JCI insight最新文献_第3页

Ablating UNG activity in a mouse model inhibits colorectal cancer growth by increasing tumor immunogenicity. 在小鼠模型中切除UNG活性通过增加肿瘤免疫原性抑制结直肠癌的生长。

IF 6.3 1区医学

JCI insight Pub Date : 2025-07-15 DOI: 10.1172/jci.insight.184435

Eric S Christenson, Brandon E Smith, Thanh J Nguyen, Alens Valentin, Soren Charmsaz, Nicole E Gross, Sarah M Shin, Alexei Hernandez, Won Jin Ho, Srinivasan Yegnasubramanian, James T Stivers

{"title":"Ablating UNG activity in a mouse model inhibits colorectal cancer growth by increasing tumor immunogenicity.","authors":"Eric S Christenson, Brandon E Smith, Thanh J Nguyen, Alens Valentin, Soren Charmsaz, Nicole E Gross, Sarah M Shin, Alexei Hernandez, Won Jin Ho, Srinivasan Yegnasubramanian, James T Stivers","doi":"10.1172/jci.insight.184435","DOIUrl":"10.1172/jci.insight.184435","url":null,"abstract":"Uracil DNA glycosylase (UNG) excises uracil and 5-fluorouracil bases from DNA and is implicated in fluorodeoxyuridine (FdU) resistance. Here we explore the effects of inhibiting UNG activity, or depleting the UNG protein, in two mouse syngeneic models for colorectal cancer. Overexpressing the uracil DNA glycosylase inhibitor protein in mismatch repair (MMR)-deficient MC38 cells injected into C57/B6 mice delayed tumor growth and prolonged survival when combined with FdU. Combining UNG inhibition with FdU numerically increased CD4+ T lymphocytes and B cells compared to FdU or UNG inhibition alone, suggesting an immune component to the effects. In contrast, shRNA depletion of UNG in the absence of FdU treatment resulted in 70% of mice clearing their tumors, and a 3-fold increase in overall survival compared to FdU. Analysis of MC38 tumor-infiltrating immune cells showed UNG depletion increased monocyte and dendritic cell populations, with CD8+ T cells also numerically increased. shRNA depletion of UNG in MMR-proficient CT-26 cells injected into Balb/C mice produced minimal benefit; the addition of anti-PD-1 antibody synergized with UNG-depletion to increase survival. Cytotoxic T cell depletion abolished the benefits of UNG depletion in both models. These findings suggest UNG inhibition and/or depletion could enhance antitumor immune response in humans.","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144642586","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

High protein does not change autophagy in human peripheral blood mononuclear cells after one hour. 高蛋白在1小时后不改变人外周血单核细胞的自噬。

IF 6.3 1区医学

JCI insight Pub Date : 2025-07-15 DOI: 10.1172/jci.insight.188845

Sanjna Singh, Célia Fourrier, Kathryn J Hattersley, Leanne K Hein, Jemima Gore, Alexis Martin, Linh Vp Dang, Barbara King, Rachael A Protzman, Paul J Trim, Leonie K Heilbronn, Julien Bensalem, Timothy J Sargeant

{"title":"High protein does not change autophagy in human peripheral blood mononuclear cells after one hour.","authors":"Sanjna Singh, Célia Fourrier, Kathryn J Hattersley, Leanne K Hein, Jemima Gore, Alexis Martin, Linh Vp Dang, Barbara King, Rachael A Protzman, Paul J Trim, Leonie K Heilbronn, Julien Bensalem, Timothy J Sargeant","doi":"10.1172/jci.insight.188845","DOIUrl":"https://doi.org/10.1172/jci.insight.188845","url":null,"abstract":"Autophagy is a catabolic quality control pathway that has been linked to neurodegenerative disease, atherosclerosis and ageing, and can be modified by nutrient availability in preclinical models. Consequently, there is immense public interest in stimulating autophagy in people. However, progress has been hampered by the lack of techniques to measure human autophagy. As a result, several key concepts in the field, including nutritional modulation of autophagy, have yet to be validated in humans. We conducted a single arm pre-post study in 42 healthy individuals, to assess whether an acute nutritional intervention could modify autophagy in humans. Two blood samples were collected per participant: after a 12 h overnight fast and 1 h post-consumption of a high protein meal. Autophagy turnover was assessed using a physiologically relevant measure of autophagic flux in peripheral blood mononuclear cells. A lysosomal inhibitor was added directly to whole blood, with the resulting build-up of autophagy marker LC3B-II designated as flux, and measured quantitatively via ELISA. Notably, consumption of a high protein meal had no impact on autophagy, with no differences between overnight fasting and postprandial autophagic flux. We observed sexual dimorphism in autophagy, with females having higher autophagic flux compared to males (p = 0.0031). Exploratory analyses revealed sex-specific correlations between autophagy, insulin and glucose signalling. Importantly, our findings show that an acute nutritional intervention (overnight fasting followed by consumption of a protein-rich meal) does not change autophagic flux in humans, highlighting the need to conduct further autophagy studies in humans.","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144642564","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Prophylactic and therapeutic neutralizing monoclonal antibody treatment prevents lethal yellow fever infection. 预防性和治疗性中和性单克隆抗体治疗可预防致死性黄热病感染。

