Immunologic Research最新文献

{"title":"Integrative multi-omics analyses suggest a candidate microbial metabolite-associated host gene network in ulcerative colitis.","authors":"Jingren Yan, Shun Ding","doi":"10.1007/s12026-026-09837-4","DOIUrl":"10.1007/s12026-026-09837-4","url":null,"abstract":"<p><p>Ulcerative colitis (UC) is associated with gut microbial dysbiosis, but the host molecular alterations potentially linked to microbially derived metabolites remain incompletely understood. We integrated Mendelian randomization (MR), microbial metabolite annotation, computational target prediction, colonic transcriptomics, network analysis, and machine learning. MiBioGen microbiome GWAS data were used as exposures and FinnGen Release 12 ULCERENTER as the outcome. Metabolites linked to MR-prioritized taxa were retrieved from GutMGene, and human targets were predicted using SwissTargetPrediction and SEA. UC-related genes were defined by integrating differential expression analysis and WGCNA and then intersected with predicted metabolite targets. MR prioritized one family and eight genera showing nominal genetically supported associations with UC, but none remained significant after Benjamini-Hochberg FDR correction. Three prioritized genera were linked to 15 microbe-metabolite records, corresponding to 13 unique metabolites; nine were retained for target prediction, yielding 277 unique predicted human targets. Transcriptomic analysis identified 1,530 DEGs and a 312-gene MEgrey60 module, with 273 overlapping genes, producing 1,569 unique UC-related genes. Their intersection with the 277 predicted targets yielded 47 candidate genes. Enrichment analyses highlighted mainly metabolic and lipid-related processes. Random Forest showed the highest mean AUC across the two independent external benchmarking cohorts, and SHAP prioritized EPHX1, HSD17B2, IGFBP5, and MMP10. IBDome analysis showed inflammation-associated expression differences in these genes. This study provides a genomics-informed, hypothesis-generating framework that prioritizes candidate microbe-metabolite-host relationships in UC for future experimental validation.</p>","PeriodicalId":13389,"journal":{"name":"Immunologic Research","volume":"74 1","pages":""},"PeriodicalIF":2.7,"publicationDate":"2026-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148890810","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Expression of TAM receptors and their ligands in unexplained recurrent pregnancy loss.","authors":"Esma Kirimlioglu, Mehmet Simsek, Farida Yıldırım Quliyeva, Necdet Demir","doi":"10.1007/s12026-026-09836-5","DOIUrl":"10.1007/s12026-026-09836-5","url":null,"abstract":"<p><p>Recurrent pregnancy loss (RPL) is clinically defined as two or more pregnancy failures before 20-24 weeks of gestation. Over 50% of RPL cases have no identified etiology and are classified as unexplained recurrent pregnancy loss (URPL). The TAM receptor tyrosine kinase (RTK) family, including TYRO3, AXL, MERTK, GAS6, and PROS1, plays critical roles in suppressing excessive inflammation and apoptosis. Although increased serum levels of these molecules have been observed in pregnancy complications such as preeclampsia, their role in URPL remains unexplored. We hypothesized that TAM receptors contribute to the immunoregulation of the maternal-fetal interface, playing a pivotal role in the development of semi-allogeneic fetuses and the pathogenesis of URPL. To test this hypothesis, we analyzed three groups: Control Endometrium (CE; n = 6), Terminated Pregnancy (TP; n = 6), and URPL (n = 6). AXL, MERTK, GAS6, and PROS1 mRNA levels were quantified by qPCR, and protein levels were evaluated using immunohistochemistry and immunoblotting. Our findings revealed a significant increase in AXL, MERTK, GAS6, and PROS1 expression in both maternal and fetal tissues of the URPL group compared to the CE and TP groups. These molecules exhibited intense perinuclear and cytoplasmic expression, particularly in immune cells and trophoblasts. This study demonstrates for the first time that AXL, MERTK, GAS6, and PROS1 are involved in URPL, highlighting their potential roles in fetal acceptance via decidual polyploid cells and in regulating inflammation and apoptosis during implantation.