Journal of Clinical Immunology最新文献

{"title":"A multi-composite disease activity score (NFKB1-DAS) for NFKB1 insufficiency.","authors":"Katharina Thoma, Pia Hassunah, Manfred Fliegauf, Gabriele Müller, Andres Caballero Garcia de Oteyza, Pavla Mrovecova, Helene Kraus, Prerana Agarwal, Maximilian Frederik Russe, Birgit Sawitzki, Lev Petrov, Katrin Vogt, Nadezhda Camacho Ordonez, Aleksandra Hirsch, Christoph B Geier, Máté Krausz, Sigune Goldacker, Natalie Frede, Stephan Ehl, Sarah Salou, Ansgar Schulz, Shahrzad Bakhtiar, Maria Fasshauer, Oliver Hausmann, Anja-Dorothee Hüfner, Martin Stanulla, Anna Luijendijk, Faranaz Atschekzei, Georgios Sogkas, Ulrich Salzer, Baerbel Keller, Michele Proietti, Klaus Warnatz, Bodo Grimbacher","doi":"10.1007/s10875-026-02081-3","DOIUrl":"https://doi.org/10.1007/s10875-026-02081-3","url":null,"abstract":"<p><p>NFKB1 encodes the p105/p50 NF-κB1 transcription factor. Heterozygous mutations in NFKB1 may lead to NFKB1 insufficiency affecting multiple organ systems. This study aimed to develop an NFKB1-Disease-Activity-Score (NFKB1-DAS), serving as a tool in future clinical trials. Based on published phenotypic data from 179 patients with 77 distinct NFKB1 variants, we drafted an initial score consisting of 42 parameters. This draft was subsequently analyzed in a multicenter cohort of 41 patients with 22 distinct pathogenic NFKB1 variants. Using a Leave-One-Out (LOO) analysis (cutoff differential value: 23.07), we identified the 21 most relevant parameters to construct the final NFKB1-DAS. Calculation of the NFKB1-DAS in 31 CTLA4-deficient patients as a comparison cohort showed higher scores in NFKB1-insufficient patients (p = 0.03 (95% CI [-0.16, -0.01]) and the NFKB1-DAS correlated with hospitalization (p = 0.01; OR 2.07 (95% CI [1.18; 3.62]). However, given the optimism bias occurring when testing the score in the cohort it was developed with and the limited case numbers, validation of the NFKB1-DAS in an unrelated cohort remains essential. Analysis of the NFKB1-DAS in patients with variants of unknown significance (VUS) in NFKB1 (n = 14) showed individual patients reaching high scores. Future studies could evaluate a possible utility of the score in assessing VUS pathogenicity. Ultimately, the proposed NFKB1-DAS represents a first step toward monitoring disease activity and treatment response in future clinical trials in NFKB1 insufficiency.</p>","PeriodicalId":15531,"journal":{"name":"Journal of Clinical Immunology","volume":"46 1","pages":""},"PeriodicalIF":4.1,"publicationDate":"2026-10-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149224235","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Delayed Reconstitution of Thymopoiesis After a Thymus Transplant.","authors":"Adam Klocperk, Barbora Obermannova, Viktor Bíly, Zainab Mohammedi Golwala, Austen Worth","doi":"10.1007/s10875-026-02069-z","DOIUrl":"10.1007/s10875-026-02069-z","url":null,"abstract":"","PeriodicalId":15531,"journal":{"name":"Journal of Clinical Immunology","volume":"46 1","pages":""},"PeriodicalIF":4.1,"publicationDate":"2026-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13645998/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149127693","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":"Correction to: Cancer Trends in Inborn Errors of Immunity: A Systematic Review and Meta‑Analysis.","authors":"Saba Fekrvand, Hassan Abolhassani, Zahra Hamidi Esfahani, Najmeh Nameh Goshay Fard, Mahboube Amiri, Helia Salehi, Amir Almasi-Hashiani, Ali Saeedi-Boroujeni, Nazanin Fathi, Maryam Mohtashami, Azadehsadat Razavi, Arash Heidari, Gholamreza Azizi, Shaghayegh Khanmohammadi, Milad Ahangarzadeh, Kiarash Saleki, Gholamreza Hassanpour, Nima Rezaei, Reza Yazdani","doi":"10.1007/s10875-026-02078-y","DOIUrl":"https://doi.org/10.1007/s10875-026-02078-y","url":null,"abstract":"","PeriodicalId":15531,"journal":{"name":"Journal of Clinical Immunology","volume":"46 1","pages":""},"PeriodicalIF":4.1,"publicationDate":"2026-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13633169/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149110367","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":"Cobalamin C Deficiency Presenting with CVID-like Immunologic Abnormalities: A Five-Patient Pediatric Case Series.","authors":"Ruxuan He, Jinrong Liu, Shunying Zhao, Haiming Yang","doi":"10.1007/s10875-026-02068-0","DOIUrl":"10.1007/s10875-026-02068-0","url":null,"abstract":"","PeriodicalId":15531,"journal":{"name":"Journal