Journal of Allergy and Clinical Immunology最新文献

{"title":"Abatacept restores dysregulated transcriptomic and proteomic profile in disorders of CTLA-4 insufficiency","authors":"Mehmet Cihangir Catak MSc ,&nbsp;Naz Surucu PhD ,&nbsp;Feyza Bayram Catak MSc ,&nbsp;Altan Kara PhD ,&nbsp;Selin Cildir BSc ,&nbsp;Royala Babayeva MD ,&nbsp;Basak Kayaoglu PhD ,&nbsp;Alper Bulutoglu MSc ,&nbsp;Baran Erman PhD ,&nbsp;Ibrahim Serhat Karakus MD ,&nbsp;Ahmad Al-Shaibi MSc ,&nbsp;Satanay Hubrack MSc ,&nbsp;Esra Karabiber MD ,&nbsp;Figen Celebi Celik MD ,&nbsp;Gamze Akgun BSc ,&nbsp;Dilek Baser MSc ,&nbsp;Sevgi Bilgic Eltan MD ,&nbsp;Asena Pinar Sefer MD ,&nbsp;Selcen Bozkurt MD ,&nbsp;Necmiye Ozturk MD ,&nbsp;Safa Baris MD","doi":"10.1016/j.jaci.2025.08.027","DOIUrl":"10.1016/j.jaci.2025.08.027","url":null,"abstract":"<div><h3>Background</h3><div>Lipopolysaccharide-responsive beige-like anchor (LRBA) deficiency and cytotoxic T lymphocyte–associated protein 4 (CTLA-4) insufficiency are rare primary immune dysregulation disorders. Both conditions result from impaired maintenance of CTLA-4, a critical inhibitory checkpoint molecule. Despite the known benefits of abatacept (a CTLA-4–Ig fusion protein) treatment, its precise immunologic effects remain unclear.</div></div><div><h3>Objective</h3><div>We comprehensively investigated the effect of abatacept therapy on patients with LRBA deficiency and CTLA-4 insufficiency using an integrative multiomics approach.</div></div><div><h3>Methods</h3><div>The study combined longitudinal flow cytometry, targeted and single-cell transcriptomics, and plasma proteomics in patients receiving abatacept treatment.</div></div><div><h3>Results</h3><div>Abatacept treatment increased thymic output and expansion of naive T and B cells while reducing memory T-cell subsets, CD4⁺ T-cell cytokine production, and CD21^low B cells. Multimodal transcriptomic and proteomic analyses revealed previously unrecognized immunopathogenic mechanisms, including increased CD28 and T-cell receptor signaling as well as compensatory upregulation of inhibitory checkpoint proteins (LAG3, TIGIT, ADORA2A, VSIR, HAVCR2) in response to CTLA-4 insufficiency. Proteomic profiling confirmed the upregulation of inflammatory mediators, including CHI3L1, CXCL13, and CSF1. Most of these transcriptomic and proteomic abnormalities were reversed after abatacept therapy; notably, gene signatures derived from lymphocytes exhibited greater normalization than those associated with myeloid cells. Furthermore, identified shared and disease-specific molecular signatures distinguished LRBA-deficient patients from those with CTLA-4 insufficiency, revealing more severe immune dysregulation in LRBA deficiency. Single-cell RNA sequencing validated the reversal of checkpoint dysregulation and the expression of inflammation-related genes across lymphoid and myeloid lineages.</div></div><div><h3>Conclusion</h3><div>Abatacept effectively corrects key immune circuits in both diseases. This integrative systems-level approach offers new mechanisms and therapeutic targets, supporting personalized intervention strategies.</div></div>","PeriodicalId":14936,"journal":{"name":"Journal of Allergy and Clinical Immunology","volume":"156 6","pages":"Pages 1725-1742"},"PeriodicalIF":11.2,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145083513","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":"Information for Readers","authors":"","doi":"10.1016/S0091-6749(25)01086-3","DOIUrl":"10.1016/S0091-6749(25)01086-3","url":null,"abstract":"","PeriodicalId":14936,"journal":{"name":"Journal of Allergy and Clinical Immunology","volume":"156 6","pages":"Page A15"},"PeriodicalIF":11.2,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145659075","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":"Kinetics of epitope-specific IgE and IgG4 in early peanut allergy development and resolution","authors":"Mayte Suárez-Fariñas PhD ,&nbsp;Kyung Won Lee PhD ,&nbsp;Maria Suprun