Journal of Experimental Medicine最新文献

{"title":"Bridging the gap between tumor and disease: Innovating cancer and glioma models.","authors":"Stefano M Cirigliano, Howard A Fine","doi":"10.1084/jem.20220808","DOIUrl":"10.1084/jem.20220808","url":null,"abstract":"<p><p>Recent advances in cancer biology and therapeutics have underscored the importance of preclinical models in understanding and treating cancer. Nevertheless, current models often fail to capture the complexity and patient-specific nature of human tumors, particularly gliomas. This review examines the strengths and weaknesses of such models, highlighting the need for a new generation of models. Emphasizing the critical role of the tumor microenvironment, tumor, and patient heterogeneity, we propose integrating our advanced understanding of glioma biology with innovative bioengineering and AI technologies to create more clinically relevant, patient-specific models. These innovations are essential for improving therapeutic development and patient outcomes.</p>","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":"222 1","pages":""},"PeriodicalIF":12.6,"publicationDate":"2025-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11614461/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142769449","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":"An unconventional purine connection.","authors":"Fabio Grassi","doi":"10.1084/jem.20241527","DOIUrl":"10.1084/jem.20241527","url":null,"abstract":"<p><p>Xu et al. (https://doi.org/10.1084/jem.20240354) define NAD-induced cell death via purinergic P2RX7 receptor in type 1 unconventional T cells, particularly intrahepatic MAIT cells that are pivotal in liver homeostasis. Therefore, P2RX7 is a potential target to modulate unconventional T cells in immunopathological conditions and cancer.</p>","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":"221 12","pages":""},"PeriodicalIF":12.6,"publicationDate":"2024-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11577275/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142668011","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":"Immunomolecular and reactivity landscapes of gut IgA subclasses in homeostasis and inflammatory bowel disease.","authors":"Sonia Tejedor Vaquero, Hadas Neuman, Laura Comerma, Xavi Marcos-Fa, Celia Corral-Vazquez, Mathieu Uzzan, Marc Pybus, Daniel Segura-Garzón, Joana Guerra, Lisa Perruzza, Roser Tachó-Piñot, Jordi Sintes, Adam Rosenstein, Emilie K Grasset, Mar Iglesias, Monica Gonzalez Farré, Joan Lop, Maria Evangelina Patriaca-Amiano, Monica Larrubia-Loring, Pablo Santiago-Diaz, Júlia Perera-Bel, Pau Berenguer-Molins, Monica Martinez Gallo, Andrea Martin-Nalda, Encarna Varela, Marta Garrido-Pontnou, Fabio Grassi, Francisco Guarner, Saurabh Mehandru, Lucia Márquez-Mosquera, Ramit Mehr, Andrea Cerutti, Giuliana Magri","doi":"10.1084/jem.20230079","DOIUrl":"10.1084/jem.20230079","url":null,"abstract":"<p><p>The human gut includes plasma cells (PCs) expressing immunoglobulin A1 (IgA1) or IgA2, two structurally distinct IgA subclasses with elusive regulation, function, and reactivity. We show here that intestinal IgA1+ and IgA2+ PCs co-emerged early in life, comparably accumulated somatic mutations, and were enriched within short-lived CD19+ and long-lived CD19- PC subsets, respectively. IgA2+ PCs were extensively clonally related to IgA1+ PCs and a subset of them presumably emerged from IgA1+ precursors. Of note, secretory IgA1 (SIgA1) and SIgA2 dually coated a large fraction of mucus-embedded bacteria, including Akkermansia muciniphila. Disruption of homeostasis by inflammatory bowel disease (IBD) was associated with an increase in actively proliferating IgA1+ plasmablasts, a depletion in long-lived IgA2+ PCs, and increased SIgA1+SIgA2+ gut microbiota. Such increase featured enhanced IgA1 reactivity to pathobionts, including Escherichia coli, combined with depletion of beneficial A. muciniphila. Thus, gut IgA1 and IgA2 emerge from clonally related PCs and show unique changes in both frequency and reactivity in IBD.