The Journal of Clinical Investigation最新文献

{"title":"Circadian rhythmicity and biopsychosocial characteristics influence opioid use in chronic low back pain.","authors":"Doriana Taccardi,Amanda M Zacharias,Hailey Gm Gowdy,Mitra Knezic,Marc Parisien,Etienne J Bisson,Zhi Yi Fang,Sara A Stickley,Elizabeth Brown,Daenis Camiré,Rosemary Wilson,Lesley N Singer,Jennifer Daly-Cyr,Manon Choinière,Zihang Lu,M Gabrielle Pagé,Luda Diatchenko,Qingling Duan,Nader Ghasemlou","doi":"10.1172/jci188620","DOIUrl":"https://doi.org/10.1172/jci188620","url":null,"abstract":"BACKGROUNDInter- and intraindividual fluctuations in pain intensity pose a major challenge to treatment efficacy, with a majority of people perceiving their pain relief as inadequate. Recent preclinical studies have identified circadian rhythmicity as a potential contributor to these fluctuations and a therapeutic target.METHODSWe therefore sought to determine the impact of circadian rhythms in people with chronic low back pain (CLBP) through a detailed characterization, including questionnaires to evaluate biopsychosocial characteristics, ecological momentary assessment (7 day e-diaries at 8:00/14:00/20:00) to observe pain fluctuations, and intraday blood transcriptomics (at 8:00/20:00) to identify genes/pathways of interest.RESULTSWhile most individuals displayed constant or variable/mixed pain phenotypes, a distinct subset had daily fluctuations of increasing pain scores (>30% change in intensity over 12 hours in ≥4/7 days). This population had no opioid users, better biopsychosocial profiles, and differentially expressed transcripts relative to other pain phenotypes. The circadian-governed neutrophil degranulation pathway was particularly enriched among arrhythmic individuals; the link between neutrophil degranulation and opioid use was further confirmed in a separate CLBP cohort.CONCLUSIONOur findings identified pain rhythmicity and the circadian expression of neutrophil degranulation pathways as indicators of CLBP outcomes, which may help provide a personalized approach to phenotyping biopsychosocial characteristics and medication use. This highlights the need to better understand the impact of circadian rhythmicity across chronic pain conditions.FUNDINGThis work was funded by grants from the Canadian Institutes of Health Research (CIHR; grant PJT-190170, to NG and MGP) and the CIHR-Strategy for Patient-Oriented Research Chronic Pain Network (grant SCA-145102, to NG, QD, LD, MGP, and MC). DT was funded by a MS Canada endMS Doctoral Research Award, AMZ by an Ontario Graduate Scholarship, HGMG by a CIHR Doctoral Research Award, MGP by a Junior 2 Research Scholarship from the Fonds de recherche du Québec - Santé, and LD by a Canadian Excellence Research Chairs and Pfizer Canada Professorship in Pain Research.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"31 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145194655","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"GPIHBP1, lipoprotein lipase, and triglyceride-rich lipoproteins in capillaries of the choroid plexus and circumventricular organs.","authors":"Wenxin Song,Madison Hung,Ellen Kozlov,Megan Hung,Anh P Tran,James Carroll,Le Phoung Nguyen,Troy L Lowe,Paul Kim,Hyesoo Jung,Yiping Tu,Joonyoung Kim,Ashley M Presnell,Julia Scheithauer,Jenna P Koerner,Ye Yang,Shino D Magaki,Christopher K Williams,Michael Ploug,Haibo Jiang,Christer Betsholtz,Maarja Andaloussi Mäe,Liqun He,Anne P Beigneux,Loren G Fong,Stephen G Young","doi":"10.1172/jci191867","DOIUrl":"https://doi.org/10.1172/jci191867","url":null,"abstract":"In peripheral tissues, an endothelial cell (EC) protein, GPIHBP1, captures lipoprotein lipase (LPL) from the interstitial spaces and transports it to the capillary lumen. LPL mediates the margination of triglyceride-rich (TG-rich) lipoproteins (TRLs) along capillaries, allowing the lipolytic processing of TRLs to proceed. TRL-derived fatty acids are used for fuel in oxidative tissues or stored in adipose tissue. In mice, GPIHBP1 is absent from capillary ECs of the brain (which uses glucose for fuel); consequently, LPL and TRL margination are absent in mouse brain capillaries. However, because fatty acids were reported to play signaling roles in the brain, we hypothesized that LPL-mediated TRL processing might occur within specialized vascular beds within the central nervous system. Here, we show that GPIHBP1 is expressed in capillary ECs of human and mouse choroid plexus (ChP) and that GPIHBP1 transports LPL (produced by adjacent ChP cells) to the capillary lumen. The LPL in ChP capillaries mediates both TRL margination and processing. Intracapillary LPL and TRL margination are absent in the ChP of Gpihbp1-/- mice. GPIHBP1 expression, intracapillary LPL, and TRL margination were also observed in the median eminence and subfornical organ, circumventricular organs implicated in the regulation of food intake.