Journal of Clinical Investigation最新文献

{"title":"Hyperinsulinemia-induced upregulation of adipocyte TPH2 contributes to peripheral serotonin production, metabolic dysfunction, and obesity.","authors":"Brian I Park, Andrew R Reeves, Ying Zhu, Robin A Wilson, Sophia C Fernandes, Kimberly K Buhman, Kelli A Lytle, Michael D Jensen, Andrew S Greenberg","doi":"10.1172/JCI190765","DOIUrl":"https://doi.org/10.1172/JCI190765","url":null,"abstract":"<p><p>Tryptophan hydroxylase (TPH) is a rate-limiting enzyme for serotonin or 5-hydroxytryptamine (5-HT) synthesis. Previously, adipocyte TPH1 has been linked to increased adipose 5-HT, reduced BAT thermogenesis, and obesity. However, the role of TPH2, a neural isoform highly expressed in obese adipose tissue, is unknown. Here, we report that adipose tissue expression of TPH2 is significantly elevated in both diet-induced obese (DIO) and ob/ob mice, as well as in obese humans. In high-fat diet (HFD)-fed mice, adipocyte TPH2 deficiency improves DIO-induced metabolic complications, enhances BAT thermogenesis, and increases intestinal energy harvesting efficiency without affecting adiposity. Conversely, TPH2 overexpression in epididymal adipocytes of chow-fed mice raises adipose and plasma 5-HT levels, suppresses BAT thermogenesis, and exacerbates obesity and metabolic dysfunction. We found that obesity-induced hyperinsulinemia upregulates adipocyte TPH2 expression via activation of mechanistic target of rapamycin complex 1 (mTORC1) and sterol regulatory element binding protein 1 (SREBP1). In humans, TPH2 mRNA levels in subcutaneous adipose tissue, but not TPH1, is positively correlated with fasting plasma insulin concentrations. In summary, our study demonstrates that obesity-associated increases in adipocyte TPH2 can regulate distal tissue physiology and energy metabolism, suggesting that TPH2 could be a potential therapeutic target for obesity and its associated complications.</p>","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":" ","pages":""},"PeriodicalIF":13.3,"publicationDate":"2025-05-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144199215","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}

{"title":"Splicing of erythroid transcription factor is associated with therapeutic response in myelodysplastic syndromes.","authors":"Srinivas Aluri, Te Ling, Ellen Fraint, Samarpana Chakraborty, Kevin Zhang, Aarif Ahsan, Leah Kravets, Gowri Poigaialwar, Rongbao Zhao, Kith Pradhan, Anitria Cotton, Kimo Bachiashvili, Jung-In Yang, Anjali Budhathoki, Beamon Agarwal, Shanisha Gordon-Mitchell, Milagros Carbajal, Srabani Sahu, Jacqueline Boultwood, Andrea Pellagatti, Ulrich Steidl, Amittha Wickrema, Satish Nandakumar, Aditi Shastri, Rajasekhar Nvs Suragani, Teresa V Bowman, John D Crispino, Sadanand Vodala, Amit Verma","doi":"10.1172/JCI189266","DOIUrl":"https://doi.org/10.1172/JCI189266","url":null,"abstract":"<p><p>Anemia is the primary clinical manifestation of myelodysplastic syndromes (MDS), but the molecular pathogenesis of ineffective erythropoiesis remains incompletely understood. Luspatercept, an activin receptor 2B (ACVRIIB-Fc) ligand trap, has been approved to treat anemia, however its molecular mechanism of action is unclear. We found that the ACVR2B, its ligand GDF11, and effector, SMAD2, are upregulated in MDS patient samples. GDF11 inhibited human erythropoiesis in vitro and caused anemia in zebrafish, effects that were abrogated by luspatercept. Upon GDF11 stimulation of human erythroid progenitors, SMAD2 binding occurred in the erythroid regulatory regions, including at GATA1 intron. Intronic SMAD2 binding led to skipping of exon 2 of GATA1, resulting in a shorter, hypomorphic isoform (GATA1s). CRISPR deletion of the SMAD2 binding intronic region decreased GATA1s production upon GDF11 stimulation. Expression of gata1s in a mouse model led to anemia, rescued by a murine ActRIIB-Fc (RAP-536). Finally, RNA-seq analysis of samples from the Phase 3 MEDALIST trial revealed that responders to Luspatercept had a higher proportion of GATA1s compared to non-responders. Moreover, the increase RBCs post-treatment was linked to a relative decrease in GATA1s isoform. Our study indicates that GDF11-mediated SMAD2 activation results in an increase in functionally impaired GATA1 isoforms, consequently contributing to anemia and influencing responses to Luspatercept in MDS.