JCI insightPub Date : 2025-06-05DOI: 10.1172/jci.insight.190992
Hasan Demirci, Jessica P Bahena-Lopez, Alina Smorodchenko, Xiao-Tong Su, Jonathan W Nelson, Chao-Ling Yang, Joshua N Curry, Xin-Peng Duan, Wen-Hui Wang, Yuliya Sharkovska, Ruisheng Liu, Duygu Elif Yilmaz, Catarina Quintanova, Katie Emberley, Ben Emery, Nina Himmerkus, Markus Bleich, David H Ellison, Sebastian Bachmann
{"title":"Distinct cell types along thick ascending limb express pathways for monovalent and divalent cation transport.","authors":"Hasan Demirci, Jessica P Bahena-Lopez, Alina Smorodchenko, Xiao-Tong Su, Jonathan W Nelson, Chao-Ling Yang, Joshua N Curry, Xin-Peng Duan, Wen-Hui Wang, Yuliya Sharkovska, Ruisheng Liu, Duygu Elif Yilmaz, Catarina Quintanova, Katie Emberley, Ben Emery, Nina Himmerkus, Markus Bleich, David H Ellison, Sebastian Bachmann","doi":"10.1172/jci.insight.190992","DOIUrl":"10.1172/jci.insight.190992","url":null,"abstract":"<p><p>Kidney thick ascending limb cells reabsorb sodium, potassium, calcium, magnesium and contribute to urinary concentration. These cells are typically viewed as a single type that recycles potassium across the apical membrane and generates a lumen-positive transepithelial voltage driving calcium and magnesium reabsorption, although variability in potassium channel expression has been reported. Additionally, recent transcriptomic analyses suggest that different cell types exist along this segment, but classifications have varied and have not led to a new consensus model. We used immunolocalization, electrophysiology and enriched single nucleus RNA-Seq to identify thick ascending limb cell types in rat, mouse and human. We identified three major TAL cell types defined by expression of potassium channels and claudins. One has apical potassium channels, low basolateral potassium conductance, and is bordered by a monovalent cation-permeable claudin. A second lacks apical potassium channels, has high basolateral potassium conductance and is bordered by calcium- and magnesium-permeable claudins. A third type also lacks apical potassium channels and has high basolateral potassium conductance, but these cells are ringed by monovalent cation-permeable claudins. The recognition of diverse cell types may resolve longstanding questions about how solute transport can be modulated selectively and how disruption of these cells leads to human disease.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-06-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144234115","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}
JCI insightPub Date : 2025-06-05DOI: 10.1172/jci.insight.186182
Iuliia M Gilchuk, Jinhui Dong, Ryan P Irving, Cameron D Buchman, Erica Armstrong, Hannah L Turner, Sheng Li, Andrew B Ward, Robert H Carnahan, James E Crowe
{"title":"Pan-H7 influenza human antibody virus neutralization depends on avidity and steric hindrance.","authors":"Iuliia M Gilchuk, Jinhui Dong, Ryan P Irving, Cameron D Buchman, Erica Armstrong, Hannah L Turner, Sheng Li, Andrew B Ward, Robert H Carnahan, James E Crowe","doi":"10.1172/jci.insight.186182","DOIUrl":"https://doi.org/10.1172/jci.insight.186182","url":null,"abstract":"<p><p>H7N9 avian influenza virus is a zoonotic influenza virus of public health concern, with a 39% mortality rate in humans. H7N9-specific prevention or treatments for humans have not been approved. We previously isolated a human monoclonal antibody (mAb) designated H7-235 that broadly reacts to diverse H7 viruses and neutralizes H7N9 viruses in vitro. Here, we report the crystal structure of H7 HA1 bound to the fragment antigen-binding region (Fab) of recombinant H7-235 (rH7-235). The crystal structure revealed that rH7-235 recognizes residues near but outside of the receptor binding site (RBS). Nevertheless, the rH7-235 IgG potently inhibits hemagglutination mediated by H7N9 viruses due to avidity effect and Fc steric hindrance. This mAb prophylactically protects mice against weight loss and death caused by challenge with lethal H7N9 viruses in vivo. rH7-235 mAb neutralizing activity alone is sufficient for protection when used at high dosed in a prophylactic setting. This study provides insights into mechanisms of viral neutralization by protective broadly reactive anti-H7 antibodies informing the rational design of therapeutics and vaccines against H7N9 influenza virus.