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"1 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145194657","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ruling in, ruling out: the clinical utility of plasma biomarkers in diagnosis of Alzheimer's disease.","authors":"Julie K Wisch,Beau M Ances","doi":"10.1172/jci198725","DOIUrl":"https://doi.org/10.1172/jci198725","url":null,"abstract":"","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"69 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145194712","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Expression of Concern for JAK2-binding long noncoding RNA promotes breast cancer brain metastasis.","authors":"Shouyu Wang,Ke Liang,Qingsong Hu,Ping Li,Jian Song,Yuedong Yang,Jun Yao,Lingegowda Selanere Mangala,Chunlai Li,Wenhao Yang,Peter K Park,David H Hawke,Jianwei Zhou,Yan Zhou,Weiya Xia,Mien-Chie Hung,Jeffrey R Marks,Gary E Gallick,Gabriel Lopez-Berestein,Elsa R Flores,Anil K Sood,Suyun Huang,Dihua Yu,Liuqing Yang,Chunru Lin","doi":"10.1172/jci200302","DOIUrl":"https://doi.org/10.1172/jci200302","url":null,"abstract":"","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"103 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145194717","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A die is cast: autologous neutralizing antibody resistance shapes the HIV reservoir during uninterrupted ART.","authors":"Nancie M Archin","doi":"10.1172/jci198353","DOIUrl":"https://doi.org/10.1172/jci198353","url":null,"abstract":"Initial efforts to control HIV infection include an autologous neutralizing antibody (aNAb) response. aNAbs bind Env trimers of the infecting HIV strain to neutralize virus but are not very effective at controlling HIV, as the virus quickly develops escape mutations to evade neutralization. Nevertheless, recent evidence suggests that aNAbs exert ongoing immune pressure on viral isolates in people living with HIV (PWH) treated with anti-retroviral therapy (ART) during chronic and early infection. In this issue of the JCI, McMyn et al. studied the dynamics of aNAb resistance in a cohort of 31 PWH treated with ART. Notably, a large proportion of HIV reservoir viral isolates were resistant to aNAb neutralization, which correlated with longer duration on uninterrupted ART, suggesting that selection for aNAb-resistant isolates occurs as reservoir cells containing neutralization-sensitive isolates are eliminated. aNAb resistance was not attributed to waning antibody response, which persisted for over 20 years despite viral suppression.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"7 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145194715","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Gut complement system: a new frontier in microbiota-host communication and intestinal homeostasis.","authors":"Xianbin Tian,Lan Zhang,Xinyang Qian,Yangqing Peng,Fengyixin Chen,Sarah Bengtson,Zhiqing Wang,Meng Wu","doi":"10.1172/jci188349","DOIUrl":"https://doi.org/10.1172/jci188349","url":null,"abstract":"The gut microbiota plays a crucial role in maintaining intestinal homeostasis and influencing various aspects of host physiology, including immune function. Recent advances have highlighted the emerging importance of the complement system, particularly the C3 protein, as a key player in microbiota-host interactions. Traditionally known for its role in innate immunity, the complement system is now recognized for its interactions with microbial communities within the gut, where it promotes immune tolerance and protects against enteric infections. This Review explores the gut complement system as a possibly novel frontier in microbiota-host communication and examines its role in shaping microbial diversity, modulating inflammatory responses, and contributing to intestinal health. We discuss the dynamic interplay between microbiota-derived signals and complement activation, with a focus on the C3 protein and its effect on both the gut microbiome and host immune responses. Furthermore, we highlight the therapeutic potential of targeting complement pathways to restore microbial balance and treat diseases such as inflammatory bowel disease and colorectal cancer. By elucidating the functions of the gut complement system, we offer insights into its potential as a target for microbiota-based interventions aimed at restoring intestinal homeostasis and preventing disease.