IF 6.3 1区医学

JCI insight Pub Date : 2025-07-15 DOI: 10.1172/jci.insight.191665

Lauren N Rust, Michael J Ricciardi, Savannah S Lutz, Sofiya Yusova, Johan J Louw, Aaron Yrizarry-Medina, Sreya Biswas, Miranda Fischer, Aaron Barber-Axthelm, Gavin Zilverberg, Lauren Bailey, Tonya Swanson, Rachael Tonelli, G W McElfresh, Brandon C Rosen, Thomas B Voigt, Christakis Panayiotou, Jack T Mauter, Noor Ghosh, Jenna Meanor, Giovana Godoy, Michael Axthelm, Jeremy Smedley, Mark K Slifka, Esper G Kallas, Gabriela Webb, Robert Zweig, Caralyn S Labriola, Benjamin N Bimber, Jonah B Sacha, David I Watkins, Benjamin J Burwitz

{"title":"Prophylactic and therapeutic neutralizing monoclonal antibody treatment prevents lethal yellow fever infection.","authors":"Lauren N Rust, Michael J Ricciardi, Savannah S Lutz, Sofiya Yusova, Johan J Louw, Aaron Yrizarry-Medina, Sreya Biswas, Miranda Fischer, Aaron Barber-Axthelm, Gavin Zilverberg, Lauren Bailey, Tonya Swanson, Rachael Tonelli, G W McElfresh, Brandon C Rosen, Thomas B Voigt, Christakis Panayiotou, Jack T Mauter, Noor Ghosh, Jenna Meanor, Giovana Godoy, Michael Axthelm, Jeremy Smedley, Mark K Slifka, Esper G Kallas, Gabriela Webb, Robert Zweig, Caralyn S Labriola, Benjamin N Bimber, Jonah B Sacha, David I Watkins, Benjamin J Burwitz","doi":"10.1172/jci.insight.191665","DOIUrl":"https://doi.org/10.1172/jci.insight.191665","url":null,"abstract":"Yellow Fever virus (YFV) infection is fatal in 5-10% of the 200,000 yearly cases. There is currently no available antiviral treatment. We showed previously that administration of 50 mg/kg of a YFV-specific neutralizing monoclonal antibody (nmAb) at 2 days post-infection (dpi), prior to the onset of severe disease, protected YFV-infected rhesus macaques from death. To further explore the clinical applicability of our nmAb MBL-YFV-01, we treated rhesus macaques with a lower dose (10 mg/kg) of this nmAb prophylactically or therapeutically at 3.5 dpi. We show that a single prophylactic or therapeutic intravenous dose of our nmAb protects rhesus macaques from death following challenge. A comprehensive analysis of 167 inflammatory cytokine and chemokines revealed that protection was associated with significantly reduced expression of 125 of these markers, including type I interferons, IL6, and CCL2. This study further expands the potential clinical use of our YFV-specific nmAb, which could be used during an outbreak for immediate prophylactic immunity or for patients with measurable serum viremia.","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144642567","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

NSD1-916aa encoded by CircNSD1 contributes to AKI-to-CKD transition through inducing ferroptosis in tubular epithelial cells. CircNSD1编码的NSD1-916aa通过诱导小管上皮细胞铁下垂参与aki向ckd的转变。

