Journal of Allergy and Clinical Immunology最新文献

{"title":"When prediction reflects prior recognition","authors":"Yuanli Yang MD","doi":"10.1016/j.jaci.2026.05.035","DOIUrl":"10.1016/j.jaci.2026.05.035","url":null,"abstract":"","PeriodicalId":14936,"journal":{"name":"Journal of Allergy and Clinical Immunology","volume":"158 4","pages":"Page 1161"},"PeriodicalIF":11.7,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148818322","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":"HECT E3 ubiquitin ligase SMURF2 orchestrates FcεRI-dependent mast cell activation and allergic responses","authors":"Jingjing Liang PhD,&nbsp;Xiang An PhD,&nbsp;Yuting Yang MD,&nbsp;Ning Wang MD,&nbsp;Suwen Qiu BSc,&nbsp;Zirong Yi MSc,&nbsp;Luofei Zhang BSc,&nbsp;Rumeng Zuo MSc,&nbsp;Fang Wang PhD,&nbsp;Wanting Huang MSc,&nbsp;Min Li PhD,&nbsp;Zengfeng Xin MD,&nbsp;Jia Chen MD,&nbsp;Wenlong Lin PhD","doi":"10.1016/j.jaci.2026.06.001","DOIUrl":"10.1016/j.jaci.2026.06.001","url":null,"abstract":"<div><h3>Background</h3><div>Cross-linking of IgE to its high-affinity receptor FcεRI on mast cells initiates intracellular signaling that drives the pathogenesis of allergic disorders, including asthma, allergic rhinitis, and atopic dermatitis. Precise regulation of mast cell signaling is essential for immune homeostasis and controlling allergic inflammation.</div></div><div><h3>Objective</h3><div>We sought to explore the functional role of HECT E3 ubiquitin ligase SMURF2 in FcεRI-dependent mast cell activation and allergic responses, as well as the expression profile in allergic disease.</div></div><div><h3>Methods</h3><div>We examined SMURF2 expression in mast cells from patients with allergic rhinitis, PBMCs and induced sputum from patients with acute asthma, and IgE-activated mast cells. The function of SMURF2 was assessed <em>in vitro</em> and in mast cell–specific <em>Smurf2</em>-deficient mice subjected to IgE-mediated anaphylaxis and ovalbumin-induced allergic airway disease. Molecular mechanisms were defined by co-immunoprecipitation and ubiquitination assays.</div></div><div><h3>Results</h3><div>SMURF2 was markedly upregulated in patient samples and stimulated mast cells. SMURF2 positively regulated IgE-dependent mast cell activation <em>in vitro</em>. Mast cell–specific <em>Smurf2</em> deficiency attenuated passive systemic anaphylaxis and ovalbumin-induced allergic airway disease. Mechanistically, SMURF2 interacted with NEDD4L and promoted its K27-linked ubiquitination and proteasomal degradation, thereby enhancing Syk-mediated FcεRI signaling.</div></div><div><h3>Conclusions</h3><div>SMURF2 is a critical positive regulator of mast cell activation and allergic responses by targeting NEDD4L for degradation to amplify Syk signaling. SMURF2 represents a potential diagnostic marker and therapeutic target for allergic diseases.</div></div>","PeriodicalId":14936,"journal":{"name":"Journal of Allergy and Clinical Immunology","volume":"158 4","pages":"Pages 1101-1116"},"PeriodicalIF":11.7,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148239339","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":"Selective elimination of mast cells via Siglec-6–targeted nanodelivery of drug payload","authors":"Ariel Helms Thames MD, PhD,&nbsp;Clayton H. Rische PhD,&nbsp;Rebecca A. Krier-Burris MS,&nbsp;Yun Cao MS,&nbsp;Andrew C. Hunt PhD,&nbsp;Natalie R. Klug,&nbsp;Stephanie R. Zelenetz PhD,&nbsp;Evan R. Burleigh,&nbsp;Rochelle Aw PhD,&nbsp;Derek A. Wong PhD,&nbsp;Zachary M. Shaver PhD,&nbsp;Kosuke Seki PhD,&nbsp;Laura Guerrero PhD,&nbsp;Regina Fernandez,&nbsp;Swagat Sharma PhD,&nbsp;Bruce S. Bochner MD,&nbsp;Michael C. Jewett PhD,&nbsp;Evan A. Scott PhD,&nbsp;Jeremy A. O’Sullivan PhD","doi":"10.1016/j.jaci.2026.05.033","DOIUrl":"10.1016/j.jaci.2026.05.033","url":null,"abstract":"<div><h3>Background</h3><div>Mast cell elimination through sialic acid immunoglobulin-like lectin 6 (Siglec-6) is a promising, yet minimally explored strategy for diseases characterized by mast cell overactivity or overproduction.