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"91 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145194713","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Neutrophil-enriched gene signature correlates with teplizumab therapy resistance in different stages of type 1 diabetes.","authors":"Gabriele Sassi,Pierre Lemaitre,Laia Fernández Calvo,Francesca Lodi,Álvaro Cortés Calabuig,Samal Bissenova,Amber Wouters,Laure Degroote,Marijke Viaene,Niels Vandamme,Lauren Higdon,Peter S Linsley,S Alice Long,Chantal Mathieu,Conny Gysemans","doi":"10.1172/jci176403","DOIUrl":"https://doi.org/10.1172/jci176403","url":null,"abstract":"Teplizumab, a humanized anti-CD3 monoclonal antibody, represents a breakthrough in autoimmune type 1 diabetes (T1D) treatment, by delaying clinical onset in stage 2 and slowing progression in early stage 3. However, therapeutic responses are heterogeneous. To better understand this variability, we applied single-cell transcriptomics to paired peripheral blood and pancreas samples from anti-mouse CD3-treated non-obese diabetic (NOD) mice and identified distinct gene signatures associated with therapy outcome, with consistent patterns across compartments. Success-associated signatures were enriched in NK/CD8⁺ T cells and other immune cell types, whereas resistance signatures were predominantly expressed by neutrophils. The immune communities underlying these response signatures were confirmed in human whole-blood sequencing data from the AbATE study at 6 months, which assessed teplizumab therapy in stage 3 T1D. Furthermore, baseline expression profiling in the human TN10 (stage 2) and AbATE (stage 3) cohorts identified immune signatures predictive of therapy response, T cell-enriched signatures in responders and neutrophil-enriched signatures in non-responders, highlighting the roles of both adaptive and innate immunity in determining teplizumab outcome. Using an elastic-net logistic regression model, we developed a 26-gene blood-based signature predicting teplizumab response (AUC = 0.97). These findings demonstrate the predictive potential of immune gene signatures and the value of transcriptomic profiling in guiding individualized treatment strategies with teplizumab in T1D.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"31 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145194770","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CTLA-4 blockade shifts the B cell repertoire towards autoimmunity.","authors":"Elif Çakan,Meng Wang,Yile Dai,Adrien Mirouse,Clarence Rachel Villanueva-Pachas,Delphine Bouis,Joshua M Boeckers,Ruchi Gera,Sally Yraita,Leslie Clapp,Ana Luisa Perdigoto,Fabien R Delmotte,Christopher Massad,Antonietta Bacchiocchi,Aaron M Ring,Yuval Kluger,Harriet M Kluger,Kevan C Herold,Eric Meffre","doi":"10.1172/jci189074","DOIUrl":"https://doi.org/10.1172/jci189074","url":null,"abstract":"Checkpoint inhibitors targeting CTLA-4 and PD-1 revolutionized the treatment of cancer patients, but their use is limited by the emergence of immune-related adverse events (irAE). We assessed autoreactive B cell frequencies in the blood of cancer patients before and after treatment with checkpoint inhibitors by testing the reactivity of recombinant antibodies cloned from single B cells. We found that anti-PD-1 and anti-CTLA-4 combination therapy induced the emergence of autoreactive mature naïve B cells, whereas central B-cell tolerance remained functional. In contrast, anti-PD-1 alone did not alter autoreactive B cell counterselection. Anti-CTLA-4 injections in humanized mice also resulted in the production of autoreactive B cells, whereas anti-PD-1 did not. We conclude that CTLA-4 but not PD-1 is required for the removal of developing autoreactive mature naïve B cells and that CTLA-4 blockade broadens the peripheral B cell repertoire which likely contains clones that promote not only irAEs but also anti-tumor responses.