IF 6.3 1区医学

JCI insight Pub Date : 2025-07-15 DOI: 10.1172/jci.insight.189130

Li Gao, Junsheng Zhang, Chaoyi Chen, Sai Zhu, Xianglong Wei, Guiqin Tang, Sheng Wang, Yukai Wang, Xinran Liu, Ling Jiang, Yonggui Wu

{"title":"NSD1-916aa encoded by CircNSD1 contributes to AKI-to-CKD transition through inducing ferroptosis in tubular epithelial cells.","authors":"Li Gao, Junsheng Zhang, Chaoyi Chen, Sai Zhu, Xianglong Wei, Guiqin Tang, Sheng Wang, Yukai Wang, Xinran Liu, Ling Jiang, Yonggui Wu","doi":"10.1172/jci.insight.189130","DOIUrl":"https://doi.org/10.1172/jci.insight.189130","url":null,"abstract":"Acute kidney injury (AKI) is characterized by a rapid decline in renal function. In severe or recurrent cases, AKI can progress to chronic kidney disease (CKD), marked by renal inflammation and fibrosis. Despite the severity of these outcomes, early-stage diagnostic tools and pharmacological interventions for AKI-to-CKD progression remain limited. In this study, we examined circular RNA (circRNA) expression profiles in mouse renal cortex tissues 14 days post-ischemia/reperfusion (I/R) injury using circRNA sequencing. The renal biopsy samples of patients after AKI exhibited reduced CircNSD1 expression, which was inversely associated with inflammation and fibrosis. Overexpression of CircNSD1 attenuated ferroptosis in vivo and in vitro, while slowing AKI-to-CKD progression. Mechanistically, CircNSD1 downregulated ACSL4 and SlC39A14 expression through histone H3 lysine 36 (H3K36) methylation, a critical pathway regulating ferroptosis after AKI or hypoxia/reoxygenation (H/R) injury. Furthermore, we identified that CircNSD1 encoded a NSD1-916aa peptide, which may functionally contribute to its observed effect. Collectively, these findings demonstrated that CircNSD1 may serve as a diagnostic and therapeutic target for early detection of AKI-to-CKD transition.","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144642566","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Cullin-3 regulates the renal baroreceptor machinery that controls renin gene expression. Cullin-3调节控制肾素基因表达的肾压力感受器机制。

IF 6.3 1区医学

JCI insight Pub Date : 2025-07-08 DOI: 10.1172/jci.insight.194075

Daria Golosova, Gaurav Kumar, Ko-Ting Lu, Patricia C Muskus Veitia, Ana Hantke Guixa, Kelsey K Wackman, Eva M Fekete, Daniel T Brozoski, Justin L Grobe, Maria Luisa S Sequeira-Lopez, R Ariel Gomez, Pablo Nakagawa, Curt D Sigmund

{"title":"Cullin-3 regulates the renal baroreceptor machinery that controls renin gene expression.","authors":"Daria Golosova, Gaurav Kumar, Ko-Ting Lu, Patricia C Muskus Veitia, Ana Hantke Guixa, Kelsey K Wackman, Eva M Fekete, Daniel T Brozoski, Justin L Grobe, Maria Luisa S Sequeira-Lopez, R Ariel Gomez, Pablo Nakagawa, Curt D Sigmund","doi":"10.1172/jci.insight.194075","DOIUrl":"https://doi.org/10.1172/jci.insight.194075","url":null,"abstract":"Mutations in Cullin-3 (CUL3) cause hypertension (HTN). We examined the role of smooth muscle cell (SMC) CUL3 in the regulation of renin gene expression. Mice with SMC-specific CUL3 deletion (S-CUL3KO) developed severe HTN with paradoxically preserved levels of plasma angiotensin peptides and renal renin expression. Cre-recombinase was active in JG cells resulting in decreased CUL3 expression. We evaluated components of the renin cell baroreceptor and revealed preserved lamin A/C but decreased integrin β1 expression in S-CUL3KO. We hypothesized that Rab proteins are involved in integrin β1 downregulation. Silencing either Rab21 or Rab5 in CUL3-deficient HEK293 cells increased integrin β1 protein. Co-immunoprecipitation revealed a direct interaction between Rab5 and CUL3. CUL3-deficiency increased Rab5 suggesting it is regulated by a CUL3-mediated mechanism and that CUL3-deficiency results in loss of Rab protein turnover leading to enhanced integrin β1 internalization. We conclude that the loss of integrin β1 from juxtaglomerular cells impairs the mechanosensory function of the renin cell baroreceptor, which underlies the persistent renin expression observed in hypertensive S-CUL3KO mice. These findings provide insights into the molecular mechanisms of HTN, revealing that dysregulation of Rab proteins and integrin β1 in the kidney due to CUL3-deficiency contributes to the development of HTN.","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144583955","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Hem1 controls T cell activation, memory, and the regulated release of immunosuppressive and proinflammatory cytokines. Hem1控制T细胞的激活、记忆以及免疫抑制和促炎细胞因子的调节释放。

