Journal of Allergy and Clinical Immunology最新文献

{"title":"Positionally distinct interferon-stimulated dermal immune-acting fibroblasts promote neutrophil recruitment in Sweet's syndrome.","authors":"Kellen J Cavagnero, Julie Albright, Fengwu Li, Edward Liu, Tatsuya Dokoshi, Rachael Bogle, Joseph Kirma, J Michelle Kahlenberg, Allison C Billi, Jennifer Fox, May P Chan, Anthony Coon, Craig J Dobry, Brian Hinds, Lam C Tsoi, Paul W Harms, Johann E Gudjonsson, Richard L Gallo","doi":"10.1016/j.jaci.2025.05.029","DOIUrl":"https://doi.org/10.1016/j.jaci.2025.05.029","url":null,"abstract":"<p><strong>Background: </strong>Sweet's syndrome is an inflammatory skin disease characterized by robust neutrophil infiltration into the dermis. Its pathogenesis and distinguishing features compared to other neutrophilic dermatoses, such as pyoderma gangrenosum, remain poorly understood.</p><p><strong>Objective: </strong>To define the cellular and molecular landscape of Sweet's syndrome skin.</p><p><strong>Methods: </strong>Single-nucleus and bulk transcriptomics were performed on archival clinical skin samples from patients with Sweet's syndrome, pyoderma gangrenosum, and healthy controls. Functional experiments were performed with primary human cells for mechanistic validation. Spatial transcriptomics with single-molecule resolution mapped cell types to tissue location.</p><p><strong>Results: </strong>A prominent interferon signature was identified in Sweet's syndrome skin greater than in tissues from pyoderma gangrenosum and healthy controls. This signature was observed in different subsets of cells, including fibroblasts that expressed interferon-induced genes. Functionally, this response was supported by analysis of cultured dermal fibroblasts that were observed to highly express neutrophil chemokines in response to activation by type I interferon. Furthermore, spatial transcriptomics revealed two positionally distinct interferon-activated fibroblast subsets: CXCL1+ fibroblasts near neutrophil infiltrates and CXCL12+ fibroblasts distal to these infiltrates.</p><p><strong>Conclusion: </strong>This study defines the cellular and molecular landscape of neutrophilic dermatoses and implicates dermal immune-acting fibroblasts in Sweet's syndrome pathogenesis through type I interferon recognition and neutrophil recruitment.</p>","PeriodicalId":14936,"journal":{"name":"Journal of Allergy and Clinical Immunology","volume":" ","pages":""},"PeriodicalIF":11.4,"publicationDate":"2025-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144293772","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":"Transcriptomic profiling of vitiligo patients shows polar immune dysregulation in involved and uninvolved skin.","authors":"Patrick M Brunner, Eden David, Ester Del Duca, Meredith Manson, Agata Kurowski, Malini P Naidu, Lauren R Port, Jesus Gay-Mimbrera, Pedro Gómez-Arias, Natalia Alkon, Jessica Beaziz Tordjman, Yeriel Estrada, Yael Renert-Yuval, Juan Ruano, Emma Guttman-Yassky","doi":"10.1016/j.jaci.2025.06.002","DOIUrl":"https://doi.org/10.1016/j.jaci.2025.06.002","url":null,"abstract":"<p><strong>Background: </strong>Vitiligo is a chronic autoimmune skin depigmenting disorder, with a major impact on quality of life. Therapeutic options are still limited, with only one topical JAK inhibitor being FDA-approved. Although vitiligo is primarily regarded as a Th1/IFN-driven disease, emerging evidence suggests the involvement of additional immune axes, but their relevance to disease pathogenesis remains unclear.</p><p><strong>Objective: </strong>To obtain a global cutaneous transcriptomic profile of lesional and nonlesional vitiligo.</p><p><strong>Methods: </strong>We performed bulk RNA-sequencing combined with real-time PCR and immunohistochemistry of skin biopsies from 15 lesional and nonlesional vitiligo samples and compared them to 14 matched healthy controls. Results were corroborated by single-cell RNA sequencing.