JCI insightPub Date : 2026-04-22DOI: 10.1172/jci.insight.172371
Ahmad Rajeh, Shahin Shahsavari, Hannah Cornman, Alexander Kollhoff, Anuj Gupta, Mindy D Szeto, Anusha Kambala, Olusola O Oladipo, Varsha Parthasarathy, Junwen Deng, Melika Marani, Shirin Shahsavari, Selina M Yossef, Vedha Vaddaraju, Waleed Adawi, Yagiz M Akiska, Davies M Gage, Sarah Wheelan, Thomas Pritchard, Madan M Kwatra, Yevgeniy R Semenov, Alexander Gusev, Won Jin Ho, Srinivasan Yegnasubramanian, Shawn G Kwatra
{"title":"Somatic mutations reveal hyperactive Notch signaling in prurigo nodularis.","authors":"Ahmad Rajeh, Shahin Shahsavari, Hannah Cornman, Alexander Kollhoff, Anuj Gupta, Mindy D Szeto, Anusha Kambala, Olusola O Oladipo, Varsha Parthasarathy, Junwen Deng, Melika Marani, Shirin Shahsavari, Selina M Yossef, Vedha Vaddaraju, Waleed Adawi, Yagiz M Akiska, Davies M Gage, Sarah Wheelan, Thomas Pritchard, Madan M Kwatra, Yevgeniy R Semenov, Alexander Gusev, Won Jin Ho, Srinivasan Yegnasubramanian, Shawn G Kwatra","doi":"10.1172/jci.insight.172371","DOIUrl":"10.1172/jci.insight.172371","url":null,"abstract":"<p><p>Prurigo nodularis (PN) is a chronic inflammatory skin disease characterized by pruritic skin nodules of unknown etiology. Little is known about genetic changes in PN pathogenesis, particularly somatic events, which are often implicated in inflammatory conditions. We thus performed whole-exome sequencing on 54 lesional and nonlesional skin biopsies from 17 patients with PN and 10 patients with atopic dermatitis (AD) for comparison. Somatic mutational analysis revealed that PN lesional skin harbors recurrent somatic mutations in fibrotic, neurotropic, and cancer-associated genes that are absent in adjacent PN nonlesional skin. Nonsynonymous mutations were most frequently present in NOTCH1 and the Notch signaling pathway, a key regulator of cellular proliferation and tissue fibrosis. In contrast, NOTCH1 mutations were absent in AD. Somatic copy-number analysis, combined with expression data, identified recurrently deleted and downregulated genes in PN lesional skin, which are associated with axonal guidance and extension. Follow-up immunofluorescence validation demonstrated increased NOTCH1 expression in PN lesional skin fibroblasts and increased Notch signaling in PN lesional dermis. Finally, a multicenter analysis revealed increased risk of NOTCH1-associated diseases in patients with PN. In characterizing the somatic landscape of PN, this study highlights the potential role of Notch pathway dysregulation in PN pathogenesis and fibrosis.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":"11 8","pages":""},"PeriodicalIF":6.1,"publicationDate":"2026-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13135409/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147771837","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}
JCI insightPub Date : 2026-04-22DOI: 10.1172/jci.insight.201946
Zuzana Tobiasova, Esen Sefik, Lingfeng Qin, Jennifer M McNiff, Gwendolyn Davis, Richard A Flavell, W Mark Saltzman, Jordan S Pober
{"title":"Endothelial MHC expression is required to initiate T cell-mediated rejection of 3D-printed skin grafts.","authors":"Zuzana Tobiasova, Esen Sefik, Lingfeng Qin, Jennifer M McNiff, Gwendolyn Davis, Richard A Flavell, W Mark Saltzman, Jordan S Pober","doi":"10.1172/jci.insight.201946","DOIUrl":"10.1172/jci.insight.201946","url":null,"abstract":"<p><p>Vascularized skins were 3D printed using single donor human fibroblasts, pericytes, keratinocytes, and endothelial cells (ECs), the latter either unmodified (WT-ECs) or deleted of MHC molecules (KO-ECs). Adult MISTRG6 immunodeficient mice neonatally inoculated with adult human hematopoietic stem cells (HSCs) received printed skin allogeneic to the HSCs and were boosted 3 weeks after grafting with human PBMCs autologous to the HSCs. HSC inoculation alone produced low levels of circulating human myeloid and lymphoid cells without affecting grafts; PBMC boosting dramatically increased circulating human CD4+ T cells and boosted CD8+ T cells only in mice with WT-EC grafts. These grafts became infiltrated by human macrophages, dendritic cells, CD4+ and CD8+ T cells and showed evidence of rejection. Shared T cell clones were present in skin and spleen. KO-EC grafts had minimal infiltration of graft or spleen without rejection, despite MHC molecule expression on other graft cell types.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":"11 8","pages":""},"PeriodicalIF":6.1,"publicationDate":"2026-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13135413/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147771849","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}
