{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,1]],"date-time":"2026-02-01T10:15:30Z","timestamp":1769940930612,"version":"3.49.0"},"reference-count":54,"publisher":"American Society of Hematology","issue":"19","content-domain":{"domain":["ashpublications.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2020,11,5]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Hemophagocytic lymphohistiocytosis (HLH) and macrophage activation syndrome (MAS) are life-threatening hyperinflammatory syndromes typically associated with underlying hematologic and rheumatic diseases, respectively. Familial HLH is associated with genetic cytotoxic impairment and thereby to excessive antigen presentation. Extreme elevation of serum interleukin-18 (IL-18) has been observed specifically in patients with MAS, making it a promising therapeutic target, but how IL-18 promotes hyperinflammation remains unknown. In an adjuvant-induced MAS model, excess IL-18 promoted immunopathology, whereas perforin deficiency had no effect. To determine the effects of excess IL-18 on virus-induced immunopathology, we infected Il18-transgenic (Il18tg) mice with lymphocytic choriomeningitis virus (LCMV; strain Armstrong). LCMV infection is self-limited in wild-type mice, but Prf1\u2212\/\u2212 mice develop prolonged viremia and fatal HLH. LCMV-infected Il18-transgenic (Il18tg) mice developed cachexia and hyperinflammation comparable to Prf1\u2212\/\u2212 mice, albeit with minimal mortality. Like Prf1\u2212\/\u2212 mice, immunopathology was largely rescued by CD8 depletion or interferon-\u03b3 (IFNg) blockade. Unlike Prf1\u2212\/\u2212 mice, they showed normal target cell killing and normal clearance of viral RNA and antigens. Rather than impairing cytotoxicity, excess IL-18 acted on T lymphocytes to amplify their inflammatory responses. Surprisingly, combined perforin deficiency and transgenic IL-18 production caused spontaneous hyperinflammation specifically characterized by CD8 T-cell expansion and improved by IFNg blockade. Even Il18tg;Prf1-haplosufficient mice demonstrated hyperinflammatory features. Thus, excess IL-18 promotes hyperinflammation via an autoinflammatory mechanism distinct from, and synergistic with, cytotoxic impairment. These data establish IL-18 as a potent, independent, and modifiable driver of life-threatening innate and adaptive hyperinflammation and support the rationale for an IL-18\u2013driven subclass of hyperinflammation.<\/jats:p>","DOI":"10.1182\/blood.2019003846","type":"journal-article","created":{"date-parts":[[2020,6,27]],"date-time":"2020-06-27T07:37:05Z","timestamp":1593243425000},"page":"2162-2174","update-policy":"https:\/\/doi.org\/10.1182\/blood.2019cm0000","source":"Crossref","is-referenced-by-count":38,"title":["Interleukin-18 and cytotoxic impairment are independent and synergistic causes of murine virus-induced hyperinflammation"],"prefix":"10.1182","volume":"136","author":[{"given":"Paul","family":"Tsoukas","sequence":"first","affiliation":[{"name":"Department of Pediatrics, University of Pittsburgh, Pittsburgh, PA;"},{"name":"Department of Rheumatology, Hospital for Sick Children, Toronto, ON, Canada;"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7635-7781","authenticated-orcid":false,"given":"Emily","family":"Rapp","sequence":"additional","affiliation":[{"name":"Department of Immunology and"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lauren","family":"Van Der Kraak","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, University of Pittsburgh, Pittsburgh, PA;"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eric S.","family":"Weiss","sequence":"additional","affiliation":[{"name":"Department of Immunology and"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5396-2532","authenticated-orcid":false,"given":"Vinh","family":"Dang","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, University of Pittsburgh, Pittsburgh, PA;"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Corinne","family":"Schneider","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, University