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-06-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144234117","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}
JCI insightPub Date : 2025-06-03DOI: 10.1172/jci.insight.188413
Silke Nuber, Harrison Hsiang, Esra'a Keewan, Tim E Moors, Sydney J Reitz, Anupama Tiwari, Gary P H Ho, Elena Su, Wolf Hahn, Marie-Alexandre Adom, Riddhima Pathak, Matthew Blizzard, Sangjune Kim, Han Seok Ko, Xiaoqun Zhang, Per Svenningsson, Dennis J Selkoe, Saranna Fanning
{"title":"Stearoyl-CoA-Desaturase Inhibition normalizes brain lipid saturation, alpha-synuclein homeostasis, and motor function in mutant Gba1-Parkinson mice.","authors":"Silke Nuber, Harrison Hsiang, Esra'a Keewan, Tim E Moors, Sydney J Reitz, Anupama Tiwari, Gary P H Ho, Elena Su, Wolf Hahn, Marie-Alexandre Adom, Riddhima Pathak, Matthew Blizzard, Sangjune Kim, Han Seok Ko, Xiaoqun Zhang, Per Svenningsson, Dennis J Selkoe, Saranna Fanning","doi":"10.1172/jci.insight.188413","DOIUrl":"https://doi.org/10.1172/jci.insight.188413","url":null,"abstract":"<p><p>Loss-of-function mutations in the GBA1 gene are a prevalent risk factor for Parkinson's disease (PD). Defining features are Lewy bodies that can be rich in α-synuclein (αS), vesicle- and other lipid membranes coupled with striatal dopamine loss and progressive motor dysfunction. Of these, lipid abnormalities are the least understood. An altered lipid metabolism in PD patient-derived neurons, carrying mutations in either GBA1, encoding for glucocerebrosidase, or αS can shift the physiological αS tetramer-monomer (T:M) equilibrium, resulting in PD phenotypes. We previously reported inhibition of stearoyl-CoA desaturase (SCD), the rate-limiting enzyme for fatty acid desaturation, stabilized αS tetramers and improved motor deficits in αS mice. Here we show that mutant GBA-PD cultured neurons have increased SCD products (monounsaturated fatty acids, MUFAS) and reduced αS T:M ratios that were improved by inhibiting SCD. Oral treatment of symptomatic L444P- and E326K Gba1 mutant mice with 5b also improved the αS T:M homeostasis and dopaminergic striatal integrity. Moreover, SCD inhibition normalized GCase maturation and dampened lysosomal and lipid-rich clustering, key features of neuropathology in GBA-PD. In conclusion, this study supports brain MUFA metabolism links GBA1 genotype and wildtype αS homeostasis to downstream neuronal and behavioral impairments, identifying SCD as a therapeutic target for GBA-PD.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144215875","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}
JCI insightPub Date : 2025-06-03DOI: 10.1172/jci.insight.190831
Joshua Rhein, Jeffrey G Chipman, Gregory J Beilman, Ross Cromarty, Kevin Escandón, Jodi Anderson, Garritt Wieking, Jarrett Reichel, Rodolfo Batres, Alexander Khoruts, Christopher M Basting, Peter Hinderlie, Zachary B Davis, Anne Eaton, Byron P Vaughn, Elnaz Eilkhani, Jeffrey T Safrit, Patrick Soon-Shiong, Jason V Baker, Nichole R Klatt, Steven G Deeks, Jeffrey S Miller, Timothy W Schacker
