Frontiers in Immunology最新文献

{"title":"Identification of shared neoantigens derived from frameshift mutations in the <i>APC</i> gene.","authors":"Peng Zhao, Clara Effenberger, Saki Matsumoto, Toshihiro Tanaka, Yusuke Nakamura, Kazuma Kiyotani","doi":"10.3389/fimmu.2025.1574955","DOIUrl":"https://doi.org/10.3389/fimmu.2025.1574955","url":null,"abstract":"<p><p>Recent advances of cancer immunotherapy have identified neoantigens as essential targets for personalized treatments. However, since neoantigens are generally unique in individual cancers, neoantigen therapies that are more broadly applicable are eagerly awaited. Shared neoantigens, derived from recurrent mutations found across multiple patients, are considered to be a challenging, but promising approach. Here we analyzed shared frameshift neoantigens derived from frameshift indels in TCGA exome sequencing data and identified 760 possible recurrent frameshift mutation clusters (FSCs) that share frameshifted open reding frames and premature stop codons. Among them, we investigated FSCs in the <i>APC</i> gene (APC-F2-1472* and APC-F3-1512*) and identified HLA-A*24:02-restricted frameshift neoantigen peptides that elicited specific CD8⁺ T cell responses. Subsequently we identified their corresponding T cell receptor (TCR) sequences and generated genetically-engineered T cells expressing these APC frameshift neoantigen-specific TCRs. These engineered T cells specifically recognized target cells presenting these neoantigens and cytotoxic activity against them, supporting the therapeutic potential of targeting APC frameshift neoantigens in cancer immunotherapy. This study provides compelling evidence for the development of neoantigen-based therapies targeting common frameshift peptides, offering a promising approach for more effective, relatively broadly applicable immunotherapeutic strategies that could benefit a subset population of cancer patients.</p>","PeriodicalId":12622,"journal":{"name":"Frontiers in Immunology","volume":"16 ","pages":"1574955"},"PeriodicalIF":5.7,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12119627/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144180542","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":"Case Report: Anti-NMDAR encephalitis associated with neurobrucellosis: causality or coexistence?","authors":"Yao Wang, Xue Ma, Chao Ma, Tangna Sun, Daidi Zhao, Hongzeng Li, Yaping Yan, Jun Guo","doi":"10.3389/fimmu.2025.1536740","DOIUrl":"https://doi.org/10.3389/fimmu.2025.1536740","url":null,"abstract":"<p><p>Human brucellosis, caused by <i>Brucella</i>, is an infectious disease with specific endemic regions, especially in pastoral areas, and may affect multiple organ systems. Neurological involvement, namely neurobrucellosis, occurs in very few of these patients. Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is the most frequent type of autoimmune encephalitis and is usually associated with tumors or herpes simplex virus infections. However, the link between the two disease entities is unknown. In this report, we present a rare case of a 29-year-old Chinese man with anti-NMDAR encephalitis associated with neurobrucellosis, with the detection of anti-NMDAR antibodies by cell-based assay and <i>Brucella melitensis</i> by metagenomic next-generation sequencing in his cerebrospinal fluid sample. The patient improved after antimicrobial treatment and immunotherapies, including steroids and intravenous immunoglobulin. This case implicates <i>Brucella</i> infection as a possible trigger for the production of anti-NMDAR antibodies, and prospective studies should reveal whether there is a casual relationship between brucellosis and anti-NMDAR antibodies.</p>","PeriodicalId":12622,"journal":{"name":"Frontiers in Immunology","volume":"16 ","pages":"1536740"},"PeriodicalIF":5.7,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12119473/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144181694","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":"Mapping autoantibody targets of full-length C-reactive protein in systemic lupus erythematosus: importance for neutrophil function and classical complement activation.","authors":"Jesper Karlsson, Lina Wirestam, Hanna Duàn, Suhana Ahmad, Daniel Appelgren, Helena Enocsson, Jonas Wetterö, Christopher Sjöwall","doi":"10.3389/fimmu.2025.1578372","DOIUrl":"https://doi.org/10.3389/fimmu.2025.1578372","url":null,"abstract":"<p><p>C-reactive protein (CRP) is an important pattern recognition molecule of innate immunity. Autoantibodies targeting CRP are common in patients with systemic lupus erythematosus (SLE) and the levels correlate with disease activity. The purpose of this study was to investigate binding sites of IgG autoantibodies on the full linear sequence of CRP and identify potential associations with clinical variables in well-characterized