Genes and immunity最新文献

{"title":"Annexin A1 regulates inflammatory-immune response and reduces pancreatic and extra- pancreatic injury during severe acute pancreatitis.","authors":"Shizhao Lin, Feihong Liang, Changgan Chen, Jiajing Lin, Yuwei Wu, Zelin Hou, Heguang Huang, Haizong Fang, Yu Pan","doi":"10.1038/s41435-025-00321-x","DOIUrl":"10.1038/s41435-025-00321-x","url":null,"abstract":"<p><p>Severe acute pancreatitis (SAP) poses significant challenges due to its complex pathophysiology, which includes inflammatory-immune responses that cause considerable damage to both the pancreas and other tissues. In this study, we explored the role of Annexin A1 (Anxa1), a glucocorticoid-regulated protein recognized for its anti-inflammatory properties, in regulating inflammation during acute pancreatitis. Using flow cytometry, single-cell RNA sequencing, and gene expression analysis, we examined how Anxa1 expression is regulated in myeloid cells throughout acute pancreatitis, employing various animal models to evaluate the consequences of modulating Anxa1 on injuries induced by SAP. Our findings revealed dynamic regulation of Anxa1 expression in myeloid cells, with mice lacking Anxa1 exhibiting worsened pancreatic injury and heightened systemic inflammation, resulting in significant damage to extra-pancreatic organs such as the lungs, liver, and kidneys. In contrast, treatment with Ac2-26, a synthetic peptide derived from Anxa1, effectively mitigated both pancreatic and extra-pancreatic inflammation and tissue damage. Overall, this study highlights the critical role of Anxa1 in modulating inflammatory responses during acute pancreatitis. Targeting Anxa1 presents a promising therapeutic strategy to mitigate pancreatic injury and prevent systemic complications associated with severe acute pancreatitis.</p>","PeriodicalId":12691,"journal":{"name":"Genes and immunity","volume":" ","pages":"124-136"},"PeriodicalIF":5.0,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143536970","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":"Hypoxia-induced autophagy in pancreatic cancer counteracts the cytotoxicity of CD8+ T cells by inhibiting the expression of MHC-I","authors":"Xianfei Zhou,&nbsp;Miaoguo Cai,&nbsp;Fan Yang,&nbsp;Luoshun Huang,&nbsp;Yisheng Ling,&nbsp;Yang Zhang,&nbsp;Hanqiu Nie,&nbsp;Renwei Xing","doi":"10.1038/s41435-024-00315-1","DOIUrl":"10.1038/s41435-024-00315-1","url":null,"abstract":"The hypoxic microenvironment is an essential feature of solid tumors. Autophagy has been controversial in its role in immune regulation. This project aims to elucidate the impact of autophagy in pancreatic cancer (PC) under specific conditions (hypoxia) on CD8+ T cells and the regulatory mechanisms behind it.The levels of HIF1α and autophagy were analyzed by western blot (WB) and immunofluorescence (IF). The effects of HIF1α on cell autophagy were assessed in normoxic or hypoxic treatments using KC7F2 (HIF-1 channel inhibitor) or chloroquine (autophagy inhibitor). CD8+ T cells were co-cultured with PC cells to assess the cytotoxicity using lactate dehydrogenase (LDH) and Hoechst/PI staining. The content of cytokines and the activation level of CD8+ T cells were measured by enzyme-linked immunosorbent assay (ELISA) and flow cytometry. MHC-I expression in PC cells (membranes) was analyzed using quantitative reverse transcription polymerase chain reaction (qRT-PCR), WB, IF, and flow cytometry. Humanized immune-reconstituted mice were applied to investigate the impact of HIF1α-induced autophagy on in vivo immunity.When cells were in hypoxia, the levels of HIF1α and autophagy were higher compared to normoxic conditions. Treatment with KC7F2 resulted in similar levels of HIF1α and autophagy as those in normoxic state. Chloroquine treatment reversed the autophagy level to the normoxic state. The autophagy level of PC cells transfected with oe-HIF1α was increased, with reduced MHC-I expression on cells (membranes), which impaired the cytotoxicity of CD8+ T cells, and thus decreasing the probability of recognition and attack by CD8+ T cells when co-cultured with them. In mice, overexpression of HIF1α hindered the immune suppressive function of CD8+ T cells and facilitated the immune escape of PC by reducing antigen presentation of MHC-I.Under hypoxia, HIF1α-induced autophagy reduces the cytotoxicity of CD8+ T cells by repressing MHC-I expression.","PeriodicalId":12691,"journal":{"name":"Genes and immunity","volume":"26 