{"title":"Impact of the IL-15 superagonist N-803 on lymphatic reservoirs of HIV.","authors":"Joshua Rhein, Jeffrey G Chipman, Gregory J Beilman, Ross Cromarty, Kevin Escandón, Jodi Anderson, Garritt Wieking, Jarrett Reichel, Rodolfo Batres, Alexander Khoruts, Christopher M Basting, Peter Hinderlie, Zachary B Davis, Anne Eaton, Byron P Vaughn, Elnaz Eilkhani, Jeffrey T Safrit, Patrick Soon-Shiong, Jason V Baker, Nichole R Klatt, Steven G Deeks, Jeffrey S Miller, Timothy W Schacker","doi":"10.1172/jci.insight.190831","DOIUrl":"https://doi.org/10.1172/jci.insight.190831","url":null,"abstract":"<p><strong>Background: </strong>NK cell function is impaired in people with HIV (PWH), hindering their potential to reduce the lymphoid tissue (LT) reservoir. The IL-15 superagonist N-803 has been shown to enhance NK and T cell function, and thus may reduce viral reservoirs.</p><p><strong>Methods: </strong>To determine the impact of N-803 on LTs, we conducted a clinical trial where 10 PWH on effective antiretroviral therapy (ART) were given three 6 mcg/kg doses of N-803 subcutaneously. We obtained PBMCs and lymph node (LN) and gut biopsies at baseline and after the last N-803 dose.</p><p><strong>Results: </strong>We found a non-statistically significant ~0.50 median log reduction in the frequency of viral(v)RNA+ and vDNA+ cells/g in the 6 participants with baseline and post-treatment LNs. In the ileum, we observed reductions of vRNA+ cells in 8/10 participants and vDNA+ cells in all participants. We also found significant inverse correlations between NK cell proliferation and the frequency of vRNA+ cells, and between NKG2A expression on NK cells and the frequency of vRNA+ cells.</p><p><strong>Conclusions: </strong>Our findings suggest N-803 may reduce the HIV reservoir in LTs of PWH on ART, an effect likely mediated by enhanced NK cell function. Controlled studies assessing the impact of NK cell therapy on HIV LTs are needed.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-06-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144234116","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":"NEXN regulates vascular smooth muscle cells phenotypic switching and neointimal hyperplasia.","authors":"Zexuan Lin, Chaojie Wang, Zhuohua Wen, Zhaohui Cai, Wenjie Guo, Xin Feng, Zengyan Huang, Rongjun Zou, Xiaoping Fan, Canzhao Liu, Hanyan Yang","doi":"10.1172/jci.insight.190089","DOIUrl":"https://doi.org/10.1172/jci.insight.190089","url":null,"abstract":"<p><p>Vascular smooth muscle cells (VSMCs) exhibit significant heterogeneity and plasticity, enabling them to switch between contractile and synthetic states, which is crucial for vascular remodeling. NEXN has been identified as a high confidence gene associated with dilated cardiomyopathy (DCM). Existing evidence indicate NEXN is involved in phenotypic switching of VSMCs. However, a comprehensive understanding of the cell-specific roles and precise mechanisms of NEXN in vascular remodeling remains elusive. Using integrative transcriptomics analysis and smooth muscle specific lineage tracing mice, we demonstrate NEXN is highly expressed in VSMCs, and the expression of NEXN is significantly reduced during the phenotypic transformation of VSMCs and intimal hyperplasia induced by vascular injury. VSMC-specific NEXN deficiency promoted the phenotypic transition of VSMCs and exacerbated neointimal hyperplasia in mice following vascular injury. Mechanistically, we found NEXN primarily mediated VSMCs proliferation and phenotypic transition through endoplasmic reticulum (ER) stress and KLF4 signaling. Inhibiting ER stress ameliorated VSMCs phenotypic transition by reducing cell cycle activity and proliferation caused by NEXN deficiency. These findings indicate targeting NEXN could be explored as a promising therapeutic approach for proliferative arterial diseases.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144180142","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}
JCI insightPub Date : 2025-05-29DOI: 10.1172/jci.insight.187904
Katrina M Kudrna, Luis F Vilches, Evan M Eilers, Shailendra K Maurya, Steven L Brody, Amjad Horani, Kristina L Bailey, Todd A Wyatt, John D Dickinson