</p>","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":"221 12","pages":""},"PeriodicalIF":12.6,"publicationDate":"2024-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11577441/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142668013","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":"Interleukin-33-activated basophils promote asthma by regulating Th2 cell entry into lung tissue.","authors":"Martijn J Schuijs, Claudia M Brenis Gomez, Fabian Bick, Justine Van Moorleghem, Manon Vanheerswynghels, Geert van Loo, Rudi Beyaert, David Voehringer, Richard M Locksley, Hamida Hammad, Bart N Lambrecht","doi":"10.1084/jem.20240103","DOIUrl":"10.1084/jem.20240103","url":null,"abstract":"<p><p>Asthma is characterized by lung eosinophilia, remodeling, and mucus plugging, controlled by adaptive Th2 effector cells secreting IL-4, IL-5, and IL-13. Inhaled house dust mite (HDM) causes the release of barrier epithelial cytokines that activate various innate immune cells like DCs and basophils that can promote Th2 adaptive immunity directly or indirectly. Here, we show that basophils play a crucial role in the development of type 2 immunity and eosinophilic inflammation, mucus production, and bronchial hyperreactivity in response to HDM inhalation in C57Bl/6 mice. Interestingly, conditional depletion of basophils during sensitization did not reduce Th2 priming or asthma inception, whereas depletion during allergen challenge did. During the challenge of sensitized mice, basophil-intrinsic IL-33/ST2 signaling, and not FcεRI engagement, promoted basophil IL-4 production and subsequent Th2 cell recruitment to the lungs via vascular integrin expression. Basophil-intrinsic loss of the ubiquitin modifying molecule Tnfaip3, involved in dampening IL-33 signaling, enhanced key asthma features. Thus, IL-33-activated basophils are gatekeepers that boost allergic airway inflammation by controlling Th2 tissue entry.</p>","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":"221 12","pages":""},"PeriodicalIF":12.6,"publicationDate":"2024-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11413418/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142288979","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":"The protozoan commensal Tritrichomonas musculis is a natural adjuvant for mucosal IgA.","authors":"Eric Yixiao Cao, Kyle Burrows, Pailin Chiaranunt, Ana Popovic, Xueyang Zhou, Cong Xie, Ayushi Thakur, Graham Britton, Matthew Spindler, Louis Ngai, Siu Ling Tai, Dragos Cristian Dasoveanu, Albert Nguyen, Jeremiah J Faith, John Parkinson, Jennifer L Gommerman, Arthur Mortha","doi":"10.1084/jem.20221727","DOIUrl":"10.1084/jem.20221727","url":null,"abstract":"<p><p>Immunoglobulin (Ig) A supports mucosal immune homeostasis and host-microbiota interactions. While commensal bacteria are known for their ability to promote IgA, the role of non-bacterial commensal microbes in the induction of IgA remains elusive. Here, we demonstrate that permanent colonization with the protozoan commensal Tritrichomonas musculis (T.mu) promotes T cell-dependent, IgA class-switch recombination, and intestinal accumulation of IgA-secreting plasma cells (PC). T.mu colonization specifically drives the expansion of T follicular helper cells and a unique ICOS+ non-Tfh cell population, accompanied by an increase in germinal center B cells. Blockade of ICOS:ICOSL co-stimulation or MHCII-expression on B cells is central for the induction of IgA following colonization by T.mu, implicating a previously underappreciated mode of IgA induction following protozoan commensal colonization. Finally, T.mu further improves the induction of IgA-secreting PC specific to orally ingested antigens and their peripheral dissemination, identifying T.mu as a \"natural adjuvant\" for IgA. Collectively, these findings propose a protozoa-driven mode of IgA induction to support intestinal immune homeostasis.