of Clinical Immunology","volume":"46 1","pages":""},"PeriodicalIF":4.1,"publicationDate":"2026-08-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13503436/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148812222","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":"Elevated IL-10 is Linked With the Expansion of T-bet^highCD21^low B Cells in Patients With Common Variable Immunodeficiency.","authors":"Victoria Cousin, Anna Graumann, Valerie Geiger, David Sökler, Patrick Bez, Sylvia Gutenberger, Cornelia Glaser, Geoffroy Andrieux, Melanie Boerries, Björn Christian Frye, Gernot Zissel, Celia Lourdes Calvillo, Javier Rodriguez-Ubreva, Esteban Ballestar, Fabian Hauck, Reinhard E Voll, Nina Chevalier, Baerbel Keller, Klaus Warnatz","doi":"10.1007/s10875-026-02058-2","DOIUrl":"10.1007/s10875-026-02058-2","url":null,"abstract":"<p><p>Common variable immunodeficiency (CVID) is frequently complicated by autoimmune and inflammatory manifestations associated with profound immune dysregulation (CVIDc), including expansion of T-bet^highCD21^low B cells (CD21^low B cells). Elevated serum IL-10 levels have repeatedly been reported in CVIDc, yet their relationship to CD21^low B-cell differentiation remains unclear. In this study, we determined a significant correlation between increased serum IL-10 levels and frequency of circulating CD21^low B cells, particularly marked in CVIDc patients. Transcriptomic and protein analyses identified multiple cellular sources of IL-10 in CVID, including monocytes, T cells, and a subset of CD21^low B cells in peripheral blood and inflamed tissues. CD21^low B cells expressed elevated levels of IL-10 receptor subunits and displayed intact IL-10-induced STAT3 signaling, indicating preserved responsiveness to IL-10. Functionally, IL-10 alone neither induced CD21^low B-cell differentiation nor inhibited IFN-γ-driven polarization. However, in vitro differentiation assays showed that IL-10 can substitute for IL-21 during CD40L/T cell-dependent differentiation of CD21^low-like B cells and promote their survival in vitro. These findings suggest that IL-10 may support the expansion and persistence of CD21^low B cells at inflammatory sites. Collectively, our data identify IL-10 as a component of the inflammatory environment associated with CD21^low B-cell expansion and suggest that IL-10 can functionally replace IL-21 during their differentiation and promote their survival in CVID-associated immune dysregulation.</p>","PeriodicalId":15531,"journal":{"name":"Journal of Clinical Immunology","volume":"46 1","pages":""},"PeriodicalIF":4.1,"publicationDate":"2026-08-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13477453/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148764633","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":"Correction to: Rare Pathogenic Variants in Mitochondrial and Inflammation-Associated Genes May Lead to Inflammatory Cardiomyopathy in Chagas Disease.","authors":"Maryem Ouarhache, Sandrine Marquet, Amanda Farage Frade, Ariela Mota Ferreira, Barbara Ianni, Rafael Ribeiro Almeida, Joao Paulo Silva Nunes, Ludmila Rodrigues Pinto Ferreira, Vagner Oliveira-Carvalho Rigaud, Darlan Cândido, Charles Mady, Ricardo Costa Fernandes Zaniratto, Paula Buck, Magali Torres, Frederic Gallardo, Pauline Andrieux, Sergio Bydlowsky, Debora Levy, Laurent Abel, Clareci Silva Cardoso, Omar Ribeiro Santos-Junior, Lea Campos Oliveira, Claudia Di Lorenzo Oliveira, Maria Do Carmo Nunes, Aurelie Cobat, Jorge Kalil, Antonio Luiz Ribeiro, Ester Cerdeira Sabino, Edecio Cunha-Neto, Christophe Chevillard","doi":"10.1007/s10875-026-02061-7","DOIUrl":"10.1007/s10875-026-02061-7","url":null,"abstract":"","PeriodicalId":15531,"journal":{"name":"Journal of Clinical Immunology","volume":"46 1","pages":""},"PeriodicalIF":4.1,"publicationDate":"2026-08-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13477482/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148758267","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":"Inborn Errors of Immunity Genotype: A Retrospective Study from the United Arab Emirates.","authors":"Farida Almarzooqi, Maram Ahmed, Maryam Mohammad Sabt, Fatma Abdulla Aljanaahi, Hiba Alblooshi","doi":"10.1007/s10875-026-02060-8","DOIUrl":"10.1007/s10875-026-02060-8","url":null,"abstract":"<p><p>Inborn errors of immunity (IEI) contribute substantially to morbidity in the Middle East and North Africa (MENA), particularly