</p><p><strong>Results: </strong>Robust inflammatory dysregulation was captured not only in lesional, but also nonlesional vitiligo skin relative to healthy controls. Lesional samples demonstrated upregulation of Th1 (OASL, CXCL9, CXCL10), Th2 (IL4, IL4R, CCL13, CCL17, CCL22, CCL26), and Th17/22 (IL20,S100A7,S100A8,S100A9, PI3) related markers. Similarly, nonlesional samples demonstrated activation of Th1 (CXCL9, OASL), Th2 (IL4R, IL10, CCL13, CCL17, CCL22), and Th17/22 (PI3, DEFB4A) associated markers. Clinical severity scores (VASI and/or VIDA) significantly and positively correlated with multiple inflammatory mediators (i.e., CXCL14, IL25, IL17RC) in lesional and/or nonlesional vitiligo skin. On a single-cell level, IL13 and IFNG expression were primarily found in nonlesional helper T cells and in lesional proliferating T cells, respectively.</p><p><strong>Conclusions: </strong>Our findings show that immune dysregulation in vitiligo involves immune axes beyond Th1/Tc1, with upregulation of particularly type 2 markers already in nonlesional skin, suggesting a role during early lesion formation.</p>","PeriodicalId":14936,"journal":{"name":"Journal of Allergy and Clinical Immunology","volume":" ","pages":""},"PeriodicalIF":11.4,"publicationDate":"2025-06-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144293773","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":"Absence of evidence to diagnose lectin pathway deficiencies with a monogenic inborn error of immunity.","authors":"Ana García-Soidán, Jennifer Dámaso-Callero, Carlos Rodríguez-Gallego","doi":"10.1016/j.jaci.2025.06.001","DOIUrl":"https://doi.org/10.1016/j.jaci.2025.06.001","url":null,"abstract":"","PeriodicalId":14936,"journal":{"name":"Journal of Allergy and Clinical Immunology","volume":" ","pages":""},"PeriodicalIF":11.4,"publicationDate":"2025-06-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144293771","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":"Mouse Th2 cell extracellular vesicles promote eosinophil survival through the surface cytokine cargo IL-3.","authors":"Kaitlyn E Bunn, Brenna G Giese-Byrne, Alexander M Blatt, Dawn C Newcomb, Heather H Pua","doi":"10.1016/j.jaci.2025.05.027","DOIUrl":"https://doi.org/10.1016/j.jaci.2025.05.027","url":null,"abstract":"<p><strong>Background: </strong>Extracellular vesicles (EVs) mediate intercellular communication during immune responses. EVs are abundant in respiratory biofluids, and the composition of EVs in the lung changes during inflammation.</p><p><strong>Objective: </strong>We aimed to quantify the contribution of T cells to airway EVs in eosinophilic lung inflammation and ascertain their function during a type 2 inflammatory response.</p><p><strong>Methods: </strong>Genetic membrane tagging was combined with single vesicle flow cytometry to quantify T cell EVs in the airways of mice challenged with ovalbumin or house dust mite. EVs were purified from mouse T helper type 2 (Th2) cell cultures and their functions on eosinophils assessed by flow cytometry and RNA sequencing. Th2 cell EVs were instilled into the lungs of mice to determine effects on lung eosinophilia. Finally, the function of an EV protein cargo was tested using inhibitors and blocking antibodies.</p><p><strong>Results: </strong>T cell EVs are increased in the airways of mice after ovalbumin or house dust mite induced inflammation. EVs secreted by Th2 cells inhibit apoptosis and induce activating pathways in eosinophils in vitro. This effect depends on re-stimulation through the T cell receptor. Th2 cell EVs prolong eosinophilia in vivo during acute eosinophilic inflammation. Th2 cell EVs carry the cytokine IL-3 as a surface cargo, which inhibits apoptosis by activating Jak1/2-dependent pro-survival programs in eosinophils.</p><p><strong>Conclusion: </strong>Th2 cell EVs promote eosinophil survival through the EV cargo IL-3, supporting a role for EVs as vehicles of cytokine-based communication in lung inflammation.