</div></div><div><h3>Objective</h3><div>We combined nanotechnology with cell-free protein synthesis to develop a therapeutic strategy (anti–Sig6-NPmidoFab) for selectively eliminating mast cells.</div></div><div><h3>Methods</h3><div>Nanocarriers are loaded with the protein kinase inhibitor midostaurin and conjugated with cell-free protein synthesis-enabled clickable, synthetically dimerized anti–Siglec-6 antibody fragments to selectively target Siglec-6–expressing mast cells.</div></div><div><h3>Results</h3><div>Using human mast cell lines and primary human mast cells as well as a Siglec-6 knock-in mouse model and a humanized mast cell malignancy mouse model, we demonstrated selective elimination of Siglec-6–positive mast cells with reduced off-target effects on Siglec-6–negative cells.</div></div><div><h3>Conclusion</h3><div>This approach offers new treatment strategies for malignant and nonmalignant mast cell–mediated disease with potential for broad application.</div></div>","PeriodicalId":14936,"journal":{"name":"Journal of Allergy and Clinical Immunology","volume":"158 4","pages":"Pages 1073-1084"},"PeriodicalIF":11.7,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148349064","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":"Common γ-chain cytokines induce an epigenomically plastic precursor-like KIT+ ILC2 state linked to immune disease susceptibility","authors":"Simone E.M. Olsthoorn MSc,&nbsp;Anne Onrust-Van Schoonhoven MSc,&nbsp;Marjolein J.W. de Bruijn BSc,&nbsp;Jochem Weekers MSc,&nbsp;Menno van Nimwegen BSc,&nbsp;Gregory van Beek BSc,&nbsp;Willem de Koning PhD,&nbsp;Lianne Trap MSc,&nbsp;Esmee K. van der Ploeg PhD,&nbsp;Geert H. van Weelden MSc,&nbsp;Mathijs A. Sanders PhD,&nbsp;Laura Surace PhD,&nbsp;James P. Di Santo PhD,&nbsp;Rudi W. Hendriks PhD,&nbsp;Ralph Stadhouders PhD","doi":"10.1016/j.jaci.2026.05.029","DOIUrl":"10.1016/j.jaci.2026.05.029","url":null,"abstract":"<div><h3>Background</h3><div>Group 2 innate lymphoid cells (ILC2s) are key effector cells of type 2 immunity. A subset of ILC2s, which expresses KIT (CD117), display increased phenotypic plasticity and have previously been linked to severe asthma and psoriasis. However, the molecular mechanisms promoting a KIT⁺ ILC2 state remain poorly understood.</div></div><div><h3>Objective</h3><div>We defined the molecular basis for the enhanced plasticity of KIT⁺ ILC2s and identified signals that induce this phenotype, including links with immune disease susceptibility.</div></div><div><h3>Methods</h3><div>We combined bulk as well as single-cell transcriptome (RNA sequencing) and epigenome (assay for transposase-accessible chromatin using sequencing) analysis with <em>in vitro</em> culture assays using primary human KIT⁺ or KIT^neg ILC2s and multipotent ILC progenitors. Epigenomic data were integrated with genetic risk variants for major human immune diseases.</div></div><div><h3>Results</h3><div>Multiomic analyses revealed that KIT⁺ ILC2s maintain a unique hybrid character marked by expression and open chromatin of genes linked to both ILC progenitors and ILC2 biology. KIT⁺ ILC2s showed extensive epigenomic priming at gene loci related to naive lymphocyte biology, tissue homing, and ILC3 effector functions, including <em>IL17</em> and <em>IL23R</em>—explaining why KIT⁺ ILC2s are poised to adopt an ILC3-like phenotype. Genetic risk variants for asthma and autoimmunity are enriched in the poised epigenome of KIT⁺ ILC2s. Common γ-chain cytokines IL-2/IL-7 induced and maintained a KIT⁺ phenotype in KIT^neg ILC2s through STAT5 activation.</div></div><div><h3>Conclusions</h3><div>Our study defines KIT⁺ ILC2s as existing in a developmentally immature state and carrying a precursor-like epigenome that promotes phenotypic plasticity and is linked to immune disease susceptibility. Importantly, we identify STAT5-mediated cytokine signals as candidates for therapeutic targeting of KIT⁺ ILC2s.