Journal of Clinical Immunology最新文献

{"title":"RNA Sequencing Addresses a 5' UTR Variant Leading to X-Linked Agammaglobulinemia and Broader Immune Dysregulation.","authors":"Kexin Xu, Bingqing Zhang, Sen Zhao, Yun Zhang, Nan Wu, Min Shen, Xuejun Zeng","doi":"10.1007/s10875-025-01971-2","DOIUrl":"10.1007/s10875-025-01971-2","url":null,"abstract":"<p><p>PURPOSE: Pathogenic variants in BTK cause X-linked agammaglobulinemia (XLA), yet some cases remain undiagnosed despite extensive genetic testing. Additionally, autoimmune complications have been increasingly reported, but the underlying etiology is still unclear. This study aimed to use RNA sequencing (RNA-seq) to resolve an undiagnosed case and characterize transcriptomic features associated with disease mechanisms of XLA. METHODS: We performed genome sequencing and RNA-seq, detected outliers against 89 controls to identify disease-causing variants, and validated functional consequences through RT-PCR. We further conducted gene set enrichment analysis (GSEA) to delineate the transcriptomic features of XLA. RESULTS: We recruited an 18-year-old male who experienced recurrent infections since infancy but developed idiopathic portal hypertension recently. He had received four noninformative genetic test results. RNA-seq enabled the identification of significantly decreased BTK expression caused by a de novo hemizygous variant (NM_000061.3:c.-32A > G) located in the 5’ UTR. Outlier analysis revealed reduced expression of genes critical for not only immunoglobulin synthesis, but also T-cell development and inflammation intensification, such as IGHM, TRBV24-1, and PLVAP. GSEA additionally revealed significant enrichment in pathways associated with immune response and inflammatory response, suggesting broader immune dysregulation. These findings align with the growing recognition of autoimmune complications in XLA. CONCLUSION: This study emphasizes the clinical utility of RNA-seq and provides a comprehensive expression profile of XLA. These findings can guide future molecular analyses in undiagnosed cases and enhance understanding of autoimmune complications in XLA, suggesting a Multidisciplinary Team approach in both diagnostic and treatment processes. </p>","PeriodicalId":15531,"journal":{"name":"Journal of Clinical Immunology","volume":" ","pages":"7"},"PeriodicalIF":4.1,"publicationDate":"2025-12-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12804217/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145751978","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exploring the Pathogens in Primary Predominantly Antibody Deficiencies of Unknown Genetic Origin.","authors":"Barbara Bergmans, Lisanne Fontane Pennock-Janssen, Eugène van Puijenbroek, Roeland van Hout, Jean-Luc Murk, Esther de Vries","doi":"10.1007/s10875-025-01970-3","DOIUrl":"10.1007/s10875-025-01970-3","url":null,"abstract":"<p><strong>Introduction: </strong>Primary 'predominantly antibody deficiencies' (PADs) are rare disorders characterized by increased susceptibility to infections, autoimmunity, allergies, and malignancies. Their low prevalence and heterogeneity often delay diagnosis, increasing morbidity and mortality. This study identifies infection patterns in PAD patients and analyzes predictors of bronchiectasis presence at PAD diagnosis (BPAD), aiming to facilitate early diagnosis and improve prognosis.</p><p><strong>Methods: </strong>Using fully monitored data on PAD patients without identified genetic origin from the ESID Registry, infection types and pathogens across PADs were compared (chi-square analysis) and predictive factors for BPAD were identified (generalized mixed-effects logistic regression). Additionally, five machine learning classifiers (logistic regression, (bagged) decision tree, random forest and support vector machines) were trained and evaluated by area under the receiver operating characteristics curve (ROC-AUC), confusion matrices and F1-score.</p><p><strong>Results: </strong>Recurrent respiratory infections were predominant in our cohort of 861 patients from 11 centers. Cultures were conducted in only 5.9-12.3% of infections. Encapsulated bacteria were most frequently isolated. The number of organ systems affected by recurrent infections, occurrence of specific serious bacterial infections, number of identified encapsulated bacteria and common variable immunodeficiency disorders (CVID) diagnosis were predictive of BPAD. Machine learning models achieved moderate discrimination (ROC-AUC range 0.679-0.746).