</p>","PeriodicalId":13389,"journal":{"name":"Immunologic Research","volume":"74 1","pages":""},"PeriodicalIF":2.7,"publicationDate":"2026-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148880266","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A novel FLNA p.Pro2469Ser variant is associated with impaired T and NK cell function and immune dysregulation.","authors":"Şerife Erdem, Ayşenur Paç Kısaarslan, Mustafa Burak Acar, Muhammet Ensar Doğan, Sümeyra Özdemir Çiçek, Pınar Garipcin, Şerife Ayaz Güner, Alper Özcan, Şule Haskoloğlu, Benhur Şirvan Çetin, Derya Altay, Mehmet Köse, Buket Daldaban Sarıca, Serkan Belkaya, Kemal Erdem Başaran, Figen Doğu, Kamile Aydan İkincioğulları, Ekrem Ünal, Ahmet Eken","doi":"10.1007/s12026-026-09823-w","DOIUrl":"10.1007/s12026-026-09823-w","url":null,"abstract":"<p><p>FLNA encodes filamin A, a ubiquitously expressed actin-binding cytoskeletal protein that cross-links actin filaments and links them to membrane-associated signaling complexes. Although FLNA has been implicated in T-cell signaling and regulatory T-cell development in murine models, its role in human immune-cell function remains incompletely understood. Here, we investigated the immunological phenotype associated with a novel hemizygous FLNA variant identified in a pediatric patient presenting with recurrent infections and inflammatory manifestations. Whole-exome sequencing revealed a hemizygous c.7405C>T (p.Pro2469Ser) variant in FLNA, which was confirmed by Sanger sequencing. Its potential impact on immune-cell function and cytoskeletal organization was evaluated using confocal microscopy, flow cytometry, and molecular assays. Patient-derived T cells showed impaired activation and proliferation following CD3/CD28 and IL-2 stimulation, accompanied by reduced CD25 and CD69 upregulation. CD4+ T cells also exhibited reduced IFN-γ, TNF-α, and IL-2 production after stimulation. Despite elevated basal phospho-STAT5 levels, IL-2-induced STAT5 phosphorylation and TCR-associated signaling responses, including pZAP70, pLCK, and p38 MAPK activation, were attenuated. Confocal imaging together with image-based quantification demonstrated altered cortical cytoskeletal organization in patient T cells despite preserved FLNA expression. In parallel, NK cells showed impaired activation responses and reduced cytotoxic activity under the assay conditions used. Increased apoptosis was observed in CD4⁺, CD8⁺, and NK-cell populations. Inflammatory cytokines were elevated in plasma and colonic tissue, whereas colonic ZO-1 and FLNA expression were reduced. Collectively, these findings indicate that the FLNA p.Pro2469Ser variant is associated with altered immune-cell signaling, disturbed cortical cytoskeletal organization, and immune dysregulation. This study expands the phenotypic spectrum linked to FLNA variants and supports a role for filamin A in human immune-cell regulation.</p>","PeriodicalId":13389,"journal":{"name":"Immunologic Research","volume":"74 1","pages":""},"PeriodicalIF":2.7,"publicationDate":"2026-08-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148864199","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Host genetic determinants of HTLV-1 infection outcomes.","authors":"Mohammad Mehdi Akbarin, Zahra Farjami, Hugo Ramírez Álvarez","doi":"10.1007/s12026-026-09833-8","DOIUrl":"10.1007/s12026-026-09833-8","url":null,"abstract":"<p><p>Human T-cell lymphotropic virus type 1 (HTLV-1) is a persistent human retrovirus associated with severe outcomes, most notably adult T-cell leukemia/lymphoma (ATLL) and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). Despite lifelong infection, only a minority of carriers develop clinical disease, highlighting a decisive role for host genetic background in shaping viral control, immune activation, and pathogenic progression. This mini-review synthesizes evidence demonstrating how inherited host genetic variation and acquired somatic alterations influence HTLV infection outcomes. Polymorphisms in HLA class I and II genes critically modulate antigen presentation and cytotoxic or helper T-cell responses, thereby regulating proviral load and immune-mediated tissue damage. Variants in cytokine, chemokine, and innate restriction factor genes, including IL28B, IL8, TRIM5α, and APOBEC family members, further influence viral persistence and inflammatory risk. In parallel, accumulating somatic mutations in TP53, CCR4, JAK/STAT components, NOTCH1, and epigenetic regulators such as TET2 and KMT2D drive clonal expansion, genomic instability, and malignant transformation in ATLL. Together, these data support a continuum model in which inherited host genetics condition viral persistence and immune pressure, while acquired genetic and epigenetic lesions determine disease phenotype and severity. Integrating host genomics with viral genetics and clonal evolution analyses will be essential for developing predictive biomarkers and personalized therapeutic strategies for HTLV-associated diseases.