</p>","PeriodicalId":14936,"journal":{"name":"Journal of Allergy and Clinical Immunology","volume":" ","pages":""},"PeriodicalIF":11.4,"publicationDate":"2025-06-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144284434","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":"Factor H-related proteins and their associated disorders.","authors":"Mihály Józsi, Barbara Uzonyi","doi":"10.1016/j.jaci.2025.05.024","DOIUrl":"https://doi.org/10.1016/j.jaci.2025.05.024","url":null,"abstract":"","PeriodicalId":14936,"journal":{"name":"Journal of Allergy and Clinical Immunology","volume":" ","pages":""},"PeriodicalIF":11.4,"publicationDate":"2025-06-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144274969","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":"Informed Clinical Decisions by Outfoxing Human FOXN1 Variants.","authors":"Christian A Wysocki, Nicolai S C van Oers","doi":"10.1016/j.jaci.2025.05.025","DOIUrl":"https://doi.org/10.1016/j.jaci.2025.05.025","url":null,"abstract":"<p><p>Thymic T cell development is orchestrated by thymic epithelial cells (TECs). The master transcriptional regulator of TECs is Forkhead Box N1 (FOXN1), which controls their differentiation, expansion and function. Biallelic founder mutations in FOXN1 caused a Nude/Severe Combined Immunodeficiency (SCID) phenotype due to congenital thymic aplasia and alopecia universalis. This established the critical role of FOXN1 in TECs and epithelial cells in the skin and nails. The emergence of newborn screening for severe T cell deficiency via the T cell receptor excision circle (TREC) assay along with exome and genome sequencing has led to dramatic increases in the number of FOXN1 variants identified. The consequent impact of the FOXN1 variants ranges from pathogenic to benign. Yet most FOXN1 mutations are listed as variants of unknown significance. Among monoallelic FOXN1 variants are some that act as dominant negatives, resulting in a transient T cell lymphopenia. In this review, the clinical impacts of diverse FOXN1 variants are categorized based on the type and location of the mutation. Knowing how these FOXN1 mutations affect protein function informs on clinical care; laboratory monitoring, prophylactic measures, and allogeneic thymic implant decisions. This review provides key functional insights into FOXN1, enabling better clinical care.</p>","PeriodicalId":14936,"journal":{"name":"Journal of Allergy and Clinical Immunology","volume":" ","pages":""},"PeriodicalIF":11.4,"publicationDate":"2025-06-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144247993","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":"Towards precision medicine: inflammatory nasal epithelial transcriptomic profiles in long COVID.","authors":"Nadia Baalbaki, Jelle M Blankestijn, Samuel W Kazer, Mahmoud I Abdel-Aziz, Lizan D Bloemsma, Harm Jan Bogaard, Merel E B Cornelissen, Cornelis M van Drunen, Daniëlle van Egmond, Esther J Nossent, Jaclyn M L Walsh, Jose Ordovas-Montanes, Korneliusz Golebski, Anke H Maitland-van der Zee","doi":"10.1016/j.jaci.2025.05.023","DOIUrl":"https://doi.org/10.1016/j.jaci.2025.05.023","url":null,"abstract":"<p><strong>Rationale and objectives: </strong>Little is known about the role of the nasal epithelium in long COVID. This study aimed to assess nasal epithelial transcriptomes of long COVID(LC) patients to unravel pathophysiological mechanisms for disease management.</p><p><strong>Methods: </strong>Medical data and transcriptomes were obtained from participants in the 'Precision Medicine for more Oxygen'(P4O2) COVID-19 cohort, at 3-6(n=40) and 12-18(n=15) months post-COVID. Cell type frequencies were estimated by deconvolution from a single-cell dataset. Hierarchical clustering identified transcriptomic clusters and cellular clusters from which differences in gene expression, gene set enrichment and pulmonary phenotypes were assessed. Functional validation was performed using CRISPR-Cas9 gene editing and in vitro assays in primary mutant nasal epithelium and gene expression comparisons were made to healthy controls(n=51).