PhD ,&nbsp;Henry T. Bahnson MS ,&nbsp;Ru-Xin Foong MBBS, PhD ,&nbsp;George Du Toit MB BCh ,&nbsp;Gideon Lack MB BCh ,&nbsp;Hugh A. Sampson MD","doi":"10.1016/j.jaci.2025.06.022","DOIUrl":"10.1016/j.jaci.2025.06.022","url":null,"abstract":"<div><h3>Background</h3><div>The development and resolution of peanut allergy (PA) was evaluated in children enrolled or screened for the Learning Early About Peanut (LEAP) intervention trial. The development of epitope-specific (es) IgE and es-IgG₄ antibodies was evaluated in a subset of these children to determine whether their PA status could be predicted at 4-11 months of age.</div></div><div><h3>Methods</h3><div>Sera from 386 children enrolled or screened as part of the LEAP trial were assayed at 4-11 months (baseline) and 60 months of age, and final allergy status was established by oral food challenge at 60 months. Es-IgE and es-IgG₄ to 64 informative peanut epitopes were analyzed by linear mixed-effect models, and machine learning was used to develop a predictive algorithm.</div></div><div><h3>Results</h3><div>Children were categorized in 4 groups: 37 developed PA early that persisted (EP), 17 developed PA early that resolved (ER), 33 developed PA later in childhood (by 60 months of age, LA), and 298 never developed PA. Differences among groups in es-IgE and es-IgG₄ were detectable at baseline. ER showed lower levels of Ara h 2_008 es-IgE and higher es-IgG₄ levels to several epitopes compared to the EP group. Both EP and ER groups had greater levels of several baseline es-IgE antibodies compared to the LA group. By 60 months, all 3 groups had significant increases in both the levels and diversity of es-IgG₄ antibodies, while es-IgE antibodies increased only in EP and LA groups and decreased in ER group. Machine learning models were predictive of persistent allergy by 60 months of age, with an average area under the curve in testing of 0.75.</div></div><div><h3>Conclusions</h3><div>These results suggest that baseline es-IgE in children sensitized in the first year of life can predict likely persistent PA.</div></div>","PeriodicalId":14936,"journal":{"name":"Journal of Allergy and Clinical Immunology","volume":"156 6","pages":"Pages 1639-1649"},"PeriodicalIF":11.2,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144547902","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":"Prostaglandin I2 signaling restrains Treg cell ST2 expression by repressing β-catenin in allergic airway inflammation","authors":"Allison E. Norlander PhD ,&nbsp;Masako Abney MS ,&nbsp;Jian Zhang MS ,&nbsp;Vasiliy V. Polosukhin MD, PhD ,&nbsp;Christopher M. Thomas BS ,&nbsp;Zachary J. Ceneviva BS ,&nbsp;Raghad AlMotairy BS ,&nbsp;Rahi Patel ,&nbsp;Jacqueline-Yvonne Cephus MS ,&nbsp;Shinji Toki PhD ,&nbsp;Weisong Zhou PhD ,&nbsp;Talal A. Chatila MD ,&nbsp;Dawn C. Newcomb PhD ,&nbsp;R. Stokes Peebles Jr. MD","doi":"10.1016/j.jaci.2025.07.028","DOIUrl":"10.1016/j.jaci.2025.07.028","url":null,"abstract":"<div><h3>Background</h3><div>T regulatory (Treg) cells dampen immune activation. Treg cells downregulate the type 2 response to innocuous environmental antigens that produce allergic airway inflammation; however, ST2-positive Treg cells promote allergic airway inflammation. Prostaglandin I₂ (PGI₂), which signals through the G protein–coupled receptor IP, promotes Treg cell function in an ovalbumin-based model of allergic airway inflammation, suggesting a role for PGI₂ signaling through the IP receptor augmenting β-catenin activity in Treg cells.</div></div><div><h3>Objective</h3><div>We sought to define the mechanisms responsible for PGI₂’s promotion of Treg cell function in the context of an environmental allergen.</div></div><div><h3>Methods</h3><div>Treg cell–specific IP-deficient mice, Treg cell fate-tracking IP-deficient mice, and Treg cell–specific IP- and β-catenin–deficient mice were exposed to an <em>Alternaria alternata</em> extract sensitization and challenge model. Bronchoalveolar lavage fluid was evaluated for cell number, cell differential, and cytokines by ELISA. Lungs were evaluated by flow cytometry and histopathology.