Genes and immunity最新文献

{"title":"A scan of pleiotropic immune mediated disease genes identifies novel determinants of baseline FVIII inhibitor status in hemophilia A.","authors":"Marcio A Almeida, Vincent P Diego, Kevin R Viel, Bernadette W Luu, Karin Haack, Rajalingam Raja, Afshin Ameri, Meera Chitlur, Natalia Rydz, David Lillicrap, Raymond G Watts, Craig M Kessler, Christopher Ramsey, Long V Dinh, Benjamin Kim, Jerry S Powell, Eron G Manusov, Juan M Peralta, Ruayda Bouls, Shirley M Abraham, Yu-Min Shen, Carlos M Murillo, Henry Mead, Paul V Lehmann, Eli J Fine, Miguel A Escobar, Satish Kumar, Barbara A Konkle, Sarah Williams-Blangero, Carol K Kasper, Laura Almasy, Shelley A Cole, John Blangero, Tom E Howard","doi":"10.1038/s41435-025-00325-7","DOIUrl":"10.1038/s41435-025-00325-7","url":null,"abstract":"<p><p>Hemophilia-A (HA) is the X-linked bleeding disorder caused by heterogeneous factor (F)VIII gene (F8)-mutations and deficiencies in plasma-FVIII-activity that prevent intrinsic-pathway mediated coagulation-amplification. Severe-HA patients (HAPs) require life-long infusions of therapeutic-FVIII-proteins (tFVIIIs) but ~30% develop neutralizing-tFVIII-antibodies called \"FVIII-inhibitors (FEIs)\". We investigated the genetics underlying the variable risk of FEI-development in 450 North American HAPs (206 and 244 respectively self-reporting black-African- or white-European-ancestry) by analyzing the genotypes of single-nucleotide-variations (SNVs) in candidate immune-mediated-disease (IMD)-genes using a binary linear-mixed model of genetic association with baseline-FEI-status, the dependent variable, while simultaneously accounting for their genetic relationships and heterogeneous-F8-mutations to prevent the statistical problem of non-independence. We a priori selected gene-centric-association-scans of pleiotropic-IMD-genes implicated in the development of either ≥2 autoimmune-/autoinflammatory-disorders (AADs) or FEIs and ≥1 AAD. We found that baseline-FEI-status was significantly associated with NOS2A (rs117382854; p = 3.2 × 10^-6) and B3GNT2 (rs10176009; p = 5.1 × 10^-6)-pleiotropic-IMD-genes known previously to function in anti-microbial-/-tumoral-immunity but not in the development of FEIs-and confirmed associations with CTLA4 (rs231780; p = 2.2 × 10^-5). We also found that baseline-FEI-status has a substantial heritability (~55%) that involves (i) a F8-mutation-specific component of ~8%, (ii) an additive-genetic contribution from SNVs in IMD-genes of ~47%, and (iii) race, which is a significant determinant independent of F8-mutation-types and non-F8-genetics.</p>","PeriodicalId":12691,"journal":{"name":"Genes and immunity","volume":" ","pages":"179-189"},"PeriodicalIF":5.0,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143967698","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Association between HLA genetics and SARS-CoV-2 infection in a large real-world cohort.","authors":"Stanley I Letovsky, Xia Cao, Jill A Hollenbach, Steven J Mack, Martin Maiers","doi":"10.1038/s41435-025-00328-4","DOIUrl":"10.1038/s41435-025-00328-4","url":null,"abstract":"<p><p>Genetic variation in the human leukocyte antigen (HLA) region is thought to influence susceptibility to and severity of a variety of infectious diseases. Several studies have explored a possible relationship between HLA genetics and SARS-CoV-2 infection, although mixed results, small sample sizes, and difficulty controlling for exposure risk have made it difficult to draw firm conclusions. Here, a dataset of 419,234 subjects with HLA genotype data and COVID-19 PCR test results was studied. A baseline analysis was performed to examine the association of non-HLA factors on COVID-19 positivity. Then, multivariate logistic regressions, incorporating single and paired HLA alleles, were performed and then corrected for significant factors from the baseline analysis. Proxies for socioeconomic status and exposure risk were significantly associated with COVID-19 positivity across all ancestry groups studied. Forty-one single HLA alleles displayed significant association with COVID-19 positivity; after controlling for socioeconomic status and exposure risk, only eight significant associations remained. Additionally, two HLA allele pairs were associated with test positivity after correction. Of all variables, socioeconomic status showed the greatest effect size. The results from this study suggest that many, if not all, of the reported associations between HLA alleles and SARS-CoV-2 infection may be spurious, owing to confounding factors.