</p>","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":"221 12","pages":""},"PeriodicalIF":12.6,"publicationDate":"2024-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11561467/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142621251","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":"Myeloid activation clears ascites and reveals IL27-dependent regression of metastatic ovarian cancer.","authors":"Brennah Murphy, Taito Miyamoto, Bryan S Manning, Gauri Mirji, Alessio Ugolini, Toshitha Kannan, Kohei Hamada, Yanfang P Zhu, Daniel T Claiborne, Lu Huang, Rugang Zhang, Yulia Nefedova, Andrew Kossenkov, Filippo Veglia, Rahul Shinde, Nan Zhang","doi":"10.1084/jem.20231967","DOIUrl":"10.1084/jem.20231967","url":null,"abstract":"<p><p>Patients with metastatic ovarian cancer (OvCa) have a 5-year survival rate of <30% due to the persisting dissemination of chemoresistant cells in the peritoneal fluid and the immunosuppressive microenvironment in the peritoneal cavity. Here, we report that intraperitoneal administration of β-glucan and IFNγ (BI) induced robust tumor regression in clinically relevant models of metastatic OvCa. BI induced tumor regression by controlling fluid tumor burden and activating localized antitumor immunity. β-glucan alone cleared ascites and eliminated fluid tumor cells by inducing intraperitoneal clotting in the fluid and Dectin-1-Syk-dependent NETosis in the omentum. In omentum tumors, BI expanded a novel subset of immunostimulatory IL27+ macrophages and neutralizing IL27 impaired BI efficacy in vivo. Moreover, BI directly induced IL27 secretion in macrophages where single agent treatment did not. Finally, BI extended mouse survival in a chemoresistant model and significantly improved chemotherapy response in a chemo-sensitive model. In summary, we propose a new therapeutic strategy for the treatment of metastatic OvCa.</p>","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":"221 12","pages":""},"PeriodicalIF":12.6,"publicationDate":"2024-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11586802/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142681722","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":"Suppression of melanoma by mice lacking MHC-II: Mechanisms and implications for cancer immunotherapy.","authors":"Hexin Shi, Dawson Medler, Jianhui Wang, Rachel Browning, Aijie Liu, Sara Schneider, Claudia Duran Bojorquez, Ashwani Kumar, Xiaohong Li, Jiexia Quan, Sara Ludwig, James J Moresco, Chao Xing, Eva Marie Y Moresco, Bruce Beutler","doi":"10.1084/jem.20240797","DOIUrl":"10.1084/jem.20240797","url":null,"abstract":"<p><p>Immune checkpoint inhibitors interfere with T cell exhaustion but often fail to cure or control cancer long-term in patients. Using a genetic screen in C57BL/6J mice, we discovered a mutation in host H2-Aa that caused strong immune-mediated resistance to mouse melanomas. H2-Aa encodes an MHC class II α chain, and its absence in C57BL/6J mice eliminates all MHC-II expression. H2-Aa deficiency, specifically in dendritic cells (DC), led to a quantitative increase in type 2 conventional DC (cDC2) and a decrease in cDC1. H2-Aa-deficient cDC2, but not cDC1, were essential for melanoma suppression and effectively cross-primed and recruited CD8 T cells into tumors. Lack of T regulatory cells, also observed in H2-Aa deficiency, contributed to melanoma suppression. Acute disruption of H2-Aa was therapeutic in melanoma-bearing mice, particularly when combined with checkpoint inhibition, which had no therapeutic effect by itself. Our findings suggest that inhibiting MHC-II may be an effective immunotherapeutic approach to enhance immune responses to cancer.