IF 6.3 1区医学

JCI insight Pub Date : 2025-07-08 DOI: 10.1172/jci.insight.174235

Alexandra Christodoulou, Nutthakarn Suwankitwat, Jacob T Tietsort, Ryan Z Culbert, Julia Y Tsai, Fatima A Tarbal, Chengsong Zhu, Brian M Iritani

{"title":"Hem1 controls T cell activation, memory, and the regulated release of immunosuppressive and proinflammatory cytokines.","authors":"Alexandra Christodoulou, Nutthakarn Suwankitwat, Jacob T Tietsort, Ryan Z Culbert, Julia Y Tsai, Fatima A Tarbal, Chengsong Zhu, Brian M Iritani","doi":"10.1172/jci.insight.174235","DOIUrl":"https://doi.org/10.1172/jci.insight.174235","url":null,"abstract":"Hematopoietic Protein-1 (Hem1) is a component of the WASP-family verprolin-homologous protein (WAVE) actin regulatory complex, which is activated downstream of multiple immune receptors. Mutations in the NCKAP1L gene encoding HEM1 have recently been found to result in severe Primary Immunodeficiency Disease (PID), characterized by recurrent respiratory infections, hyperinflammation, autoimmunity, and high mortality. However, how loss of Hem1 results in PID is unclear. To define the importance of Hem1 specifically in T cells, we generated constitutive and T cell specific Hem1 null mice. Hem1 deficient T cells exhibited an increased shift from naïve to memory T cells, and increased ratio of immunosuppressive regulatory to effector T cells. Loss of Hem1 resulted in hallmarks of T cell exhaustion including T cell lymphopenia, decreased activation and proliferation, increased expression of PD-1 and Tim3, and increased IL-10 production. In vitro TCR stimulation of CD4 T cells resulted in increased production of Th1 (IFN), Th2 (IL-5, IL-13), Th17 (IL-17, IL-22), and Treg (IL-10) cytokines. This correlated with reduced F-actin, increased expression of CD107a, and increased granzyme release indicative of increased granule membrane fusion and exocytosis. These results suggest that Hem-1 is critical for maintaining T cell activation, homeostasis and regulated cytokine production following antigen encounter.","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144583957","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Susceptibility of alpha1 antitrypsin deficiency variants to polymer blocking therapy. α 1抗胰蛋白酶缺乏变异对聚合物阻断治疗的易感性。

IF 6.3 1区医学

JCI insight Pub Date : 2025-07-08 DOI: 10.1172/jci.insight.194354

Riccardo Ronzoni, Ibrahim F Aldobyian, Elena Miranda, Narinder Heyer-Chauhan, Emma Lk Elliston, Juan Pérez, Annamaria Fra, James A Irving, David A Lomas