SLE patients; a secondary aim was to investigate the effect of an epitope-based synthesized peptide motif on neutrophil functions. The levels of anti-CRP and SLE-associated antibodies were assessed, and a microarray-based linear epitope mapping was performed to detect binding sites on the full CRP monomer. We observed that anti-CRP antibodies bind to a variety of linear epitopes with a higher prevalence in SLE compared to healthy blood donors. Eleven unique epitopes were identified, of which five were found exclusively in SLE. Furthermore, we show that patients with anticardiolipin IgG and/or anti-β2GPI IgG antibodies have a higher number of positive CRP epitopes, and some CRP autoantibody-specificities associate with antiphospholipid antibodies, disease activity, and classical complement activation. In addition, one identified motif was selected, synthesized, and used for studying neutrophil function. This peptide showed modulatory capacity on neutrophil oxidative burst and chemotaxis, but not on neutrophil extracellular trap formation. Our results implicate a wide variation of anti-CRP autoantibody binding motifs of the linear structure of CRP in SLE patients. Some epitopes have the potential to modify innate host responses of relevance to the pathogenesis of SLE.</p>","PeriodicalId":12622,"journal":{"name":"Frontiers in Immunology","volume":"16 ","pages":"1578372"},"PeriodicalIF":5.7,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12119686/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144181730","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":"Corrigendum: Microbiota-derived extracellular vesicles: current knowledge, gaps, and challenges in precision nutrition.","authors":"Elvira Marquez-Paradas, Maria Torrecillas-Lopez, Luna Barrera-Chamorro, Jose L Del Rio-Vazquez, Teresa Gonzalez-de la Rosa, Sergio Montserrat-de la Paz","doi":"10.3389/fimmu.2025.1599029","DOIUrl":"https://doi.org/10.3389/fimmu.2025.1599029","url":null,"abstract":"<p><p>[This corrects the article DOI: 10.3389/fimmu.2025.1514726.].</p>","PeriodicalId":12622,"journal":{"name":"Frontiers in Immunology","volume":"16 ","pages":"1599029"},"PeriodicalIF":5.7,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12120555/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144183626","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":"Bioinformatics analyses of the proteome of <i>Holothuria tubulosa</i> coelomic fluid and the first evidence of primary cilium in coelomocyte cells.","authors":"Laura La Paglia, Manuela Mauro, Vincenzo Arizza, Alfonso Urso, Sugár Simon, Laszlo Drahos, Vita di Stefano, Claudio Luparello, Mirella Vazzana, Aiti Vizzini","doi":"10.3389/fimmu.2025.1539751","DOIUrl":"https://doi.org/10.3389/fimmu.2025.1539751","url":null,"abstract":"<p><p>The holothurian immune system is characterized by complex defense mechanisms that act through humoral and cellular pathways. Coelomocites are the cellular component of coelomic fluid, and they are involved in host defense, stress response, wound healing, organ regeneration, and tissue homeostasis. The close phylogenetic relationship between <i>Holothuria tubulosa</i> and chordate phylum makes it a good model for studying the evolution of immune processes. To elucidate the immune landscape in <i>H. tubulosa</i>, we applied an approach combining proteomic analysis of coelomic fluid separated into cellular fraction and extracellular fraction and bioinformatics and in silico analyses. A Search Tool for the Retrieval of Interacting Genes/Protein analysis indicated a highly functional homology to the human protein of immune recognition factors, non-canonical immune-related proteins, signaling molecules, and effector protein, cytoskeleton, and actin remodeling, and provided the first evidence in invertebrate immune cells of an intracellular protein fraction linked to ancestral structure resembling primary cilium involved in cell signaling.</p>","PeriodicalId":12622,"journal":{"name":"Frontiers in Immunology","volume":"16 ","pages":"1539751"},"PeriodicalIF":5.7,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12119288/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144181015","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":"Relationship between advanced lung cancer inflammation index and all-cause and cause-specific mortality among chronic inflammatory airway diseases patients: a population-based study.","authors":"Zhuanbo Luo, Peixu Chen, Shiyu Chen, Xue Kong, Hongying Ma, Chao Cao","doi":"10.3389/fimmu.2025.1585927","DOIUrl":"https://doi.org/10.3389/fimmu.2025.1585927","url":null,"abstract":"&lt;p&gt;&lt;strong&gt;Background: &lt;/strong&gt;Chronic inflammatory airway diseases (CIAD), such as asthma, chronic bronchitis, and chronic obstructive pulmonary disease, pose a significant threat to public health, with its prognosis closely tied to the body's inflammation level and nutritional status. As a composite indicator, the advanced lung cancer inflammation index (ALI) integrates inflammation and nutritional status. Despite its potential utility, the link between ALI and the prognosis of patients with CIAD remains unexplored. This study aimed to investigate this relationship.