</p>","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":" ","pages":""},"PeriodicalIF":13.3,"publicationDate":"2025-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144159092","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}

{"title":"Chemotaxis overrides killing response in alloreactive cytotoxic T-cells providing vascular immune privilege during cellular rejection.","authors":"T Barba, M Oberbarnscheidt, G Franck, C Gao, S This, M Rabeyrin, C Roufosse, L Moran, A Koenig, V Mathias, C Saison, V Dubois, N Pallet, D Anglicheau, B Lamarthée, A Hertig, E Morelon, A Hot, H Paidassi, T Defrance, A Nicoletti, J P Duong-Van-Huyen, Y Xu-Dubois, F G Lakkis, O Thaunat","doi":"10.1172/JCI155191","DOIUrl":"https://doi.org/10.1172/JCI155191","url":null,"abstract":"<p><p>Graft endothelial cells (ECs) express donor alloantigens and encounter cytotoxic T lymphocytes (CTLs) but are generally spared during T cell-mediated rejection (TCMR), which predominantly affects epithelial structures. The mechanisms underlying this vascular immune privilege are unclear. Transcriptomic analyses and endothelial-mesenchymal transition assessments confirmed that the graft endothelium is preserved during TCMR. Co-culture experiments revealed that endothelial and epithelial cells are equally susceptible to CTL-mediated lysis, ruling out cell-intrinsic protection. Intravital microscopy of murine kidney grafts and single-cell RNA sequencing of human renal allografts demonstrated that CTL interactions with ECs are transient compared to epithelial cells. This disparity is mediated by a chemotactic gradient produced by graft stromal cells, guiding CTLs away from ECs toward epithelial targets. In vitro, chemotaxis overrode TCR-induced cytotoxicity, preventing endothelial damage. Finally, analysis of TCMR biopsies revealed that disruption of the chemotactic gradient correlates with endothelialitis lesions, linking its loss to vascular damage. These findings challenge the traditional view of cell-intrinsic immune privilege, proposing a cell-extrinsic mechanism where chemotaxis preserves graft vasculature during TCMR. This mechanism may have implications beyond transplantation, highlighting its role in maintaining vascular integrity across pathological conditions.</p>","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":" ","pages":""},"PeriodicalIF":13.3,"publicationDate":"2025-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144173927","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}

{"title":"Phospho-RPA2 predicts response to platinum and PARP inhibitors in homologous recombination-proficient ovarian cancer.","authors":"Angela Schab, Amanda Compadre, Rebecca Drexler, Megan Loeb, Kevin Rodriguez, Joshua Brill, Shariska Harrington, Carmen Sandoval, Brooke Sanders, Lindsay Kuroki, Carolyn McCourt, Andrea R Hagemann, Premal Thaker, David Mutch, Matthew Powell, Violeta Serra, Ian S Hagemann, Ann E Walts, Beth Y Karlan, Sandra Orsulic, Katherine Fuh, Lulu Sun, Priyanka Verma, Elena Lomonosova, Peinan Zhao, Dineo Khabele, Mary M Mullen","doi":"10.1172/JCI189511","DOIUrl":"10.1172/JCI189511","url":null,"abstract":"<p><strong>Background: </strong>Treatment of tubo-ovarian high-grade serous carcinoma (HGSC) includes cytoreductive surgery, platinum-based chemotherapy, and often poly (ADP-ribose) polymerase (PARP) inhibitors. While homologous recombination (HR)-deficiency is a well-established predictor of therapy sensitivity, over 50% of HR-proficient HGSC also exhibit sensitivity. Currently, there are no biomarkers to identify which HR-proficient HGSCs will be sensitive to standard-of-care therapy. Replication stress may serve as a key determinant of response.