{"title":"mTOR signaling regulates the development of airway mucous cell metaplasia associated with severe asthma.","authors":"Katrina M Kudrna, Luis F Vilches, Evan M Eilers, Shailendra K Maurya, Steven L Brody, Amjad Horani, Kristina L Bailey, Todd A Wyatt, John D Dickinson","doi":"10.1172/jci.insight.187904","DOIUrl":"https://doi.org/10.1172/jci.insight.187904","url":null,"abstract":"<p><p>In asthma, airway epithelial remodeling is characterized by aberrant goblet cell metaplastic differentiation accompanied by epithelial cell hyperplasia and hypertrophy. These pathologic features in severe asthma indicate a loss of control of proliferation, cell size, differentiation, and migration. mTOR is a highly conserved pathway that regulates protein synthesis, cell size, and proliferation. We hypothesized that the balance between mTOR and autophagy regulates mucous cell metaplasia. Airways from individuals with severe asthma showed increased mTOR signaling by RPS6 phosphorylation, which was reproduced using an IL-13-activated model of primary human airway epithelial cells (hAECs). mTOR inhibition by rapamycin led to a decrease of IL-13-mediated cell hypertrophy, hyperplasia, and MUC5AC mucous metaplasia. BrdU labeling during IL-13-induced mucous metaplasia confirmed that mTOR was associated with increased basal-to-apical hAEC migration. mTOR activation by genetic deletion of Tsc2 in cultured mouse AECs increased IL-13-mediated hyperplasia, hypertrophy, and mucous metaplasia. Transcriptomic analysis of IL-13-stimulated hAEC identified mTOR-dependent expression of genes associated with epithelial migration and cytoskeletal organization. In summary, these findings point to IL-13-dependent and independent roles of mTOR signaling in the development of pathogenic epithelial changes contributing to airway obstruction in severe asthma.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-05-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144187017","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}
JCI insightPub Date : 2025-05-27DOI: 10.1172/jci.insight.176676
Marija Landekic, Isabelle Angers, Yongbiao Li, Marie-Christine Guiot, Marc-André Déry, Annie Beauchamp, Lucie Roussel, Annie Boisvert, Wen Bo Zhou, Christina Gavino, Julia Luo, Stéphane Bernier, Makayla Kazimerczak-Brunet, Yichun Sun, Brendan Snarr, Michail S Lionakis, Robert T Wheeler, Irah L King, Salman Qureshi, Maziar Divangahi, Donald C Vinh
{"title":"A CARD9-deficiency mouse model recapitulates human chronic CNS candidiasis, identifying defective monocytic-cell responses in immunopathogenesis.","authors":"Marija Landekic, Isabelle Angers, Yongbiao Li, Marie-Christine Guiot, Marc-André Déry, Annie Beauchamp, Lucie Roussel, Annie Boisvert, Wen Bo Zhou, Christina Gavino, Julia Luo, Stéphane Bernier, Makayla Kazimerczak-Brunet, Yichun Sun, Brendan Snarr, Michail S Lionakis, Robert T Wheeler, Irah L King, Salman Qureshi, Maziar Divangahi, Donald C Vinh","doi":"10.1172/jci.insight.176676","DOIUrl":"https://doi.org/10.1172/jci.insight.176676","url":null,"abstract":"<p><p>Human Caspase Recruitment Domain Containing Protein 9 (CARD9) deficiency predisposes to invasive fungal disease, particularly by Candida spp. Distinctly, CARD9-deficiency causes chronic central nervous system (CNS) candidiasis. Currently, no animal model recapitulates the chronicity of disease, precluding a better understanding of immunopathogenesis. We established a knock-in mouse homozygous for the recurring p.Y91H mutation (Y91HKI) and, in parallel to Card9-/- mice, titrated the intravenous fungal inoculum to the CARD9-genotype to develop a model of chronic invasive candidiasis. Strikingly, CARD9-deficient mice had predominantly CNS involvement, with neurological symptoms appearing late during infection and progressive brain fungal burden in the absence of fulminant sepsis, reflecting the human syndrome. Mononuclear cell aggregation at fungal lesions in the brain correlated with increased MHCII+Ly6C+ monocyte numbers at day 1 post-infection in WT and Y91HKI mice, but not in Card9-/- mice. At day 4 post-infection, neutrophils and additional Ly6C+ monocytes were recruited to the CARD9-deficient brain. As in humans, Y91HKI mutant mice demonstrated cerebral multinucleated giant cells and granulomata. Subtle immunologic differences between the hypomorphic (p.Y91H) and null mice were noted, perhaps explaining some of the variability seen in humans. Our work established a disease-recapitulating animal model to specifically decipher chronic CNS candidiasis due to CARD9 deficiency.