</p>","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":"221 12","pages":""},"PeriodicalIF":12.6,"publicationDate":"2024-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11528124/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142521984","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":"Auto-Abs neutralizing type I IFNs in patients with severe Powassan, Usutu, or Ross River virus disease.","authors":"Adrian Gervais, Paul Bastard, Lucy Bizien, Céline Delifer, Pierre Tiberghien, Chaturaka Rodrigo, Francesca Trespidi, Micol Angelini, Giada Rossini, Tiziana Lazzarotto, Francesca Conti, Irene Cassaniti, Fausto Baldanti, Francesca Rovida, Alessandro Ferrari, Davide Mileto, Alessandro Mancon, Laurent Abel, Anne Puel, Aurélie Cobat, Charles M Rice, Dániel Cadar, Jonas Schmidt-Chanasit, Johannes F Scheid, Jacob E Lemieux, Eric S Rosenberg, Marianna Agudelo, Stuart G Tangye, Alessandro Borghesi, Guillaume André Durand, Emilie Duburcq-Gury, Braulio M Valencia, Andrew R Lloyd, Anna Nagy, Margaret M MacDonald, Yannick Simonin, Shen-Ying Zhang, Jean-Laurent Casanova","doi":"10.1084/jem.20240942","DOIUrl":"10.1084/jem.20240942","url":null,"abstract":"<p><p>Arboviral diseases are a growing global health concern. Pre-existing autoantibodies (auto-Abs) neutralizing type I interferons (IFNs) can underlie encephalitis due to West Nile virus (WNV) (∼40% of patients) and tick-borne encephalitis (TBE, due to TBE virus [TBEV]) (∼10%). We report here that these auto-Abs can also underlie severe forms of rarer arboviral infections. Auto-Abs neutralizing high concentrations of IFN-α2, IFN-β, and/or IFN-ω are present in the single case of severe Powassan virus (POWV) encephalitis studied, two of three cases of severe Usutu virus (USUV) infection studied, and the most severe of 24 cases of Ross River virus (RRV) disease studied. These auto-Abs are not found in any of the 137 individuals with silent or mild infections with these three viruses. Thus, auto-Abs neutralizing type I IFNs underlie an increasing list of severe arboviral diseases due to Flaviviridae (WNV, TBEV, POWV, USUV) or Togaviridae (RRV) viruses transmitted to humans by mosquitos (WNV, USUV, RRV) or ticks (TBEV, POWV).</p>","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":"221 12","pages":""},"PeriodicalIF":12.6,"publicationDate":"2024-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11533500/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142558021","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":"Human ITGAV variants are associated with immune dysregulation, brain abnormalities, and colitis.","authors":"Sina Ghasempour, Neil Warner, Rei Guan, Marco M Rodari, Danton Ivanochko, Ryder Whittaker Hawkins, Ashish Marwaha, Jan K Nowak, Yijing Liang, Daniel J Mulder, Lorraine Stallard, Michael Li, Daniel D Yu, Fred G Pluthero, Vritika Batura, Mo Zhao, Iram Siddiqui, Julia E M Upton, Jessie M Hulst, Walter H A Kahr, Roberto Mendoza-Londono, Fabienne Charbit-Henrion, Lies H Hoefsloot, Anis Khiat, Diana Moreira, Eunice Trindade, Maria do Céu Espinheira, Isabel Pinto Pais, Marjolein J A Weerts, Hannie Douben, Daniel Kotlarz, Scott B Snapper, Christoph Klein, James J Dowling, Jean-Philippe Julien, Marieke Joosten, Nadine Cerf-Bensussan, Spencer A Freeman, Marianna Parlato, Tjakko J van Ham, Aleixo M Muise","doi":"10.1084/jem.20240546","DOIUrl":"10.1084/jem.20240546","url":null,"abstract":"<p><p>Integrin heterodimers containing an Integrin alpha V subunit are essential for development and play critical roles in cell adhesion and signaling. We identified biallelic variants in the gene coding for Integrin alpha V (ITGAV) in three independent families (two patients and four fetuses) that either caused abnormal mRNA and the loss of functional protein or caused mistargeting of the integrin. This led to eye and brain abnormalities, inflammatory bowel disease, immune dysregulation, and other developmental issues. Mechanistically, the reduction of functional Integrin αV resulted in the dysregulation of several pathways including TGF-β-dependent signaling and αVβ3-regulated immune signaling. These effects were confirmed using immunostaining, RNA sequencing, and functional studies in patient-derived cells. The genetic deletion of itgav in zebrafish recapitulated patient phenotypes including retinal and brain defects and the loss of microglia in early development as well as colitis in juvenile zebrafish with reduced SMAD3 expression and transcriptional regulation. Taken together, the ITGAV variants identified in this report caused a previously unknown human disease characterized by brain and developmental defects in the case of complete loss-of-function and atopy, neurodevelopmental defects, and colitis in cases of incomplete loss-of-function.