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Methods: &lt;/strong&gt;We gathered data from the National Health and Nutrition Examination Survey (NHANES) from 2013 to 2018. The National Death Index was used to calculate mortality until December 31, 2019. Kaplan-Meier analysis was employed to investigate the relationships between ALI and all-cause and cause-specific mortality in patients with CIAD. Furthermore, weighted univariable and multivariable Cox proportional hazards models were employed to further examine their relationship. Multiple factors that could impact the results were adjusted in the analysis. We also utilized a restricted cubic spline analysis to estimate the non-linear relationships between ALI and all-cause and cause-specific mortality rates in patients with CIAD. Finally, subgroup and sensitivity analyses were conducted to ensure the reliability of the findings.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Results: &lt;/strong&gt;The study involved 2,884 CIAD patients. An elevated ALI was significantly related to a decreased risk of all-cause mortality, as well as mortality from cardiovascular and respiratory diseases among CIAD patients. Results from RCS analysis revealed a reverse J-shaped non-linear association between ALI and all-cause mortality in CIAD patients, with an inflection point at 99 (p for nonlinearity &lt;0.0001). The inflection point in the J-shaped relationship represents the ALI value with the lowest risk of mortality. For ALI values below 99, a 10-unit rise in ALI was linked to a 14% reduction in the risk of all-cause mortality (HR: 0.86, 95% CI:0.81-0.92, Ptrend=0.01). Conversely, if ALI exceeded 99, a 10-unit increase in ALI resulted in a 3% rise in the risk of all-cause mortality (HR: 1.03, 95% CI:1.01-1.06, Ptrend=0.02). A similar J-shaped association was observed in mortality due to cardiovascular and respiratory diseases, with inflection points at 94 and 96, respectively. These findings were consistent across sociodemographic and prior disease-related subgroups, and remained stable in sensitivity analyses.&lt;/p&gt;&lt;p&gt;&lt;strong&gt;Conclusion: &lt;/strong&gt;This study revealed a novel association between elevated ALI level and reduced all-cause and cause-specific mortality risk in patients with CIAD. Furthermore, the relationship between ALI and mortality rates from all cause, as well as cardiovascular and respiratory diseases, exhibited an non-linear, J-shaped curve. These findings underscore the importance of maintaining optimal","PeriodicalId":12622,"journal":{"name":"Frontiers in Immunology","volume":"16 ","pages":"1585927"},"PeriodicalIF":5.7,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12119279/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144181185","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":"An exploratory study on the metagenomic and proteomic characterization of hypothyroidism in the first half of pregnancy and correlation with Th1/Th2 balance.","authors":"Chenchen Zhang, Yajuan Xu, Miao Zhang, Jingjing Li, Zongzong Sun, Yixin Wang, Pengkun Lin","doi":"10.3389/fimmu.2025.1500866","DOIUrl":"https://doi.org/10.3389/fimmu.2025.1500866","url":null,"abstract":"<p><strong>Objective: </strong>To explore the gut microbiota and proteomic characteristics of hypothyroidism in the first half of pregnancy (referred to as hypothyroidism in the first half of pregnancy) and its association with Th (T helper cells, Th)1/Th2 balance using metagenomics combined with proteomics.</p><p><strong>Methods: </strong>Stool and blood samples were collected from 20 hypothyroid (hypothyroidism group) and normal pregnant women (normal group) in the first half of pregnancy. Flora and proteomic characteristics were analyzed using metagenomics sequencing and 4D-DIA proteomics. Th1 and Th2 cells were quantified, and cytokine levels were measured using cellular micro-bead arra. The enzyme-linked immunosorbent test (ELISA) was utilized to assess differential proteins.</p><p><strong>Results: </strong>(1) Metagenomic sequencing revealed distinct microbial profiles: The β-diversity of gut microbiota was diminished in the hypothyroidism group (p < 0.05). LEfSe analysis identified <i>Phocaeicola vulgatus</i> and <i>Bacteroides fragilis</i> enriched in the hypothyroidism group (p<0.05), and Kyoto Encyclopedia of Genes and Genomes(KEGG) analysis showed significant enrichment in pathways related to peptidoglycan biosynthesis and glycerol ester metabolism.