</p>","PeriodicalId":13389,"journal":{"name":"Immunologic Research","volume":"74 1","pages":""},"PeriodicalIF":2.7,"publicationDate":"2026-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13518425/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148828001","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mortality in Behçet's Syndrome in a non-endemic population: a 25-year cohort study.","authors":"Mônica Raquel de Souza Aquino, Barbara Bayeh, Carolina Ejnisman, Fabio Augusto da Rocha Specian, Rafael Bassara Macedo, Pedro Cargnelutti de Araujo, Guilherme Diogo Silva, Gisela Tinone, Rafael Alves Cordeiro, Thiago Quadrante Freitas, Henrique Ayres Mayrink Giardini","doi":"10.1007/s12026-026-09832-9","DOIUrl":"10.1007/s12026-026-09832-9","url":null,"abstract":"<p><p>Mortality in Behçet's syndrome (BS) has been consistently associated with neurological and vascular involvement in studies from endemic regions. However, data from non-endemic countries remain limited. This study aimed to evaluate long-term mortality and identify factors associated with mortality in a large Brazilian cohort of patients with BS. We conducted a retrospective cohort study including 303 adult patients diagnosed with BS and followed at a tertiary referral center in São Paulo, Brazil, between January 2000 and December 2024. Demographic, clinical, comorbidity, and treatment data were collected. Mortality rates were assessed, and factors associated with mortality were analyzed using unadjusted Cox proportional hazards models, with hazard ratios (HRs) and 95% confidence intervals (CIs). Among the 303 patients included, 61.6% were female, with a median follow-up of 117 months (IQR 55-184). A total of 162 patients (53.4%) were lost to follow-up. Eight deaths (2.6%) occurred during the study period. Given the limited number of events, only exploratory, unadjusted analyses were performed. Pulmonary artery aneurysm (HR 28.44, 95% CI 3.32-243.52; p = 0.002), central nervous system (CNS) parenchymal involvement (HR 6.81, 95% CI 1.65-28.06; p = 0.008), diabetes mellitus (HR 6.72, 95% CI 1.67-27.03; p = 0.007), and malignancy (HR 8.81, 95% CI 2.02-38.50; p = 0.004) were associated with increased mortality. Our exploratory analyses suggest that vascular and neurological involvement, particularly pulmonary artery aneurysm and CNS parenchymal disease, may be associated with increased mortality in our population.</p>","PeriodicalId":13389,"journal":{"name":"Immunologic Research","volume":"74 1","pages":""},"PeriodicalIF":2.7,"publicationDate":"2026-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13518407/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148828029","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Reprogramming immunometabolism: linking nutrient sensing, cell death, and therapeutic innovation.","authors":"Priya Sharma","doi":"10.1007/s12026-026-09831-w","DOIUrl":"10.1007/s12026-026-09831-w","url":null,"abstract":"<p><p>Development of Immunometabolism as a central paradigm in the modern immunology has revolutionized the understanding of metabolism from being a passive supplier of energy to an important determinant of immune cell fate and function. Immune cells are activated, differentiated, survive and undergo programmed cell death through the activity of distinct metabolic programs, including those involving glycolysis, oxidative phosphorylation (OXPHOS), nutrient sensing through Mechanistic Target of Rapamycin (mTOR), AMP-Activated Protein Kinase (AMPK), and HIF‑1α. Rapid proliferation and production of cytokines by effector T cells and pro-inflammatory macrophages is mediated by glycolysis, while persistence and tolerance by memory T cells and reparative macrophages is mediated by oxidative metabolism. Metabolic input and output are also coupled with immune specialization and cell death mechanisms, such as apoptosis, Pyroptosis and ferroptosis, via