Journal of Allergy and Clinical Immunology最新文献

{"title":"Sputum eosinophil peroxidase: Building a better biomarker for eosinophilic asthma","authors":"","doi":"10.1016/j.jaci.2024.07.004","DOIUrl":"10.1016/j.jaci.2024.07.004","url":null,"abstract":"","PeriodicalId":14936,"journal":{"name":"Journal of Allergy and Clinical Immunology","volume":null,"pages":null},"PeriodicalIF":11.4,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141599912","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}

{"title":"Downregulation of otulin induces inflammasome activation in neutrophilic asthma","authors":"","doi":"10.1016/j.jaci.2024.03.021","DOIUrl":"10.1016/j.jaci.2024.03.021","url":null,"abstract":"<div><h3>Background</h3><p><span>Neutrophilic asthma (NA) is a severe asthma<span> phenotype associated with steroid resistance and IL-1β overproduction; however, the exact mechanism remains unclear. Moreover, the dysfunction of TNF-α </span></span>signaling pathway<span>, a regulator of IL-1β production, was associated with the deficiency of ovarian tumor<span> protease<span> deubiquitinase with linear linkage specificity (otulin) in autoimmune patients.</span></span></span></p></div><div><h3>Objective</h3><p>We hypothesized that otulin downregulation<span><span> in macrophages (Mφ) could trigger Mφ activation via the nucleotide-binding domain, leucine-rich repeat, and pyrin<span> domain-containing protein 3 (NLRP3) </span></span>inflammasome<span> signaling pathway.</span></span></p></div><div><h3>Methods</h3><p><span><span>We assessed the expressions of otulin in blood monocyte subsets from NA patients and in alveolar Mφ from NA mice. Additionally, we evaluated the functional consequences of otulin deficiency in bone marrow–derived Mφ. The effects of inhibiting receptor-interacting </span>protein kinase<span> (RIPK)-1 and RIPK-3 on neutrophils<span> and group 3 innate lymphoid cells (ILC3s) were assessed </span></span></span><em>in vitro</em> and <em>in vivo</em>.</p></div><div><h3>Results</h3><p><span>When comparing nonclassical monocytes, a significant downregulation of otulin in the intracellular components was observed in NA patients compared to healthy controls (</span><em>P</em><span> = .005). Moreover, isolated alveolar Mφ from the NA mice exhibited lower otulin expression compared to those from control mice. After otulin knockdown in bone marrow–derived Mφ, we observed spontaneous IL-1β production depending on NLRP3 inflammasome<span>. Moreover, the infiltrated neutrophils and ILC3s were significantly decreased by combined treatment of RIPK-1 and RIPK-3 inhibitors through blocking IL-1β release in NA.</span></span></p></div><div><h3>Conclusions</h3><p>IL-1β overproduction caused by a deficiency of otulin, an upstream triggering factor, could be a promising diagnostic and therapeutic target for NA.</p></div>","PeriodicalId":14936,"journal":{"name":"Journal of Allergy and Clinical Immunology","volume":null,"pages":null},"PeriodicalIF":11.4,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140850335","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}

{"title":"Urinary eicosanoid levels in early life and risk of atopic disease in childhood","authors":"","doi":"10.1016/j.jaci.2024.05.022","DOIUrl":"10.1016/j.jaci.2024.05.022","url":null,"abstract":"<div><h3>Background</h3><p>Eicosanoids are lipid mediators including thromboxanes (TXs), prostaglandins (PGs), and leukotrienes with a pathophysiological role in established atopic disease. However, their role in the inception of disease is unclear. This study aimed to investigate the association between urinary eicosanoids in early life and development of atopic disease.</p></div><div><h3>Methods</h3><p>This study quantified the levels of 21 eicosanoids in urine from children from the COPSAC₂₀₁₀ (Copenhagen Prospective Studies on Asthma in Childhood 2010) (age 1 year, n = 450) and VDAART (Vitamin D Antenatal Asthma Reduction Trial) (age 3 years, n = 575) mother-child cohorts and analyzed the associations with development of wheeze/asthma, atopic dermatitis, and biomarkers of type-2 inflammation, applying false discovery rate of 5% (FDR5%) multiple testing correction.</p></div><div><h3>Results</h3><p>In both cohorts, analyses adjusted for environmental determinants showed that higher TXA₂ eicosanoids in early life were associated with increased risk of developing atopic dermatitis (<em>P</em> &lt; FDR5%) and type-2 inflammation (<em>P</em> &lt; .05). In VDAART, lower PGE₂ and PGI₂ eicosanoids and higher isoprostanes were also associated with increased risk of atopic dermatitis (<em>P</em> &lt; FDR5%). For wheeze/asthma, analyses in COPSAC₂₀₁₀ showed that lower isoprostanes and PGF₂ eicosanoids and higher PGD₂ eicosanoids at age 1 year associated with an increased risk at age 1-10 years (<em>P</em> &lt; .05), whereas analyses in VDAART showed that lower PGE₂ and higher TXA₂ eicosanoids at age 3 years associated with an increased risk at 6 years (<em>P</em> &lt; FDR5%).</p></div><div><h3>Conclusions</h3><p>This study suggests that early life perturbations in the eicosanoid metabolism are present before the onset of atopic disease in childhood, which provides pathophysiological insight in the inception of atopic diseases.</p></div>","PeriodicalId":14936,"journal":{"name":"Journal of Allergy and Clinical Immunology","volume":null,"pages":null},"PeriodicalIF":11.4,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0091674924005657/pdfft?md5=674926dbff551ea9ee1e59da8d169e68&pid=1-s2.0-S0091674924005657-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141200037","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}