</p><p><strong>Discussion: </strong>This study highlights the predominance of recurrent and encapsulated bacterial respiratory tract infections in PAD and the underutilization of microbiological cultures. Generalized mixed-effects logistic regression best predicted BPAD. Clinicians should consider immunologic evaluation in patients presenting with serious bacterial infections, multi-system recurrent infections or the repeated isolation of encapsulated bacteria in unusually severe or recurrent infections.</p>","PeriodicalId":15531,"journal":{"name":"Journal of Clinical Immunology","volume":" ","pages":"6"},"PeriodicalIF":5.7,"publicationDate":"2025-12-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12795866/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145742839","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exaggerated IFN-I Response in Long COVID PBMCs Following Exposure to Viral Mimics.","authors":"Bart Humer, Julia C Berentschot, Cornelia G van Helden-Meeuwsen, L Martine Bek, Maaike de Bie, Tobias M Defesche, Chantal A Boly, Manon Drost, Merel E Hellemons, Willem A Dik, Marjan A Versnel","doi":"10.1007/s10875-025-01969-w","DOIUrl":"10.1007/s10875-025-01969-w","url":null,"abstract":"<p><strong>Purpose: </strong>Long COVID (LC) is a long-term debilitating disease of which the exact pathophysiology is unknown. A dysregulated immune response resulting in hyperresponsive immune cells is hypothesized as a key mechanism in the development of LC. Several studies suggest that acute infections can leave lasting epigenetic changes, which result in heightened immune reactivity. Upon stimulation, these primed immune cells may exhibit exaggerated responses. This form of epigenetic memory can contribute to altered immune dynamics, particularly in response to induction of type I Interferons (IFN-I) pathway activation using a viral mimic. Therefore, we investigated if LC patients exhibit a hyperresponsive response towards viral mimics in comparison with healthy controls (HC).</p><p><strong>Methods: </strong>PBMCs of two distinct LC cohorts, characterized by a different disease course and duration, were collected and transfected using Lyovec with the cGAS and RIG-I agonists G3-YSD and 3p-RNA followed by measurement of IFN-I bioactivity with a reporter cell line.</p><p><strong>Results: </strong>Transfection of PBMCs of LC patients with the cGAS and RIG-I agonists resulted in increased IFN-I bioactivity in comparison with HC. Unsupervised hierarchical clustering revealed two distinct clusters, each predominantly composed of either patients or HC. In addition, a moderate correlation between RIG-I stimulation with 3p-RNA and fatigue severity scores was found.</p><p><strong>Conclusion: </strong>These data show a hyperresponsive phenotype of immune cells of LC patients upon stimulation with viral mimics. The current availability of biologicals and small molecule inhibitors that interfere with aberrant IFN-I pathway activation underscores the importance of pursuing future investigations into this phenomenon.</p>","PeriodicalId":15531,"journal":{"name":"Journal of Clinical Immunology","volume":" ","pages":"5"},"PeriodicalIF":5.7,"publicationDate":"2025-12-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12795936/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145723578","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"IgA and IgM-enriched Immunoglobulins in Primary Immunodeficiencies: a Pilot Study.","authors":"Aurore Collet, Benjamin Coiffard, Emmanuel Ledoult, Claire Fieschi, Morgane Cheminant, Alexandra Serris, Felipe Suarez, Sébastien Sanges, Antoine Neel, Raphaële Nove-Josserand, Sarah Stabler, Kinan El Husseini, Alice Huault, Pierre Cougoul, Christelle Mausservey, Nadim Cassir, Floriane Mirgot, Bertrand Meresse, Arnaud Dendooven, Sandrine Poizot, Tanguy Le Scornet, Anne-Sophie Bravard, Anne Conrad, Manon Levêque, Jehane Fadlallah, Cléa Melenotte, Chloë Dumas De La Roque, Claire Tinevez, Wadih Abou Chahla, Sylvain Dubucquoi, Myriam Labalette, Bénédicte Neven, Marion Malphettes, Nicolas Schleinitz, Lionel Galicier, Jean-François Viallard, Guy Gorochov, Guillaume Lefèvre","doi":"10.1007/s10875-025-01966-z","DOIUrl":"10.1007/s10875-025-01966-z","url":null,"abstract":"<p><strong>Purpose: </strong>Despite well-conducted replacement therapy with polyvalent immunoglobulins (IgRT), some patients with primary immunodeficiencies (PID) continue to experience recurrent or chronic infections. IgA and IgM, essential for mucosal and complement-mediated immunity, are absent or minimal in standard immunoglobulin products. The aim of this study is to evaluate the safety and clinical evolution profiles in PID patients with undetectable IgA/IgM levels and persistent infections despite standard IgRT, after introduction of an IgA- and IgM-enriched immunoglobulin preparation (IgGAM, Pentaglobin^®).</p><p><strong>Methods: </strong>A compassionate use program (CUP) in France enrolled 20 PID patients with undetectable IgA/IgM levels, receiving IgGAM IV infusions every 7-14 days. Tolerance, infection frequency, hospitalizations, and biological markers (Ig levels, complement activation, salivary IgA) were analyzed prospectively.</p><p><strong>Results: </strong>Twenty patients were included in the CUP at the time of analysis. No severe adverse event was reported. Half of the patients experienced mild to moderate hypersensitivity symptoms. Mean antibiotic courses dropped from 5.4 to 2.3/year (p = 0.0009) and mean number of hospitalizations decreased from 2.6 to 1.2/year (p = 0.01). Median serum IgA and IgM levels increased three months after IgGAM start. IgM and low levels of IgA were detected in saliva samples, suggesting at least a transient transfer of IgA/IgM from IgGAM into mucosal fluids.</p><p><strong>Conclusion: </strong>In patients with severe PID and undetectable IgA/IgM, IgGAM was associated with reduced infections and hospitalizations. Controlled studies are needed to confirm the benefit of IgA/M enriched immunoglobulin preparations in PID patients with persistent and/or recurrent respiratory or digestive infections.</p>","PeriodicalId":15531,"journal":{"name":"Journal of Clinical Immunology","volume":" ","pages":"2"},"PeriodicalIF":5.7,"publicationDate":"2025-11-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12783217/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145633660","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Exosomes in Autoimmunity: Mediators of Autoantigen Presentation and Targets for Therapeutic Intervention in Autoimmune Diseases.","authors":"Hailah M Almohaimeed, Amany I Almars, Wajnat A Tounsi, Zuhair M Mohammedsaleh, Rajashree Panigrahi, Indu Singh, Surbhi Singh, Bikram Dhara, Daniel Ejim Uti","doi":"10.1007/s10875-025-01965-0","DOIUrl":"10.1007/s10875-025-01965-0","url":null,"abstract":"<p><p>Exosomes, as integral mediators of cellular communication, have emerged as crucial players in the pathogenesis and potential treatment of autoimmune diseases. This review explores the dual role of exosomes in mediating autoantigen presentation and their impact on immune dysregulation. Exosomes, by virtue of their cargo-comprising proteins, peptides, and nucleic acids-can influence immune tolerance, potentially leading to the breakdown of self-tolerance and the perpetuation of autoimmune responses. They carry and present autoantigens directly to T cells or indirectly via antigen-presenting cells, thereby initiating and sustaining immune reactions characteristic of autoimmune disorders. Furthermore, the review delves into the therapeutic implications of targeting exosomal pathways, discussing strategies such as inhibiting exosome biogenesis, modifying exosomal content, and blocking exosome uptake by immune cells. Such interventions present promising avenues for developing novel treatments aimed at mitigating autoimmune responses. By harnessing the unique properties of exosomes, future research may pave the way for innovative therapeutic strategies that offer more precise and personalized treatment options for patients suffering from autoimmune diseases.