</p><p><strong>Results: </strong>At 3-6 and 12-18 months, transcriptomes associated with inflammatory pathways(padj<0.05). Transcriptomic and cellular clusters were identified and were related to inflammation and ciliogenesis(padj<0.05). Comparison of transcriptomes of patients with and without pulmonary radiological abnormalities resulted in 613 significantly differentially expressed genes(padj<0.05). Upregulated inflammatory genes were observed in patients with abnormalities. SMURF1 expression was significantly increased in patients with compared to those without abnormalities and healthy controls. SMURF1^-/- mutant nasal epithelial cells produced significantly lower levels(p<0.05) of pro-inflammatory cytokines upon virus exposure compared to controls.</p><p><strong>Conclusion: </strong>Nasal epithelium in LC exhibits persistent inflammatory states. SMURF1 upregulation potentially contributes to an exacerbated inflammatory state in nasal epithelium of patients with radiological abnormalities. This study demonstrates the importance of understanding these inflammatory profiles within a clinical context and emphasizes the need for further assessment and validation of SMURF1's role in LC.</p>","PeriodicalId":14936,"journal":{"name":"Journal of Allergy and Clinical Immunology","volume":" ","pages":""},"PeriodicalIF":11.4,"publicationDate":"2025-06-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144247995","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":"Mast cells modulate macrophage biology through release of pre-stored CSF1.","authors":"Daniel Kovacs, Klaus Heger, Piero Giansanti, Caterina Iuliano, Felix Meissner, Matthias Mann, Jan Böttcher, Ruppert Öllinger, Roland Rad, Freya Tammer, Vanessa Gölling, Theodor Zeng, Ali Masjedi, Tanja Groll Dr Med Vet, Axel Roers, Magda Babina, Maria S Robles, Markus Moser, Susanne Kaesler, Katja Steiger Dr Med Vet, Tilo Biedermann, Marc Schmidt-Supprian","doi":"10.1016/j.jaci.2025.05.022","DOIUrl":"https://doi.org/10.1016/j.jaci.2025.05.022","url":null,"abstract":"<p><strong>Background: </strong>Mast cells are tissue-resident immune cells present in connective tissues throughout the body. They exert diverse functions in immunity by rapidly releasing a plethora of preformed mediators, including proteoglycans, cytokines, and proteases, which are stored in cytoplasmic granules.</p><p><strong>Objective: </strong>Our aim was to systematically and globally identify mast cell-released protein mediators and elucidate their functions.</p><p><strong>Methods: </strong>We analysed the secretomes of antigen-activated primary mouse mast cells using quantitative mass spectrometry-based proteomics and conducted follow-up studies in vitro, ex vivo and using mast cell-specific genetic mouse models.</p><p><strong>Results: </strong>We identified CSF1 as a novel preformed mast cell mediator present in the granules of all connective tissue-type mast cells. We further show that the mast cell secretome can induce macrophage differentiation and a unique polarisation pattern via CSF1 and other mediators. Mast cell-derived CSF1 has systemic functions, as mast cell-specific CSF1-deficient mice have lower serum CSF1 levels and reduced numbers of circulating monocytes. In addition, using an orthotopic transplantation-based melanoma mouse model, we show that loss of mast cell-derived CSF1 promotes cancer cell expansion. Finally, we demonstrate that CSF1 is also prestored and released by human mast cells.</p><p><strong>Conclusion: </strong>CSF1 is an evolutionarily conserved, constitutive mast cell granule component. Mast cell degranulation induces macrophage differentiation and a unique polarisation state, the former being completely dependent on CSF1, while the latter is only modulated.</p>","PeriodicalId":14936,"journal":{"name":"Journal of Allergy and Clinical Immunology","volume":" ","pages":""},"PeriodicalIF":11.4,"publicationDate":"2025-06-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144247994","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":"Eosinophil-derived neurotoxin and eosinophil cationic protein are key molecules for blister formation in bullous pemphigoid.","authors":"Takamasa Ito, Ayame Kimura, Ken Muramatsu, Ken Natsuga, Takuya Kawamura, Sho Katayama, Chihiro Shiiya, Kentaro Izumi, Hiroaki Iwata, Hideyuki Ujiie","doi":"10.1016/j.jaci.2025.04.028","DOIUrl":"https://doi.org/10.1016/j.jaci.2025.04.028","url":null,"abstract":"<p><strong>Background: </strong>Eosinophils, which are multifunctional leukocytes, play pivotal roles in tissue repair, immune responses against pathogens, and the pathogenesis of various diseases, including neoplasms and inflammatory conditions such as asthma and atopic dermatitis. Despite advancements in understanding eosinophil biology and recruitment, the specific roles of eosinophil granule proteins in eosinophil-associated autoimmune diseases remain incompletely understood.