</div></div>","PeriodicalId":14936,"journal":{"name":"Journal of Allergy and Clinical Immunology","volume":"158 4","pages":"Pages 1117-1132"},"PeriodicalIF":11.7,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148271696","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":"Site-Specific Cutaneous Inflammation: Mechanisms and Therapeutic Implications","authors":"Sahiti Marella,Shuai Shao,Lam C. Tsoi,Shruti Naik,Bogi Andersen,Heidi H. Kong,Maksim V. Plikus,Muzlifah Haniffa,Johann E. Gudjonsson","doi":"10.1016/j.jaci.2026.09.026","DOIUrl":"https://doi.org/10.1016/j.jaci.2026.09.026","url":null,"abstract":"","PeriodicalId":14936,"journal":{"name":"Journal of Allergy and Clinical Immunology","volume":"16 1","pages":""},"PeriodicalIF":14.2,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149209270","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":"News & Notes-AAAAI","authors":"","doi":"10.1016/S0091-6749(26)00603-2","DOIUrl":"10.1016/S0091-6749(26)00603-2","url":null,"abstract":"","PeriodicalId":14936,"journal":{"name":"Journal of Allergy and Clinical Immunology","volume":"158 4","pages":"Pages A22-A23"},"PeriodicalIF":11.7,"publicationDate":"2026-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149095603","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":"Autosomal recessive HOXA3 deficiency causes congenital athymia and laryngeal malformation.","authors":"Sarah S Dinges, Marita Bosticardo, Anke Hirschfelder, Francesca Pala, Johannes Kopp, Viktor Glaser, Johannes Gru Nhagen, Giuseppe Sangiorgio, Lisa Ehlers, Pawel Durek, Olga Staudacher, Mirjam Völler, Austen Worth, Uwe Kölsch, Zainab M Golwala, Nadine Unterwalder, Erwin Lankes, Karl-Ulrich Schunck, Frederik Heinrich, Kayla Amini, Stavros Loukogeorgakis, Evey Howley, Heather Kenney, Hendrik S Fischer, Sven C Weber, Oliver Blankenstein, Christian Meisel, Anke Wendt, Harald Stachelscheid, Angela Kaindl, Christoph Bu Hrer, Anita Balázs, Mir-Farzin Mashreghi, Julia K Polansky, Dimitrios L Wagner, E Graham Davies, Marcus A Mall, Alexandra Y Kreins, Luigi D Notarangelo, Horst von Bernuth","doi":"10.1016/j.jaci.2026.09.010","DOIUrl":"https://doi.org/10.1016/j.jaci.2026.09.010","url":null,"abstract":"<p><strong>Background: </strong>Approximately 10% of patients with Severe Combined Immunodeficiency (SCID) phenotype lack a known genetic cause. In particular, the molecular basis of thymic defects is poorly understood. Homeobox (HOX) genes encode conserved transcription factors that control spatial body development. The function of human HOXA3 is undefined.</p><p><strong>Objective: </strong>We characterize the first human with HOXA3 deficiency and investigate the role of HOXA3 in immune system development.</p><p><strong>Methods: </strong>We performed clinical and immunological phenotyping, as well as genetic sequencing. A homozygous nonsense variant in HOXA3 was identified, and functionally validated including RT-PCR, western blot, assessment of transcriptional activity and intracellular localization of HOXA3. We report clinical management and course.</p><p><strong>Results: </strong>The homozygous HOXA3 nonsense variant generates a truncated protein with cytoplasmic retention and reduced transcriptional activity. The clinical phenotype includes craniofacial and cervical anomalies, severe laryngopharyngeal malformation with epiglottic hypoplasia causing dysphagia and aspiration, central breathing disorder, and thymus aplasia. T-cell maturation in artificial thymic organoids (ATO) and recovery after thymus transplantation establish the T-cell defect as non-hematopoietic.</p><p><strong>Conclusion: </strong>Human HOXA3 has non-redundant roles for the development of larynx and thymus. HOXA3 deficiency is a novel, life-threatening multisystem disorder. It is the first human Homeobox-gene disease causing congenital athymia. These findings expand the diagnostic gene panel for patients with a SCID phenotype and indicate epiglottic hypoplasia as a new specific co-morbidity of congenital athymia.</p><p><strong>Key messages: </strong>Homeobox A3 (HOXA3) deficiency is a novel cause of congenital athymia, characterized by craniofacial and cervical anomalies, and life-threatening laryngeal malformation. Human HOXA3, unlike murine Hoxa3, may be redundant for parathyroid and thyroid gland development. The loss of the homeodomain causes cytoplasmic retention of the HOXA3 protein, leading to reduced transcriptional activity.