Journal of Clinical Immunology最新文献

{"title":"Investigating Chromosomal Radiosensitivity in Inborn Errors of Immunity: Insights from DNA Repair Disorders and Beyond.","authors":"Elien Beyls, Evi Duthoo, Lynn Backers, Karlien Claes, Marieke De Bruyne, Lore Pottie, Victoria Bordon, Carolien Bonroy, Simon J Tavernier, Kathleen B M Claes, Anne Vral, Ans Baeyens, Filomeen Haerynck","doi":"10.1007/s10875-025-01858-2","DOIUrl":"10.1007/s10875-025-01858-2","url":null,"abstract":"<p><p>Human inborn errors of immunity (IEI) represent a diverse group of genetic disorders affecting the innate and/or adaptive immune system. Some IEI entities comprise defects in DNA repair factors, resulting in (severe) combined immunodeficiencies, bone marrow failure, predisposition to malignancies, and potentially resulting in radiosensitivity (RS). While other IEI subcategories such as common variable immunodeficiency (CVID) and immune dysregulation disorders also associate with lymphoproliferative and malignant complications, the occurrence of RS phenotypes in the broader IEI population is not well characterized. Nonetheless, identifying RS in IEI patients through functional testing is crucial to reconsider radiation-related therapeutic protocols and to improve overall patient management. This study aimed to investigate chromosomal RS in a diverse cohort of 107 IEI patients using the G0 cytokinesis-block micronucleus (MN) assay. Our findings indicate significant variability in RS across specific genetic and phenotypical subgroups. Severe RS was detected in all ataxia-telangiectasia (AT) patients, a FANCI deficient and ERCC6L2 deficient patient, but not in any other IEI patient included in this cohort. Age emerged as an influencing factor for both spontaneous and radiation-induced MN yields, while the manifestation of additional clinical features, including infection susceptibility, immune dysregulation, or malignancies did not associate with increased MN levels. Our extensive analysis of RS in the IEI population underscores the clinical importance of RS assessment in AT patients and supports RS testing in all IEI patients suspected of having a DNA repair disorder associated with RS.</p>","PeriodicalId":15531,"journal":{"name":"Journal of Clinical Immunology","volume":"45 1","pages":"75"},"PeriodicalIF":7.2,"publicationDate":"2025-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11825639/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143408124","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":"Early Haploidentical Hematopoietic Stem Cell Transplantation Provides Rapid Leukocyte and Immune Reconstitution in AK2 Patient Identified by TREC Newborn Screening.","authors":"Alphan Cicek, Friedhelm R Schuster, Janel O Boyle, Manfred Hoenig, Roland Meisel, Sujal Ghosh","doi":"10.1007/s10875-025-01863-5","DOIUrl":"10.1007/s10875-025-01863-5","url":null,"abstract":"<p><p>Reticular dysgenesis (RD) is a rare inborn error of immune cell formation defined by severe combined immunodeficiency, agranulocytosis and sensorineural deafness. We report a case of successful haploidentical maternal hematopoietic stem cell transplantation (HSCT) in a boy with RD detected by TREC newborn screening. The patient was admitted to our hospital at 2 weeks of age and was kept in laminar-air flow / hepa-filtered isolation until HSCT was performed at 8 weeks of age with a busulfan, fludarabine conditioning regime. Except few episodes of acute skin graft-versus-host disease (aGVHD) the peritransplant period was uneventful. The patient was discharged 7 weeks post-HSCT. At 18 months of age cochlear implants were placed. The patient was thriving well, showed full donor chimerism and a T cell count > 1000 TCRab + CD3 + cells/µl after one year. Our case highlights that severely immune-compromised patients with RD benefit from early diagnosis by newborn screening, immediate isolation to prevent infections, and early haploidentical HSCT to overcome neonatal neutropenia and establish protective immunity.