Pub Date : 2025-01-07DOI: 10.1038/s41435-024-00316-0
Jingyang Liu, Qingge Guo, Guangming Liu, Weiping Wang, Xiuxiu Jin, Bingtao Hao, Bo Lei
Acute posterior multifocal placoid pigment epitheliopathy (APMPPE) is an exceptionally rare inflammatory disorder affecting choroid and retinal pigment epithelial (RPE) cells. Although recent studies suggest an immune-driven nature, the underlying etiology of APMPPE remains elusive. In this study, we conducted a comprehensive investigation on the peripheral blood mononuclear cells (PBMCs) profile of an APMPPE patient using single-cell RNA sequencing. Our analysis revealed striking transcriptional alterations in monocytes within the PBMCs, identifying five distinct subpopulations: S100A12, CD16, pro-inflammatory, megakaryocyte-like, and NK-like monocyte subsets. Employing pseudotime inference, we observed a shift in APMPPE monocytes towards differentiation into inflammation-associated pro-inflammatory monocytes and a CD16 monocyte trajectory. Furthermore, we identified IFITM3 as a key player in the immune response driving the pathogenesis of APMPPE. Notably, two disease-relevant subgroups of monocytes, pro-inflammatory and CD16 monocytes, were implicated in APMPPE. CD16 monocytes, in particular, were involved in melanogenesis, suggesting that the abnormal expression of melanin in monocytes might result from autoimmune responses against pigment-enriched RPE cells. This study provided a comprehensive view of immune landscape in APMPPE, shedding light on the previously unrecognized contributions of pro-inflammatory and CD16 monocytes to this autoimmune condition.
{"title":"Immune pathogenic response landscape of acute posterior multifocal placoid pigment epitheliopathy revealed by scRNA sequencing","authors":"Jingyang Liu, Qingge Guo, Guangming Liu, Weiping Wang, Xiuxiu Jin, Bingtao Hao, Bo Lei","doi":"10.1038/s41435-024-00316-0","DOIUrl":"10.1038/s41435-024-00316-0","url":null,"abstract":"Acute posterior multifocal placoid pigment epitheliopathy (APMPPE) is an exceptionally rare inflammatory disorder affecting choroid and retinal pigment epithelial (RPE) cells. Although recent studies suggest an immune-driven nature, the underlying etiology of APMPPE remains elusive. In this study, we conducted a comprehensive investigation on the peripheral blood mononuclear cells (PBMCs) profile of an APMPPE patient using single-cell RNA sequencing. Our analysis revealed striking transcriptional alterations in monocytes within the PBMCs, identifying five distinct subpopulations: S100A12, CD16, pro-inflammatory, megakaryocyte-like, and NK-like monocyte subsets. Employing pseudotime inference, we observed a shift in APMPPE monocytes towards differentiation into inflammation-associated pro-inflammatory monocytes and a CD16 monocyte trajectory. Furthermore, we identified IFITM3 as a key player in the immune response driving the pathogenesis of APMPPE. Notably, two disease-relevant subgroups of monocytes, pro-inflammatory and CD16 monocytes, were implicated in APMPPE. CD16 monocytes, in particular, were involved in melanogenesis, suggesting that the abnormal expression of melanin in monocytes might result from autoimmune responses against pigment-enriched RPE cells. This study provided a comprehensive view of immune landscape in APMPPE, shedding light on the previously unrecognized contributions of pro-inflammatory and CD16 monocytes to this autoimmune condition.","PeriodicalId":12691,"journal":{"name":"Genes and immunity","volume":"26 2","pages":"75-90"},"PeriodicalIF":4.5,"publicationDate":"2025-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12006025/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142947683","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}
Pub Date : 2024-12-23DOI: 10.1038/s41435-024-00315-1
Xianfei Zhou, Miaoguo Cai, Fan Yang, Luoshun Huang, Yisheng Ling, Yang Zhang, Hanqiu Nie, Renwei Xing
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.
{"title":"Hypoxia-induced autophagy in pancreatic cancer counteracts the cytotoxicity of CD8+ T cells by inhibiting the expression of MHC-I","authors":"Xianfei Zhou, Miaoguo Cai, Fan Yang, Luoshun Huang, Yisheng Ling, Yang Zhang, Hanqiu Nie, 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}
Pub Date : 2024-12-17DOI: 10.1038/s41435-024-00310-6
A. Inkeri Lokki, Michael Triebwasser, Emma Daly, The FINNPEC Core Investigator Group, Mitja I. Kurki, Markus Perola, Kirsi Auro, Jane E. Salmon, Java Anuja, Mark Daly, John P. Atkinson, Hannele Laivuori, Seppo Meri
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.