</p>","PeriodicalId":15531,"journal":{"name":"Journal of Clinical Immunology","volume":" ","pages":"3"},"PeriodicalIF":5.7,"publicationDate":"2025-11-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12783187/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145633649","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"TAP-I Deficiency Presenting With Chronic Granulomatous Rubella Virus-Driven Cutaneous Ulceration: A Case Report and Scoping Literature Review.","authors":"Mark J Ponsford, Emily M Carne, Kathryn Bramhall, Kristin Ladell, Ludmila Perelygina, Aung Saw, Kelly Miners, Sian Llewellyn-Lacey, Simon Kollnberger, Ian Tully, Sian Hughes, Hywel Williams, Manju Kalavala, Venetia Bigley, Daniel Farewell, David A Price, Stephen L Walker, Kathleen E Sullivan, Stephen Jolles","doi":"10.1007/s10875-025-01919-6","DOIUrl":"10.1007/s10875-025-01919-6","url":null,"abstract":"<p><p>Autosomal recessive mutations in TAP1, TAP2, TAPBP, or B2M, are associated with major histocompatibility complex (MHC) class I deficiency. Individuals may present with granulomatous skin ulceration, but the underlying antigenic triggers remain largely unknown. We identified TAP1 deficiency in a 32-year-old female referred with a 7-year history of localized skin ulceration. Histologic immunofluorescence revealed that rubella virus (RuV) infection was a likely driver of the associated inflammation, and modest clinical improvement was observed following topical calcineurin inhibition. To better define the natural history, clinical, and immunological manifestations of this condition, we also performed a scoping literature review. We identified 45 unique individuals from 36 reports with a combined follow-up duration of 1,184 patient years. Chronic necrotizing granulomatous skin lesions and childhood-onset bronchiectasis were common. Five deaths were reported (median age 36 years), typically linked to respiratory complications. Phenotypic heterogeneity was evident, with at least four individuals reaching adulthood without clinical symptoms. Diagnostic delay frequently exceeded a decade amongst symptomatic individuals, with misdiagnosis of granulomatous disease prompting systemic immunosuppression and infection-related morbidity. The presence of an abnormal CD8⁺ T-cell count or a history of consanguinity offered low sensitivity for MHC I deficiency (~ 50%), indicating a low threshold for further investigation is required for correct diagnosis. Graphical review of case reports identified morphologically similar lesions in other MHC I-deficient individuals. These findings suggest that the phenomenon of MHC I deficiency is underreported and that diagnosis should prompt testing for RuV.</p>","PeriodicalId":15531,"journal":{"name":"Journal of Clinical Immunology","volume":" ","pages":"1"},"PeriodicalIF":5.7,"publicationDate":"2025-11-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12774932/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145633874","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Monocyte/macrophage-derived NLRP3 Promotes the Onset and Progression of Ankylosing Spondylitis Via the NOD-like Receptor Pathway.","authors":"Jiarui Chen, Chengqian Huang, Tianyou Chen, Sitan Feng, Jiang Xue, Zhongxian Zhou, Shengsheng Huang, Tuo Liang, Rongqing He, Boli Qin, Xiaopeng Qin, Sen Mo, Chenxing Zhou, Shaofeng Wu, Wendi Wei, Hao Li, Zhaojun Lu, Yingying Qin, Shian Liao, Liyi Chen, Xinli Zhan, Chong Liu","doi":"10.1007/s10875-025-01961-4","DOIUrl":"10.1007/s10875-025-01961-4","url":null,"abstract":"<p><strong>Background and objectives: </strong>Ankylosing spondylitis (AS) is a chronic immune-mediated inflammatory disease primarily affecting the axial skeleton. Despite significant advances, its pathogenic mechanisms remain unclear, posing challenges to early diagnosis and effective treatment. This study aims to elucidate the pathogenic pathways of AS and explore potential therapeutic strategies.</p><p><strong>Methods: </strong>Blood routine test results from AS and non-AS patients were collected, and t-tests and logistic regression analyses were performed on blood cell count parameters. Key findings from the blood tests were validated using GEO transcriptomic datasets. Single-cell data from GEO were then used to conduct in-depth analyses of immune cell subsets and their functions. To validate findings, single-cell sequencing was performed on bone marrow samples collected from AS and fracture control patients, followed by pathway analysis through GSEA. Finally, upstream regulatory mechanisms and potential therapeutic agents were investigated.