mitochondrial bioenergetics and production of Reactive Oxygen Species (ROS). Altered immunometabolism is linked to a variety of pathologies: competition for nutrients in tumor physiology leads to T cell exhaustion; an unchecked glycolytic pathway maintains a state of autoimmune inflammation; pathogens exploit host metabolism to escape immunological control; and metabolic diseases, such as obesity and diabetes, foster chronic low‑grade inflammation. Therapies such as rapamycin, metformin, glycolysis and glutamine inhibitors, and metabolic adjuvants in vaccines underscore the translational potential of targeting metabolic checkpoints. But there are still debates on the specificity of the metabolic intervention, the balance between the effector and regulation responses, and the restrictions of the existing experimental models. New strategies, such as single-cell metabolomics and precision medicine, are expected to bring in more sophisticated ways for fine-tuning immune metabolism. Immunometabolism is thus a paradigm shift, with metabolism now being at the heart of immune regulation, and providing new opportunities for critical evaluation and translational innovation in cancer, autoimmunity, infections and metabolic disease.</p>","PeriodicalId":13389,"journal":{"name":"Immunologic Research","volume":"74 1","pages":""},"PeriodicalIF":2.7,"publicationDate":"2026-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148818359","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Multifocal HPV16-positive squamous cell carcinomas in CTLA-4 haploinsufficiency: expanding the spectrum of virus-associated malignancies.","authors":"Christian Arvei Moen, Kristin Greve-Isdahl Mohn, Alexander Marks, Thea E Hetland Falkenthal, Patrick Juliebø-Jones, Hans Jørgen Aarstad, Svein Erik Moe, Christian Beisland, Daniela Elena Costea, Elisabet Ognedal, Eirik Bratland, Hildegunn Høberg Vetti, Ellen Berget","doi":"10.1007/s12026-026-09830-x","DOIUrl":"10.1007/s12026-026-09830-x","url":null,"abstract":"<p><p>Cytotoxic T-lymphocyte associated protein 4 (CTLA-4) haploinsufficiency is an inborn error of immunity characterized by immune dysregulation, autoimmunity, lymphoproliferation, and an increased risk of malignancy. While susceptibility to oncogenic viral infections has been proposed, the relationship between CTLA-4 haploinsufficiency and human papillomavirus (HPV)-driven carcinogenesis remains poorly characterized. We describe a patient with CTLA-4 haploinsufficiency who developed multiple HPV-associated malignancies. Clinical, pathological, virological, and genetic data were reviewed. Germline genetic testing was performed using whole-exome sequencing, and HPV DNA analysis was conducted on available tumor specimens. A man with a history of alopecia totalis and autoimmune thyroiditis developed five distinct malignancies by the age of 50 years, including Epstein-Barr virus (EBV)-associated gastric Hodgkin lymphoma, cutaneous squamous cell carcinoma (SCC), and three independent HPV16-positive SCCs involving the oral cavity, anus, and penis. Germline testing identified CTLA-4 haploinsufficiency caused by a likely pathogenic CTLA4 variant, c.406C > T (p.Pro136Ser). No additional germline variants associated with hereditary cancer predisposition were detected. HPV DNA analysis demonstrated HPV16 positivity in all three mucosal SCCs. This case expands the spectrum of malignancies associated with CTLA-4 haploinsufficiency and suggests that persistent high-risk HPV infection may represent an underrecognized complication of this disorder. The occurrence of three independent HPV16-positive SCCs raises the possibility that CTLA-4 deficiency predisposes to HPV-driven carcinogenesis and supports further investigation of HPV surveillance and cancer prevention strategies in affected individuals.