiveWe investigated the potential role of yes‐associated protein (YAP) underlying the mechanism of excessive epithelial Mucin5AC expression in CRSwNP in a hypoxic model.MethodsTissue biopsies of CRSwNP (<jats:italic>n</jats:italic> = 60), chronic rhinosinusitis without nasal polyps (CRSsNP) (<jats:italic>n</jats:italic> = 9) and healthy controls (<jats:italic>n</jats:italic> = 30) were investigated together with a well‐established hypoxic model of primary human nasal epithelial cells (hNECs). The expression levels of hypoxia inducible factor (HIF)‐1α and YAP, and the effect of the signaling axis on mucus secretion in hNECs were analyzed.ResultsWe observed a significant elevated expression levels of YAP in patients with CRSwNP and CRSsNP compared to controls. In addition, HIF‐1α expression of CRSwNP was higher than that of control group. Under hypoxic conditions, HIF‐1α was found to regulate the upregulation of YAP in hNECs. Further investigations revealed that HIF‐1α facilitated the activation and nuclear localization of active‐YAP by reducing the phosphorylation of YAP. This mechanism appeared to be linked to HIF‐1α‐mediated inhibition of LATS 1 phosphorylation and subsequent YAP degradation. HIF‐1α was shown to promote the expression of P63 and the levels of Mucin5AC in hNECs by enhancing YAP activation.ConclusionOur findings indicated that hypoxia enhances YAP activation by decreasing p‐LATS 1 and YAP phosphorylation. This has the potential to impact on the proliferation of basal cells and the differentiation of goblet cells in CRSwNP, ultimately leading to a pathological condition characterized by excessive Mucin5AC expression.","PeriodicalId":122,"journal":{"name":"Allergy","volume":"216 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2024-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142610121","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Lele Sun, Qing Zhao, Suiting Ao, Tingting Liu, Zhenzhen Wang, Jiabao You, Zihao Mi, Yonghu Sun, Xiaotong Xue, Monday O. Ogese, Joshua Gardner, Xiaoli Meng, Dean J. Naisbitt, Hong Liu, Furen Zhang
BackgroundSevere cutaneous adverse reactions (SCARs) mediated by cytotoxic T lymphocytes are a series of life‐threatening conditions with a mortality of 4%–20%. The clinical application of tumor necrosis factor‐alpha (TNF‐α) antagonist improves the outcome of some SCARs patients; however, this is complicated by the elusive and varied immunopathogenesis.AimTo investigate whether IgE antibody responses to HEMAs are associated with AD, its severity, and response to dupilumab.MethodsTo clarify the precise process and optimize the therapy regimen of SCARs, we performed single‐cell sequencing, in vitro functional and clinical analysis of patients with SCARs.ResultsWe observed that TNF‐α breaks drug‐specific T‐cell tolerance by inhibiting the expression of V‐type immunoglobulin domain‐containing suppressor of T‐cell activation (VISTA). Furthermore, TNF‐α generated a positive feedback loop in the early phase of drug‐specific T‐cell activation, whereby B cells acted reciprocally on the corresponding T cells to reinforce TNF‐α cytokine expression. In contrast, this pathway of TNF‐α‐VISTA signaling did not operate in memory effector T cells. Drug‐specific memory effector T‐cell responses were inhibited by increasing Treg cell expression in a negative feedback loop, with TNF‐α antagonists preventing the inhibitory effect. These observations align with the clinical analysis that early but not late intervention with TNF‐α antagonists significantly improved outcomes in SCARs patients.ConclusionOur findings defining feedback regulation of VISTA and Treg cells by TNF‐α in different stages of the drug‐specific T‐cell response and, indicate that a Treg agonists, instead of TNF‐α antagonists, could be used for treatment of patients with progressive SCARs.