{"title":"Susceptibility of alpha1 antitrypsin deficiency variants to polymer blocking therapy.","authors":"Riccardo Ronzoni, Ibrahim F Aldobyian, Elena Miranda, Narinder Heyer-Chauhan, Emma Lk Elliston, Juan Pérez, Annamaria Fra, James A Irving, David A Lomas","doi":"10.1172/jci.insight.194354","DOIUrl":"https://doi.org/10.1172/jci.insight.194354","url":null,"abstract":"The Z variant (Glu342Lys) causes alpha1 antitrypsin (AAT) to self-assemble into polymer chains that accumulate within hepatocytes causing liver disease and exposing a cryptic epitope recognised by the 2C1 monoclonal antibody (mAb). They can be blocked by the small molecule '716 that stabilises an intermediate on the polymerisation pathway. We have characterised 23 mutants of AAT in a cellular model to establish: (i) their ability to form intracellular polymers; (ii) whether polymer formation could be prevented by '716; and (iii) whether the polymers expose the 2C1 cryptic epitope. Most of the variants, including Mprocida (Leu41Pro), Mherleen (Pro369Leu), Mduarte (Asp256Val), Lfrankfurt (Pro255Thr), Yorzinuovi (Pro391His), Mwurzburg (Pro369Ser) and p.289S accumulated as intracellular polymers. Eleven formed polymers that were resistant to '716, including Mprocida, Mmalton (ΔPhe51), Lfrankfurt, Mduarte, S (Glu264Val), Mherleen, and Yorzinuovi. The '716 resistant mutants localise to a region of the AAT molecule separate from the binding site of the small molecule and form polymers that are less well-recognised by the 2C1 mAb. They are fully recognised by a novel 8A7 mAb that we developed to have a broader specificity. Our data suggest that individuals with these mutations are unlikely to benefit from treatment with '716 or its derivatives.","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144583958","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Gene therapy enhances deoxyribonuclease I treatment in anti-myeloperoxidase glomerulonephritis. 基因治疗增强抗髓过氧化物酶肾小球肾炎的脱氧核糖核酸酶I治疗。

IF 6.3 1区医学

JCI insight Pub Date : 2025-07-08 DOI: 10.1172/jci.insight.188951

Anne Cao Le, Virginie Oudin, Jonathan Dick, Maliha A Alikhan, Timothy A Gottschalk, Lu Lu, Kate E Lawlor, Daniel Koo Yuk Cheong, Mawj Mandwie, Ian E Alexander, A R Kitching, Poh-Yi Gan, Grant J Logan, Kim M O'Sullivan

{"title":"Gene therapy enhances deoxyribonuclease I treatment in anti-myeloperoxidase glomerulonephritis.","authors":"Anne Cao Le, Virginie Oudin, Jonathan Dick, Maliha A Alikhan, Timothy A Gottschalk, Lu Lu, Kate E Lawlor, Daniel Koo Yuk Cheong, Mawj Mandwie, Ian E Alexander, A R Kitching, Poh-Yi Gan, Grant J Logan, Kim M O'Sullivan","doi":"10.1172/jci.insight.188951","DOIUrl":"https://doi.org/10.1172/jci.insight.188951","url":null,"abstract":"Extracellular DNA (ecDNA) released from injured and dying cells powerfully induces injurious inflammation. In this study we define the role of ecDNA in systemic vasculitis affecting the kidney, using human kidney biopsies and murine models of myeloperoxidase anti-neutrophil cytoplasmic antibody-associated glomerulonephritis (MPO-ANCA GN). Twice daily administration of intravenous DNase I (ivDNase I) in two models of anti-MPO GN reduced glomerular deposition of ecDNA, histological injury, leukocyte infiltration and NETosis. Comprehensive investigation into DNase I modes of action revealed that after exposure to MPO, DNase I reduced lymph node DC numbers and their activation status, resulting in decreased frequency of MPO-specific CD4 effector T cells (IFN-, and IL-17A producing), and reductions in dermal anti-MPO delayed type hypersensitivity responses. To overcome the translational obstacle of the short half-life of DNase I (<5 hours), we tested an adeno-associated viral vector encoding DNase I (vec-DNase I). The method of DNase I delivery was more effective, as in addition to the histological and anti-inflammatory changes described above, a single vector treatment also reduced circulating MPO-ANCA titers and albuminuria. These results indicate ecDNA is a potent driver of anti-MPO GN and that DNase I is a potential therapeutic that can be delivered using gene technology.","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144600414","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Human pegivirus alters brain and blood immune and transcriptomic profiles of patients with Parkinson's disease. 人类培吉病毒改变帕金森病患者的大脑和血液免疫和转录组谱。

IF 6.3 1区医学

JCI insight Pub Date : 2025-07-08 DOI: 10.1172/jci.insight.189988

Barbara A Hanson, Xin Dang, Pouya Jamshidi, Alicia Steffens, Kaleigh Copenhaver, Zachary S Orban, Bernabe Bustos, Steven J Lubbe, Rudolph J Castellani, Igor J Koralnik