</p>","PeriodicalId":12691,"journal":{"name":"Genes and immunity","volume":" ","pages":"213-221"},"PeriodicalIF":5.0,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12170163/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144005552","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Transcript-targeted antigen mapping reveals the potential of POSTN splicing junction epitopes in glioblastoma immunotherapy.","authors":"Zujian Xiong, Chaim T Sneiderman, Chloe R Kuminkoski, Jared Reinheimer, Lance Schwegman, ReidAnn E Sever, Ahmed Habib, Baoli Hu, Sameer Agnihotri, Dhivyaa Rajasundaram, Pascal O Zinn, Thomas G Forsthuber, Ian F Pollack, Xuejun Li, Itay Raphael, Gary Kohanbash","doi":"10.1038/s41435-025-00326-6","DOIUrl":"10.1038/s41435-025-00326-6","url":null,"abstract":"<p><p>Tumor antigens are crucial for T-cell mediated immunotherapy, but identified antigens for gliomas remain limited. Aberrant splicing variants are commonly expressed in tumors, resulting in unique tumor isoforms with potential antigenic properties. Herein, we analyzed multi-omics data from 587 glioma patients and assembled a library of putative tumor-enriched isoform antigens (TIA) and corresponding peptides presented on each HLA-I allele. We constructed an individual-specific TIA peptide candidate repertoire for each patient based on their TIA expression and HLA-I haplotypes. TIAs were highly expressed, enriched with glioma malignancy, and demonstrated strong HLA-binding affinity. We focused on periostin isoform-203 (POSTN-203), which was associated with poor survival of patients and contained multiple predicted HLA-restricted peptide epitopes. A selected HLA-A11-restricted peptide from POSTN-203 (POSTN-203_A11) induced antigen-specific T-cell responses against both peptide-pulsed and POSTN-203-expressing glioma cells in an HLA-specific manner. Our findings highlight TIAs as a promising source of immunogenic antigens and POSTN-203 as a potential promising target for glioma immunotherapy.</p>","PeriodicalId":12691,"journal":{"name":"Genes and immunity","volume":" ","pages":"190-199"},"PeriodicalIF":5.0,"publicationDate":"2025-06-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143779786","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Integrative multi-omics reveal NSUN2 facilitates glycolysis and histone lactylation-driven immune evasion in renal carcinoma.","authors":"Kunpeng Wang, Fanyi Kong, Xue Han, Yunlai Zhi, Hai Wang, Chuanli Ren, Hui Wang","doi":"10.1038/s41435-025-00336-4","DOIUrl":"https://doi.org/10.1038/s41435-025-00336-4","url":null,"abstract":"<p><p>Clear cell renal carcinoma (ccRCC) is the most prevalent and aggressive subtype of kidney cancer. Targeting ccRCC metabolism is a promising therapeutic strategy, and some metabolic targets are currently undergoing clinical trials. Here, we collected multiple ccRCC clinical cohorts, including bulk RNA sequencing and single-cell sequencing datasets, to investigate mitochondrial metabolic genes' prognostic and therapeutic potential. Integrating 10 machine learning algorithms, we constructed 117 predictive models, with the optimal model selected and defined as Mitoscore for patient stratification and treatment. Furthermore, NSUN2, an RNA 5-methylcytosine (m5C) methyltransferase, was identified as the most important gene in the model and selected for further gene function experiments in vitro and in vivo. NSUN2 promoted cell proliferation, migration, and invasion; reprogrammed glycolysis metabolism and histone lactylation levels via maintaining NEO1 mRNA stability. In addition, NSUN2 increased PD-L1 expression in tumor cells via the MYC/POM121/CD274 axis in a lactylation-dependent manner. Knockdown of NSUN2 enhanced CD8 T cell killing effects in vitro, along with TNF-α + T cell infiltration in vivo. These results highlight that mitochondrial genes are optional therapeutic targets and prognostic markers; NSUN2 promotes mitochondrial glycolysis and histone lactylation in an m5C-dependent manner, thereby resulting in PD-L1-mediated immune escape, which elucidates novel NSUN2-mediated crosstalk between glycolysis and immune evasion.</p>","PeriodicalId":12691,"journal":{"name":"Genes and immunity","volume":" ","pages":""},"PeriodicalIF":5.0,"publicationDate":"2025-05-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144142371","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Macrophage inhibition in the alleviation of nonalcoholic steatohepatitis caused by bariatric surgery.","authors":"Qianwen Zheng, Shizhou Deng, Xiyu Chen, Yayun Wang, Yanling Yang","doi":"10.1038/s41435-025-00334-6","DOIUrl":"https://doi.org/10.1038/s41435-025-00334-6","url":null,"abstract":"<p><p>The incidence of nonalcoholic steatohepatitis (NASH) is increasing worldwide, and effective treatment is urgently needed. To understand the molecular mechanisms behind the effectiveness of bariatric surgery in treating NASH, we integrated single-cell and bulk RNA sequencing data to identify the role of liver macrophage polarization in alleviating NASH and screen possible drugs for treatment. Analysis revealed that bariatric surgery alleviates NASH by inhibiting liver M1 macrophage polarization with 12 differentially expressed M1 macrophage-related genes. Additionally, 56 potentially effective drugs were predicted for NASH treatment. These findings shed light on the effectiveness of bariatric surgery in treating NASH and offer potential drug candidates for further exploration.