{"title":"The Editors’ Choice","authors":"","doi":"10.1016/j.jaci.2024.07.013","DOIUrl":"10.1016/j.jaci.2024.07.013","url":null,"abstract":"","PeriodicalId":14936,"journal":{"name":"Journal of Allergy and Clinical Immunology","volume":null,"pages":null},"PeriodicalIF":11.4,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142136941","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}

{"title":"DAB2IP associates with hereditary angioedema: Insights into the role of VEGF signaling in HAE pathophysiology","authors":"","doi":"10.1016/j.jaci.2024.05.017","DOIUrl":"10.1016/j.jaci.2024.05.017","url":null,"abstract":"<div><h3>Background</h3><p>In the recent years, there was an important improvement in the understanding of the pathogenesis of hereditary angioedema (HAE). Notwithstanding, in a large portion of patients with unknown mutation (HAE-UNK) the genetic cause remains to be identified.</p></div><div><h3>Objectives</h3><p>To identify new genetic targets associated with HAE, a large Argentine family with HAE-UNK spanning 3 generations was studied.</p></div><div><h3>Methods</h3><p>Whole exome sequencing was performed on affected family members to identify potential genetic variants associated with HAE-UNK. <em>In silico</em> analyses and experimental studies were applied to assess the role of the identified gene variant.</p></div><div><h3>Results</h3><p>A missense variant (p.D239N) in <em>DAB2IP</em> was identified. The variant occurred in the C2-domain, the region interacting with vascular endothelial growth factor receptor 2 (VEGFR2). It was found to be rare, and predicted to have a detrimental effect on the functionality of DAB2IP. Protein structure modeling predicted changes in the mutant p.D239N protein structure, impacting protein stability. The p.D239N variant affected the subcellular localization of VEGFR2. Cells transfected with the DAB2IP-239N transcript exhibited an intracellular distribution, and VEGFR2 remained associated with the cell membrane. The altered localization pattern indicated reduced colocalization of the mutant protein with VEGFR2, suggesting a diminished ability of VEGFR2 binding.</p></div><div><h3>Conclusions</h3><p>The study identified a novel missense variant (p.D239N) in <em>DAB2IP</em> in a family with HAE-UNK and highlighted the role of dysregulated VEGF-mediated signaling in altered endothelial permeability. DAB2IP loss-of-function pathogenic variants lead to the impairment of the endothelial VEGF/VEGFR2 ligand system and represent a new pathophysiologic cause of HAE-UNK.</p></div>","PeriodicalId":14936,"journal":{"name":"Journal of Allergy and Clinical Immunology","volume":null,"pages":null},"PeriodicalIF":11.4,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141186012","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}