of Pittsburgh, Pittsburgh, PA;"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Edwin","family":"Klein","sequence":"additional","affiliation":[{"name":"Division of Laboratory Animal Resources, University of Pittsburgh, Pittsburgh, PA;"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3718-6422","authenticated-orcid":false,"given":"Jennifer","family":"Picarsic","sequence":"additional","affiliation":[{"name":"Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA;"},{"name":"Division of Pathology, Department of Pediatrics, Cincinnati Children\u2019s Hospital Medical Center, Cincinnati, OH; and"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rosalba","family":"Salcedo","sequence":"additional","affiliation":[{"name":"Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7936-447X","authenticated-orcid":false,"given":"C. Andrew","family":"Stewart","sequence":"additional","affiliation":[{"name":"Cancer and Inflammation Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3837-5337","authenticated-orcid":false,"given":"Scott W.","family":"Canna","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, University of Pittsburgh, Pittsburgh, PA;"},{"name":"Department of Immunology and"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"234","reference":[{"issue":"3","key":"2020110511281014200_B1","doi-asserted-by":"crossref","first-page":"824","DOI":"10.1016\/j.jaip.2018.11.050","article-title":"Hemophagocytic lymphohistiocytosis: clinical presentations and diagnosis","volume":"7","author":"Risma","year":"2019","journal-title":"J Allergy Clin Immunol Pract"},{"issue":"7","key":"2020110511281014200_B2","doi-asserted-by":"crossref","first-page":"1059","DOI":"10.1002\/art.41285","article-title":"On the alert for cytokine storm: immunopathology in COVID-19","volume":"72","author":"Henderson","year":"2020","journal-title":"Arthritis Rheumatol"},{"issue":"3","key":"2020110511281014200_B3","doi-asserted-by":"crossref","first-page":"618","DOI":"10.1182\/blood-2010-12-324533","article-title":"Perforin is a critical physiologic regulator of T-cell activation","volume":"118","author":"Lykens","year":"2011","journal-title":"Blood"},{"issue":"3","key":"2020110511281014200_B4","doi-asserted-by":"crossref","first-page":"307","DOI":"10.1084\/jem.20140964","article-title":"Failed CTL\/NK cell killing and cytokine hypersecretion are directly linked through prolonged synapse time","volume":"212","author":"Jenkins","year":"2015","journal-title":"J Exp Med"},{"issue":"24","key":"2020110511281014200_B5","doi-asserted-by":"crossref","first-page":"6582","DOI":"10.1182\/blood-2011-01-329607","article-title":"Disruption of MyD88 signaling suppresses hemophagocytic lymphohistiocytosis in mice","volume":"117","author":"Krebs","year":"2011","journal-title":"Blood"},{"issue":"3","key":"2020110511281014200_B6","doi-asserted-by":"crossref","first-page":"735","DOI":"10.1182\/blood-2003-10-3413","article-title":"An animal model of hemophagocytic lymphohistiocytosis (HLH): CD8+ T cells and interferon gamma are essential for the disorder","volume":"104","author":"Jordan","year":"2004","journal-title":"Blood"},{"issue":"6","key":"2020110511281014200_B7","doi-asserted-by":"crossref","first-page":"1203","DOI":"10.1084\/jem.20102538","article-title":"Hemophagocytosis causes a consumptive anemia of inflammation","volume":"208","author":"Zoller","year":"2011","journal-title":"J Exp Med"},{"issue":"1","key":"2020110511281014200_B8","doi-asserted-by":"crossref","first-page":"166","DOI":"10.1136\/annrheumdis-2015-209020","article-title":"Elevated circulating levels of interferon-\u03b3 and interferon-\u03b3-induced chemokines characterise patients with macrophage activation syndrome complicating systemic juvenile idiopathic arthritis","volume":"76","author":"Bracaglia","year":"2017","journal-title":"Ann Rheum Dis"},{"issue":"13","key":"2020110511281014200_B9","doi-asserted-by":"crossref","first-page":"1442","DOI":"10.1182\/blood-2017-12-820852","article-title":"Interleukin-18 diagnostically distinguishes and pathogenically promotes human