</p>","PeriodicalId":15531,"journal":{"name":"Journal of Clinical Immunology","volume":"45 1","pages":"74"},"PeriodicalIF":7.2,"publicationDate":"2025-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11813986/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143391037","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":"Pulmonary Aspergillosis and Low HIES Score in a Family with STAT3 N-Terminal Domain Mutation.","authors":"Suiane Lima de Souza, Takaki Asano, Virpi Glumoff, Salla Keskitalo, Keela Pikkarainen, Timi Martelius, Meri Kaustio, Janna Saarela, Outi Kuismin, Elisa Lappi-Blanco, Airi Jartti, Fredrik Yannopoulos, Leena Tiitto, Mikko R J Seppänen, Bertrand Boisson, Jean-Laurent Casanova, Markku Varjosalo, Timo Hautala, Zhi Chen","doi":"10.1007/s10875-025-01867-1","DOIUrl":"10.1007/s10875-025-01867-1","url":null,"abstract":"<p><p>Signal transducer and activator of transcription 3 (STAT3) plays a key role in leukocytic and non-leukocytic cells. Germ line mutations in STAT3, which are mainly found in the SH2, DNA binding and transactivation domains, can be loss- or gain-of-function (LOF and GOF). STAT3 N-terminal domain (NTD) mutations are rare, and their biological effects remain incompletely understood. We explored the significance of STAT3 NTD p.Trp37* variant in a patient with chronic pulmonary aspergillosis and a low Hyper-IgE syndrome (HIES) score. In cell culture models, the expression of full-length p.Trp37* allele showed shorter STAT3 protein expression suggesting a re-initiation (Met99 or Met143). STAT3 activity using luciferase reporter assay showed a twofold-increased activity of the STAT3 p.Trp37* STAT3 protein compared with WT STAT3 at basal level and upon IL-6 stimulation. In contrast, the activity of the short pTrp37* peptide (amino acids 1 to 37) was amorphic but without dominant negative (DN) effect on transcriptional activity or STAT3 Tyr705 phosphorylation. The proteins initiated at Met99 and Met143 were surprisingly hypermorphic. In carriers' peripheral blood mononuclear cells (PBMCs), both WT and mutated STAT3 mRNA were equally present and the global amount of STAT3 protein was not significantly reduced. In stimulated heterozygous carriers' PBMCs, however, STAT3 Tyr705 phosphorylation and Th17 were reduced but not completely abolished. This suggests a DN effect of an unknown product of the p.Trp37* allele. Transcriptomics analysis of PBMCs from the index revealed selectively distinct gene expression. We conclude that heterozygosity for the NTD p.Trp37* STAT3 mutation defines a novel allelic form of STAT3 deficiency, associated with a chronic pulmonary aspergillosis and minor signs of HIES.</p>","PeriodicalId":15531,"journal":{"name":"Journal of Clinical Immunology","volume":"45 1","pages":"73"},"PeriodicalIF":7.2,"publicationDate":"2025-02-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11811237/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143382594","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: Dissecting Secondary Immunodeficiency: Identification of Primary Immunodeficiency within B-Cell Lymphoproliferative Disorders.","authors":"María Palacios-Ortega, Teresa Guerra-Galán, Adolfo Jiménez-Huete, José María García-Aznar, Marc Pérez-Guzmán, Maria Dolores Mansilla-Ruiz, Ángela Villegas Mendiola, Cristina Pérez López, Elsa Mayol Hornero, Alejandro Peixoto Rodriguez, Ascensión Peña Cortijo, Marta Polo Zarzuela, Marta Mateo Morales, Eduardo Anguita Mandly, Maria Cruz Cárdenas, Alejandra Carrero, Carlos Jiménez García, Estefanía Bolaños, Belén Íñigo, Fiorella Medina, Eduardo de la Fuente, Juliana Ochoa-Grullón, Blanca García-Solís, Yolanda García-Carmona, Miguel Fernández-Arquero, Celina Benavente-Cuesta, Rebeca Pérez de Diego, Nicholas Rider, Silvia Sánchez-Ramón","doi":"10.1007/s10875-025-01865-3","DOIUrl":"10.1007/s10875-025-01865-3","url":null,"abstract":"","PeriodicalId":15531,"journal":{"name":"Journal of Clinical Immunology","volume":"45 