1","pages":"45-53"},"PeriodicalIF":5.0,"publicationDate":"2024-12-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142882007","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":"Understanding rare genetic variants within the terminal pathway of complement system in preeclampsia","authors":"A. Inkeri Lokki,&nbsp;Michael Triebwasser,&nbsp;Emma Daly,&nbsp;The FINNPEC Core Investigator Group,&nbsp;Mitja I. Kurki,&nbsp;Markus Perola,&nbsp;Kirsi Auro,&nbsp;Jane E. Salmon,&nbsp;Java Anuja,&nbsp;Mark Daly,&nbsp;John P. Atkinson,&nbsp;Hannele Laivuori,&nbsp;Seppo Meri","doi":"10.1038/s41435-024-00310-6","DOIUrl":"10.1038/s41435-024-00310-6","url":null,"abstract":"Preeclampsia is a common multifactorial disease of pregnancy. Dysregulation of complement activation is among emerging candidates responsible for disease pathogenesis. In a targeted exomic sequencing study of 609 women with preeclampsia and 2092 non-preeclamptic controls, we identified 14 variants within nine genes coding for components of the membrane attack complex (MAC, C5b-9) that are associated with preeclampsia. We found two rare missense variants in the C5 gene that predispose to preeclampsia (rs200674959: I1296V, OR (CI95) = 24.13 (1.25–467.43), p value = 0.01 and rs147430470: I330T, OR (CI95) = 22.75 (1.17–440.78), p value = 0.01). In addition, one predisposing rare variant and one protective rare variant were discovered in C6 (rs41271067: D396G, OR (CI95) = 2.93 (1.18–7.10), p value = 0.01 and rs114609505: T190I, 0.02 OR (CI95) = 0.47 (0.22–0.92), p value = 0.02). The results suggest that variants in the terminal complement pathway predispose to preeclampsia.","PeriodicalId":12691,"journal":{"name":"Genes and immunity","volume":"26 1","pages":"22-26"},"PeriodicalIF":5.0,"publicationDate":"2024-12-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41435-024-00310-6.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142846497","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":"FGL1 facilitates rather than suppresses anticancer immunity against microsatellite instable gastric cancer","authors":"Zhenyuan Qian,&nbsp;Xufan Cai,&nbsp;Jianzhang Wu,&nbsp;Kun Ke,&nbsp;Zaiyuan Ye,&nbsp;Fang Wu","doi":"10.1038/s41435-024-00314-2","DOIUrl":"10.1038/s41435-024-00314-2","url":null,"abstract":"Microsatellite instability (MSI) is a phenotype characterized by changes in the sequence length of microsatellites in tumor cells and is closely linked to tumorigenesis and prognosis. Immune checkpoint inhibitors have shown good therapeutic effects in gastric cancer (GC) with MSI-high (MSI-H). However, the role of the novel immune checkpoint fibrinogen-like protein 1 (FGL1) in GC treatment has not been fully investigated. FGL1 expression in GC tissues and the difference in FGL1 immune infiltration between MSI/ microsatellite stability (MSS) patients were analyzed by bioinformatics and were verified in clinical samples. Xenograft models of MSS and MSI GC were constructed in human immune reconstitution mice, and FGL1 expression in tumors was detected. Immunofluorescence and immunohistochemistry were used to assay the infiltration of immune cells in the two types of mice. Cytotoxicity and chemotaxis tests were used to detect the toxicity and chemotaxis of CD8+T cells to GC cells, respectively. The cytokine content was detected by enzyme-linked immunosorbent assay. The therapeutic effects of FGL1 antibody on different types of GC were analyzed by xenograft mouse models. FGL1 exhibited significantly higher expression in GC, and its expression and immune cell infiltration levels were significantly higher in MSI GC than in MSS GC. CD8+T cells were significantly more effective in killing and chemotaxis of MSI GC cells than MSS GC cells. The FGL1 antibody was more effective in treating MSI GC.The novel immunosuppressor FGL1 antibody exerts a good therapeutic influence on MSI GC. These findings provide a basis for the development of drugs targeting FGL1 for MSI GC treatment.","PeriodicalId":12691,"journal":{"name":"Genes and immunity","volume":"26 1","pages":"36-44"},"PeriodicalIF":5.0,"publicationDate":"2024-12-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142821801","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":"Correction: Roles of TULA-family proteins in T cells and autoimmune diseases","authors":"Hua Wang,&nbsp;Patrick Concannon,&nbsp;Yan Ge","doi":"10.1038/s41435-024-00311-5","DOIUrl":"10.1038/s41435-024-00311-5","url":null,"abstract":"","PeriodicalId":12691,"journal":{"name":"Genes and immunity","volume":"26 1","pages":"63-63"},"PeriodicalIF":5.0,"publicationDate":"2024-12-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.nature.com/articles/s41435-024-00311-5.