and murine macrophage activation syndrome","volume":"131","author":"Weiss","year":"2018","journal-title":"Blood"},{"issue":"1","key":"2020110511281014200_B10","doi-asserted-by":"crossref","first-page":"47","DOI":"10.1182\/bloodadvances.2018025858","article-title":"Treatment of refractory hemophagocytic lymphohistiocytosis with emapalumab despite severe concurrent infections","volume":"3","author":"Lounder","year":"2019","journal-title":"Blood Adv"},{"issue":"23","key":"2020110511281014200_B11","doi-asserted-by":"crossref","first-page":"LBA","DOI":"10.1182\/blood.V126.23.LBA-3.LBA-3","article-title":"A novel targeted approach to the treatment of hemophagocytic lymphohistiocytosis (HLH) with an anti-interferon gamma (IFN\u03b3) monoclonal antibody (mAb), NI-0501: first results from a pilot phase 2 study in children with primary HLH","volume":"126","author":"Jordan","year":"2015","journal-title":"Blood"},{"issue":"5","key":"2020110511281014200_B12","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1093\/intimm\/dxy012","article-title":"Convergent pathways of the hyperferritinemic syndromes","volume":"30","author":"Schulert","year":"2018","journal-title":"Int Immunol"},{"issue":"9","key":"2020110511281014200_B13","doi-asserted-by":"crossref","first-page":"439","DOI":"10.1007\/s11926-014-0439-2","article-title":"Genetic defects in cytolysis in macrophage activation syndrome","volume":"16","author":"Zhang","year":"2014","journal-title":"Curr Rheumatol Rep"},{"issue":"1","key":"2020110511281014200_B14","doi-asserted-by":"crossref","first-page":"53","DOI":"10.1186\/1546-0096-12-S1-P53","article-title":"Mutations of familial hemophagocytic lymphohistiocytosis (FHL) related genes and abnormalities of cytotoxicity function tests in patients with macrophage activation syndrome (MAS) occurring in systemic juvenile idiopathic arthritis (sJIA)","volume":"12","author":"Bracaglia","year":"2014","journal-title":"Ped Rheumatol"},{"issue":"7","key":"2020110511281014200_B15","doi-asserted-by":"crossref","first-page":"1180","DOI":"10.1093\/infdis\/jiv550","article-title":"Whole-exome sequencing reveals mutations in genes linked to hemophagocytic lymphohistiocytosis and macrophage activation syndrome in fatal cases of H1N1 influenza","volume":"213","author":"Schulert","year":"2016","journal-title":"J Infect Dis"},{"issue":"3","key":"2020110511281014200_B16","doi-asserted-by":"crossref","first-page":"550","DOI":"10.1002\/1529-0131(200103)44:3<550::AID-ANR103>3.0.CO;2-5","article-title":"Levels of interleukin-18 and its binding inhibitors in the blood circulation of patients with adult-onset Still\u2019s disease","volume":"44","author":"Kawashima","year":"2001","journal-title":"Arthritis Rheum"},{"issue":"9","key":"2020110511281014200_B17","doi-asserted-by":"crossref","first-page":"1645","DOI":"10.1093\/rheumatology\/keq133","article-title":"Distinct cytokine profiles of systemic-onset juvenile idiopathic arthritis-associated macrophage activation syndrome with particular emphasis on the role of interleukin-18 in its pathogenesis","volume":"49","author":"Shimizu","year":"2010","journal-title":"Rheumatology (Oxf)"},{"issue":"2","key":"2020110511281014200_B18","doi-asserted-by":"crossref","first-page":"361","DOI":"10.1093\/rheumatology\/kez282","article-title":"IL-18 as a biomarker linking systemic juvenile idiopathic arthritis and macrophage activation syndrome","volume":"59","author":"Yasin","year":"2019","journal-title":"Rheumatology (Oxf)"},{"issue":"10","key":"2020110511281014200_B19","doi-asserted-by":"crossref","first-page":"1140","DOI":"10.1038\/ng.3089","article-title":"An activating NLRC4 inflammasome mutation causes autoinflammation with recurrent macrophage activation syndrome","volume":"46","author":"Canna","year":"2014","journal-title":"Nat Genet"},{"issue":"10","key":"2020110511281014200_B20","doi-asserted-by":"crossref","first-page":"1135","DOI":"10.1038\/ng.3066","article-title":"Mutation of NLRC4 causes a syndrome of enterocolitis and autoinflammation","volume":"46","author":"Romberg","year":"2014","journal-title":"Nat