</div></div><div><h3>Results</h3><div>Utilizing Treg cell–specific IP-deficient mice, we found that loss of PGI₂ signaling impaired Treg cell–suppressive function in response to <em>A alternata;</em> specifically, we found enhanced type 2 cytokine production, eosinophil infiltration, vascular remodeling, and numbers of ST2-positive Treg cells compared to controls. We found that dual IP and β-catenin deficiency in Treg cells prevented the enhanced type 2 response and the further increase in ST2-positive Treg cells via prevention of an increase in GATA3 expression in response to <em>A alternata.</em></div></div><div><h3>Conclusions</h3><div>Together, these data further support the importance of PGI₂ signaling within Treg cells to their support functionality and demonstrate that PGI₂ prevents Treg cell dysfunction through downregulation of β-catenin.</div></div>","PeriodicalId":14936,"journal":{"name":"Journal of Allergy and Clinical Immunology","volume":"156 6","pages":"Pages 1679-1692.e9"},"PeriodicalIF":11.2,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144851146","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":"Artificial intelligence biomarker detects high-risk childhood asthma subgroup for respiratory infections and exacerbations","authors":"Young J. Juhn MD, MPH ,&nbsp;Chung-Il Wi MD ,&nbsp;Euijung Ryu PhD ,&nbsp;Katherine S. King MS ,&nbsp;Sunghwan Sohn PhD ,&nbsp;Elham Sagheb MS ,&nbsp;Greg Jenkins MS ,&nbsp;David Watson PhD ,&nbsp;Miguel A. Park MD ,&nbsp;Sergio E. Chiarella MD ,&nbsp;Hirohito Kita MD ,&nbsp;Mir Ali MD ,&nbsp;W. Charles Huskins MD ,&nbsp;Elizabeth H. Ristagno MD ,&nbsp;Imad Absah MD ,&nbsp;Charles Grose MD ,&nbsp;Kathy Ihrke RN ,&nbsp;Elizabeth A. Krusemark AS ,&nbsp;Thanai Pongdee MD ,&nbsp;Björn Nordlund PhD ,&nbsp;Hongfang Liu PhD","doi":"10.1016/j.jaci.2025.07.031","DOIUrl":"10.1016/j.jaci.2025.07.031","url":null,"abstract":"<div><h3>Background</h3><div>Asthma is associated with an increased risk of acute respiratory infections (ARI). Little is known about whether natural language processing (NLP)-powered digital biomarkers can identify a high-risk asthma subgroup for ARI during early childhood.</div></div><div><h3>Objective</h3><div>We assessed whether a digital biomarker could identify a high-risk subgroup of childhood asthma for ARI.</div></div><div><h3>Methods</h3><div>We applied validated NLP algorithms for Predetermined Asthma Criteria (NLP-PAC) and Asthma Predictive Index (NLP-API) to electronic health records of the 1997-2016 Mayo Clinic Birth Cohort. We categorized the cohort into 4 subgroups: both criteria positive (NLP⁻PAC⁺/NLP⁻API⁺), PAC positive only (NLP⁻PAC⁺), API positive only (NLP⁻API⁺), and both criteria negative (NLP⁻PAC⁻/NLP⁻API⁻). We assessed the risk of 5 medically attended ARI (pneumonia, frequent group A streptococcal pharyngeal infection, <em>Bordetella pertussis,</em> influenza A/B, and respiratory syncytial virus infection) and asthma exacerbation defined by NLP algorithms at 3 years of age among the 4 subgroups. We also examined whether such associations emerged during the first 3 years of life.</div></div><div><h3>Results</h3><div>There were 22,370 eligible subjects (51% male and 81% White). The NLP⁻PAC⁺/NLP⁻API⁺ subgroup had the highest risk of pneumonia, influenza A/B, and asthma exacerbation compared to other groups. No significant differences were found in other ARI. The same subgroup had the highest occurrence of pneumonia, influenza A/B, and respiratory syncytial virus infection, compared to other groups, during the first 3 years of life.</div></div><div><h3>Conclusion</h3><div>NLP⁻PAC⁺/NLP⁻API⁺ can be a novel digital biomarker for a high-risk subgroup of childhood asthma for pneumonia, influenza A/B, and asthma exacerbation. This phenotype may emerge early in life.