</p><p><strong>Capsule summary: </strong>We describe HOXA3 deficiency as the 8^th genetically defined cause of congenital athymia, facilitating life-saving thymus transplantation for future patients. Life-threatening laryngeal malformations provide a clinical diagnostic clue for congenital athymia.</p>","PeriodicalId":14936,"journal":{"name":"Journal of Allergy and Clinical Immunology","volume":" ","pages":""},"PeriodicalIF":11.7,"publicationDate":"2026-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149074942","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 signatures preceding serious asthma exacerbations among non-Hispanic Black individuals.","authors":"Baojun Wu, Mao Yang, Donglei Hu, Samantha Hochstadt, David E Lanfear, Jonathan Witonsky, Esteban G Burchard, Elad Ziv, L Keoki Williams","doi":"10.1016/j.jaci.2026.08.024","DOIUrl":"https://doi.org/10.1016/j.jaci.2026.08.024","url":null,"abstract":"","PeriodicalId":14936,"journal":{"name":"Journal of Allergy and Clinical Immunology","volume":" ","pages":""},"PeriodicalIF":11.7,"publicationDate":"2026-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149074639","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":"Mepolizumab long-term remodeling effect in severe asthma responders: The MESILICO study.","authors":"Konstantinos Porpodis, Ioanna Tsiouprou, Petros Bakakos, Grigoris Stratakos, Argyrios Tzouvelekis, Paschalis Steiropoulos, Konstantinos Katsoulis, Konstantinos Kostikas, Katerina M Antoniou, Andriana I Papaioannou, Nikoletta Rovina, Paraskevi Katsaounou, Nicoleta Pastelli, Stavros Tryfon, Evangelia Fouka, Nikolaos Tzanakis, Stelios Loukides, Kalliopi Domvri","doi":"10.1016/j.jaci.2026.08.029","DOIUrl":"10.1016/j.jaci.2026.08.029","url":null,"abstract":"<p><strong>Background: </strong>The MESILICO (Efficacy of Mepolizumab in patients with latE-onset Severe eosInophiLic asthma and fIxed obstruCtiOn) study has provided evidence on the effect of mepolizumab, an anti-IL-5 biologic, on airway remodeling in patients with severe asthma at 12 months posttreatment.</p><p><strong>Objective: </strong>We sought to investigate the longer-term effect of mepolizumab on airway structural remodeling.</p><p><strong>Methods: </strong>Forty-seven patients were recruited, who initiated mepolizumab (100 mg mepolizumab subcutaneously), of whom 41 were enrolled in the bronchoscopy substudy. At 3 years, the participants underwent further bronchoscopic airway sampling, and remodeling indices were measured along with submucosal eosinophils, tissue immunoexpression of mucin 5AC, E-cadherin, and number of FOXP3⁺ cells.</p><p><strong>Results: </strong>Thirty-five of the initial 47 patients in the cohort completed 3 years of treatment, associated with significant improvements in lung function and biomarkers and a decrease in exacerbation events (P < .05). Twenty-five of the 41 patients enrolled in the substudy were submitted to bronchoscopy after 3 years of treatment. There was a significant sustained reduction from baseline in subbasement membrane thickness, airway smooth muscle area, airway smooth muscle layer thickness, and epithelial damage, as well as a decrease in the number of tissue eosinophils (all P < .001). Additional improvements were seen at 3 years for mucin 5AC and E-cadherin histoscores and FOXP3⁺ regulatory-like cells.</p><p><strong>Conclusions: </strong>This is the first study supporting the possibility that sustained IL-5 blockade may contribute to long-term structural airway improvement and may be consistent with disease modification in severe eosinophilic asthma.