</p>","PeriodicalId":12691,"journal":{"name":"Genes and immunity","volume":" ","pages":""},"PeriodicalIF":5.0,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144077436","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Lipid metabolism-related genes are involved in the formation of macrophage extracellular traps in allergic airway inflammation.","authors":"Haixia Wang, Bin Ma, Yuanmin Jia, Hui Wei, Danyang Li, Junlian Gu, Ou Chen, Shouwei Yue","doi":"10.1038/s41435-025-00319-5","DOIUrl":"10.1038/s41435-025-00319-5","url":null,"abstract":"<p><p>Recent studies have highlighted the critical role of lipid metabolism in macrophages concerning lung inflammation. However, it remains unclear whether lipid metabolism is involved in macrophage extracellular traps (METs). We analyzed the GSE40885 dataset from the GEO database using weighted correlation network analysis (WGCNA) and further selection using the least absolute shrinkage and selection operator (LASSO) regression. We identified ABCA1, SLC44A2, and C3 as key genes jointly involved in lipid metabolism and METs. Additionally, immune infiltration analysis was performed using the Xcell and CIBERSORT algorithms, while single-cell transcriptome analysis was utilized using data from the Tabula Muris database. The expression of key genes was validated in external datasets (GSE42606, GSE27066, GSE137268, and GSE256534). Notably, our results indicated that ABCA1 expression was elevated in patients experiencing acute asthma exacerbations, which aligned with its expression trend in lipopolysaccharide (LPS)-induced macrophages. However, ABCA1 expression was reduced in cases of chronic and severe asthma. Results from immunofluorescence (IF), SYTOX Green staining, and Western blot analyses suggested that ABCA1 may play a role in the formation of METs both in vivo and in vitro. In conclusion, this study indicates that ABCA1 may be involved in METs. ABCA1 may represent a promising therapeutic target for asthma.</p>","PeriodicalId":12691,"journal":{"name":"Genes and immunity","volume":" ","pages":"96-110"},"PeriodicalIF":5.0,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142947694","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Long noncoding RNA PARAL1 regulates myeloid dendritic cell differentiation and TLR signaling.","authors":"Raza Ali Naqvi, Araceli Valverde, Deepak Shukla, Afsar Naqvi","doi":"10.1038/s41435-025-00323-9","DOIUrl":"10.1038/s41435-025-00323-9","url":null,"abstract":"<p><p>Dendritic cells (DCs) are professional antigen presentation cells (APCs) that bridge innate and adaptive immune functions to contain pathogenic threats. Long noncoding RNAs (lncRNAs) are implicated in regulating biological processes, including inflammation and immunity. However, the knowledge of myeloid DC-expressed lncRNA repertoire and their regulatory functions is limited. Here we profiled lncRNA expression kinetics during monocyte-to-DC (moDC) differentiation and characterized their functional roles. Our RNA-seq data identified a repertoire of differentially expressed lncRNAs associated with moDC differentiation and a large subset of these lncRNAs are distinct from M1 or M2 macrophages. We selected two DC-enriched lncRNAs and observed that PARAL1 silencing, or overexpression modulates DC surface markers expression. Importantly, PARAL1 RNAi significantly reduced, while its overexpression upregulated the levels of multiple TLRs. Upon treatment with TLR agonists PARAL1 knockdown cells exhibit reduced NF-κB, IRF3 and IRF7 phosphorylation substantiating its role in potentiating TLR signaling. Mechanistically, PARAL1 silencing showed significant downregulation of multiple NF-κB-induced genes and time-dependent inhibition of proinflammatory cytokine secretion upon challenge with TLR agonists. Finally, PARAL1 RNAi in DCs significantly impaired antigen processing and presentation to T cells. Overall, this study characterized novel functions of PARAL1 in regulating DC differentiation, TLR-dependent innate immunity and activation of adaptive immune response.