JCI insightPub Date : 2026-04-22DOI: 10.1172/jci.insight.207149
Peter S Linsley, Fariba Barahmand-Pour-Whitman, Elisa Balmas, Hannah A DeBerg, Kaitlin J Flynn, Alex K Hu, Mario G Rosasco, Janice Chen, Colin O'Rourke, Elisavet Serti, Vivian H Gersuk, Keshav Motwani, Howard R Seay, Todd M Brusko, William W Kwok, Cate Speake, Carla J Greenbaum, Gerald T Nepom, Karen Cerosaletti
{"title":"Corrigendum to: Autoreactive T cell receptors with shared germline-like α chains in type 1 diabetes.","authors":"Peter S Linsley, Fariba Barahmand-Pour-Whitman, Elisa Balmas, Hannah A DeBerg, Kaitlin J Flynn, Alex K Hu, Mario G Rosasco, Janice Chen, Colin O'Rourke, Elisavet Serti, Vivian H Gersuk, Keshav Motwani, Howard R Seay, Todd M Brusko, William W Kwok, Cate Speake, Carla J Greenbaum, Gerald T Nepom, Karen Cerosaletti","doi":"10.1172/jci.insight.207149","DOIUrl":"10.1172/jci.insight.207149","url":null,"abstract":"","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":"11 8","pages":""},"PeriodicalIF":6.1,"publicationDate":"2026-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13135385/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147771764","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}
JCI insightPub Date : 2026-04-22DOI: 10.1172/jci.insight.189107
Rithika Behera, Yuechen Zhou, Peter H Gerges, Jingyu Fan, Tracy Tabib, Alyxzandria M Gaydosik, Mengqi Huang, Jishnu Das, Elena Pachera, Amela Hukara, Ying Tang, Florian Renoux, Miranda Tai, Oliver Distler, Gabriela Kania, Stephen Y Chan, Harinder Singh, Eleanor Valenzi, Robert Lafyatis
{"title":"FOSL2 regulates endothelial cell state and chromatin accessibility in systemic sclerosis pulmonary vascular remodeling.","authors":"Rithika Behera, Yuechen Zhou, Peter H Gerges, Jingyu Fan, Tracy Tabib, Alyxzandria M Gaydosik, Mengqi Huang, Jishnu Das, Elena Pachera, Amela Hukara, Ying Tang, Florian Renoux, Miranda Tai, Oliver Distler, Gabriela Kania, Stephen Y Chan, Harinder Singh, Eleanor Valenzi, Robert Lafyatis","doi":"10.1172/jci.insight.189107","DOIUrl":"10.1172/jci.insight.189107","url":null,"abstract":"<p><p>Systemic sclerosis (SSc) is characterized by fibrosis and vasculopathy affecting the skin and internal organs, leading to multiorgan dysfunction. Injury of microvascular endothelial cells (ECs) in SSc impairs blood flow and causes tissue ischemia, leading to vascular complications such as Raynaud's, digital ulcers, and pulmonary hypertension (PH). PH in SSc presents as group 1 pulmonary arterial hypertension or as group 3 PH related to hypoxia and interstitial lung disease (ILD), both major causes of mortality. Analysis of multiome data from SSc ILD-PH lungs inferred transcription factors regulating EC phenotype, including FOSL2. Overexpression of FOSL2 in transgenic mice (Fosl2tg) leads to vascular changes mirroring human SSc-PH, such as intimal thickening and fibrosis. scRNA-Seq analysis of altered EC gene expression in Fosl2tg mice showed strong overlap with altered EC gene expression in SSc-ILD-PH. Overlapping as well as discrete EC gene expression in Sugen/hypoxia- and hypoxia-treated mice suggested that FOSL2 regulates both hypoxia-dependent and -independent pathways in Fosl2tg mice and SSc-ILD-PH. A deep learning model, ChromBPNet, inferred increased AP-1 binding at base pair resolution in SSc-ILD-PH ECs, and binding to the same motifs was found upon FOSL2 overexpression in primary vascular ECs, highlighting FOSL2's key role in driving the pathological changes seen in SSc-ILD-PH.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":"11 8","pages":""},"PeriodicalIF":6.1,"publicationDate":"2026-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13135392/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147771842","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}
JCI insightPub Date : 2026-04-22DOI: 10.1172/jci.insight.197108
Matheus Lobo, Furkan Bahar, Julia L Schnabel, Joao P Duprat Neto, Aniket Shetty, Karam Khaddour, Manisha Thakuria, Ann W Silk, James A DeCaprio