{"title":"ALOX15+ M2 macrophages contribute to epithelial remodeling in eosinophilic chronic rhinosinusitis with nasal polyps","authors":"","doi":"10.1016/j.jaci.2024.04.019","DOIUrl":"10.1016/j.jaci.2024.04.019","url":null,"abstract":"<div><h3>Background</h3><p><span><span>Epithelial remodeling is a prominent feature of eosinophilic chronic rhinosinusitis with </span>nasal polyps (eCRSwNP), and infiltration of </span>M2 macrophages plays a pivotal role in the pathogenesis of eCRSwNP, but the underlying mechanisms remain undefined.</p></div><div><h3>Objective</h3><p>We sought to investigate the role of ALOX15⁺ M2 macrophages in the epithelial remodeling of eCRSwNP.</p></div><div><h3>Methods</h3><p><span><span><span>Digital spatial transcriptomics and single-cell sequencing analyses were used to characterize the epithelial remodeling and cellular infiltrate in eCRSwNP. </span>Hematoxylin and </span>eosin staining, immunohistochemical staining, and immunofluorescence staining were used to explore the relationship between ALOX15</span>⁺ M2 (CD68⁺<span>CD163</span>⁺<span>) macrophages and epithelial remodeling. A coculture<span> system of primary human nasal epithelial cells (hNECs) and the macrophage cell line THP-1 was used to determine the underlying mechanisms.</span></span></p></div><div><h3>Results</h3><p><span><span>Spatial transcriptomics analysis showed the upregulation of epithelial remodeling–related genes, such as </span>Vimentin<span> and matrix metalloproteinase 10, and enrichment of epithelial-mesenchymal transition (EMT)-related pathways, in the epithelial areas in eCRSwNP, with more abundance of epithelial basal, goblet, and glandular cells. Single-cell analysis identified that ALOX15</span></span>⁺, rather than ALOX15⁻, M2 macrophages were specifically highly expressed in eCRSwNP. CRSwNP with high ALOX15⁺ M2^{THP-1-IL-4+IL-13} macrophages had more obvious epithelial remodeling features and increased genes associated with epithelial remodeling and integrity of epithelial morphology versus that with low ALOX15⁺ M2^{THP-1-IL-4+IL-13} macrophages. IL-4/IL-13–polarized M2^{THP-1-IL-4+IL-13} macrophages upregulated expressions of EMT-related genes in hNECs, including Vimentin, TWIST1, Snail, and ZEB1. ALOX15 inhibition in M2^{THP-1-IL-4+IL-13} macrophages resulted in reduction of the EMT-related transcripts in hNECs. Blocking chemokine (C-C motif) ligand 13 signaling inhibited M2^{THP-1-IL-4+IL-13} macrophage–induced EMT alteration in hNECs.</p></div><div><h3>Conclusions</h3><p>ALOX15⁺ M2 macrophages are specifically increased in eCRSwNP and may contribute to the pathogenesis of epithelial remodeling via production of chemokine (C-C motif) ligand 13.</p></div>","PeriodicalId":14936,"journal":{"name":"Journal of Allergy and Clinical Immunology","volume":null,"pages":null},"PeriodicalIF":11.4,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140851625","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}

{"title":"Loss of the TRPM4 channel in humans causes immune dysregulation with defective monocyte migration","authors":"","doi":"10.1016/j.jaci.2024.02.026","DOIUrl":"10.1016/j.jaci.2024.02.026","url":null,"abstract":"<div><h3>Background</h3><p>TRPM4 is a broadly expressed, calcium-activated, monovalent cation channel that regulates immune cell function in mice and cell lines. Clinically, however, partial loss- or gain-of-function mutations in <em>TRPM4</em> lead to arrhythmia and heart disease, with no documentation of immunologic disorders.</p></div><div><h3>Objective</h3><p>To characterize functional cellular mechanisms underlying the immune dysregulation phenotype in a proband with a mutated <em>TRPM4</em> gene.</p></div><div><h3>Methods</h3><p>We employed a combination of biochemical, cell biological, imaging, omics analyses, flow cytometry, and gene editing approaches.</p></div><div><h3>Results</h3><p>We report the first human cases to our knowledge with complete loss of the TRPM4 channel, leading to immune dysregulation with frequent bacterial and fungal infections. Single-cell and bulk RNA sequencing point to altered expression of genes affecting cell migration, specifically in monocytes. Inhibition of TRPM4 in T cells and the THP-1 monocyte cell line reduces migration. More importantly, primary T cells and monocytes from TRPM4 patients migrate poorly. Finally, CRISPR knockout of <em>TRPM4</em> in THP-1 cells greatly reduces their migration potential.</p></div><div><h3>Conclusion</h3><p>Our results demonstrate that TRPM4 plays a critical role in regulating immune cell migration, leading to increased susceptibility to infections.</p></div>","PeriodicalId":14936,"journal":{"name":"Journal of Allergy and Clinical Immunology","volume":null,"pages":null},"PeriodicalIF":11.4,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0091674924004664/pdfft?md5=8996f7d3bb97d3fff169ea4bf972894e&pid=1-s2.0-S0091674924004664-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140943649","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}