</p>","PeriodicalId":12691,"journal":{"name":"Genes and immunity","volume":" ","pages":"151-165"},"PeriodicalIF":5.0,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143500543","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Roles of immunoglobulin GM and KM allotypes and Fcγ receptor 2 A genotypes in humoral immunity to a conserved microbial polysaccharide in pulmonary diseases.","authors":"Janardan P Pandey, Paul J Nietert, Aryan M Namboodiri, Christine Kimball, Patrick A Flume","doi":"10.1038/s41435-024-00318-y","DOIUrl":"10.1038/s41435-024-00318-y","url":null,"abstract":"<p><p>Immunoglobulin GM (γ marker) and KM (κ marker) allotypes-encoded by immunoglobulin heavy chain G (IGHG) and immunoglobulin κ constant (IGKC) genes-have been shown to be associated with immune responsiveness to a variety of self and nonself antigens. The aim of the present investigation was to determine whether allelic variation at the GM and KM loci was associated with antibody responsiveness to poly-N-acetyl-D-glucosamine (PNAG), a broadly-conserved surface polysaccharide expressed by many microbial pathogens. In addition, we wished to determine whether Fcγ receptor 2 A (FCGR2A) genotypes, which have been shown to be risk factors for some pathogens, also influenced antibody responses to PNAG. DNA from 257 patients with various pulmonary diseases (PD) was genotyped for several GM, KM, and FCGR2A alleles, and plasma were characterized for anti-PNAG IgG antibodies. The levels of IgG4 antibodies to PNAG were associated with FCGR2A genotypes (p = 0.01). Also, KM and FCGR2A alleles epistatically contributed to anti-PNAG IgG3 antibody responses: subjects with KM 1/1 or KM 1/3 and homozygous for the R allele of FCGR2A had the highest levels of anti-PNAG IgG3 antibodies compared to all other genotype combinations. If confirmed by larger studies, these results are potentially relevant to immunotherapy against many PNAG-expressing infectious pathogens.</p>","PeriodicalId":12691,"journal":{"name":"Genes and immunity","volume":" ","pages":"91-95"},"PeriodicalIF":5.0,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12006017/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142947697","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Multi-omics clustering analysis carries out the molecular-specific subtypes of thyroid carcinoma: implicating for the precise treatment strategies.","authors":"Zhenglin Wang, Qijun Han, Xianyu Hu, Xu Wang, Rui Sun, Siwei Huang, Wei Chen","doi":"10.1038/s41435-025-00322-w","DOIUrl":"10.1038/s41435-025-00322-w","url":null,"abstract":"<p><p>Thyroid cancer (TC) is the most prevalent endocrine malignancy worldwide. This study aimed to explore the molecular subtypes and improve the selection of targeted therapies. We used multi-omics data from 539 patients with DNA methylation, gene mutations, mRNA, lncRNA, and miRNA expressions. This study employed consensus clustering algorithms to identify molecular subtypes and used various bioinformatics tools to analyze genetic alterations, signaling pathways, immune infiltration, and responses to chemotherapy and immunotherapy. Two prognostically relevant TC subtypes, CS1 and CS2, were identified. CS2 was associated with a poorer prognosis of shorter progression-free survival times (P < 0.001). CS1 exhibited higher copy number alterations but a lower tumor mutation burden than CS2. CS2 exhibited activation in cell proliferation and immune-related pathways. Drug sensitivity analysis indicated CS2's higher sensitivity to cisplatin, doxorubicin, paclitaxel, and sunitinib, whereas CS1 was more sensitive to bicalutamide and FH535. The different activated pathways and sensitivity to drugs for the subtypes were further validated in an external cohort. Twenty-four paired tumors and adjacent normal tissues by immunohistochemical staining further demonstrated the prognostic value of CXCL17. In conclusion, we identified two distinct molecular subtypes of TC with significant implications for prognosis, genetic alterations, pathway activation, and treatment response.</p>","PeriodicalId":12691,"journal":{"name":"Genes and immunity","volume":" ","pages":"137-150"},"PeriodicalIF":5.0,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143556633","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The need for Cre-loci controls in conditional mouse experiments: Mrp8-cre transgene predisposes mice to antibody-induced arthritis.","authors":"Zhongwei Xu, Laura Romero-Castillo, Àlex Moreno-Giró, Rajan Kumar Pandey, Rikard Holmdahl","doi":"10.1038/s41435-024-00313-3","DOIUrl":"10.1038/s41435-024-00313-3","url":null,"abstract":"<p><p>The Cre/loxP system is extensively utilized to pinpoint gene functions in specific cell types or developmental stages, typically without major disturbance to the host's genome. However, we found that the random insertion of the Mrp8-cre transgene significantly promotes the host's innate immune response. This effect is characterized by elevated susceptibility to cartilage antibody-induced arthritis, likely due to interference with genes near the insertion site. These findings underscore the potential biological disturbances caused by random transgene integration, and the necessity for stringent control strategies to avoid biased interpretations when using Cre-conditional strains.</p>","PeriodicalId":12691,"journal":{"name":"Genes and immunity","volume":" ","pages":"169-172"},"PeriodicalIF":5.0,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12006020/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142779013","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}