{"title":"High tumor mutational burden and PIK3CA mutations correlate with poor Merkel cell carcinoma-specific survival.","authors":"Matheus Lobo, Furkan Bahar, Julia L Schnabel, Joao P Duprat Neto, Aniket Shetty, Karam Khaddour, Manisha Thakuria, Ann W Silk, James A DeCaprio","doi":"10.1172/jci.insight.197108","DOIUrl":"10.1172/jci.insight.197108","url":null,"abstract":"<p><p>Merkel cell carcinoma (MCC) is a neuroendocrine carcinoma of the skin characterized by poor prognosis. This study aimed to explore the relationship between genetic alterations, tumor mutational burden (TMB), and MCC-specific survival (MCC-SS) in patients who underwent genomic profiling of tumors with OncoPanel. Univariate and multivariable analysis were used to assess the impact of genetic alterations on MCC-SS. Of the 188 identified patients, 164 were included in the analysis. The cohort had a mean age of 72.4 years (SD = 11.03), including 61.6% male. The median TMB was 5.32 (IQR = 3.04-25.53). Kaplan-Meier curves by high versus low TMB were significantly different (log-rank test, P = 0.017). PIK3CA (adjusted P = 0.003), SETBP1 (adjusted P = 0.002), KDR (adjusted P = 0.028), and RET (adjusted P = 0.033) were selected for multivariable analysis. In the multivariable regressions, only PIK3CA (HR = 2.07 [95% CI, 1.10-3.88]; P = 0.024) remained significant. PIK3CA remained significant across prespecified sensitivity analyses. In this study, high TMB and PIK3CA alterations were associated with poor MCC-SS. Identifying a higher-risk subgroup may inform risk stratification and motivate further evaluation of PI3K pathway targeting in future studies.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":"11 8","pages":""},"PeriodicalIF":6.1,"publicationDate":"2026-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13135387/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147771851","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}
JCI insightPub Date : 2026-04-22DOI: 10.1172/jci.insight.204535
Yuxuan Meng, Jakub Kubiak, Zuzanna Dzieniak, Lorna Fowler, Rose Avient, Jason Hopley, Linyulong Li, Chaoran Li, Yuan Tian, Bruno Charbit, Colin J Chu
{"title":"Spatial proteomic mapping of the human and mouse retina using IBEX.","authors":"Yuxuan Meng, Jakub Kubiak, Zuzanna Dzieniak, Lorna Fowler, Rose Avient, Jason Hopley, Linyulong Li, Chaoran Li, Yuan Tian, Bruno Charbit, Colin J Chu","doi":"10.1172/jci.insight.204535","DOIUrl":"10.1172/jci.insight.204535","url":null,"abstract":"<p><p>We generated a comparative spatial proteomic atlas of the human and mouse retina using a highly multiplexed immunohistochemistry technique called iterative bleaching extends multiplexity (IBEX). We refined the IBEX workflow by integrating an antibody dissociation option alongside chemical bleaching. This dual strategy enabled removal of the entire antibody complex, permitting the flexible use of antibodies from the same host species across iterative cycles. We coupled this workflow with super-resolution imaging via deconvolution and applied it to the retina of healthy humans and WT mice and the Crb1rd8 mouse model. We successfully imaged over 25 protein markers on human and mouse tissue sections, generating spatial atlases of the major retinal cell populations. Cross-species protein expression was compared to scRNA-seq datasets to identify protein and transcript disparities. Super-resolution IBEX delineated the ultrastructural features of the outer limiting membrane (OLM), identifying CD44 as a core structural component tightly colocalized with a highly organized F-actin belt within Müller glial endfeet. Using the Crb1rd8 mouse model, disruption of this complex was spatially associated with rosette formation and OLM structural failure. In summary, spatial proteomic atlases of the human and mouse retina were used to reveal insights into the arrangement of major retinal cell populations and OLM structure.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":"11 8","pages":""},"PeriodicalIF":6.1,"publicationDate":"2026-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13135386/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147771815","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":"A stromal platform for robust expansion of functional IL-10-producing B cells for immune regulation.","authors":"Ryo Kawakami, Keisuke Imabayashi, Akemi Baba, Yuichi Saito, Kazuhiko Kawata, Yutaro Yada, Airi Shibata, Rinka Ito, Ryo Kurasawa, Ryota Higuchi, Sungyeon Park, Hiroaki Niiro, Shinya Tanaka, Yoshihiro Baba","doi":"10.1172/jci.insight.197393","DOIUrl":"10.1172/jci.insight.197393","url":null,"abstract":"<p><p>IL-10-producing