</div></div>","PeriodicalId":14936,"journal":{"name":"Journal of Allergy and Clinical Immunology","volume":"156 6","pages":"Pages 1547-1555.e4"},"PeriodicalIF":11.2,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144930466","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":"Long-term prophylactic treatment with deucrictibant for angioedema due to acquired C1-inhibitor deficiency","authors":"Mats de Lange MD,&nbsp;Remy S. Petersen MD, PhD,&nbsp;Lauré M. Fijen MD, PhD,&nbsp;Danny M. Cohn MD, PhD","doi":"10.1016/j.jaci.2025.07.033","DOIUrl":"10.1016/j.jaci.2025.07.033","url":null,"abstract":"<div><h3>Background</h3><div>Angioedema due to acquired C1-inhibitor deficiency (AAE-C1INH) is a rare disorder characterized by recurrent episodes of angioedema due to excessive bradykinin release. Deucrictibant, an oral B2 receptor antagonist, is currently under development for long-term prophylactic and on-demand treatment in hereditary angioedema. In a recent small double-blind, placebo-controlled crossover trial (EudraCT no. 2021-000720-36), all 3 participants with AAE-C1INH had complete control of angioedema during 8 weeks of treatment with deucrictibant immediate-release capsule.</div></div><div><h3>Objective</h3><div>We investigated the long-term efficacy and safety of deucrictibant extended-release tablet as prophylactic treatment in patients with AAE-C1INH.</div></div><div><h3>Methods</h3><div>In this open-label, single-arm study, patients with AAE-C1INH received deucrictibant 40 mg extended-release tablet once daily. The primary end point was the time-normalized number of investigator-confirmed angioedema attacks per 28 days of exposure to deucrictibant compared to baseline.</div></div><div><h3>Results</h3><div>Four patients with AAE-C1INH were enrolled, 3 of whom were rolled over from the randomized controlled trial of immediate-release deucrictibant. The on-treatment follow-up duration in this study ranged from 563 to 612 days. The mean monthly attack rates at baseline were 1.2, 1.2, 0.9, and 2.1, respectively (mean, 1.35). One mild abdominal attack was reported by one patient 2 days after initiation of deucrictibant treatment; the remaining patients were attack-free during the treatment period. The mean monthly angioedema attack rate for all patients was 0.01. No treatment-related adverse events were reported.</div></div><div><h3>Conclusion</h3><div>Deucrictibant extended-release tablet effectively prevented angioedema attacks in patients with AAE-C1INH, with no safety concerns.</div></div>","PeriodicalId":14936,"journal":{"name":"Journal of Allergy and Clinical Immunology","volume":"156 6","pages":"Pages 1650-1655"},"PeriodicalIF":11.2,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144955022","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":"Impact of race-based spirometry equations on guideline-based asthma management in clinical trials","authors":"Cynthia M. Visness PhD ,&nbsp;Christine A. Sorkness PharmD ,&nbsp;Ronald Sorkness PhD ,&nbsp;Peter J. Gergen MD ,&nbsp;Michael Nodzenski PhD ,&nbsp;Daniel J. Jackson MD ,&nbsp;National Institute of Allergy and Infectious Diseases–sponsored Childhood Asthma in Urban Settings Network","doi":"10.1016/j.jaci.2025.08.012","DOIUrl":"10.1016/j.jaci.2025.08.012","url":null,"abstract":"<div><h3>Background</h3><div>The American Thoracic Society recently recommended that race- and ethnicity-specific equations for spirometry be replaced with race-neutral equations. This change could have implications for asthma management.</div></div><div><h3>Objective</h3><div>Our aim was to examine the effect of race-specific versus race-neutral spirometry reference equations on the resultant guideline-directed asthma therapy in a study population with a high proportion of Black children.