in the United Arab Emirates (UAE), where high consanguinity increases the prevalence of autosomal-recessive and complex genetic disorders. Regional IEI genomic data remain limited, and population-specific variants are underrepresented in global databases, limiting diagnostic accuracy and precision-medicine implementation. We retrospectively reviewed 2,500 patients assigned immunodeficiency-related ICD codes over ten years at two tertiary centers in Al Ain, UAE. Based on the availability of genetic testing reports for inborn errors of immunity, 232 patients (~ 9%) were included in the analysis. Variants were annotated using American College of Medical Genetics and Genomics guidelines and open-access resources, including Ensembl and ClinVar, and genes were classified according to the International Union of Immunological Societies framework. Allele frequencies were reported based on gnomAD and the Emirati Genome Project. Reported variants were systematically reclassified using Franklin, VarSome, ClinGen, and HGMD, where available. Based on original reports, 245 IEI-related variant observations were identified across 107 genes: 99 (40.4%) pathogenic/likely pathogenic, 68 (27.8%) benign/likely benign, and 78 (31.8%) variants of uncertain significance (VUS). Following reclassification, pathogenic/likely pathogenic variants increased to 107 (43.7%), VUS decreased to 54 (22.0%), and benign/likely benign variants increased to 76 (31.0%). Recurrent genes included ATM, DOCK8, RAG1, RAG2, UNC13D, LRBA, MEFV, and NLRP3, and 7.8% of patients carried multiple IEI-related variants. This study provides one of the largest genomic characterizations of IEI in the UAE and demonstrates that systematic variant reinterpretation improves diagnostic accuracy, underscoring the importance of population-specific genomic resources for precision medicine.</p>","PeriodicalId":15531,"journal":{"name":"Journal of Clinical Immunology","volume":"46 1","pages":""},"PeriodicalIF":4.1,"publicationDate":"2026-08-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13597621/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149025013","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":"Immune Dysregulation in Down Syndrome: Implications for Infectious Susceptibility and Vaccine Response.","authors":"Sofía Solari-Hernández, Enrique González-Madrid, Pablo A González, Susan M Bueno, Alexis M Kalergis","doi":"10.1007/s10875-026-02054-6","DOIUrl":"10.1007/s10875-026-02054-6","url":null,"abstract":"<p><p>Down syndrome (DS), caused by trisomy 21, is characterized by complex immune dysregulation that increases susceptibility to infections and alters vaccine responsiveness. Gene dosage effects involving interferon receptor loci on chromosome 21 contribute to chronic type I interferon hyperactivation, sustained JAK-STAT signaling, and persistent expression of interferon-stimulated genes. This baseline inflammatory state is accompanied by quantitative and functional defects in both innate and adaptive immunity, including impaired neutrophil chemotaxis, pro-inflammatory monocyte polarization, reduced naïve T- and B-cell compartments, restricted antigen receptor diversity, diminished class-switched memory B cells, and features of accelerated immunosenescence. Clinically, these immune alterations are associated with an increased risk of severe respiratory viral infections, such as respiratory syncytial virus, influenza, and SARS-CoV-2, as well as reduced magnitude and durability of vaccine-induced immunity. Cohort studies in both pediatric and adult populations have reported higher rates of hospitalization and mortality, along with lower peak antibody titers and more rapid waning of immunity following vaccination. This review integrates molecular, cellular, and clinical evidence to define the interferon-driven immune phenotype in DS and its implications for susceptibility to infection and vaccination response. A mechanistic understanding of this immune landscape provides a framework for developing tailored preventive strategies and optimizing vaccination approaches in this vulnerable population.