B cells exert immunosuppressive effects, yet their low abundance and poor in vitro viability have limited their therapeutic application. Here, we developed a stromal coculture system using MS5 cells engineered to express human CD40L, BAFF, and IFN-β1 (MS5-3F, for \"3 factors\"), which enables robust induction and greater than 1000-fold expansion of human IL-10-producing B cells. The expanded cells showed phenotypic and transcriptional profiles characteristic of unswitched (IgM+) plasmablasts and potently suppressed CD4+ T cell proliferation in an IL-10-dependent manner. MS5-3F-expanded B cells also increased the frequency of regulatory T cells in vitro, an effect that was not abrogated by IL-10/IL-10R blockade, suggesting contributions from additional mechanisms. IL-10 production originated predominantly from naive B cells, rather than memory B cells. Furthermore, B cells from patients with systemic lupus erythematosus, despite impaired IL-10 production under conventional conditions, were efficiently differentiated into IL-10-producing B cells using this system. The expanded cells showed minimal IgG-secreting output. Our platform offers a scalable strategy for generating human regulatory B cells, laying the foundation for B cell-based immunotherapies.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":"11 8","pages":""},"PeriodicalIF":6.1,"publicationDate":"2026-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13135411/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147771761","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}
JCI insightPub Date : 2026-04-22DOI: 10.1172/jci.insight.198388
Meilyn Cruz-Soca, Adriana Córdova-Casanova, Jennifer Faundez-Contreras, Nicolás W Martínez, Francesca Vaccaro-Rivera, Sebastián Bazaes-Astorga, Cristian Gutiérrez-Rojas, Felipe S Gallardo, Daniela L Rebolledo, Felipe A Court, Jerold Chun, Carlos P Vio, Soledad Matus, Juan Carlos Casar, Enrique Brandan
{"title":"Lysophosphatidic acid mediates skeletal muscle fibrosis in denervation via activation of YAP/TAZ.","authors":"Meilyn Cruz-Soca, Adriana Córdova-Casanova, Jennifer Faundez-Contreras, Nicolás W Martínez, Francesca Vaccaro-Rivera, Sebastián Bazaes-Astorga, Cristian Gutiérrez-Rojas, Felipe S Gallardo, Daniela L Rebolledo, Felipe A Court, Jerold Chun, Carlos P Vio, Soledad Matus, Juan Carlos Casar, Enrique Brandan","doi":"10.1172/jci.insight.198388","DOIUrl":"10.1172/jci.insight.198388","url":null,"abstract":"<p><p>Lysophosphatidic acid (LPA) is a bioactive lipid that signals through G protein-coupled receptors (LPA1-6) and regulates multiple cellular processes, including fibrosis. Although LPA signaling has been implicated in fibrotic diseases in several organs, its role in skeletal muscle remains unclear. Here, we show that LPA/LPA1 signaling promotes fibrogenesis after sciatic nerve transection. Denervation induces differential expression of LPA signaling axis components and a transient early increase in intramuscular LPA levels. Pharmacological inhibition of LPA1/3 with Ki16425, or genetic deletion of LPA1, reduces extracellular matrix accumulation and expansion of fibro/adipogenic progenitors (FAPs) in denervated muscle. Although LPA blockade suppresses atrophy-related gene expression, it does not fully preserve myofiber size. Mechanistically, denervation increases YAP/TAZ expression, nuclear localization in FAPs, and transcriptional activity, effects that are attenuated by LPA axis inhibition. Furthermore, pharmacological inhibition of YAP/TAZ with verteporfin reduces fibrosis after denervation, supporting their role as critical downstream mediators. Finally, transient denervation activates the LPA axis, promotes muscle fibrosis, reduces axonal density in the sciatic nerve, and increases neuromuscular junction instability, effects reversed by Ki16425. Together, these findings identify the LPA/LPA1/YAP/TAZ pathway as a key driver of denervation-induced muscle fibrosis and a potential therapeutic target in neuromuscular disorders.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":"11 8","pages":""},"PeriodicalIF":6.1,"publicationDate":"2026-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13135410/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147771754","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}
JCI insightPub Date : 2026-04-22DOI: 10.1172/jci.insight.190875