</p><p><strong>Methods: </strong>We evaluated phospho-RPA2-T21 (pRPA2) foci via immunofluorescence as a biomarker of replication stress in formalin-fixed, paraffin-embedded HGSC samples collected at diagnosis from patients treated with platinum chemotherapy (discovery cohort: n=31, validation cohort: n=244) or PARP inhibitors (n=63). Recurrent HGSCs (n=38) were also analyzed. pRPA2 score was calculated using automated imaging analysis.</p><p><strong>Results: </strong>Samples were defined as pRPA2-High if >16% of cells had ≥2 pRPA2 foci on automated analysis. In the discovery cohort, HR-proficient, pRPA2-High HGSCs demonstrated significantly higher rates of a chemotherapy response score of 3 to platinum chemotherapy than HR-proficient, pRPA2-Low HGSCs. In the validation cohort, patients with HR-proficient, pRPA2-High HGSCs had significantly longer survival after platinum treatment than those with HR-proficient, pRPA2-Low HGSCs. Additionally, the pRPA2 assay effectively predicted survival outcomes in patients treated with PARP inhibitors and in recurrent HGSC samples.</p><p><strong>Conclusion: </strong>Our study underscores the importance of considering replication stress marker, such as pRPA2, alongside HR status in therapeutic planning. This approach has the potential to increase the number of patients receiving effective therapy while reducing unnecessary toxicity.</p>","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":" ","pages":""},"PeriodicalIF":13.3,"publicationDate":"2025-05-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144109884","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}

{"title":"Genetic variants predisposing to increased risk of kidney stone disease.","authors":"Catherine E Lovegrove, Michelle Goldsworthy, Jeremy Haley, Diane Smelser, Caroline Gorvin, Fadil M Hannan, Anubha Mahajan, Mohnish Suri, Omid Sadeghi-Alavijeh, Shabbir H Moochhala, Daniel P Gale, David Carey, Michael V Holmes, Dominic Furniss, Rajesh V Thakker, Sarah A Howles","doi":"10.1172/JCI186915","DOIUrl":"https://doi.org/10.1172/JCI186915","url":null,"abstract":"<p><strong>Background: </strong>Kidney stone disease (KSD) affects ~10% of adults, is heritable, and associated with mineral metabolic abnormalities.</p><p><strong>Methods: </strong>Genetic variants and pathways increasing KSD risk via calcium and phosphate homeostasis were ascertained using genome-wide association analyses, region-specific Mendelian randomization (MR), and genetic colocalization. Utility of pathway modulation was estimated via drug-target MR, and effects of variants on calcium-sensing receptor (CaSR)-signaling characterized.</p><p><strong>Results: </strong>Seventy-nine independent KSD-associated genetic signals at 71 loci were identified. MR identified three loci affecting KSD risk via increased serum calcium or decreased serum phosphate concentrations (odds ratios for genomic regions=4.30, 11.42, and 13.83 per 1 standard deviation alteration; p<5.6x10-10). Colocalization analyses defined putative, non-coding KSD-causing variants estimated to account for 11-19% of KSD cases in proximity to diacylglycerol kinase delta (DGKD), a CaSR-signalling partner; solute carrier family 34 member 1 (SLC34A1), a renal sodium-phosphate transporter; and cytochrome P450 family 24 subfamily A member 1 (CYP24A1), which degrades 1,25-dihydroxyvitamin D. Drug- target MR indicated that reducing serum calcium by 0.08mmol/L via CASR, DGKD, or CYP24A1, or increasing serum phosphate by 0.16mmol/L via SLC34A1 may reduce KSD relative risk by up to 90%. Furthermore, reduced DGKδ expression and KSD-associated DGKD missense variants impaired CaSR-signal transduction in vitro, which was ameliorated by cinacalcet, a positive CaSR-allosteric modulator.