</p>","PeriodicalId":15531,"journal":{"name":"Journal of Clinical Immunology","volume":"46 1","pages":""},"PeriodicalIF":4.1,"publicationDate":"2026-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13534213/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148874270","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":"IgG4-Related Hepatic Disease Unmasking Hepatic Actinomycosis.","authors":"Anissa Desmoulin, Jasmine Muyard, Laure-Marie Dardaud, Anne-Gaëlle Leroy, Sabine Revuz","doi":"10.1007/s10875-026-02049-3","DOIUrl":"10.1007/s10875-026-02049-3","url":null,"abstract":"<p><strong>Purpose: </strong>Hepatic actinomycosis is a rare granulomatous disease caused by an opportunistic Gram-positive bacillus of the genus Actinomyces. We report an unusual association between hepatic actinomycosis and IgG-4 related disease.</p><p><strong>Case description: </strong>A 70-year-old man was admitted to the University Hospital of Reunion Island for asthenia and abdominal pain. Laboratory tests showed hepatic cholestasis and inflammatory reaction without cytolysis. The computer tomography scanner (CT scan) revealed a large hepatic mass in segment IV. IgG4 related disease (IgG4-RD) was diagnosed following liver biopsy. Despite the use of corticosteroids, the lesions progressed. A new biopsy was performed and a PCR test returned positive for Actinomyces spp. We observed patient improvement after 4 months of treatment with amoxicillin and discontinuation of corticosteroids.</p><p><strong>Conclusions: </strong>Clinical presentation, imaging characteristics, and diagnostic challenges are strikingly similar between hepatic actinomycosis and IgG4-related disease. However, distinguishing between these two disorders is essential - as the treatment of one may worsen the course of the other. Knowing and understanding the interactions between these two disorders can only be achieved through an integrated and collaborative approach involving various disciplines.</p>","PeriodicalId":15531,"journal":{"name":"Journal of Clinical Immunology","volume":" ","pages":""},"PeriodicalIF":4.1,"publicationDate":"2026-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13569593/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148470953","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":"A Detrimental NFKB2 Missense Variant is Associated with Hypogammaglobulinemia.","authors":"Manfred Fliegauf, Laura Gamez-Diaz, Pavla Mrovecova, Chiara Milena God, Valerie Flavia Geiger, Nadezhda Camacho-Ordonez, Sara Posadas-Cantera, Cliodhna Murray, Klaus Warnatz, Baerbel Keller, Bodo Grimbacher","doi":"10.1007/s10875-026-02051-9","DOIUrl":"10.1007/s10875-026-02051-9","url":null,"abstract":"<p><p>NFKB2 encodes the precursor p100 which undergoes processing to generate the mature NF-κB2 transcription factor subunit p52. Most of the known pathogenic NFKB2 variants render p100 un-processable and are typically linked to immunodeficiency disorders with antibody deficiency, susceptibility to infections and often autoimmunity. We describe a heterozygous germline NFKB2 missense variant (c.781C>T; R261W) associated with antibody deficiency and recurrent respiratory tract infections in a German family with incomplete penetrance. Patient-derived cells had reduced p52 levels, indicating protein insufficiency as the primary defect. Characterization of the R261W variant in vitro employing overexpression of EGFP-fused wildtype and mutant p100/p52 in HEK293T cells revealed restricted levels of mutant p100, suggesting unsustainable protein expression while maintenance of mutant p52 was almost precluded, confirming a detrimental protein defect. Enforced p100-processing driven by constitutively active NF-κB inducing kinase (NIK) caused subnuclear aggregation of mutant EGFP-p52 while DNA-binding activity was undetectable. Although ectopically over-expressed EGFP-p52-R261W also formed intra-nuclear aggregates - a previously established diagnostic indicator of protein-decaying NFKB1 mutations - its DNA-binding ability was not abolished. In summary, the single amino acid substitution R261W in the N-terminal Rel-homology domain of p100/p52 causes protein loss, particularly of the mature subunit p52. This genetic condition is associated with an inheritable form of hypogammaglobulinemia with mild clinical symptoms. We therefore recommend genetic screening for NFKB2 loss-of-expression variants in mildly affected patients with recurrent respiratory tract infections.</p>","PeriodicalId":15531,"journal":{"name":"Journal of Clinical Immunology","volume":"46 1","pages":""},"PeriodicalIF":4.1,"publicationDate":"2026-07-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13356095/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148421414","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}