</p>","PeriodicalId":13389,"journal":{"name":"Immunologic Research","volume":"74 1","pages":""},"PeriodicalIF":2.7,"publicationDate":"2026-08-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13506675/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148818355","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"\"IL-40: A novel immunoregulatory axis at the crossroads of inflammation, tissue remodeling, and cancer immunity\".","authors":"Parisa Ahmadi, Sina Mozaffari-Jovin, Tola Abdulsattar Faraj, Fatemeh Tavassoli Razavi, Zahra Javanmardi, Afsane Fadaee, Hassan Doulabi, Seyed-Alireza Esmaeili","doi":"10.1007/s12026-026-09827-6","DOIUrl":"10.1007/s12026-026-09827-6","url":null,"abstract":"<p><p>Interleukin-40 (IL-40), encoded by the C17orf99 gene, is a recently identified B cell-associated cytokine that bridges innate and adaptive immune responses. Since its discovery in 2017, IL-40 has emerged as a pleiotropic immunoregulatory factor with broad implications in human diseases. Elevated IL-40 levels are consistently reported across systemic and organ-specific autoimmune disorders, including rheumatoid arthritis, systemic lupus erythematosus, Sjögren's syndrome, systemic sclerosis, and autoimmune thyroid diseases. In these conditions, IL-40 correlates with disease activity, inflammatory burden, and adverse outcomes. Mechanistically, beyond B-cell differentiation and IgA production, IL-40 induces neutrophil extracellular trap (NET) formation (NETosis), triggering extracellular release of peptidylarginine deiminase 4. PAD4 catalyzes citrullination of intracellular proteins, converting arginine to citrulline residues, generating neoepitopes that break immune tolerance and drive anti-citrullinated protein antibody (ACPA) production-a hallmark of rheumatoid arthritis and related autoimmunities. Beyond autoimmunity, dysregulated IL-40 is observed in viral infections (COVID-19, Epstein-Barr virus), sepsis, and pneumonia, suggesting roles in host defense, systemic inflammation, and immunopathology. IL-40 deficiency impairs IgA homeostasis and alters gut microbiota, implicating it in mucosal immunity and microbiome crosstalk. In oncology, aberrant IL-40 expression is reported in solid tumors (breast cancer, hepatocellular carcinoma) and hematologic malignancies (acute/chronic myeloid leukemias, Hodgkin lymphoma), indicating context-dependent functions in tumor biology. Elevated IL-40 in obesity, metabolic syndrome, type 2 diabetes, and allergic diseases further implicates this cytokine in low-grade chronic inflammation and hypersensitivity. Overall, IL-40 represents a promising immunoregulatory cytokine with diagnostic and therapeutic potential across immune-mediated diseases and cancer. However, current evidence remains largely observational and animal-based, while mechanistic and clinical investigations are scarce. Future research should prioritize identifying IL-40 receptor(s) and downstream signaling pathways through well-designed cellular and molecular studies, alongside large-scale multicenter trials, to fully elucidate its biological functions and clinical utility.</p>","PeriodicalId":13389,"journal":{"name":"Immunologic Research","volume":"74 1","pages":""},"PeriodicalIF":2.7,"publicationDate":"2026-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148792623","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Overcoming resistance to immune checkpoint inhibitors in cancer: translational mechanisms, dynamic biomarkers, clinically actionable combination strategies, and comparative checkpoint biology.","authors":"Rumeysa Berra Karataş, Yaren Alras, Sarenur Teki̇ner, Kaan Zıkşahna, Selim Merdan, Murat Ihlamur","doi":"10.1007/s12026-026-09824-9","DOIUrl":"10.1007/s12026-026-09824-9","url":null,"abstract":"<p><p>Immune checkpoint inhibitors (ICIs) have reshaped cancer therapy by restoring antitumor immune activity, yet primary and acquired resistance continue to limit durable clinical benefit. This review integrates the major tumor-intrinsic and tumor-extrinsic mechanisms that drive ICI resistance, including defective antigen presentation, impaired interferon signaling, oncogenic and epigenetic immune escape programs, metabolic rewiring, suppressive myeloid and stromal circuits, abnormal vasculature, and progressive T-cell dysfunction. We discuss these mechanisms in the context of the cancer-immunity cycle and tumor immunotypes, emphasizing how immune-desert, immune-excluded, inflamed-but-suppressed, and adaptive-resistance phenotypes may require different therapeutic strategies. Building on this framework, we evaluate clinically actionable combination approaches, including dual-checkpoint blockade, myeloid and stromal remodeling, radiotherapy or targeted agents to increase tumor antigenicity, DNA damage response-directed combinations, anti-angiogenic strategies, and interventions aimed at preserving or restoring T-cell fitness. Practical considerations for