(2) Proteomic analysis demonstrated downregulation of Diacylglycerol Kinase Kappa (DGKK) and P05109|S10A8(S10A8) proteins in the hypothyroidism group, with marked enrichment in the KEGG pathways for vascular smooth muscle contraction and phosphatidylinositol signaling. (3) ELISA validation confirmed that the proteins DGKK and S10A8 were downregulated in pregnant women in the hypothyroidism group.</p><p><strong>Conclusion: </strong>Increased <i>P. vulgatus</i> and <i>B. fragilis</i>, decreased DGKK and S10A8 proteins, and a left shift in the Th1/Th2 balance in patients with hypothyroidism in the first half of pregnancy may be associated with the development of the disease.</p>","PeriodicalId":12622,"journal":{"name":"Frontiers in Immunology","volume":"16 ","pages":"1500866"},"PeriodicalIF":5.7,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12120637/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144181796","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 characteristics, prognosis, and predictive modeling in class IV ± V lupus nephritis.","authors":"Anjing Wang, Yunlong Qin, Yan Xing, Zixian Yu, Liuyifei Huang, Jinguo Yuan, Yueqing Hui, Mei Han, Guoshuang Xu, Jin Zhao, Shiren Sun","doi":"10.3389/fimmu.2025.1580146","DOIUrl":"https://doi.org/10.3389/fimmu.2025.1580146","url":null,"abstract":"<p><strong>Objective: </strong>The objective of this study is to compare the clinical features and survival outcomes of class IV ± V lupus nephritis (LN) patients, identify risk factors, and develop an accurate prognostic model.</p><p><strong>Methods: </strong>This study enrolled patients diagnosed with class IV ± V LN by renal biopsy at Xijing Hospital from December 2013 to June 2023. The composite endpoint of the study was defined as a decline in the estimated glomerular filtration rate (eGFR) by more than 50%, progression to end stage renal disease, or death, whichever came first. The eGFR was calculated utilizing the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula. ESRD is defined as an eGFR less than 15ml/min/1.73m², necessitating the commencement of chronic dialysis (hemodialysis or peritoneal dialysis) or kidney transplantation. We compared the baseline features and survival prognosis between patients with class IV ± V LN. The prognostic model was developed using machine learning algorithms and Cox regression. The model's performance was evaluated in terms of discrimination, calibration, and risk classification using the concordance index (C-index), integrated brier score (IBS), net reclassification index (NRI), and integrated discrimination improvement (IDI), respectively.</p><p><strong>Results: </strong>A total of 313 patients were enrolled for this study, including 156 class IV and 157 class IV+V LN. During the median follow-up period of 42.6 (17.0, 83.4) months, 35 (22.4%) class IV and 38 (24.2%) class IV+V LN patients experienced combined events. Class IV and class IV+V patients have similar clinical manifestations, treatment strategies, and long-term prognosis, despite class IV having a higher chronic index (CI) score (<i>P</i> < 0.001). Seven eligible variables (eGFR, CI, age, basophil percentage, red blood cell count, mean arterial blood pressure, and uric acid) were selected to develop the random survival forest (RSF) model. This model demonstrated the best performance with a C-index of 0.771 (0.667, 0.848) and an IBS of 0.144 (0.132, 0.154). The IDI and NRI in the testing set further confirmed that the RSF model exhibited superior risk classification and discrimination capabilities.</p><p><strong>Conclusion: </strong>Class IV ± V LN was similar in clinical manifestations, treatment strategies, and long-term prognosis, despite differences in pathological features. The RSF model we established for class IV ± V LN patients, incorporating seven risk factors, exhibits superior survival prediction and provides more precise prognostic stratification.</p>","PeriodicalId":12622,"journal":{"name":"Frontiers in Immunology","volume":"16 ","pages":"1580146"},"PeriodicalIF":5.7,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12119475/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144183625","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":"Bispecific antibody targeting shared indel-derived neoantigen of APC.","authors":"Clara Effenberger, Xiaojing Wu, Peng Zhao, Saki Matsumoto, Yusuke Nakamura, Kazuma Kiyotani","doi":"10.3389/fimmu.2025.1574958","DOIUrl":"https://doi.org/10.3389/fimmu.2025.1574958","url":null,"abstract":"<p><p>T cells play a pivotal role in cancer immunotherapy by recognizing tumor-specific neoantigens presented on HLA molecules, which are specifically expressed on cancer cells. While neoantigens are generally unique to individual cancers, certain neoantigens, known as 'shared neoantigens' that are common in a subset of cancer patients, represent promising