{"title":"Integrin β1–mediated mast cell immune-surveillance of blood vessel content","authors":"","doi":"10.1016/j.jaci.2024.03.022","DOIUrl":"10.1016/j.jaci.2024.03.022","url":null,"abstract":"<div><h3>Background</h3><p>IgE-mediated degranulation of mast cells (MCs) provides rapid protection against environmental hazards, including animal venoms. A fraction of tissue-resident MCs intimately associates with blood vessels. These perivascular MCs were reported to extend projections into the vessel lumen and to be the first MCs to acquire intravenously injected IgE, suggesting that IgE loading of MCs depends on their vascular association.</p></div><div><h3>Objective</h3><p>We sought to elucidate the molecular basis of the MC–blood vessel interaction and to determine its relevance for IgE-mediated immune responses.</p></div><div><h3>Methods</h3><p>We selectively inactivated the <em>Itgb1</em> gene, encoding the β1 chain of integrin adhesion molecules (ITGB1), in MCs by conditional gene targeting in mice. We analyzed skin MCs for blood vessel association, surface IgE density, and capability to bind circulating antibody specific for MC surface molecules, as well as <em>in vivo</em> responses to antigen administered via different routes.</p></div><div><h3>Results</h3><p>Lack of ITGB1 expression severely compromised MC–blood vessel association. ITGB1-deficient MCs showed normal densities of surface IgE but reduced binding of intravenously injected antibodies. While their capacity to degranulate in response to IgE ligation <em>in vivo</em> was unimpaired, anaphylactic responses to antigen circulating in the vasculature were largely abolished.</p></div><div><h3>Conclusions</h3><p>ITGB1-mediated association of MCs with blood vessels is key for MC immune surveillance of blood vessel content, but is dispensable for slow steady-state loading of endogenous IgE onto tissue-resident MCs.</p></div>","PeriodicalId":14936,"journal":{"name":"Journal of Allergy and Clinical Immunology","volume":null,"pages":null},"PeriodicalIF":11.4,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0091674924003622/pdfft?md5=e7d269bf6654b7742c11e7df2102438f&pid=1-s2.0-S0091674924003622-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140860220","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}

{"title":"A pediatric randomized, controlled trial of German cockroach subcutaneous immunotherapy","authors":"","doi":"10.1016/j.jaci.2024.04.022","DOIUrl":"10.1016/j.jaci.2024.04.022","url":null,"abstract":"<div><h3>Background</h3><p>Cockroach allergy contributes to morbidity among urban children with asthma. Few trials address the effect of subcutaneous immunotherapy (SCIT) with cockroach allergen among these at-risk children.</p></div><div><h3>Objectives</h3><p>We sought to determine whether nasal allergen challenge (NAC) responses to cockroach allergen would improve following 1 year of SCIT.</p></div><div><h3>Methods</h3><p><span>Urban children with asthma, who were cockroach-sensitized and reactive on NAC, participated in a year-long randomized double-blind placebo-controlled SCIT trial using German cockroach extract. The primary endpoint was the change in mean Total Nasal Symptom Score (TNSS) during NAC after 12 months of SCIT. Changes in nasal </span>transcriptomic<span> responses during NAC, skin prick test wheal<span> size, serum allergen-specific antibody production, and T-cell responses to cockroach allergen were assessed.</span></span></p></div><div><h3>Results</h3><p>Changes in mean NAC TNSS did not differ between SCIT-assigned (n = 28) versus placebo-assigned (n = 29) participants (<em>P</em><span> = .63). Nasal transcriptomic<span> responses correlated with TNSS, but a treatment effect was not observed. Cockroach serum-specific IgE decreased to a similar extent in both groups, while decreased cockroach skin prick test wheal size was greater among SCIT participants (</span></span><em>P</em> = .04). A 200-fold increase in cockroach serum-specific IgG₄ was observed among subjects receiving SCIT (<em>P</em> &lt; .001) but was unchanged in the placebo group. T-cell IL-4 responses following cockroach allergen stimulation decreased to a greater extent among SCIT versus placebo (<em>P</em> = .002), while no effect was observed for IL-10 or IFN-γ.</p></div><div><h3>Conclusions</h3><p><span>A year of SCIT failed to alter NAC TNSS and nasal transcriptome responses to cockroach allergen challenge despite systemic effects on allergen-specific skin tests, induction of serum-specific IgG</span>₄ serum production and down-modulation of allergen-stimulated T-cell responses.</p></div>","PeriodicalId":14936,"journal":{"name":"Journal of Allergy and Clinical Immunology","volume":null,"pages":null},"PeriodicalIF":11.4,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140891134","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}

{"title":"CME Calendar-AAAAI","authors":"","doi":"10.1016/S0091-6749(24)00755-3","DOIUrl":"10.1016/S0091-6749(24)00755-3","url":null,"abstract":"","PeriodicalId":14936,"journal":{"name":"Journal of Allergy and Clinical Immunology","volume":null,"pages":null},"PeriodicalIF":11.4,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S0091674924007553/pdfft?md5=938fe9789db3aec13955e6f2b14adcca&pid=1-s2.0-S0091674924007553-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142136608","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}