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"1 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145194772","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Altered immune and metabolic molecular pathways drive islet cell dysfunction in human type 1 diabetes.","authors":"Theodore Dos Santos,Xiao-Qing Dai,Robert C Jones,Aliya F Spigelman,Hannah M Mummey,Jessica D Ewald,Cara E Ellis,James G Lyon,Nancy Smith,Austin Bautista,Jocelyn E Manning Fox,Norma F Neff,Angela M Detweiler,Michelle Tan,Rafael Arrojo E Drigo,Jianguo Xia,Joan Camunas-Soler,Kyle J Gaulton,Stephen R Quake,Patrick E MacDonald","doi":"10.1172/jci195267","DOIUrl":"https://doi.org/10.1172/jci195267","url":null,"abstract":"Type 1 diabetes (T1D) is characterized by the autoimmune destruction of most insulin-producing β-cells, along with dysregulated glucagon secretion from pancreatic α-cells. We conducted an integrated analysis that combines electrophysiological and transcriptomic profiling, along with machine learning, of islet cells from T1D donors. The few surviving β-cells exhibit altered electrophysiological properties and transcriptomic signatures indicative of increased antigen presentation, metabolic reprogramming, and impaired protein translation. In α-cells, we observed hyper-responsiveness and increased exocytosis, which are associated with upregulated immune signaling, disrupted transcription factor localization and lysosome homeostasis, as well as dysregulation of mTORC1 complex signaling. Notably, key genetic risk signals for T1D were enriched in transcripts related to α-cell dysfunction, including MHC class I, which were closely linked with α-cell dysfunction. Our data provide what we believe are novel insights into the molecular underpinnings of islet cell dysfunction in T1D, highlighting pathways that may be leveraged to preserve residual β-cell function and modulate α-cell activity. These findings underscore the complex interplay between immune signaling, metabolic stress, and cellular identity in shaping islet cell phenotypes in T1D.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"18 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145194771","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Plasminogen Activator Inhibitor-1 promotes aortic aging-like pathophysiology in humans and mice.","authors":"Alireza Khoddam,Anthony Kalousdian,Mesut Eren,Saul Soberanes,Andrew Decker,Elizabeth J Lux,Benjamin W Zywicki,Brian Dinh,Bedirhan Boztepe,Baljash S Cheema,Carla M Cuda,Hiam Abdala-Valencia,Arun Sivakumar,Toshio Miyata,Lisa D Wilsbacher,Douglas E Vaughan","doi":"10.1172/jci196714","DOIUrl":"https://doi.org/10.1172/jci196714","url":null,"abstract":"Plasminogen activator inhibitor-1 (PAI-1), encoded by SERPINE1, contributes to age-related cardiovascular diseases (CVD) and other aging-related pathologies. Humans with a heterozygous loss-of-function SERPINE1 variant exhibit protection against aging and cardiometabolic dysfunction. We engineered a mouse model mimicking the human mutation (Serpine1TA700/+) and compared cardiovascular responses with wild-type littermates. Serpine1TA700/+ mice lived 20% longer than littermate controls. Under L-NG-Nitro-arginine methyl ester (L-NAME)-induced vascular stress, Serpine1TA700/+ mice exhibited diminished pulse wave velocity (PWV), lower systolic hypertension (SBP), and preserved left ventricular diastolic function compared to controls. Conversely, PAI-1-overexpressing mice exhibited measurements indicating accelerated cardiovascular aging. Single cell transcriptomics of Serpine1TA700/+ aortas revealed a vascular-protective mechanism with downregulation of extracellular matrix regulators Ccn1 and Itgb1. Serpine1TA700/+ aortas were also enriched in a cluster of smooth muscle cells that exhibited plasticity. Finally, PAI-1 pharmacological inhibition normalized SBP and reversed L-NAME-induced PWV elevation. These findings demonstrate that PAI-1 reduction protects against cardiovascular aging-related phenotypes, while PAI-1 excess promotes vascular pathological changes. Taken together, PAI-1 inhibition represents a promising strategy to mitigate age-related CVD.","PeriodicalId":520097,"journal":{"name":"The Journal of Clinical Investigation","volume":"26 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145194718","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}