</div></div><div><h3>Methods</h3><div>We pooled and harmonized data on 2076 children and adolescents across 4 Inner-City Asthma Consortium studies that had all used a computer-asssisted algorithm for management of asthma medication. The asthma control level was recalculated, first by using the percent predicted FEV₁ values derived from the 2012 race-specific equations and then by using those derived from the Global Lung Initiative GLI Global race-neutral equations. The calculated control level was then used to determine the recommendation for treatment step changes.</div></div><div><h3>Results</h3><div>Among urban Black children not already at the highest recommended inhaled corticosteroid doses, 18% would have been assigned a higher medication step at study entry when using the race-neutral rather than race-specific reference equations to assess asthma control. A very small number of children in other race or ethnicity groups had a recommendation for a higher medication step.</div></div><div><h3>Conclusion</h3><div>The transition to use of race-neutral values for measures of lung function has the potential to reduce racial bias in diagnosing and treating asthma.</div></div>","PeriodicalId":14936,"journal":{"name":"Journal of Allergy and Clinical Immunology","volume":"156 6","pages":"Pages 1752-1755"},"PeriodicalIF":11.2,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144954567","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":"Genetic determinants of the complement and coagulation pathways in invasive meningococcal disease","authors":"Evangelos Bellos PhD ,&nbsp;Karin van Leeuwen ,&nbsp;Amedine Duret MBBChir ,&nbsp;Stephanie Hodeib PhD ,&nbsp;Meg Mashbat PhD ,&nbsp;Daniela S. Kohlfuerst PhD ,&nbsp;Navin P. Boeddha PhD ,&nbsp;Luregn J. Schlapbach PhD ,&nbsp;Victoria J. Wright PhD ,&nbsp;Colin G. Fink PhD ,&nbsp;Michiel van der Flier PhD ,&nbsp;Marcel van Deuren PhD ,&nbsp;Tom Sprong PhD ,&nbsp;Margarita López-Trascasa PhD ,&nbsp;Alberto López-Lera PhD ,&nbsp;Federico Martinón-Torres PhD ,&nbsp;Antonio Salas PhD ,&nbsp;Dilys Santillo ,&nbsp;Werner Zenz PhD ,&nbsp;Gertjan J. Driessen PhD ,&nbsp;Isabel Delany","doi":"10.1016/j.jaci.2025.09.011","DOIUrl":"10.1016/j.jaci.2025.09.011","url":null,"abstract":"<div><h3>Background</h3><div>The complement and coagulation pathways are implicated in the systemic manifestations of invasive meningococcal disease (MD). However, the genetic landscape of these 2 interconnected plasma proteolytic pathways has not been systematically explored.</div></div><div><h3>Objective</h3><div>We sought to investigate how genetic variation in the complement and coagulation pathways contributes to invasive MD.</div></div><div><h3>Methods</h3><div>Whole-exome sequencing (WES) and high-coverage amplicon-based sequencing were performed in a large series of 229 patients with MD. A group of 275 patients with other invasive bacterial infections was used as a control cohort.</div></div><div><h3>Results</h3><div>WES data showed an enrichment of rare variants in the complement and coagulation genes in MD, namely, <em>CFP</em> and <em>FCGR2A</em>. In a subcohort of severe MD, <em>CFP</em> and <em>SERPINE1</em> were enriched for rare variants compared with the control cohort. Combining the amplicon panel and the WES data sets, 1 mild hemophilia A case, 5 properdin mutated individuals, and 4 digenic complement deficiencies were identified. In addition, a significant copy number variant association in the <em>CFH</em>/<em>CFHR1-5</em> gene cluster was reported. This provides strong support for the role of complement regulation in MD. Furthermore, there are pathogenic variants in <em>VWF</em>, <em>PROS1</em>, <em>and SERPINC1</em>, relevant to coagulation and fibrinolysis.</div></div><div><h3>Conclusions</h3><div>The study demonstrates the value of a mechanistic pathway approach to describe the genetic landscape of infectious disease, particularly in understanding its course and outcome. Notably, we identify complement-mediated thrombotic microangiopathy as a key pathophysiologic mechanism involved, particularly in MD.