immunotherapeutic targets. We previously identified an immunogenic shared frameshift neoantigen, 1472SP2, derived from recurrent frameshift indel mutation cluster (APC-F2-1472*) in the <i>APC</i> gene and presented on HLA-A24:02. In this study, we attempted to identify an antibody targeting a complex formed by the APC 1472SP2 neoantigen and HLA-A24. Using the phage display library screening, we isolated single-chain variable fragments (scFvs) that specifically recognize the 1472SP2/HLA-A24 complex. We then designed a bispecific antibody (BsAb) that would connect T cells via an anti-CD3 scFv to the cancer-specific 1472SP2 presented on the HLA-A24 molecule. ELISA analysis revealed that BsAb specifically recognized both 1472SP2-HLA-A24 monomer and CD3 protein. When T cells were co-cultured with antigen-presenting cells expressing HLA-A24:02, IFN-γ release and cytotoxicity were observed only in the presence of 1472SP2-BsAb, indicating that the 1472SP2-BsAb effectively activated T cells to lyse target cells presenting this neoantigen. This approach implies an off-the-shelf, cancer selective approach to target cancers expressing shared neoantigens for patients who are difficult to treat with conventional therapies.</p>","PeriodicalId":12622,"journal":{"name":"Frontiers in Immunology","volume":"16 ","pages":"1574958"},"PeriodicalIF":5.7,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12119644/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144179946","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":"Granulomatous lymphocytic interstitial lung disease in common variable immune deficiency: an in-depth clinical, immunological, functional and radiological exploration with a focus on its management, challenged by chronic CMV infection.","authors":"Mattia Moratti, Gioacchino Schifino, Francesco Baccelli, Simona Ferrari, Elisabetta Magrini, Mirna Bassi, Aldo Guerrieri, Maurizio Zompatori, Marcello Lanari, Francesca Conti","doi":"10.3389/fimmu.2025.1589052","DOIUrl":"https://doi.org/10.3389/fimmu.2025.1589052","url":null,"abstract":"<p><strong>Background: </strong>Common variable immune deficiency (CVID) is the most prevalent inborn error of immunity (IEI), marked by diverse clinical-immunological phenotypes and significant immune-dysregulation, including granulomatous lymphocytic interstitial lung disease (GLILD). GLILD is a severe manifestation of CVID, contributing to reduced life expectancy and a challenging diagnosis due to its insidious and non-specific clinical course. Current management strategies for GLILD rely on expert opinion due to a lack of randomized controlled trials (RCTs).</p><p><strong>Objectives: </strong>This study aims to provide a comprehensive immunophenotypical characterization of CVID patients with and without GLILD, investigate predictive biomarkers for GLILD development, and explore therapeutic strategies, particularly during concomitant SARS-CoV-2 and chronic cytomegalovirus (CMV) infections.</p><p><strong>Sources: </strong>Primary data were collected from a cohort of 25 patients with CVID who underwent high-resolution computed tomography (HRCT), immunophenotyping, and serum immunoglobulin analysis at diagnosis and after immunoglobulin replacement therapy. Existing literature on CVID and GLILD biomarkers, immunological profiles, and therapeutic interventions informed comparative analyses.</p><p><strong>Content: </strong>Patients with GLILD exhibited distinct immunophenotypical features, including reduced regulatory T-cells, CD8+ naïve, central memory T-cells, and B-cell subsets (memory and switched memory), alongside increased CD21low B-cells and naïve B-cells, indicative of chronic inflammation-driven immune activation. IgA and IgG4 concentrations were significantly lower in patients with GLILD at diagnosis. Immunosuppressive therapy, predominantly mycophenolate mofetil (MMF), demonstrated favorable clinical and functional outcomes, though radiological progression persisted in some cases. CMV infection in patients with GLILD on immunosuppressants resulted in favorable outcomes, underscoring the importance of personalized treatment strategies.</p><p><strong>Implications: </strong>This study highlights novel immunological markers and clinical-radiological patterns as potential predictors for GLILD, advocating for their integration into diagnostic and monitoring frameworks to reduce reliance on invasive histopathology. Future research should focus on validating biomarkers and conducting RCTs to establish evidence-based guidelines for GLILD management.</p>","PeriodicalId":12622,"journal":{"name":"Frontiers in Immunology","volume":"16 ","pages":"1589052"},"PeriodicalIF":5.7,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12119541/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144181546","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}