{"title":"Feedback regulation of VISTA and Treg by TNF‐α controls T cell responses in drug allergy","authors":"Lele Sun, Qing Zhao, Suiting Ao, Tingting Liu, Zhenzhen Wang, Jiabao You, Zihao Mi, Yonghu Sun, Xiaotong Xue, Monday O. Ogese, Joshua Gardner, Xiaoli Meng, Dean J. Naisbitt, Hong Liu, Furen Zhang","doi":"10.1111/all.16393","DOIUrl":"https://doi.org/10.1111/all.16393","url":null,"abstract":"BackgroundSevere cutaneous adverse reactions (SCARs) mediated by cytotoxic T lymphocytes are a series of life‐threatening conditions with a mortality of 4%–20%. The clinical application of tumor necrosis factor‐alpha (TNF‐α) antagonist improves the outcome of some SCARs patients; however, this is complicated by the elusive and varied immunopathogenesis.AimTo investigate whether IgE antibody responses to HEMAs are associated with AD, its severity, and response to dupilumab.MethodsTo clarify the precise process and optimize the therapy regimen of SCARs, we performed single‐cell sequencing, in vitro functional and clinical analysis of patients with SCARs.ResultsWe observed that TNF‐α breaks drug‐specific T‐cell tolerance by inhibiting the expression of V‐type immunoglobulin domain‐containing suppressor of T‐cell activation (VISTA). Furthermore, TNF‐α generated a positive feedback loop in the early phase of drug‐specific T‐cell activation, whereby B cells acted reciprocally on the corresponding T cells to reinforce TNF‐α cytokine expression. In contrast, this pathway of TNF‐α‐VISTA signaling did not operate in memory effector T cells. Drug‐specific memory effector T‐cell responses were inhibited by increasing Treg cell expression in a negative feedback loop, with TNF‐α antagonists preventing the inhibitory effect. These observations align with the clinical analysis that early but not late intervention with TNF‐α antagonists significantly improved outcomes in SCARs patients.ConclusionOur findings defining feedback regulation of VISTA and Treg cells by TNF‐α in different stages of the drug‐specific T‐cell response and, indicate that a Treg agonists, instead of TNF‐α antagonists, could be used for treatment of patients with progressive SCARs.","PeriodicalId":122,"journal":{"name":"Allergy","volume":"1 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2024-11-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142598100","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
A. Rousseaux, B. Misme‐Aucouturier, M. Le Romancer, R. Villette, M. Larsen, M. De Carvalho, G. Bouchaud, E. Perrin, S. Barbarot, C. Brosseau, M. Bodinier
{"title":"A Gestational Supplementation With 2′‐Fucosyllactose Is an Effective Strategy to Prevent Food Allergy","authors":"A. Rousseaux, B. Misme‐Aucouturier, M. Le Romancer, R. Villette, M. Larsen, M. De Carvalho, G. Bouchaud, E. Perrin, S. Barbarot, C. Brosseau, M. Bodinier","doi":"10.1111/all.16396","DOIUrl":"https://doi.org/10.1111/all.16396","url":null,"abstract":"","PeriodicalId":122,"journal":{"name":"Allergy","volume":"36 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2024-11-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142598101","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
G. Varricchi, R. Poto, M. Lommatzsch, G. Brusselle, F. Braido, J. C. Virchow, G. W. Canonica
Although airway remodeling in severe and/or fatal asthma is stil considered irreversible, its individual components as a cause of clinical symptoms and/or lung function changes remain largely unknown. While inhaled glucocorticoids have not consistently been shown to affect airway remodeling, biologics targeting specific pathways of airway inflammation have been shown to improve lung function, mucus plugging, and airway structural changes that can exceed those seen with glucocorticoids. This superiority of biologic treatment, which cannot be solely explained by insufficient doses or limited durations of glucocorticoid therapies, needs to be further explored. For this field of research, we propose a novel classification of the potential effects of biologics on airway remodeling into three temporal effects: early effects (days to weeks, primarily modulating inflammatory processes), late effects (months to years, predominantly affecting structural changes), and potential preventive effects (outcomes of early treatment with biologics). For the identification of potential preventive effects of biologics, we call for studies exploring the impact of early biological treatment on airway remodeling in patients with moderate‐to‐severe asthma, which should be accompanied by a long‐term evaluation of clinical parameters, biomarkers, treatment burden, and socioeconomic implications.
{"title":"Biologics and airway remodeling in asthma: early, late, and potential preventive effects","authors":"G. Varricchi, R. Poto, M. Lommatzsch, G. Brusselle, F. Braido, J. C. Virchow, G. W. Canonica","doi":"10.1111/all.16382","DOIUrl":"https://doi.org/10.1111/all.16382","url":null,"abstract":"Although airway remodeling in severe and/or fatal asthma is stil considered irreversible, its individual components as a cause of clinical symptoms and/or lung function changes remain largely unknown. While inhaled glucocorticoids have not consistently been shown to affect airway remodeling, biologics targeting specific pathways of airway inflammation have been shown to improve lung function, mucus plugging, and airway structural changes that can exceed those seen with glucocorticoids. This superiority of biologic treatment, which cannot be solely explained by insufficient doses or limited durations of glucocorticoid therapies, needs to be further explored. For this field of research, we propose a novel classification of the potential effects of biologics on airway remodeling into three temporal effects: <jats:italic>early effects</jats:italic> (days to weeks, primarily modulating inflammatory processes), <jats:italic>late effects</jats:italic> (months to years, predominantly affecting structural changes), and potential <jats:italic>preventive effects</jats:italic> (outcomes of early treatment with biologics). For the identification of potential <jats:italic>preventive effects</jats:italic> of biologics, we call for studies exploring the impact of early biological treatment on airway remodeling in patients with moderate‐to‐severe asthma, which should be accompanied by a long‐term evaluation of clinical parameters, biomarkers, treatment burden, and socioeconomic implications.","PeriodicalId":122,"journal":{"name":"Allergy","volume":"9 1","pages":""},"PeriodicalIF":12.4,"publicationDate":"2024-11-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142597069","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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