1","pages":"72"},"PeriodicalIF":7.2,"publicationDate":"2025-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11805864/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143364975","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":"Interstitial Lung Disease in a Girl with Prolidase Deficiency.","authors":"Chunna Xu, Lei Zhang, Yu Tang, Haiming Yang, Yuelin Shen","doi":"10.1007/s10875-025-01861-7","DOIUrl":"10.1007/s10875-025-01861-7","url":null,"abstract":"","PeriodicalId":15531,"journal":{"name":"Journal of Clinical Immunology","volume":"45 1","pages":"71"},"PeriodicalIF":7.2,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11794399/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143189317","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: Anifrolumab in Monogenic Lupus caused by TREX1 Mutation.","authors":"Patricia Moran-Alvarez, Virginia Messia, Valentina Matteo, Francesca Soscia, Giusi Prencipe, Fabrizio De Benedetti, Antonella Insalaco","doi":"10.1007/s10875-025-01864-4","DOIUrl":"10.1007/s10875-025-01864-4","url":null,"abstract":"","PeriodicalId":15531,"journal":{"name":"Journal of Clinical Immunology","volume":"45 1","pages":"70"},"PeriodicalIF":7.2,"publicationDate":"2025-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11790795/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143080220","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: Quantifying the Diagnostic Odyssey Burden Among Persons with Inborn Errors of Immunity.","authors":"Sarina Nikzad, Rebekah Johnson, Christopher Scalchunes, Nicholas L Rider","doi":"10.1007/s10875-025-01859-1","DOIUrl":"10.1007/s10875-025-01859-1","url":null,"abstract":"","PeriodicalId":15531,"journal":{"name":"Journal of Clinical Immunology","volume":"45 1","pages":"69"},"PeriodicalIF":7.2,"publicationDate":"2025-01-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11779763/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143059234","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":"Hematopoietic Stem Cell Transplantation Corrects IL-2Rβ Deficiency.","authors":"Fai AlQahtani, Manar AlGhamdi, Mofareh AlZahrani, Anas M AlAzami, Sultan Al-Buhairi, Hamoud Al-Mousa","doi":"10.1007/s10875-025-01860-8","DOIUrl":"10.1007/s10875-025-01860-8","url":null,"abstract":"","PeriodicalId":15531,"journal":{"name":"Journal of Clinical Immunology","volume":"45 1","pages":"68"},"PeriodicalIF":7.2,"publicationDate":"2025-01-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11772453/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143046472","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":"ATM Expression and Activation in Ataxia Telangiectasia Patients with and without Class Switch Recombination Defects.","authors":"Fereshte Salami, Tannaz Moeini Shad, Nazanin Fathi, Hanieh Mojtahedi, Marzie Esmaeili, Sepideh Shahkarami, Ladan Gol Mohammad Pour Afrakoti, Parisa Amirifar, Samaneh Delavari, Hassan Nosrati, Azadehsadat Razavi, Mohammad Reza Ranjouri, Mahsa Yousefpour, Zahra Hamidi Esfahani, Gholamreza Azizi, Mahmoudreza Ashrafi, Nima Rezaei, Reza Yazdani, Hassan Abolhassani","doi":"10.1007/s10875-025-01857-3","DOIUrl":"10.1007/s10875-025-01857-3","url":null,"abstract":"<p><strong>Background: </strong>Ataxia telangiectasia mutated (ATM) kinase plays a critical role in DNA double-strand break (DSB) repair. Ataxia telangiectasia (A-T) patients exhibit abnormalities in immunoglobulin isotype expression and class switch recombination (CSR). This study investigates the role of residual ATM kinase expression and activity in the severity of A-T disease.</p><p><strong>Methods: </strong>A-T patients with defined genetic diagnoses were classified based on CSR and based on the severity of their medical complications. Isolated peripheral blood mononuclear cells from any patient were evaluated before and after exposure to 0.5 Gy ionizing radiation for one minute. Western blotting was performed to identify the expression of ATM and phosphorylated ATM (p-ATM) proteins compared to age-sex-matched healthy controls.