</p><p><strong>Objective: </strong>We sought to investigate the role of eosinophils in the pathogenesis of autoimmune blistering dermatoses.</p><p><strong>Methods: </strong>We used 2 distinct bullous pemphigoid (BP) mouse models using STAT6-deficient mice and T-box transcription factor 21-deficient mice. Eosinophil granule proteins were examined in sera and skin samples from patients with BP, and their effects on dermal-epidermal separation were assessed in vitro.</p><p><strong>Results: </strong>STAT6-deficient mice exhibited reduced subepidermal blister formation and eosinophil infiltration in 2 BP mouse models. IgG subclass differences and complement deficiency were not involved in subepidermal blister formation in vitro. Eosinophil-derived neurotoxin and eosinophil cationic protein were substantially elevated and localized within bullous areas of skin samples from patients with BP. Importantly, these proteins significantly impaired keratinocyte adhesion in vitro.</p><p><strong>Conclusions: </strong>Eosinophil-derived neurotoxin and eosinophil cationic protein play a critical role in subepidermal blister formation in BP.</p>","PeriodicalId":14936,"journal":{"name":"Journal of Allergy and Clinical Immunology","volume":" ","pages":""},"PeriodicalIF":11.4,"publicationDate":"2025-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144247992","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":"Antigen-Specific Immune Responses and Microbiota Interactions in Skin: Insights into Autoimmune Skin Diseases and.","authors":"Hayato Takahashi, Keitaro Fukuda, Yoshihiro Ito, Masayuki Amagai","doi":"10.1016/j.jaci.2025.05.021","DOIUrl":"https://doi.org/10.1016/j.jaci.2025.05.021","url":null,"abstract":"<p><p>The skin plays a vital role in serving as a physical and immunological barrier against external insults while orchestrating complex immune responses. Autoimmune skin diseases including pemphigus, vitiligo, and alopecia areata, illustrate the intricate interplay between antigen-specific immunity and tissue-specific pathologies. Pemphigus serves as a model to understand the dynamics of peripheral immune tolerance and the interplay between humoral and cellular autoimmunity, emphasizing the role of regulatory T cells in controlling autoreactive responses. Similarly, vitiligo and alopecia areata highlight the pathological contribution of resident memory CD8⁺ T cells and IFN-γ signaling, identifying potential therapeutic targets like the IL-15 signaling pathway to address disease intractability. In addition to autoimmune mechanisms, the skin microbiota profoundly influences local and systemic immune responses. Commensals like Staphylococcus epidermidis promote homeostasis by regulating barrier integrity, T cell activation, and wound repair, while dysbiosis exacerbates immune dysregulation. Innovative strategies, including the use of genetically modified microorganisms to stimulate antigen-specific immunity, hold promise for next-generation therapies. This review underscores the significance of antigen-specific immunity in skin diseases and the emerging role of microbiota in modulating immune responses. Future research into these areas is pivotal for advancing targeted therapies and understanding the interconnectedness of skin health and systemic immunity.</p>","PeriodicalId":14936,"journal":{"name":"Journal of Allergy and Clinical Immunology","volume":" ","pages":""},"PeriodicalIF":11.4,"publicationDate":"2025-06-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144225560","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}