</div></div>","PeriodicalId":14936,"journal":{"name":"Journal of Allergy and Clinical Immunology","volume":"156 6","pages":"Pages 1743-1751.e4"},"PeriodicalIF":11.2,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145127026","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":"Bruton tyrosine kinase modulates systemic immune activation to bacterial translocation in primary antibody deficiencies","authors":"Hsi-en Ho MD ,&nbsp;Lin Radigan MBBS ,&nbsp;Jingjing Qi PhD ,&nbsp;Vladimir Roudko PhD ,&nbsp;Michael J. Storek PhD ,&nbsp;Jo Hsuan Lee MS ,&nbsp;Ramsay Fuleihan MD ,&nbsp;Kathleen Sullivan MD, PhD ,&nbsp;Seunghee Kim-Schulze PhD ,&nbsp;Charlotte Cunningham-Rundles MD, PhD","doi":"10.1016/j.jaci.2025.09.019","DOIUrl":"10.1016/j.jaci.2025.09.019","url":null,"abstract":"<div><h3>Background</h3><div>Bacterial translocation is a shared phenomenon in common variable immunodeficiency (CVID) and X-linked agammaglobulinemia (XLA). In CVID, bacterial translocation is linked to systemic immune activation and chronic inflammatory manifestations.</div></div><div><h3>Objective</h3><div>We investigated whether the absence of functional Bruton tyrosine kinase (BTK) in XLA is associated with protection against systemic inflammation driven by bacterial translocation, and to assess whether BTK inhibition could modulate these inflammatory responses in CVID.</div></div><div><h3>Methods</h3><div>Clinical data from the US national registry were analyzed to compare the incidence of inflammatory complications between CVID and XLA. Serum immune profiling was conducted to assess systemic immune activation associated with bacterial translocation in both disorders. In parallel, <em>ex vivo</em> stimulation assays were used to evaluate the effects of BTK inhibition on microbial translocation–driven inflammatory responses in CVID.</div></div><div><h3>Results</h3><div>XLA patients, who lack BTK, were significantly protected from the inflammatory complications commonly observed in CVID. Despite comparable levels of bacterial translocation, serum cytokine profiling revealed that XLA patients exhibited markedly reduced immune activation, with lower levels of IFN-γ pathway mediators (IFN-γ, IL-12b, IL-18, CXCL9), proinflammatory cytokines (TNF-α, TNF-β, IL-6), chemokines related to host–commensal junctures (CCL19, CCL23, CCL3), and markers of monocyte and T-cell activation. XLA and CVID exhibited differential host responses to bacterial translocation stimuli <em>in vivo</em> and <em>ex vivo,</em> with reduced IFN-γ, proinflammatory cytokines, and monocyte responses in XLA. Translating these findings, we showed that the use of BTK inhibitors (rilzabrutinib, PCI-29732) in inflammatory CVID peripheral blood mononuclear cells recapitulated the <em>in vivo</em> differences between CVID and XLA, and effectively attenuated pathogenic immune responses to bacterial translocation stimuli.</div></div><div><h3>Conclusions</h3><div>These findings identify BTK as a key host modifier mediating the systemic effects of bacterial translocation. Inhibiting BTK activity in CVID may provide a novel therapeutic strategy to mitigate chronic inflammatory complications in this primary antibody deficiency.</div></div>","PeriodicalId":14936,"journal":{"name":"Journal of Allergy and Clinical Immunology","volume":"156 6","pages":"Pages 1693-1705.e5"},"PeriodicalIF":11.2,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145203881","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":"Reading the code of epitope-specific IgE: Predicting persistence and resolution in peanut allergy","authors":"George N. Konstantinou MD, PhD, MSc, MC (Army), FAAAAI ,&nbsp;Lydia Su Yin Wong MBBS ,&nbsp;Anna Nowak-Wegrzyn MD, PhD","doi":"10.1016/j.jaci.2025.10.014","DOIUrl":"10.1016/j.jaci.2025.10.014","url":null,"abstract":"","PeriodicalId":14936,"journal":{"name":"Journal of Allergy and Clinical Immunology","volume":"156 6","pages":"Pages 1520-1522"},"PeriodicalIF":11.2,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145383255","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}