</p><p><strong>Conclusion: </strong>DGKD-, SLC34A1-, and CYP24A1-associated variants linked to reduced CaSR-signal transduction, increased urinary phosphate excretion, and impaired 1,25-dihydroxyvitamin D inactivation, respectively, are common causes of KSD. Genotyping patients with KSD may facilitate personalised KSD-risk stratification and targeted pharmacomodulation of associated pathways to prevent KSD.</p>","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":" ","pages":""},"PeriodicalIF":13.3,"publicationDate":"2025-05-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144076973","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}

{"title":"LAG3 regulates antibody responses in a murine model of kidney transplantation.","authors":"Michael Nicosia, Ran Fan, Juyeun Lee, Gabriella L All, Victoria Gorbacheva, José Ignacio Valenzuela, Yosuke Yamamoto, Ashley Beavers, Nina Dvorina, William M Baldwin Iii, Eduardo Chuluyan, Motoo Araki, Brian T Gaudette, Robert L Fairchild, Booki Min, Anna Valujskikh","doi":"10.1172/JCI172988","DOIUrl":"https://doi.org/10.1172/JCI172988","url":null,"abstract":"<p><p>Lymphocyte activation gene-3 (LAG3) is a coinhibitory receptor expressed by various immune cells. While immunomodulatory potential of LAG3 is being explored in cancer and autoimmunity, there is no information on its role following organ transplantation. Our study investigated the functions of LAG3 in a mouse model of renal allograft rejection. LAG3-/- recipients rapidly reject MHC-mismatched renal allografts that are spontaneously accepted by WT recipients, with graft histology characteristic of antibody mediated rejection (ABMR). Depletion of recipient B cells but not CD8+ T cells significantly extended kidney allograft survival in LAG3-/- recipients. Treatment of WT recipients with an antagonistic LAG3 antibody enhanced anti-donor immune responses and induced kidney damage associated with chronic rejection. The studies of conditional LAG3-/- recipients and mixed bone marrow chimeras demonstrated that LAG3 expression on either T or B cells is sufficient to regulate anti-donor humoral immunity but not to induce acute allograft rejection. The numbers and proinflammatory functions of graft-infiltrating NK cells were markedly increased in LAG3-/- recipients suggesting that LAG3 also regulates the effector stage of ABMR. These results are the first to identify LAG3 as a regulator of immune responses to kidney allografts and a potential therapeutic target for ABMR prevention and treatment.</p>","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":" ","pages":""},"PeriodicalIF":13.3,"publicationDate":"2025-05-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143987820","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}

{"title":"OCA-B promotes pathogenic maturation of stem-like CD4+ T cells and autoimmune demyelination.","authors":"Erik P Hughes, Amber R Syage, Elnaz Mirzaei Mehrabad, Thomas E Lane, Benjamin T Spike, Dean Tantin","doi":"10.1172/JCI187862","DOIUrl":"https://doi.org/10.1172/JCI187862","url":null,"abstract":"<p><p>Stem-like T cells selectively contribute to autoimmunity, but the activities that promote their pathogenicity are incompletely understood. Here, we identify the transcription coregulator OCA-B as a driver of the pathogenic maturation of stem-like CD4+ T cell to promote autoimmune demyelination. Using two human multiple sclerosis (MS) datasets, we show that POU2AF1, the gene encoding OCA-B, is elevated in CD4+ T cells from MS patients. We show that T cell-intrinsic OCA-B loss protects mice from experimental autoimmune encephalomyelitis (EAE) while preserving responses to viral CNS infection. In EAE models driven by antigen reencounter, OCA-B deletion nearly eliminates CNS infiltration, proinflammatory cytokine production and clinical disease. OCA-B-expressing CD4+ T cells of mice primed with autoantigen express an encephalitogenic gene program and preferentially confer disease. In a relapsing-remitting EAE model, OCA-B loss protects mice specifically at relapse. During remission, OCA-B promotes the expression of Tcf7, Slamf6, and Sell in proliferating CNS T cell populations. At relapse timepoints, OCA-B loss results in both the accumulation of an immunomodulatory CD4+ T cell population expressing Ccr9 and Bach2, and loss of pro-inflammatory gene expression from Th17 cells. These results identify OCA-B as a driver of pathogenic CD4+ T cells.