Journal of Clinical Immunology最新文献

{"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":5.7,"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":"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":5.7,"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":"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":5.7,"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":"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":5.7,"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}

{"title":"Whole Genome Sequencing in 25 Families with Suspected Inborn Errors of Immunity: Diagnostic Yield and Clinical Relevance of Genome-wide Analysis.","authors":"Jong Kwon Lee, Ja-Hyun Jang, Doo Ri Kim, Areum Shin, Jong-Ho Park, Young-Gon Kim, Jong-Won Kim, Yae-Jean Kim, Eun-Suk Kang","doi":"10.1007/s10875-025-01947-2","DOIUrl":"10.1007/s10875-025-01947-2","url":null,"abstract":"<p><strong>Introduction: </strong>Inborn errors of immunity (IEIs) constitute a diverse group of more than 500 disorders resulting from pathogenic variants in over 500 causative genes, with most being monogenic diseases. The use of exome sequencing based on next-generation sequencing technologies has significantly advanced the discovery of causative variants underlying IEIs and has achieved diagnostic yields of up to 40%. Despite these advances, a substantial proportion of patients still remain genetically undiagnosed due to limitations in detecting deep intronic or structural variants. Accordingly, we applied whole-genome sequencing to a cohort of patients suspected of IEIs in order to evaluate its diagnostic yield and capacity to identify novel structural genomic alterations.</p><p><strong>Methods: </strong>We analyzed data from 25 probands presenting with suspected IEIs based on clinical features, who were enrolled through the National Bio-Big Data Program's whole genome sequencing (WGS) project at Samsung Medical Center, spanning July 2020 to February 2022. The study utilized a stepwise analytical protocol involving initial candidate gene panel analysis for detecting small variants, subsequent investigation of structural variants, and then a genotype-driven approach utilizing in-house bioinformatics pipelines. All identified variants were assessed for pathogenicity in accordance with the 2015 ACMG/AMP guidelines for the interpretation of sequence variants.</p><p><strong>Results: </strong>Causative variants were detected in 10 (40%) probands using candidate gene panel analysis, which included BTK, CYBB, DKC1, DNAH11, DNAH5, IL2RG, NFKB2, PIK3CD and SH2D1A. Genotype-driven analysis identified pathogenic variants in two (8%) probands involving NF1 and PTPN11, while an additional five (20%) probands were found to have structural variants, including BTK, LRBA and SH2D1A. In total, genetic analysis revealed causative variants in 60% of patients. Variants of uncertain significance were identified in four cases among three probands (12%).</p><p><strong>Conclusion: </strong>WGS facilitated the robust identification of causative genetic variants, including complex structural changes. These results suggest that employing WGS in patients suspected of IEIs could provide additional diagnostic yield.</p>","PeriodicalId":15531,"journal":{"name":"Journal of Clinical Immunology","volume":" ","pages":"170"},"PeriodicalIF":4.1,"publicationDate":"2025-11-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12722325/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145582164","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":"The Spectrum of Bacterial Infection in a Large Cohort of Chinese Pediatric Patients with Inborn Errors of Immunity: A Nine-year, Retrospective, Single-center Study.","authors":"Xiaodan Zhu, Pan Fu, Wenjie Wang, Wenjing Ying, Bijun Sun, Jia Hou, Xiaoying Hui, Jinqiao Sun, Chuanqing Wang, Qinhua Zhou, Xiaochuan Wang","doi":"10.1007/s10875-025-01964-1","DOIUrl":"10.1007/s10875-025-01964-1","url":null,"abstract":"<p><strong>Purpose: </strong>This study aimed to investigate the spectrum of bacterial infections in children with inborn error of immunity (IEIs).</p><p><strong>Methods: </strong>Pediatric patients with IEIs and positive for bacteria considered to be pathogenic were included in this retrospective study.