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142800389","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":"GXYLT2: an emerging therapeutic target and predictive biomarker for anti-PD-1 efficacy in clear cell renal cell carcinoma","authors":"Tuanjie Guo,&nbsp;Jinyuan Chen,&nbsp;Xiangyin Tan,&nbsp;Heting Tang,&nbsp;Xuan Wang,&nbsp;Siteng Chen,&nbsp;Xiang Wang","doi":"10.1038/s41435-024-00312-4","DOIUrl":"10.1038/s41435-024-00312-4","url":null,"abstract":"There are studies reporting that glucoside xylosyltransferase 2 (GXYLT2) has a role in promoting tumor progression, but its role in clear cell renal cell carcinoma (ccRCC) remains unclear. In this study, RT-qPCR and western blotting were employed to detect the expression level of GXYLT2. RNA interference assays were used to knock down GXYLT2. CCK-8, wound healing assays, clone formation assays, and Transwell assays were utilized to investigate the function of GXYLT2. Bioinformatics analysis was used to explore the tumor microenvironment and potential biological mechanisms. We found that the expression level of GXYLT2 in ccRCC was higher than that in adjacent normal renal tissues. Patients with high GXYLT2 expression have worse clinical outcomes. Knockdown of GXYLT2 inhibits the proliferation, invasion, migration, and clone formation ability of ccRCC cells. Enrichment analysis uncovered that GXYLT2 participates in Wnt, cell cycle, and actin cytoskeleton regulation signaling pathways. After receiving anti-PD-1 therapy, patients with high GXYLT2 expression had longer progression-free survival compared with those with low GXYLT2 expression. In conclusion, GXYLT2 is a novel potential therapeutic target for ccRCC. Meanwhile, GXYLT2 can be used as a novel marker for predicting immunotherapeutic response.","PeriodicalId":12691,"journal":{"name":"Genes and immunity","volume":"26 1","pages":"27-35"},"PeriodicalIF":5.0,"publicationDate":"2024-12-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142784959","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 role of NLRP3 and NLRP12 inflammasomes in glioblastoma","authors":"Sushmita Rajkhowa,&nbsp;Sushmita Jha","doi":"10.1038/s41435-024-00309-z","DOIUrl":"10.1038/s41435-024-00309-z","url":null,"abstract":"Glioblastoma (GBM) is the deadliest malignant brain tumor, with a survival of less than 14 months after diagnosis. The highly invasive nature of GBM makes total surgical resection challenging, leading to tumor recurrence and declined survival. The heterocellular composition of the GBM reprograms its microenvironment, favoring tumor growth, proliferation, and migration. The innate immune cells in the GBM tumor microenvironment, including microglia, astrocytes, and macrophages, express pattern recognition receptors such as NLRs (Nucleotide-binding domain and leucine-rich repeat-containing) that sense pathogen- and damage-associated molecular patterns initiating inflammation. Upon activation, NLRP3 promotes inflammation by NLRP3 inflammasome formation. Auto-proteolytic cleavage and activation of Caspase-1 within the inflammasome leads to caspase-1-mediated cleavage, activation, and conversion of pro-IL-1ß and pro-IL-18 to IL-1ß and IL-18, leading to pyroptosis. In contrast, NLRP12 downregulates inflammatory responses in microglia and macrophages by regulating the NF-κB pathway. NLRP3 and NLRP12 have been implicated in the disease pathophysiology of several cancers with cell-context-dependent, pro- or anti-tumorigenic roles. In this review, we discuss the current literature on the mechanistic roles of NLRP3 and NLRP12 in GBM and the gaps in the scientific literature in the context of GBM pathophysiology with potential for targeted therapeutics.","PeriodicalId":12691,"journal":{"name":"Genes and immunity","volume":"25 6","pages":"541-551"},"PeriodicalIF":5.0,"publicationDate":"2024-11-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142739252","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":"Neoantigen-specific mRNA/DC vaccines for effective anticancer immunotherapy","authors":"Wenli Zhang,&nbsp;Jiahao Guan,&nbsp;Wenwen Wang,&nbsp;Guo Chen,&nbsp;Li Fan,&nbsp;Zifan Lu","doi":"10.1038/s41435-024-00305-3","DOIUrl":"10.1038/s41435-024-00305-3","url":null,"abstract":"The development of personalized anticancer vaccines based on neoantigens represents a new direction in cancer immunotherapy. The latest advancement in dendritic cell (DC) tumor vaccine construction involves loading DC with mRNA-encoding neoantigens, which