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144159106","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}
JCI insightPub Date : 2025-05-27DOI: 10.1172/jci.insight.169105
Katja Wittenzellner, Manuel Lengl, Stefan Röhrl, Carlo Maurer, Christian Klenk, Aristeidis Papargyriou, Laura Schmidleitner, Nicole Kabella, Akul Shastri, David E Fresacher, Farid Harb, Nawal Hafez, Stefanie Bärthel, Daniele Lucarelli, Carmen Escorial-Iriarte, Felix Orben, Rupert Öllinger, Ellen Emken, Lisa Fricke, Joanna Madej, Patrick Wustrow, I Ekin Demir, Helmut Friess, Tobias Lahmer, Roland M Schmid, Roland Rad, Günter Schneider, Bernhard Kuster, Dieter Saur, Oliver Hayden, Klaus Diepold, Maximilian Reichert
{"title":"Label-free single cell phenotyping to determine tumor cell heterogeneity in pancreatic cancer in real-time.","authors":"Katja Wittenzellner, Manuel Lengl, Stefan Röhrl, Carlo Maurer, Christian Klenk, Aristeidis Papargyriou, Laura Schmidleitner, Nicole Kabella, Akul Shastri, David E Fresacher, Farid Harb, Nawal Hafez, Stefanie Bärthel, Daniele Lucarelli, Carmen Escorial-Iriarte, Felix Orben, Rupert Öllinger, Ellen Emken, Lisa Fricke, Joanna Madej, Patrick Wustrow, I Ekin Demir, Helmut Friess, Tobias Lahmer, Roland M Schmid, Roland Rad, Günter Schneider, Bernhard Kuster, Dieter Saur, Oliver Hayden, Klaus Diepold, Maximilian Reichert","doi":"10.1172/jci.insight.169105","DOIUrl":"https://doi.org/10.1172/jci.insight.169105","url":null,"abstract":"<p><p>Resistance to chemotherapy of pancreatic ductal adenocarcinoma (PDAC) is largely driven by intratumoral heterogeneity (ITH) due to tumor cell plasticity and clonal diversity. In order to develop novel strategies to overcome this defined mechanism of resistance, tools to monitor and quantify ITH in a rapid and scalable fashion are needed urgently. Here, we employed label-free digital holographic microscopy (DHM) to characterize ITH in PDAC. We established a robust experimental and machine learning analysis pipeline to perform single cell phenotyping based on DHM-derived phase images of PDAC cells in suspension. Importantly, we are able to detect dynamic changes in tumor cell differentiation and heterogeneity of distinct PDAC subtypes upon induction of epithelial-to-mesenchymal transition and under treatment-imposed pressure in murine and patient-derived model systems. This platform allows us to assess phenotypic ITH in PDAC on a single cell level in real-time. Implementing this technology into the clinical workflow has the potential to fundamentally increase our understanding of tumor heterogeneity during evolution and treatment response.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-05-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144159111","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}
JCI insightPub Date : 2025-05-22DOI: 10.1172/jci.insight.187392
Michal Navon, Noam Ben-Shalom, Maya Dadiani, Michael Mor, Ron Yefet, Michal Bakalenik-Gavry, Dana Chat, Nora Balint-Lahat, Iris Barshack, Ilan Tsarfaty, Einav Nili Gal-Yam, Natalia T Freund