Genet"},{"issue":"13","key":"2020110511281014200_B21","doi-asserted-by":"crossref","first-page":"1430","DOI":"10.1182\/blood-2017-06-789552","article-title":"Unopposed IL-18 signaling leads to severe TLR9-induced macrophage activation syndrome in mice","volume":"131","author":"Girard-Guyonvarc\u2019h","year":"2018","journal-title":"Blood"},{"issue":"2","key":"2020110511281014200_B22","doi-asserted-by":"crossref","first-page":"237","DOI":"10.1002\/JLB.CE0118-025RR","article-title":"Indeed, IL-18 is more than an inducer of IFN-\u03b3","volume":"104","author":"Dinarello","year":"2018","journal-title":"J Leukoc Biol"},{"issue":"9","key":"2020110511281014200_B23","doi-asserted-by":"crossref","first-page":"2782","DOI":"10.1002\/art.24750","article-title":"Defective phosphorylation of interleukin-18 receptor \u03b2 causes impaired natural killer cell function in systemic-onset juvenile idiopathic arthritis","volume":"60","author":"de Jager","year":"2009","journal-title":"Arthritis Rheum"},{"issue":"1","key":"2020110511281014200_B24","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1002\/art.39933","article-title":"Inflammatory gene expression profile and defective interferon-\u03b3 and granzyme K in natural killer cells from systemic juvenile idiopathic arthritis patients","volume":"69","author":"Put","year":"2017","journal-title":"Arthritis Rheumatol"},{"issue":"3","key":"2020110511281014200_B25","doi-asserted-by":"crossref","first-page":"263","DOI":"10.1016\/j.cytogfr.2014.10.001","article-title":"Hemophagocytic lymphohistiocytosis (HLH): a heterogeneous spectrum of cytokine-driven immune disorders","volume":"26","author":"Brisse","year":"2015","journal-title":"Cytokine Growth Factor Rev"},{"issue":"6","key":"2020110511281014200_B26","doi-asserted-by":"crossref","first-page":"2264","DOI":"10.1172\/JCI43157","article-title":"Repeated TLR9 stimulation results in macrophage activation syndrome-like disease in mice","volume":"121","author":"Behrens","year":"2011","journal-title":"J Clin Invest"},{"issue":"1","key":"2020110511281014200_B27","doi-asserted-by":"crossref","first-page":"167","DOI":"10.1016\/j.jviromet.2007.08.025","article-title":"Quantitative PCR technique for detecting lymphocytic choriomeningitis virus in vivo","volume":"147","author":"McCausland","year":"2008","journal-title":"J Virol Methods"},{"key":"2020110511281014200_B28","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1016\/j.trsl.2016.07.023","article-title":"Use of a mouse model to identify a blood biomarker for IFN\u03b3 activity in pediatric secondary hemophagocytic lymphohistiocytosis","volume":"180","author":"Buatois","year":"2017","journal-title":"Translat Res"},{"key":"2020110511281014200_B29","first-page":"e57473","article-title":"ExCYT: a graphical user interface for streamlining analysis of high-dimensional cytometry data","volume":"143","author":"Sidhom","year":"2019","journal-title":"J Vis Exp"},{"issue":"2","key":"2020110511281014200_B30","doi-asserted-by":"crossref","first-page":"335","DOI":"10.1002\/art.41076","article-title":"Genetic deficiency of IFNgamma reveals IFNgamma-independent manifestations of murine hemophagocytic lymphohistiocytosis","volume":"72","author":"Burn","year":"2019","journal-title":"Arthritis Rheumatol"},{"issue":"17","key":"2020110511281014200_B31","doi-asserted-by":"crossref","first-page":"2113","DOI":"10.1182\/blood-2015-12-688960","article-title":"Polygenic mutations in the cytotoxicity pathway increase susceptibility to develop HLH immunopathology in mice","volume":"127","author":"Sepulveda","year":"2016","journal-title":"Blood"},{"issue":"9","key":"2020110511281014200_B32","doi-asserted-by":"crossref","first-page":"1427","DOI":"10.1182\/blood-2014-09-602946","article-title":"A novel immunoregulatory role for NK-cell cytotoxicity in protection from HLH-like immunopathology in mice","volume":"125","author":"Sepulveda","year":"2015","journal-title":"Blood"},{"key":"2020110511281014200_B33","doi-asserted-by":"crossref","first-page":"289","DOI":"10.3389\/fimmu.2013.00289","article-title":"Interleukin-18 