allows for rapid production and is suitable for personalized preparation. Cell-penetrating peptides (CPPs) are emerging as biological delivery systems in which negatively charged nucleic acids can be wound onto the cationic CPP backbone to form nanoscale complexes. This preparation method facilitates standardization. If DC can express and present neoantigen mRNA at high levels, it holds promising application potential. In this study, we developed a neoantigen-mRNA/DC vaccine using candidate neoantigens from mouse colon cancer (MC38) and examined its immune and antitumor effects. The results demonstrated that neoantigen-mRNA/DC vaccines induced strong T cell immune responses and exhibited significant antitumor effects, effectively preventing tumor growth. Our study provides an experimental basis for further optimizing the preparation of DC vaccines and reducing their costs.","PeriodicalId":12691,"journal":{"name":"Genes and immunity","volume":"25 6","pages":"514-524"},"PeriodicalIF":5.0,"publicationDate":"2024-11-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142727857","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 TULA-family proteins in T cells and autoimmune diseases","authors":"Hua Wang,&nbsp;Patrick Concannon,&nbsp;Yan Ge","doi":"10.1038/s41435-024-00300-8","DOIUrl":"10.1038/s41435-024-00300-8","url":null,"abstract":"The T cell Ubiquitin Ligand (TULA) protein family contains two members, UBASH3A and UBASH3B, that display similarities in protein sequence and domain structure. Both TULA proteins act to repress T cell activation via a combination of overlapping and nonredundant functions. UBASH3B acts mainly as a phosphatase that suppresses proximal T cell receptor (TCR) signaling. In contrast, UBASH3A acts primarily as an adaptor protein, interacting with other proteins (including UBASH3B) in T cells upon TCR stimulation and resulting in downregulation of TCR signaling and NF-κB signaling. Human genetic and functional studies have revealed another notable distinction between UBASH3A and UBASH3B: numerous genome-wide association studies have identified statistically significant associations between genetic variants in and around the UBASH3A gene and at least seven different autoimmune diseases, suggesting a key role of UBASH3A in autoimmunity. However, the evidence for an independent role of UBASH3B in autoimmune disease is limited. This review summarizes key findings regarding the roles of TULA proteins in T cell biology and autoimmunity, highlights the commonalities and differences between UBASH3A and UBASH3B, and speculates on the individual and joint effects of TULA proteins on T cell signaling.","PeriodicalId":12691,"journal":{"name":"Genes and immunity","volume":"26 1","pages":"54-62"},"PeriodicalIF":5.0,"publicationDate":"2024-11-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142667225","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":"Epigenetics behind CD8+ T cell activation and exhaustion","authors":"Hao Zu,&nbsp;Xiaoqin Chen","doi":"10.1038/s41435-024-00307-1","DOIUrl":"10.1038/s41435-024-00307-1","url":null,"abstract":"CD8+ T cells play a critical role in specific immunity. In recent years, cell therapy has been emerging rapidly. The specific cytotoxic capabilities of these cells enable them to precisely identify and kill cells presenting specific antigens. This has demonstrated promise in the treatment of autoimmune diseases and cancers, with wide-ranging applications and value. However, in some diseases, such as tumors and chronic infections, T cells may adopt an exhausted phenotype, resulting in a loss of cytotoxicity and limiting their further application. Epigenetics plays a significant role in the differentiation and regulation of gene expression in cells. There is extensive evidence indicating that epigenetic remodeling plays an important role in T cell exhaustion. Therefore, further understanding its role in CD8+ T cell function can provide insights into the programmatic regulation of CD8+ T cells from a genetic perspective and overcome these diseases. We attempted to describe the relationship between the activation, function, and exhaustion mechanisms of CD8+ T cells, as well as epigenetics. This understanding makes it possible for us to address the aforementioned issues.","PeriodicalId":12691,"journal":{"name":"Genes and immunity","volume":"25 6","pages":"525-540"},"PeriodicalIF":5.0,"publicationDate":"2024-11-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142618619","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}