</p>","PeriodicalId":14936,"journal":{"name":"Journal of Allergy and Clinical Immunology","volume":" ","pages":""},"PeriodicalIF":11.7,"publicationDate":"2026-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149074118","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":"Leniolisib and rapamycin in activated PI3Kδ syndrome: Retrospective European Society for Immunodeficiencies registry-based analysis.","authors":"Beatrice Rivalta, Martin Wolkewitz, Maaike Kusters, Annette Uhlmann, Valentina Guarnieri, Wadih Abou-Chahla, Dalila Adjaoud, Nathalie Aladjidi, Corinne Armari-Alla, Saba Azarnoush, Safa Baris, Vincent Barlogis, Federica Barzaghi, Ulrich Baumann, Marketa Bloomfield, Damien Bodet, David Boutboul, Valentina Boz, Selcen Bozkurt, Giorgia Bucciol, Caterina Cancrini, Emilie Catherinot, Marina Cavazzana, Morgane Cheminant, Matteo Chinello, Peter Ciznar, Francesca Conti, Giorgio Costagliola, Virgil Dalm, Maud D'Aveni-Piney, Olov Ekwall, Efrem Eren, Zelimir Eric, Evangelia Farmaki, Anders Fasth, Claire Fieschi, Alain Fischer, Benjamin Fournier, Lionel Galicier, Sujal Ghosh, Antonios Gkantaras, Yves Hatchuel, Anna Hilfanova, Manfred Hoenig, Eric Jeziorski, Stephen Jolles, Elif Karakoc-Aydiner, Sara S Kilic, Ayca Kiykim, Julia Körholz, Guillaume Le Guenno, Francesco Licciardi, Lorenzo Lodi, Vassilios Lougaris, José Manuel Lucena, Marion Malphettes, Antonio Marzollo, Tania N Masmas, Andrea Meinhardt, Etienne Merlin, Isabelle Meyts, Tomas Milota, Mattia Moratti, Nabila Moussouni, Olaf Neth, Christopher Nunes-Gomes, Süheyla Ocak, Peter Olbrich, Esra Özek Yücel, Ahmet Özen, Jana Pachlopnik Schmid, Paolo Palma, Isabelle Pellier-Landreau, Antoinette Perlat, Capucine Picard, Seraina Prader, Silvia Ricci, Jacques Riviere, Veronica Santilli, Francoise Sarrot-Reynauld, Nicolas Schleinitz, Rik Schrijvers, Ansgar Schulz, Catharina Schuetz, Anna Sediva, Michaela Semeraro, Svetlana Sharapova, Georgios Sogkas, Maarja Soomann, Pere Soler-Palacín, Felipe Suarez, Giulio Tessarin, Alberto Tommasini, Johannes Trück, Koen van Aerde, Joris van Montfrans, Clementien Vermont, Katharina Wustrau, Yulia Zharankova, Despina Moshous, Bénédicte Neven, Markus G Seidel, Anita Chandra, Julian Thalhammer, Sven Kracker, Stephan Ehl, Nizar Mahlaoui, Reem Elfeky, Maria Elena Maccari","doi":"10.1016/j.jaci.2026.09.014","DOIUrl":"10.1016/j.jaci.2026.09.014","url":null,"abstract":"<p><strong>Background: </strong>Activated PI3Kδ syndrome (APDS) is a rare inborn error of immunity characterized by variable immune dysregulation, recurrent infections, and increased risk of malignancy. Clinical management is challenging. Rapamycin has been widely used off-label to control immune dysregulation, while the selective PI3Kδ (phosphatidylinositol 3-kinase delta) inhibitor leniolisib has recently become available as a disease-specific targeted therapy. Real-world data on these treatment approaches remain limited.</p><p><strong>Objective: </strong>We assessed real-world treatment indications, clinical course, immunologic changes, and tolerability in patients with APDS treated with rapamycin and leniolisib.</p><p><strong>Methods: </strong>We performed a retrospective analysis of the European Society for Immunodeficiencies APDS registry including 95 APDS patients, 81 treated with rapamycin and/or 28 with leniolisib through a Managed Access Program. Clinical manifestations, immunologic parameters, and treatment-associated complications were assessed.</p><p><strong>Results: </strong>Lymphoproliferation was the predominant indication (81% and 52%, respectively) for treatment initiation. Overall responses (complete or partial) were observed in 67% of rapamycin- and 64% of leniolisib-treated patients. Across other disease manifestations, responses were documented in 35% and 50% of patients. Leniolisib was initiated for recurrent infections in 3 patients, whereas recurrent infections were not a primary indication for rapamycin. Treatment interruption due to adverse events occurred only in the rapamycin group. Lymphoma cases were observed during follow-up.</p>","PeriodicalId":14936,"journal":{"name":"Journal of Allergy and Clinical Immunology","volume":" ","pages":""},"PeriodicalIF":11.7,"publicationDate":"2026-09-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149074854","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}