and IL-18 binding protein","volume":"4","author":"Dinarello","year":"2013","journal-title":"Front Immunol"},{"issue":"15","key":"2020110511281014200_B34","doi-asserted-by":"crossref","first-page":"8161","DOI":"10.1128\/JVI.00889-12","article-title":"Progressive loss of memory T cell potential and commitment to exhaustion during chronic viral infection","volume":"86","author":"Angelosanto","year":"2012","journal-title":"J Virol"},{"issue":"1","key":"2020110511281014200_B35","doi-asserted-by":"crossref","first-page":"27","DOI":"10.4049\/jimmunol.171.1.27","article-title":"Cutting edge: rapid in vivo killing by memory CD8 T cells","volume":"171","author":"Barber","year":"2003","journal-title":"J Immunol"},{"issue":"suppl 2","key":"2020110511281014200_B36","first-page":"178","article-title":"OP0204 emapalumab, an interferon gamma (IFN-Y)-blocking monoclonal antibody, in patients with macrophage activation syndrome (MAS) complicating systemic juvenile idiopathic arthritis (SJIA)","volume":"78","author":"Benedetti","year":"2019","journal-title":"Ann Rheum Dis"},{"issue":"7","key":"2020110511281014200_B37","doi-asserted-by":"crossref","first-page":"1764","DOI":"10.1002\/art.37958","article-title":"Interferon-\u03b3 mediates anemia but is dispensable for fulminant toll-like receptor 9-induced macrophage activation syndrome and hemophagocytosis in mice","volume":"65","author":"Canna","year":"2013","journal-title":"Arthritis Rheum"},{"issue":"2","key":"2020110511281014200_B38","doi-asserted-by":"crossref","first-page":"67","DOI":"10.4049\/immunohorizons.1800003","article-title":"CD8 T cell memory increases immunopathology in the perforin-deficient model of hemophagocytic lymphohistiocytosis secondary to TNF-\u03b1","volume":"2","author":"Taylor","year":"2018","journal-title":"Immunohorizons"},{"issue":"7","key":"2020110511281014200_B39","doi-asserted-by":"crossref","first-page":"3124","DOI":"10.4049\/jimmunol.1501035","article-title":"Mouse cytomegalovirus infection in BALB\/c mice resembles virus-associated secondary hemophagocytic lymphohistiocytosis and shows a pathogenesis distinct from primary hemophagocytic lymphohistiocytosis","volume":"196","author":"Brisse","year":"2016","journal-title":"J Immunol"},{"issue":"6","key":"2020110511281014200_B40","doi-asserted-by":"crossref","first-page":"1638","DOI":"10.1016\/j.jaci.2014.11.030","article-title":"Hemophagocytic lymphohistiocytosis in 2 patients with underlying IFN-\u03b3 receptor deficiency","volume":"135","author":"Tesi","year":"2015","journal-title":"J Allergy Clin Immunol"},{"issue":"5446","key":"2020110511281014200_B41","doi-asserted-by":"crossref","first-page":"1957","DOI":"10.1126\/science.286.5446.1957","article-title":"Perforin gene defects in familial hemophagocytic lymphohistiocytosis","volume":"286","author":"Stepp","year":"1999","journal-title":"Science"},{"issue":"12","key":"2020110511281014200_B42","doi-asserted-by":"crossref","first-page":"2237","DOI":"10.1093\/rheumatology\/kew300","article-title":"Elevated serum levels of free interleukin-18 in adult-onset Still\u2019s disease","volume":"55","author":"Girard","year":"2016","journal-title":"Rheumatology (Oxf)"},{"key":"2020110511281014200_B43","doi-asserted-by":"crossref","first-page":"100","DOI":"10.1016\/j.cca.2015.12.009","article-title":"Biochemical and inflammatory aspects in patients with severe sepsis and septic shock: the predictive role of IL-18 in mortality","volume":"453","author":"Eidt","year":"2016","journal-title":"Clin Chim Acta"},{"issue":"2","key":"2020110511281014200_B44","doi-asserted-by":"crossref","first-page":"275","DOI":"10.1097\/CCM.0000000000001402","article-title":"Interleukin-1 receptor blockade is associated with reduced mortality in sepsis patients with features of the macrophage activation syndrome: re-analysis of a prior Phase III trial","volume":"44","author":"Shakoory","year":"2016","journal-title":"Crit Care Med"},{"issue":"1","key":"2020110511281014200_B45","doi-asserted-by":"crossref","first-page":"172","DOI":"10.1186\/s12916-017-0930-5","article-title":"Macrophage