</p>","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":" ","pages":""},"PeriodicalIF":13.3,"publicationDate":"2025-04-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144015976","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}

{"title":"Lymphatic dysfunction in lupus contributes to cutaneous photosensitivity and lymph node B cell responses.","authors":"Mir J Howlader, William G Ambler, Madhavi Latha S Chalasani, Aahna Rathod, Ethan S Seltzer, Ji Hyun Sim, Jinyeon Shin, Noa Schwartz, William D Shipman Iii, Dragos C Dasoveanu, Camila B Carballo, Ecem Sevim, Salma Siddique, Yurii Chinenov, Scott A Rodeo, Doruk Erkan, Raghu P Kataru, Babak J Mehrara, Theresa T Lu","doi":"10.1172/JCI168412","DOIUrl":"https://doi.org/10.1172/JCI168412","url":null,"abstract":"<p><p>Patients with systemic lupus erythematosus (SLE) are photosensitive, developing skin inflammation with even ambient ultraviolet radiation (UVR), and this cutaneous photosensitivity can be associated with UVR-induced flares of systemic disease, which can involve increased autoantibodies and further end organ injury. Mechanistic insight into the link between the skin responses and autoimmunity is limited. Signals from skin are transmitted directly to the immune system via lymphatic vessels, and here we show evidence for potentiation of UVR-induced lymphatic flow dysfunction in SLE patients and murine models. Improving lymphatic flow by manual lymphatic drainage (MLD) or with a transgenic model with increased lymphatic vessels reduces both cutaneous inflammation and lymph node B and T cell responses, and long term MLD reduces splenomegaly and titers of a number of autoantibodies. Mechanistically, improved flow restrains B cell responses in part by stimulating a lymph node fibroblastic reticular cell-monocyte axis. Our results point to lymphatic modulation of lymph node stromal function as a link between photosensitive skin responses and autoimmunity and as a therapeutic target in lupus, provide insight into mechanisms by which the skin state regulates draining lymph node function, and suggest the possibility of MLD as an accessible and cost-effective adjunct to add to ongoing medical therapies for lupus and related diseases.</p>","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":" ","pages":""},"PeriodicalIF":13.3,"publicationDate":"2025-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144013231","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}

{"title":"IL-7-mediated expansion of autologous lymphocytes increases CD8+ VLA-4 expression and accumulation in glioblastoma models.","authors":"Kirit Singh, Kelly M Hotchkiss, Sarah L Cook, Pamy Noldner, Ying Zhou, Eliese M Moelker, Chelsea O Railton, Emily E Blandford, Bhairavy J Puviindran, Shannon E Wallace, Pamela K Norberg, Gary E Archer, Beth H Shaz, Katayoun Ayasoufi, John H Sampson, Mustafa Khasraw, Peter E Fecci","doi":"10.1172/JCI181471","DOIUrl":"https://doi.org/10.1172/JCI181471","url":null,"abstract":"<p><p>The efficacy of T cell-activating therapies against glioma is limited by an immunosuppressive tumor microenvironment and tumor-induced T cell sequestration. We investigated whether peripherally infused non-antigen specific autologous lymphocytes (ALT) could accumulate in intracranial tumors. We observed that non-specific autologous CD8+ ALT cells can indeed accumulate in this