</p>","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":"221 12","pages":""},"PeriodicalIF":12.6,"publicationDate":"2024-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11554753/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142621340","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":"Heterozygous BTNL8 variants in individuals with multisystem inflammatory syndrome in children (MIS-C).","authors":"Evangelos Bellos, Dilys Santillo, Pierre Vantourout, Heather R Jackson, Amedine Duret, Henry Hearn, Yoann Seeleuthner, Estelle Talouarn, Stephanie Hodeib, Harsita Patel, Oliver Powell, Sophya Yeoh, Sobia Mustafa, Dominic Habgood-Coote, Samuel Nichols, Leire Estramiana Elorrieta, Giselle D'Souza, Victoria J Wright, Diego Estrada-Rivadeneyra, Adriana H Tremoulet, Kirsten B Dummer, Stejara A Netea, Antonio Condino-Neto, Yu Lung Lau, Esmeralda Núñez Cuadros, Julie Toubiana, Marisol Holanda Pena, Frédéric Rieux-Laucat, Charles-Edouard Luyt, Filomeen Haerynck, Jean Louis Mège, Samya Chakravorty, Elie Haddad, Marie-Paule Morin, Özge Metin Akcan, Sevgi Keles, Melike Emiroglu, Gulsum Alkan, Sadiye Kübra Tüter Öz, Sefika Elmas Bozdemir, Guillaume Morelle, Alla Volokha, Yasemin Kendir-Demirkol, Betul Sözeri, Taner Coskuner, Aysun Yahsi, Belgin Gulhan, Saliha Kanik-Yuksek, Gulsum Iclal Bayhan, Aslinur Ozkaya-Parlakay, Osman Yesilbas, Nevin Hatipoglu, Tayfun Ozcelik, Alexandre Belot, Emilie Chopin, Vincent Barlogis, Esra Sevketoglu, Emin Menentoglu, Zeynep Gokce Gayretli Aydin, Marketa Bloomfield, Suzan A AlKhater, Cyril Cyrus, Yuriy Stepanovskiy, Anastasiia Bondarenko, Fatma Nur Öz, Meltem Polat, Jiří Fremuth, Jan Lebl, Amyrath Geraldo, Emmanuelle Jouanguy, Michael J Carter, Paul Wellman, Mark Peters, Rebeca Pérez de Diego, Lindsey Ann Edwards, Christopher Chiu, Mahdad Noursadeghi, Alexandre Bolze, Chisato Shimizu, Myrsini Kaforou, Melissa Shea Hamilton, Jethro A Herberg, Erica G Schmitt, Agusti Rodriguez-Palmero, Aurora Pujol, Jihoon Kim, Aurélie Cobat, Laurent Abel, Shen-Ying Zhang, Jean-Laurent Casanova, Taco W Kuijpers, Jane C Burns, Michael Levin, Adrian C Hayday, Vanessa Sancho-Shimizu","doi":"10.1084/jem.20240699","DOIUrl":"10.1084/jem.20240699","url":null,"abstract":"<p><p>Multisystem inflammatory syndrome in children (MIS-C) is a rare condition following SARS-CoV-2 infection associated with intestinal manifestations. Genetic predisposition, including inborn errors of the OAS-RNAseL pathway, has been reported. We sequenced 154 MIS-C patients and utilized a novel statistical framework of gene burden analysis, \"burdenMC,\" which identified an enrichment for rare predicted-deleterious variants in BTNL8 (OR = 4.2, 95% CI: 3.5-5.3, P < 10-6). BTNL8 encodes an intestinal epithelial regulator of Vγ4+γδ T cells implicated in regulating gut homeostasis. Enrichment was exclusive to MIS-C, being absent in patients with COVID-19 or bacterial disease. Using an available functional test for BTNL8, rare variants from a larger cohort of MIS-C patients (n = 835) were tested which identified eight variants in 18 patients (2.2%) with impaired engagement of Vγ4+γδ T cells. Most of these variants were in the B30.2 domain of BTNL8 implicated in sensing epithelial cell status. These findings were associated with altered intestinal permeability, suggesting a possible link between disrupted gut homeostasis and MIS-C-associated enteropathy triggered by SARS-CoV-2.</p>","PeriodicalId":15760,"journal":{"name":"Journal of Experimental Medicine","volume":"221 12","pages":""},"PeriodicalIF":12.6,"publicationDate":"2024-12-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11586762/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142686992","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}