</p><p><strong>Results: </strong>In severe A-T patients (n = 6), the majority (66.7%) had frameshift mutations, while 33.3% had nonsense mutations in the ATM gene. The mild group (n = 3) had two cases of splice errors and one missense mutation. All patients with CSR defect had elevated IgM serum levels, whereas all switched immunoglobulins were reduced in them. Expression of ATM and p-ATM proteins was significantly lower (p = 0.01) in all patients compared to healthy controls, both pre-and post- and post-radiation. Additionally, low ATM and p-ATM protein expression levels were linked with the clinical severity of patients but were not correlated with CSR defects.</p><p><strong>Conclusion: </strong>Expression and activation of ATM protein were defective in A-T patients compared to healthy controls. Altered expression of ATM and p-ATM proteins may have potential clinical implications for prognostic evaluation and symptom severity assessment in individuals with A-T.</p>","PeriodicalId":15531,"journal":{"name":"Journal of Clinical Immunology","volume":"45 1","pages":"67"},"PeriodicalIF":7.2,"publicationDate":"2025-01-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11762072/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143032863","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":"Hypomorphic RAG2 Deficiency Promotes Selection of Self-Reactive B Cells.","authors":"Christopher D Thouvenel, Christopher M Tipton, Yasuhiro Yamazaki, Ting-Ting Zhang, Stacey Rylaarsdam, Jennifer R Hom, Catherine Snead, Chengsong Zhu, Quan-Zhen Li, Yu Nee Lee, Tomoki Kawai, Neshatul Haque, Michael T Zimmermann, Sivasankaran Munusamy Ponnan, Shaun W Jackson, Rich G James, Ignacio Sanz, Luigi D Notarangelo, Troy R Torgerson, Hans D Ochs, David J Rawlings, Eric J Allenspach","doi":"10.1007/s10875-024-01849-9","DOIUrl":"https://doi.org/10.1007/s10875-024-01849-9","url":null,"abstract":"<p><p>Reduced function or hypomorphic variants in recombination-activating genes (RAG) 1 or 2 result in a broad clinical phenotype including common variable immunodeficiency (CVID) and even adult-onset disease. Milder RAG variants are less characterized. Here we describe the longitudinal course of a milder combined RAG deficiency in 3 of 7 siblings sharing the same RAG2 mutations over a 50-year study. Whole-genome and repertoire sequencing, bacteriophage immunizations, and deep immunophenotyping were used to compare affected and unaffected family members. The clinical phenotype of three affected siblings with hypomorphic RAG deficiency ranged from combined immunodeficiency and early mortality to a late-onset CID with hyper-IgM phenotype. T cells were remarkably similar across affected siblings, yet CDR3 skewing and regulatory T cell defects were not observed. B cell analysis showed elevated unswitched CD27+ and CD21^low cells as well as features of an autoreactive antibody repertoire and presence of secreted autoantibodies, yet no clinical autoimmunity was present. Most striking was an expanded polyclonal marginal zone-like B cell population (IgM+IgD+CD27+) utilizing the self-reactive unmutated VH4-34 receptor demonstrating that hypomorphic RAG deficiency can promote expansion of self-reactive B cells. This process, however, was not sufficient to trigger clinical autoimmunity. Utilizing multiple approaches, we functionally measured the specific RAG2 variant effects and assessed how selection and secondary triggers altered the BCR repertoire and immunophenotype overtime. Overall, we demonstrate a broad disease spectrum in siblings with identical hypomorphic RAG deficiency, highlighting that phenotypic divergence can result from expansion of IgM + memory B cells.</p>","PeriodicalId":15531,"journal":{"name":"Journal of Clinical Immunology","volume":"45 1","pages":"66"},"PeriodicalIF":7.2,"publicationDate":"2025-01-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11735530/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143056032","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}