activation-like syndrome: an immunological entity associated with rapid progression to death in sepsis","volume":"15","author":"Kyriazopoulou","year":"2017","journal-title":"BMC Med"},{"issue":"1","key":"2020110511281014200_B46","doi-asserted-by":"crossref","first-page":"74","DOI":"10.1016\/j.cyto.2013.09.007","article-title":"Sustained elevation of serum interleukin-18 and its association with hemophagocytic lymphohistiocytosis in XIAP deficiency","volume":"65","author":"Wada","year":"2014","journal-title":"Cytokine"},{"issue":"4","key":"2020110511281014200_B47","doi-asserted-by":"crossref","first-page":"1122","DOI":"10.1016\/j.jaci.2019.06.017","article-title":"Severe autoinflammation in 4 patients with C-terminal variants in cell division control protein 42 homolog (CDC42) successfully treated with IL-1 inhibition","volume":"144","author":"Gernez","year":"2019","journal-title":"J Allergy Clin Immunol"},{"issue":"12","key":"2020110511281014200_B48","doi-asserted-by":"crossref","first-page":"2778","DOI":"10.1084\/jem.20190147","article-title":"A novel disorder involving dyshematopoiesis, inflammation, and HLH due to aberrant CDC42 function","volume":"216","author":"Lam","year":"2019","journal-title":"J Exp Med"},{"issue":"8","key":"2020110511281014200_B49","doi-asserted-by":"crossref","first-page":"1777","DOI":"10.1084\/jem.20190669","article-title":"Inherited IL-18BP deficiency in human fulminant viral hepatitis","volume":"216","author":"Belkaya","year":"2019","journal-title":"J Exp Med"},{"issue":"5","key":"2020110511281014200_B50","doi-asserted-by":"crossref","first-page":"1698","DOI":"10.1016\/j.jaci.2016.10.022","article-title":"Life-threatening NLRC4-associated hyperinflammation successfully treated with IL-18 inhibition","volume":"139","author":"Canna","year":"2017","journal-title":"J Allergy Clin Immunol"},{"issue":"3","key":"2020110511281014200_B51","doi-asserted-by":"crossref","first-page":"292","DOI":"10.1067\/mpd.2003.110","article-title":"Natural killer cell dysfunction in patients with systemic-onset juvenile rheumatoid arthritis and macrophage activation syndrome","volume":"142","author":"Grom","year":"2003","journal-title":"J Pediatr"},{"issue":"2","key":"2020110511281014200_B52","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1016\/S1074-7613(00)80470-7","article-title":"Counting antigen-specific CD8 T cells: a reevaluation of bystander activation during viral infection","volume":"8","author":"Murali-Krishna","year":"1998","journal-title":"Immunity"},{"issue":"19","key":"2020110511281014200_B53","doi-asserted-by":"crossref","first-page":"E2627","DOI":"10.1073\/pnas.1515793113","article-title":"Targeting IL-17A attenuates neonatal sepsis mortality induced by IL-18","volume":"113","author":"Wynn","year":"2016","journal-title":"Proc Natl Acad Sci USA"},{"issue":"1","key":"2020110511281014200_B54","first-page":"127","article-title":"Critical role for perforin and Fas-dependent killing of dendritic cells in the control of inflammation","volume":"119","author":"Chen","year":"2012"}],"container-title":["Blood"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/ashpublications.org\/blood\/article-pdf\/136\/19\/2162\/1780375\/bloodbld2019003846.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"http:\/\/ashpublications.org\/blood\/article-pdf\/136\/19\/2162\/1780375\/bloodbld2019003846.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2020,11,5]],"date-time":"2020-11-05T16:30:22Z","timestamp":1604593822000},"score":1,"resource":{"primary":{"URL":"https:\/\/ashpublications.org\/blood\/article\/136\/19\/2162\/461193\/Interleukin18-and-cytotoxic-impairment-are"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,11,5]]},"references-count":54,"journal-issue":{"issue":"19","published-print":{"date-parts":[[2020,11,5]]}},"URL":"https:\/\/doi.org\/10.1182\/blood.2019003846","relation":{},"ISSN":["0006-4971","1528-0020"],"issn-type":[{"value":"0006-4971","type":"print"},{"value":"1528-0020","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,11,5]]}}}