</p><p><strong>Results: </strong>This study identified a classical monocyte-macrophage-inflammatory macrophage differentiation trajectory in AS, demonstrating that monocytes/macrophages play a critical role in AS pathogenesis via the NOD-like receptor signaling pathway, primarily mediated by NLRP3. Several regulatory factors, including hsa-miR-3682-3p, AR, IRF4, MYB, RUNX1, and TAL1, were found to modulate NLRP3 expression. Additionally, various chemical compounds, anticancer drugs, and cinnamaldehyde were identified as potential therapeutic agents targeting NLRP3.</p><p><strong>Conclusion: </strong>In AS, the classical monocyte-macrophage-inflammatory macrophage differentiation pathway is enhanced, with monocyte/macrophage-derived NLRP3 driving disease progression via the NOD-like receptor signaling pathway. Regulatory factors and potential therapeutic agents targeting NLRP3 were identified, offering new insights into AS pathogenesis and therapeutic strategies.</p>","PeriodicalId":15531,"journal":{"name":"Journal of Clinical Immunology","volume":" ","pages":"169"},"PeriodicalIF":4.1,"publicationDate":"2025-11-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12689755/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145604331","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Natural History of Swiss Infants with Non-SCID T-cell Lymphopenia Detected by Newborn Screening: A Cohort Study.","authors":"Maarja Soomann, Seraina Prader, Philipp K A Agyeman, Geraldine Blanchard-Rohner, Michael Buettcher, Christian R Kahlert, Nicole Ritz, Aikaterini Theodoropoulou, Jana Pachlopnik Schmid, Johannes Trück","doi":"10.1007/s10875-025-01945-4","DOIUrl":"10.1007/s10875-025-01945-4","url":null,"abstract":"<p><strong>Background: </strong>Newborn screening (NBS) by quantification of T-cell receptor excision circles (TREC) identifies a considerable number of infants with T-cell lymphopenia (TCL) other than severe combined immunodeficiency (SCID). While some of these children have well-defined inborn errors of immunity (IEI), many lack a clear genetic diagnosis, complicating their management and causing prognostic uncertainty.</p><p><strong>Objective: </strong>To characterize the natural history of non-SCID TCL detected through NBS in Swiss infants between 2019 and 2023.</p><p><strong>Methods: </strong>Clinical, genetic and laboratory data from all non-SCID TCL cases were extracted from the national NBS registry and analyzed.</p><p><strong>Results: </strong>Out of 435 985 screened infants, 42 patients were identified with non-SCID, non-congenital athymia TCL, without an obvious secondary cause. A clear genetic diagnosis of IEI was established in 20 (48%) patients. Infants with confirmed IEI had significantly lower total T-cell, CD4 + T-cell and recent thymic emigrant (RTE) counts on initial lymphocyte phenotyping. In contrast, those with an unclear genetic diagnosis despite full investigations demonstrated faster normalization of total T-cell counts (hazard ratio 5.2, 95% CI 1.9 to 14.5, p = 0.001). All infants with initial CD4 + T-cell < 0.3 × 10⁹/L showed minimal recovery of T-cell counts and remained on long-term prophylactic measures. All infants with an unclear genetic diagnosis despite investigations were able to discontinue prophylaxis at median age 6 months without experiencing opportunistic or severe infections.</p><p><strong>Conclusion: </strong>Infants with non-SCID TCL identified by NBS represent a heterogenous group, ranging from severe, persistent TCL to mild, transient lymphopenia. Management should be tailored based on individual immunological and genetic profiles.</p>","PeriodicalId":15531,"journal":{"name":"Journal of Clinical Immunology","volume":"45 1","pages":"166"},"PeriodicalIF":4.1,"publicationDate":"2025-11-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12647285/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145604308","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Clinical and Immunological Impact of JAK Inhibition in Concurrent Down Syndrome and STAT1 Gain of Function.","authors":"Pilar Blanco-Lobo, Paula Gilabert-Prieto, Beatriz de Felipe, David Moreno-Fuentes, Paloma Guisado Hernández, Ana Ortiz-Ramírez, Anna Mensa-Vilaró, Juan I Aróstegui, Natalia Palmou, Valle Velasco Gonzalez, Ángela Deyà Martinez, Jan Ramakers, José Ivorra-Cortés, Cristina Roca, Elisa Cordero, Inmaculada Guillen, Nicolás Valerdiz Menéndez, José Manuel Lucena, Mirella Gaboli, Peter Olbrich, Olaf Neth","doi":"10.1007/s10875-025-01957-0","DOIUrl":"10.1007/s10875-025-01957-0","url":null,"abstract":"<p><strong>Purpose: </strong>Down