context, despite endogenous T cell sequestration in bone marrow. Rates of intratumoral accumulation were markedly increased when expanding lymphocytes with IL-7 compared to IL-2. Pre-treatment with IL-7 ALT also enhanced the efficacy of multiple tumor-specific and non-tumor-specific T cell-dependent immunotherapies against orthotopic murine and human xenograft gliomas. Mechanistically, we detected increased VLA-4 on mouse and human CD8+ T cells following IL-7 expansion, with increased transcription of genes associated with migratory integrin expression (CD9). We also observed that IL-7 increases S1PR1 transcription in human CD8+ T cells, which we have shown to be protective against tumor-induced T cell sequestration. These observations demonstrate that expansion with IL-7 enhances the capacity of ALT to accumulate within intracranial tumors, and that pre-treatment with IL-7 ALT can boost the efficacy of subsequent T cell-activating therapies against glioma. Our findings will inform the development of future clinical trials where ALT pre-treatment can be combined with T cell-activating therapies.</p>","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":" ","pages":""},"PeriodicalIF":13.3,"publicationDate":"2025-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143994527","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}

{"title":"Exploring [11C]CPPC as a CSF1R-targeted PET imaging marker for early Parkinson's disease severity.","authors":"Kelly A Mills, Yong Du, Jennifer M Coughlin, Catherine A Foss, Andrew G Horti, Katelyn R Jenkins, Yana Skorobogatova, Ergi Spiro, Chelsie S Motley, Robert F Dannals, Wojciech G Lesniak, Jae-Jin Song, Yu Ree Choi, Javier Redding-Ochoa, Juan C Troncoso, Valina L Dawson, Tae-In Kam, Martin G Pomper, Ted M Dawson","doi":"10.1172/JCI186591","DOIUrl":"https://doi.org/10.1172/JCI186591","url":null,"abstract":"<p><strong>Background: </strong>Microglia-mediated brain immune changes play a role in the pathogenesis of Parkinson's disease (PD) but imaging microglia in living people with PD has relied on positron emission tomography (PET) ligands that lack specificity in labeling immune cells in the nervous system. We aimed to develop imaging of colony stimulating factor 1 receptor (CSF1R) as a microglial-sensitive marker of innate immunity.</p><p><strong>Methods: </strong>Immunohistochemistry using a CSF1R antibody evaluated colocalization with Iba-1 in PD (n = 4) and control (n = 4) human brain samples. Autoradiography using a CSF1R tritiated ligand in PD (n = 5) and controls (n = 4) human brain samples was performed to obtain Bmax. PET imaging using a CSF1R radioligand was performed in 10 controls and 12 people with PD and VT was compared between groups and correlated with disease severity.</p><p><strong>Results: </strong>Immunohistochemistry of CSF1R in human brain shows colocalization with Iba-1 and is significantly increased in PD compared to controls. Autoradiography revealed significantly increased CSF1R ligand binding in the inferior parietal cortex of PD patients. [11C]CPPC PET showed higher binding in people with moderate PD compared to controls and correlated with more severe motor disability and poorer verbal fluency.</p><p><strong>Conclusion: </strong>This study underscores the significance of CSF1R imaging as a promising biomarker for brain immune function in Parkinson's disease, which may be associated with cognitive and motor disease severityFUNDING. PET imaging: the Michael J. Fox Foundation and the RMS Family Foundation. Radiotracer development: NIH (R01AG066464 and P41 EB024495). Postmortem brain tissues: NIH P30 AG066507 and BIOCARD study NIH U19 AG033655.</p>","PeriodicalId":15469,"journal":{"name":"Journal of Clinical Investigation","volume":" ","pages":""},"PeriodicalIF":13.3,"publicationDate":"2025-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143969009","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}