{"title":"Human pegivirus alters brain and blood immune and transcriptomic profiles of patients with Parkinson's disease.","authors":"Barbara A Hanson, Xin Dang, Pouya Jamshidi, Alicia Steffens, Kaleigh Copenhaver, Zachary S Orban, Bernabe Bustos, Steven J Lubbe, Rudolph J Castellani, Igor J Koralnik","doi":"10.1172/jci.insight.189988","DOIUrl":"10.1172/jci.insight.189988","url":null,"abstract":"Parkinson's disease (PD) is a neurodegenerative disorder with both genetic and environmental factors contributing to pathogenesis. Viral infections are potential environmental triggers that influence PD pathology. Using ViroFind, an unbiased platform for whole virome sequencing, along with quantitative PCR (qPCR), we identified human pegivirus (HPgV) in 5 of 10 (50%) of PD brains, confirmed by IHC in 2 of 2 cases, suggesting an association with PD. All 14 age- and sex-matched controls were HPgV negative. HPgV-brain positive patients with PD showed increased neuropathology by Braak stage and Complexin-2 levels, while those positive in the blood had higher IGF-1 and lower pS65-ubiquitin, supporting disruption in metabolism or mitophagy in response to HPgV. RNA-Seq revealed altered immune signaling in HPgV-infected PD samples, including consistent suppression of IL-4 signaling in both the brain and blood. Longitudinal analysis of blood samples showed a genotype-dependent viral response, with HPgV titers correlating directly with IL-4 signaling in a LRRK2 genotype-dependent manner. YWHAB was a key hub gene in the LRRK2 genotypic response, which exhibited an altered relationship with immune-related factors, including NFKB1, ITPR2, and LRRK2 itself, in patients with PD who are positive for HPgV. These results suggest a role for HPgV in shaping PD pathology and highlight the complex interplay between viral infection, immunity, and neuropathogenesis.","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":"10 13","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12244338/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144583968","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

An amphiregulin reporter mouse enables transcriptional and clonal expansion analysis of reparative lung Tregs. 双调节蛋白报告小鼠可用于修复性肺Tregs的转录和克隆扩增分析。

IF 6.3 1区医学

JCI insight Pub Date : 2025-07-08 DOI: 10.1172/jci.insight.187245

Lucas F Loffredo, Katherine A Kaiser, Adam Kornberg, Samhita Rao, Kenia de Los Santos-Alexis, Arnold Han, Nicholas Arpaia

{"title":"An amphiregulin reporter mouse enables transcriptional and clonal expansion analysis of reparative lung Tregs.","authors":"Lucas F Loffredo, Katherine A Kaiser, Adam Kornberg, Samhita Rao, Kenia de Los Santos-Alexis, Arnold Han, Nicholas Arpaia","doi":"10.1172/jci.insight.187245","DOIUrl":"10.1172/jci.insight.187245","url":null,"abstract":"Regulatory T cells (Tregs) are known to play critical roles in tissue repair via provision of growth factors, such as amphiregulin (Areg). Areg-producing Tregs have previously been difficult to study because of an inability to isolate live Areg-producing cells. In this report, we created a reporter mouse to detect Areg expression in live cells (AregThy1.1). We employed influenza A and bleomycin models of lung damage to sort Areg-producing and non-Areg-producing Tregs for transcriptomic analyses. Single-cell RNA-Seq revealed distinct subpopulations of Tregs and allowed transcriptomic comparisons of damage-induced populations. Single-cell TCR sequencing showed that Treg clonal expansion was biased toward Areg-producing Tregs and largely occurred within damage-induced subgroups. Gene module analysis revealed functional divergence of Tregs into immunosuppression-oriented and tissue repair-oriented groups, leading to identification of candidate receptors for induction of repair activity in Tregs. We tested these using an ex vivo assay for Treg-mediated tissue repair, identifying 4-1BB agonism as a mechanism for reparative activity induction. Overall, we demonstrate that the AregThy1.1 mouse is a promising tool for investigating tissue repair activity in leukocytes.","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":"10 13","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144583966","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0