syndrome (DS) and STAT1 gain-of-function (GOF) share clinical and molecular features, including persistent inflammation. We aimed to investigate whether the coexistence of DS and a STAT1 GOF mutation in a patient synergistically enhances interferon (IFN) signaling and exacerbates inflammatory responses, posing additional management challenges. Two patients (P1 and P2) were studied: P1, with DS and a heterozygous p.P326S STAT1 variant, and P2, with the STAT1 p.P326S variant only. Individuals with isolated DS or STAT1 GOF served as controls. IFN receptor subunits (IFNγR1/R2 and IFNαR1/R2) and responses to IFNα/γ stimulation were analyzed using flow cytometry and RT-PCR. Whole blood type I IFN signature and serum cytokines were evaluated using NanoString and Luminex assays. P1 experienced recurrent infections, chronic mucocutaneous candidiasis, interstitial pneumonitis, and pulmonary hypertension. P2 presented with esophageal candidiasis, dysphagia, and stenosis. The p.P326S variant led to increased STAT1/pSTAT1 levels in response to IFNα/γ. Both patients showed significant clinical improvement with the Janus kinase (JAK) inhibitor ruxolitinib. However, P1's key biomarkers (STAT1 levels, IFN signature, TNFα, IL-6) remained altered, indicating persistent inflammation despite clinical improvement. This first report of a STAT1 GOF variant in DS provides a unique \"experiment of nature\", offering insights into the interplay between trisomy 21 and STAT1-mediated immune dysregulation. Although ruxolitinib demonstrated clinical benefits, the persistent inflammation observed in P1 highlights the need for further strategies to achieve complete immune resolution. These findings emphasize the importance of comprehensive genetic and immunological assessments in individuals with DS, particularly when immune dysfunction is suspected.</p>","PeriodicalId":15531,"journal":{"name":"Journal of Clinical Immunology","volume":"45 1","pages":"167"},"PeriodicalIF":4.1,"publicationDate":"2025-11-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12647292/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145604310","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CXCL13 as a Biomarker of Complex Common Variable Immunodeficiency.","authors":"Ioasaf Karafotias, Helene Martini, Charlotte V Lee, Terrence T J Hunter, Padmalal Gurugama, Mary Guckian, Rachael Steven, Stephen Jolles, Mark Peakman, David Fear, Mohammad A A Ibrahim","doi":"10.1007/s10875-025-01963-2","DOIUrl":"10.1007/s10875-025-01963-2","url":null,"abstract":"<p><strong>Background: </strong>Common Variable Immunodeficiency (CVID) is a group of heterogeneous disorders with common denominators of impaired antibody production and function, and recurrent infections. Currently, prognostic biomarkers for CVID are limited. CXCL13 is a critical regulator of germinal centre responses and antibody production, with T follicular helper (Tfh) cells as a major source, and acts as a potent B cell chemoattractant. Serum levels of CXCL13 are increased in chronic inflammatory conditions and malignancy.</p><p><strong>Objectives: </strong>We aimed to explore whether serum CXCL13 levels are altered in CVID and whether they can categorise the patients based on their clinical and immune phenotype.</p><p><strong>Methods: </strong>We compared the serum levels of CXCL13 between CVID and healthy donors (HD) and associated them with the clinical and immune phenotype of the patients.</p><p><strong>Results: </strong>The serum levels of CXCL13 were higher in CVID, especially in female patients, as compared to HD, and were positively correlated with the number of clinical complications in CVID and the total peripheral circulating Tfh cells (cTfh). CVID patients with higher levels of CXCL13 were more likely to have clinical complications and/or high frequency of CD21^low B cells or low frequency of switched memory B cells.</p><p><strong>Conclusions: </strong>CXCL13 can categorise heterogeneous patients with CVID and be used as a biomarker of complex disease.</p>","PeriodicalId":15531,"journal":{"name":"Journal of Clinical Immunology","volume":"45 1","pages":"168"},"PeriodicalIF":4.1,"publicationDate":"2025-11-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12647345/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145604288","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}