Mingce Zhang,Remy R Cron,Niansheng Chu,Junior Nguyen,Scott M Gordon,Esraa M Eloseily,T Prescott Atkinson,Peter Weiser,Mark R Walter,Portia A Kreiger,Scott W Canna,Edward M Behrens,Randy Q Cron
{"title":"DOCK8 在细胞因子风暴综合征中的作用","authors":"Mingce Zhang,Remy R Cron,Niansheng Chu,Junior Nguyen,Scott M Gordon,Esraa M Eloseily,T Prescott Atkinson,Peter Weiser,Mark R Walter,Portia A Kreiger,Scott W Canna,Edward M Behrens,Randy Q Cron","doi":"10.1016/j.jaci.2024.10.004","DOIUrl":null,"url":null,"abstract":"BACKGROUND\r\nCytokine storm syndromes (CSS), including hemophagocytic lymphohistiocytosis (HLH), are increasingly recognized as hyperinflammatory states leading to multi-organ failure and death. Familial HLH (FHL) in infancy results from homozygous genetic defects in perforin-mediated cytolysis by CD8 T-lymphocytes and natural killer (NK) cells. Later onset CSS are frequently associated with heterozygous defects in FHL genes, but genetic etiologies for most are unknown. We identified rare DOCK8 variants in CSS patients.\r\n\r\nOBJECTIVE\r\nWe explore the role of CSS patient-derived DOCK8 mutations on cytolytic activity in NK cells. We further study effects of DOCK8 deficiency in murine models of CSS.\r\n\r\nMETHODS\r\nDOCK8 cDNA from 2 unrelated CSS patients with different missense mutations were introduced into human NK-92 NK cells by foamy virus transduction. NK cell degranulation (CD107a), cytolytic activity against K562 target cells, and interferon-gamma (IFNγ) production were explored by flow cytometry. A third CSS patient DOCK8 mRNA splice acceptor site variant was explored by exon trapping. Dock8-/- mice were assessed for features of CSS (weight loss, splenomegaly, hepatic inflammation, cytopenias, and IFNγ levels) upon challenge with lymphocytic choriomeningitis virus (LCMV) and excess IL-18.\r\n\r\nRESULTS\r\nBoth patient DOCK8 missense mutations decreased cytolytic function in NK cells in a partial dominant-negative fashion in vitro. The patient DOCK8 splice variant disrupted mRNA splicing in vitro. LCMV infection promoted CSS in Dock8-/- mice and interacted with excess IL-18 limiting T-cell numbers while promoting CD8 T-cell hyperactivation.\r\n\r\nCONCLUSION\r\nMutations in DOCK8 may contribute to CSS-like hyperinflammatory states by altering cytolytic function in a threshold model of disease.","PeriodicalId":14936,"journal":{"name":"Journal of Allergy and Clinical Immunology","volume":"31 1","pages":""},"PeriodicalIF":11.4000,"publicationDate":"2024-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Role of DOCK8 in Cytokine Storm Syndromes.\",\"authors\":\"Mingce Zhang,Remy R Cron,Niansheng Chu,Junior Nguyen,Scott M Gordon,Esraa M Eloseily,T Prescott Atkinson,Peter Weiser,Mark R Walter,Portia A Kreiger,Scott W Canna,Edward M Behrens,Randy Q Cron\",\"doi\":\"10.1016/j.jaci.2024.10.004\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"BACKGROUND\\r\\nCytokine storm syndromes (CSS), including hemophagocytic lymphohistiocytosis (HLH), are increasingly recognized as hyperinflammatory states leading to multi-organ failure and death. Familial HLH (FHL) in infancy results from homozygous genetic defects in perforin-mediated cytolysis by CD8 T-lymphocytes and natural killer (NK) cells. Later onset CSS are frequently associated with heterozygous defects in FHL genes, but genetic etiologies for most are unknown. We identified rare DOCK8 variants in CSS patients.\\r\\n\\r\\nOBJECTIVE\\r\\nWe explore the role of CSS patient-derived DOCK8 mutations on cytolytic activity in NK cells. We further study effects of DOCK8 deficiency in murine models of CSS.\\r\\n\\r\\nMETHODS\\r\\nDOCK8 cDNA from 2 unrelated CSS patients with different missense mutations were introduced into human NK-92 NK cells by foamy virus transduction. NK cell degranulation (CD107a), cytolytic activity against K562 target cells, and interferon-gamma (IFNγ) production were explored by flow cytometry. A third CSS patient DOCK8 mRNA splice acceptor site variant was explored by exon trapping. Dock8-/- mice were assessed for features of CSS (weight loss, splenomegaly, hepatic inflammation, cytopenias, and IFNγ levels) upon challenge with lymphocytic choriomeningitis virus (LCMV) and excess IL-18.