sequencing and patient selection are highlighted according to resistance phenotype, prior ICI exposure, disease tempo, biomarker status, and toxicity risk. We further outline a dynamic biomarker approach that moves beyond single baseline assays by integrating longitudinal tissue and blood-based readouts, including circulating tumor DNA, immune-cell states, soluble immune mediators, T-cell receptor dynamics, and reassessment at progression to guide adaptive therapy. Finally, selected non-oncologic and special clinical contexts, including chronic infections, solid organ transplantation, pre-existing autoimmune disease, and neuroinflammatory or neurodegenerative conditions, are discussed as comparative checkpoint-biology models rather than as separate therapeutic indications. These settings illustrate how chronic antigen exposure, immune exhaustion, tolerance disruption, and immune-related toxicity can inform the understanding of adaptive immune resistance in malignancy. Overall, this review provides a translational framework for matching ICI resistance biology with rational combination strategies and evolving biomarker-guided treatment decisions.</p>","PeriodicalId":13389,"journal":{"name":"Immunologic Research","volume":"74 1","pages":""},"PeriodicalIF":2.7,"publicationDate":"2026-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148792588","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Hidden Burden: Liver and Gastrointestinal Involvement in Chronic Granulomatous Disease.","authors":"Zehra Genç Ozbay, Saliha Esenboga, Elif Soyak Aytekin, Deniz İlgün Gürel, Ersin Gümüş, Hayriye Hizarcioglu Gulsen, Barış Kuşkonmaz, İnci Nur Saltık-Temizel, Hasan Özen, Hülya Demir, Deniz Cagdas","doi":"10.1007/s12026-026-09829-4","DOIUrl":"10.1007/s12026-026-09829-4","url":null,"abstract":"<p><p>Chronic granulomatous disease (CGD) is a primary immunodeficiency characterized by defective reactive oxygen species production, leading to recurrent infections, chronic inflammation, and immune dysregulation. Hepatic and gastrointestinal (GI) involvement are major contributors to disease-related morbidity. To evaluate hepatic and GI involvement in patients with CGD and to assess their associations with clinical features and outcomes. This retrospective single-center cohort study included 80 patients diagnosed with CGD between 1984 and 2025. Demographic, clinical, laboratory, genetic, and outcome data were analyzed. Hepatic and GI involvement were defined based on clinical, radiological, endoscopic, and histopathological findings. The cohort was predominantly male (63.8%), with a median age at diagnosis of 3.5 years and a high rate of parental consanguinity (62.5%). Hepatic involvement was identified in 52.5% of patients, most commonly hepatomegaly (42.5%), followed by hepatic abscesses (15%) and steatosis (11.3%). Gastrointestinal involvement was documented in 10% of patients, with inflammatory bowel disease (IBD) occurring in 8.8%, typically presenting with diarrhea, rectal bleeding, and abdominal pain. Growth failure (42.2% of children) and chronic diarrhea (21.3%) were also common clinical features. During follow-up, 17 patients (21.3%) died. Mortality was numerically higher among patients with hepatic involvement than among those without (26.2% vs. 15.8%), although the difference was not statistically significant. In exploratory multivariable Cox regression analysis, elevated alanine aminotransferase (ALT) levels at diagnosis were associated with mortality (HR 4.78, p = 0.020), whereas no independent predictors of hepatic or gastrointestinal involvement were identified. CGD is a complex disorder characterized by both susceptibility to infection and immune dysregulation. Hepatic and GI manifestations represent important components of the disease spectrum. Elevated ALT levels at the time of CGD diagnosis were associated with mortality in exploratory multivariable analysis, suggesting that baseline liver function assessment at diagnosis, together with longitudinal monitoring, may provide prognostic information, although this finding requires confirmation in larger prospective studies.</p>","PeriodicalId":13389,"journal":{"name":"Immunologic Research","volume":"74 1","pages":""},"PeriodicalIF":2.7,"publicationDate":"2026-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148792554","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}