子痫前期是一种常见的多因素妊娠疾病。补体激活失调是疾病发病机制的新兴候选因素之一。在一项针对609名先兆子痫女性和2092名非先兆子痫对照组的靶向外显子组测序研究中，我们在9个编码膜攻击复合物（MAC, C5b-9）成分的基因中发现了14个与先兆子痫相关的变异。我们发现两个罕见的C5基因错义变异(rs200674959: I1296V, OR （CI95) = 24.13 (1.25-467.43)， p值= 0.01）和rs147430470: I330T， OR （CI95) = 22.75 (1.17-440.78)， p值= 0.01）易患子痫前期。此外，在C6 (rs41271067: D396G, OR （CI95) = 2.93 (1.18 ~ 7.10)， p值= 0.01）和rs114609505: T190I， 0.02 OR （CI95) = 0.47 (0.22 ~ 0.92)， p值= 0.02）中发现1个易感稀有变异和1个保护性稀有变异。结果表明，终末补体通路的变异易导致子痫前期。
{"title":"Understanding rare genetic variants within the terminal pathway of complement system in preeclampsia","authors":"A. Inkeri Lokki, Michael Triebwasser, Emma Daly, The FINNPEC Core Investigator Group, Mitja I. Kurki, Markus Perola, Kirsi Auro, Jane E. Salmon, Java Anuja, Mark Daly, John P. Atkinson, Hannele Laivuori, 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}
Pub Date : 2024-12-13DOI: 10.1038/s41435-024-00314-2
Zhenyuan Qian, Xufan Cai, Jianzhang Wu, Kun Ke, Zaiyuan Ye, Fang Wu
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.
{"title":"FGL1 facilitates rather than suppresses anticancer immunity against microsatellite instable gastric cancer","authors":"Zhenyuan Qian, Xufan Cai, Jianzhang Wu, Kun Ke, Zaiyuan Ye, 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}
Pub Date : 2024-12-09DOI: 10.1038/s41435-024-00311-5
Hua Wang, Patrick Concannon, Yan Ge
{"title":"Correction: Roles of TULA-family proteins in T cells and autoimmune diseases","authors":"Hua Wang, Patrick Concannon, 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}
Pub Date : 2024-12-05DOI: 10.1038/s41435-024-00312-4
Tuanjie Guo, Jinyuan Chen, Xiangyin Tan, Heting Tang, Xuan Wang, Siteng Chen, Xiang Wang
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.
{"title":"GXYLT2: an emerging therapeutic target and predictive biomarker for anti-PD-1 efficacy in clear cell renal cell carcinoma","authors":"Tuanjie Guo, Jinyuan Chen, Xiangyin Tan, Heting Tang, Xuan Wang, Siteng Chen, 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}
Pub Date : 2024-12-04DOI: 10.1038/s41435-024-00313-3
Zhongwei Xu, Laura Romero‐Castillo, Àlex Moreno-Giró, Rajan Kumar Pandey, Rikard Holmdahl
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.
{"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":"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.","PeriodicalId":12691,"journal":{"name":"Genes and immunity","volume":"26 2","pages":"169-172"},"PeriodicalIF":4.5,"publicationDate":"2024-12-04","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}
Pub Date : 2024-11-27DOI: 10.1038/s41435-024-00309-z
Sushmita Rajkhowa, Sushmita Jha
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.
{"title":"The role of NLRP3 and NLRP12 inflammasomes in glioblastoma","authors":"Sushmita Rajkhowa, 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}
Pub Date : 2024-11-26DOI: 10.1038/s41435-024-00305-3
Wenli Zhang, Jiahao Guan, Wenwen Wang, Guo Chen, Li Fan, Zifan Lu
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.
开发基于新抗原的个性化抗癌疫苗是癌症免疫疗法的一个新方向。树突状细胞（DC）肿瘤疫苗构建的最新进展是用编码新抗原的 mRNA 负载 DC，这种方法可以快速生产并适合个性化制备。细胞穿透肽（CPPs）是一种新兴的生物递送系统，带负电荷的核酸可缠绕在阳离子 CPP 骨架上形成纳米级复合物。这种制备方法有利于标准化。如果 DC 能高水平表达和呈现新抗原 mRNA，那么它将具有广阔的应用前景。在本研究中，我们利用小鼠结肠癌（MC38）的候选新抗原开发了一种新抗原-mRNA/DC 疫苗，并考察了其免疫和抗肿瘤效果。结果表明，新抗原-mRNA/DC 疫苗能诱导强烈的 T 细胞免疫反应，并表现出显著的抗肿瘤效果，有效阻止肿瘤生长。我们的研究为进一步优化 DC 疫苗的制备和降低成本提供了实验基础。
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Pub Date : 2024-11-18DOI: 10.1038/s41435-024-00300-8
Hua Wang, Patrick Concannon, Yan Ge
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.
T 细胞泛素配体（TULA）蛋白家族包含两个成员，即 UBASH3A 和 UBASH3B，它们在蛋白序列和结构域结构上具有相似性。这两种 TULA 蛋白都通过重叠和非冗余的功能抑制 T 细胞的活化。UBASH3B 主要作为磷酸酶抑制近端 T 细胞受体（TCR）信号传导。相反，UBASH3A 主要作为一种适配蛋白，在 TCR 刺激下与 T 细胞中的其他蛋白（包括 UBASH3B）相互作用，导致 TCR 信号和 NF-κB 信号下调。人类基因和功能研究揭示了 UBASH3A 和 UBASH3B 之间的另一个显著区别：大量全基因组关联研究发现，UBASH3A 基因及其周围的基因变异与至少七种不同的自身免疫疾病之间存在统计学意义上的显著关联，这表明 UBASH3A 在自身免疫中发挥着关键作用。然而，关于 UBASH3B 在自身免疫疾病中的独立作用的证据却很有限。本综述总结了有关 TULA 蛋白在 T 细胞生物学和自身免疫中作用的主要发现，强调了 UBASH3A 和 UBASH3B 之间的共性和差异，并推测了 TULA 蛋白对 T 细胞信号传导的单独和联合作用。
{"title":"Roles of TULA-family proteins in T cells and autoimmune diseases","authors":"Hua Wang, Patrick Concannon, 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}
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