{"title":"Unique characteristics of autoantibodies targeting MET in patients with breast and lung cancer.","authors":"Michal Navon, Noam Ben-Shalom, Maya Dadiani, Michael Mor, Ron Yefet, Michal Bakalenik-Gavry, Dana Chat, Nora Balint-Lahat, Iris Barshack, Ilan Tsarfaty, Einav Nili Gal-Yam, Natalia T Freund","doi":"10.1172/jci.insight.187392","DOIUrl":"10.1172/jci.insight.187392","url":null,"abstract":"<p><p>The presence of B cells in tumors is correlated with favorable prognosis and efficient response to immunotherapy. While tumor-reactive antibodies have been detected in several cancer types, identifying antibodies that specifically target tumor-associated antigens remains a challenge. Here, we investigated the antibodies spontaneously elicited during breast and lung cancer that bind the cancer-associated antigen MET. We screened patients with lung (n = 25) and breast (n = 75) cancer and found that 13% had antibodies binding to both the recombinant ectodomain of MET, and the ligand binding part of MET, SEMA. MET binding in the breast cancer cohort was significantly correlated with hormone receptor-positive status. We further conducted immunoglobulin sequencing of peripheral MET-enriched B cells from 6 MET-reactive patients. The MET-enriched B cell repertoire was found to be polyclonal and prone to non-IgG1 subclass. Nine monoclonal antibodies were cloned and analyzed, and these exhibited MET binding, low thermostability, and high polyreactivity. Among these, antibodies 87B156 and 69B287 effectively bound to tumor cells and inhibited MET-expressing breast cancer cell lines. Overall, our data demonstrate that some patients with breast and lung cancer develop polyreactive antibodies that cross-react with MET. These autoantibodies have a potential contribution to immune responses against tumors.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":"10 10","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12129041/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144119498","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}
{"title":"Involvement of impaired carnitine-induced fatty acid oxidation in experimental and human diabetic kidney disease.","authors":"Sakuya Ito, Kensei Taguchi, Goh Kodama, Saori Kubo, Tomofumi Moriyama, Yuya Yamashita, Yunosuke Yokota, Yosuke Nakayama, Yusuke Kaida, Masami Shinohara, Kyoko Tashiro, Keisuke Ohta, Sho-Ichi Yamagishi, Kei Fukami","doi":"10.1172/jci.insight.179362","DOIUrl":"https://doi.org/10.1172/jci.insight.179362","url":null,"abstract":"<p><p>Diabetic kidney disease (DKD) is the leading cause of end stage kidney disease. Kidney tubular cells have a high energy demand, dependent on fatty acid oxidation (FAO). Although carnitine is indispensable for FAO, the pathological role of carnitine deficiency in DKD is not fully understood. We showed here that ectopic lipid accumulation due to impaired FAO increased in patients with DKD and inversely correlated with renal function. OCTN2 deficient mice exhibited systemic carnitine deficiency with increased renal lipid accumulation. Cell death and inflammation were induced in OCTN2-deficient, but not wild-type tubular cells exposed to high salt and high glucose. Compared with SDT fatty rats, uninephrectomized SDT fatty rats fed with 0.3% NaCl had higher lipid accumulation and exhibited increased urinary albumin excretion with renal dysfunction and tubulointerstitial injury, all of which were ameliorated by L-carnitine supplementation via stimulating FAO and mitochondrial biogenesis. In our single-center randomized control trial with patients undergoing peritoneal dialysis, L-carnitine supplementation preserved residual renal function and increased urine volume, the latter of which was correlated with improvement of tubular injury. The present study demonstrates the pathological role of impairment of carnitine-induced FAO in DKD, suggesting that L-carnitine supplementation is a potent therapeutic strategy for this devastating disorder.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.3,"publicationDate":"2025-05-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144127307","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}
求助内容：
应助结果提醒方式：
京公网安备 11010802042870号