\\r\\n\\r\\nRESULTS\\r\\nBoth patient DOCK8 missense mutations decreased cytolytic function in NK cells in a partial dominant-negative fashion in vitro. The patient DOCK8 splice variant disrupted mRNA splicing in vitro. LCMV infection promoted CSS in Dock8-/- mice and interacted with excess IL-18 limiting T-cell numbers while promoting CD8 T-cell hyperactivation.\\r\\n\\r\\nCONCLUSION\\r\\nMutations in DOCK8 may contribute to CSS-like hyperinflammatory states by altering cytolytic function in a threshold model of disease.\",\"PeriodicalId\":14936,\"journal\":{\"name\":\"Journal of Allergy and Clinical Immunology\",\"volume\":\"31 1\",\"pages\":\"\"},\"PeriodicalIF\":11.4000,\"publicationDate\":\"2024-10-16\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Journal of Allergy and Clinical Immunology\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1016/j.jaci.2024.10.004\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"ALLERGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Allergy and Clinical Immunology","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1016/j.jaci.2024.10.004","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"ALLERGY","Score":null,"Total":0}
BACKGROUND
Cytokine storm syndromes (CSS), including hemophagocytic lymphohistiocytosis (HLH), are increasingly recognized as hyperinflammatory states leading to multi-organ failure and death. Familial HLH (FHL) in infancy results from homozygous genetic defects in perforin-mediated cytolysis by CD8 T-lymphocytes and natural killer (NK) cells. Later onset CSS are frequently associated with heterozygous defects in FHL genes, but genetic etiologies for most are unknown. We identified rare DOCK8 variants in CSS patients.
OBJECTIVE
We explore the role of CSS patient-derived DOCK8 mutations on cytolytic activity in NK cells. We further study effects of DOCK8 deficiency in murine models of CSS.
METHODS
DOCK8 cDNA from 2 unrelated CSS patients with different missense mutations were introduced into human NK-92 NK cells by foamy virus transduction. NK cell degranulation (CD107a), cytolytic activity against K562 target cells, and interferon-gamma (IFNγ) production were explored by flow cytometry. A third CSS patient DOCK8 mRNA splice acceptor site variant was explored by exon trapping. Dock8-/- mice were assessed for features of CSS (weight loss, splenomegaly, hepatic inflammation, cytopenias, and IFNγ levels) upon challenge with lymphocytic choriomeningitis virus (LCMV) and excess IL-18.
RESULTS
Both patient DOCK8 missense mutations decreased cytolytic function in NK cells in a partial dominant-negative fashion in vitro. The patient DOCK8 splice variant disrupted mRNA splicing in vitro. LCMV infection promoted CSS in Dock8-/- mice and interacted with excess IL-18 limiting T-cell numbers while promoting CD8 T-cell hyperactivation.
CONCLUSION
Mutations in DOCK8 may contribute to CSS-like hyperinflammatory states by altering cytolytic function in a threshold model of disease.
期刊介绍:
The Journal of Allergy and Clinical Immunology is a prestigious publication that features groundbreaking research in the fields of Allergy, Asthma, and Immunology. This influential journal publishes high-impact research papers that explore various topics, including asthma, food allergy, allergic rhinitis, atopic dermatitis, primary immune deficiencies, occupational and environmental allergy, and other allergic and immunologic diseases. The articles not only report on clinical trials and mechanistic studies but also provide insights into novel therapies, underlying mechanisms, and important discoveries that contribute to our understanding of these diseases. By sharing this valuable information, the journal aims to enhance the diagnosis and management of patients in the future.