</p><p><strong>Results: </strong>In this study, 1811 medical records of IEI inpatients were reviewed, and 243 IEI patients with 290 hospitalizations were enrolled. A total of 361 strains were detected, of which, 83 (22.99%) were gram-positive bacteria, and 278 (77.01%) were gram-negative bacteria. The main bacteria isolated from different IEI classifications were different. Patients with combined immunodeficiencies were more likely to have Klebsiella pneumoniae (12.68%) and Pseudomonas aeruginosa (12.68%) isolated. Patients with predominant antibody deficiencies were more prone to the isolation of Haemophilus influenzae (31.82%) and Moraxella catarrhalis (13.64%). Patients with congenital defects of phagocytes were more frequently associated with the isolation of K. pneumoniae (16.84%) and Escherichia coli (11.58%). Patients with different classifications of IEI were susceptible to specific bacteria. Salmonella was often isolated from patients with defects in intrinsic and innate immunity (4.23%), and Staphylococcus aureus was often isolated from patients with combined immunodeficiencies with syndromic features (5.52%). The percentages of methicillin-resistant S. aureus, carbapenem-resistant E. coli, K. pneumoniae, P. aeruginosa, and Acinetobacter baumannii in IEI patients were55.57%, 38.10%, 25.71%, 25.81%, and 70.59%, respectively, and these values were greater than those in non-IEI patients.</p><p><strong>Conclusion: </strong>Children with IEIs exhibit a unique spectrum of bacterial infections. Bacteria isolated from children with IEIs have high antimicrobial resistance.</p>","PeriodicalId":15531,"journal":{"name":"Journal of Clinical Immunology","volume":"45 1","pages":"163"},"PeriodicalIF":5.7,"publicationDate":"2025-11-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12628442/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145541119","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":"Neurological Phenotypes of SOCS1 Haploinsufficiency: Insights from Functional and Histological Investigations.","authors":"Serena Palmeri, Ignazia Prigione, Francesca Schena, Marie Jeanpierre, Arinna Bertoni, Federica Penco, Paola Bocca, Genny Del Zotto, Sara Massucco, Consuelo Venturi, Angelo Schenone, Gino Tripodi, Giada Recchi, Marina Lanciotti, Maurizio Miano, Caterina Matucci-Cerinic, Gianmaria Viglizzo, Riccardo Papa, Frédéric Rieux-Laucat, Roberta Caorsi, Marco Gattorno, Stefano Volpi","doi":"10.1007/s10875-025-01958-z","DOIUrl":"10.1007/s10875-025-01958-z","url":null,"abstract":"<p><p>Suppressor of cytokine signaling 1 (SOCS1) haploinsufficiency is a recently described inborn error of immunity characterized by autoimmunity, inflammation, lymphoproliferation, and increased infection susceptibility. SOCS1, a negative regulator of cytokine signaling via the JAK/STAT pathway, explains the condition's broad phenotypic variability. Single nucleotide polymorphisms in SOCS1 have been linked to multiple sclerosis (MS), and SOCS1 mimetics have shown efficacy in MS animal models. However, neurological involvement has not been previously reported in patients with SOCS1 insufficiency. We describe a family with a heterozygous SOCS1 variant, highlighting neurological manifestations such as MS, autoimmune encephalitis, and recurrent complex regional pain syndrome as novel features. Next-Generation Sequencing and segregation analysis were performed on PBMCs from patients and healthy donors. Functional studies included luciferase reporter assays in HeLa cells expressing the SOCS1 mutant, flow cytometry for phenotypic analysis, and gene expression profiling of the type-I interferon (IFN) signature. Intraepidermal nerve fiber density was evaluated via immunohistochemistry on skin biopsy. Genetic analysis confirmed the variant's inheritance. Transfected cells carrying the SOCS1 variant showed increased STAT1 transcriptional activity after IFN-γ stimulation. Elevated STAT5 phosphorylation and T-cell proliferation were observed in response to IL-2. Peripheral blood revealed an elevated IFN signature during relapse. Skin biopsy showed reduced intraepidermal nerve fiber density. This report expands the clinical spectrum of SOCS1-related disorders to include neurological symptoms, emphasizing SOCS1's critical role in regulating inflammation in the central and peripheral nervous systems.</p>","PeriodicalId":15531,"journal":{"name":"Journal of Clinical Immunology","volume":"45 1","pages":"165"},"PeriodicalIF":5.7,"publicationDate":"2025-11-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12628480/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145541162","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":"STAT-1 gain-of-function CMC: Remission of Oral Candidiasis during PD-1 Inhibitor Treatment of Oral Cancer.","authors":"Jannik Helweg-Larsen, Ditte Marie L Saunte, Line Borgwardt, Claus Andrup Kristensen, Hanne Marquart","doi":"10.1007/s10875-025-01948-1","DOIUrl":"10.1007/s10875-025-01948-1","url":null,"abstract":"","PeriodicalId":15531,"journal":{"name":"Journal of Clinical Immunology","volume":"45 1","pages":"164"},"PeriodicalIF":5.7,"publicationDate":"2025-11-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12628487/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145541187","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}