Erika Della Mina, Carlos G El-Haddad, Timothy A West, Clara Wt Chung, Jing Jing Li, Vivienne Lea, Elissa K Deenick, Filomeen Haerynck, Jean-Laurent Casanova, Anne Puel, Cindy S Ma, Stuart G Tangye, Alisa Kane
{"title":"Inherited human CARD9 deficiency impairs lymphoid cell, but not fibroblast, IL-17-mediated immunity.","authors":"Erika Della Mina, Carlos G El-Haddad, Timothy A West, Clara Wt Chung, Jing Jing Li, Vivienne Lea, Elissa K Deenick, Filomeen Haerynck, Jean-Laurent Casanova, Anne Puel, Cindy S Ma, Stuart G Tangye, Alisa Kane","doi":"10.1172/jci.insight.190875","DOIUrl":"10.1172/jci.insight.190875","url":null,"abstract":"<p><p>Nearly 100 individuals have been identified who carry deleterious biallelic germline variants in CARD9 and experience life-threatening, invasive fungal infections caused by Ascomycetes but are otherwise resistant to other infectious agents. CARD9 is an adaptor protein expressed predominantly in myeloid cells, which functions downstream of dectin receptors, pattern recognition receptors for fungal antigens, to activate innate immune responses. The impact of CARD9 deficiency on lymphocytes, however, is less clear. We deciphered the functional consequences and delineated mechanisms of disease in a patient (P1) with a nonsense germline homozygous CARD9 variant (c.673A>T/p.K225*) and invasive Candida disease. P1's PBMCs expressed truncated CARD9 and showed significantly reduced cytokine production in response to fungal ligands. P1 had reduced frequencies of circulating memory CD4+ TH17-like (CCR6+CXCR3-) cells. In addition, in vitro differentiation of P1's naive CD4+ T cells into IL-17A/IL-17F-secreting cells was greatly impaired. Consistent with impaired responses of innate and adaptive immune cells from P1 in vitro, proportions of Candida-specific CD4+ T cells were strongly and selectively diminished. Our findings suggest that the CARD9 variant identified in P1 is pathogenic, affecting not only CARD9-induced immunity mediated by myeloid cells but also CD4+ T cell-intrinsic IL-17-dependent immunity and Candida-specific T cell responses.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":"11 8","pages":""},"PeriodicalIF":6.1,"publicationDate":"2026-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13135412/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147771829","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}
JCI insightPub Date : 2026-04-21DOI: 10.1172/jci.insight.202213
Misbah Rashid, Lei Wang, Zhenzhong Cui, Oksana Gavrilova, Huiyan Lu, Kozo Kaibuchi, Sarah Zeitlmayr, Thomas Gudermann, Andreas Breit, Jürgen Wess
{"title":"Mice lacking beta-arrestin-2 in melanocortin 4 receptor-expressing neurons show marked metabolic deficits.","authors":"Misbah Rashid, Lei Wang, Zhenzhong Cui, Oksana Gavrilova, Huiyan Lu, Kozo Kaibuchi, Sarah Zeitlmayr, Thomas Gudermann, Andreas Breit, Jürgen Wess","doi":"10.1172/jci.insight.202213","DOIUrl":"https://doi.org/10.1172/jci.insight.202213","url":null,"abstract":"<p><p>Hypothalamic melanocortin 4 receptors (MC4Rs) play a central role in regulating food intake and energy homeostasis. In fact, inactivating mutations in the MC4R gene are the most common form of monogenic obesity. Agonist activation of MC4Rs reduces food intake by modulating hypothalamic signaling circuits. Thus, a detailed understanding of the signaling pathways that regulate MC4R activity is of considerable translational relevance. Ligand-activated MC4Rs interact not only with heterotrimeric G proteins but can also recruit beta-arrestin-2 (barr2) to the receptor. The potential functional role of barr2 in regulating the anorectic effects of MC4R signaling remains unexplored. In the present study, we used mutant mouse models to demonstrate that MC4R-mediated activation of barr2/ERK signaling in MC4R neurons of the paraventricular nucleus leads to reduced food intake. We also found that the appetite-suppressing effect of setmelanotide, an MC4R agonist approved by the FDA for the treatment of certain types of obesity, requires the presence of barr2 in MC4R-containing neurons. These data suggest that MC4R agonists able to promote MC4R/barr2 interactions with high efficacy may become useful as appetite-suppressing drugs.</p>","PeriodicalId":14722,"journal":{"name":"JCI insight","volume":" ","pages":""},"PeriodicalIF":6.1,"publicationDate":"2026-04-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147771721","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}
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