{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,29]],"date-time":"2026-10-29T22:57:05Z","timestamp":1793314625578,"version":"4.5.0"},"reference-count":43,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2019,12,15]],"date-time":"2019-12-15T00:00:00Z","timestamp":1576368000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100000050","name":"National Heart, Lung, and Blood Institute","doi-asserted-by":"publisher","award":["R01\u2010HL112836"],"award-info":[{"award-number":["R01\u2010HL112836"]}],"id":[{"id":"10.13039\/100000050","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000060","name":"National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["R01\u2010AI121250"],"award-info":[{"award-number":["R01\u2010AI121250"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100007253","name":"Nancy Taylor Foundation for Chronic Diseases","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100007253","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["acrjournals.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Arthritis &amp; Rheumatology"],"published-print":{"date-parts":[[2020,2]]},"abstract":"<jats:sec><jats:title>Objective<\/jats:title><jats:p>Familial hemophagocytic lymphohistiocytosis (FHLH) is a complex cytokine storm syndrome caused by genetic abnormalities rendering CD8+ T cells and natural killer cells incapable of cytolytic killing. In murine models of FHLH, interferon\u2010\u03b3 (IFN\u03b3) produced by CD8+ T cells has been identified as a critical mediator of disease, and an IFN\u03b3\u2010blocking antibody (emapalumab) has recently been approved by the Food and Drug Administration. However, development of hemophagocytic lymphohistiocytosis (HLH)\/macrophage activation syndrome (MAS) in patients who are genetically unresponsive to IFN\u03b3 questions the absolute necessity of IFN\u03b3 in driving disease. This study was undertaken to determine the necessity of IFN\u03b3 in driving HLH.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>IFN\u03b3<jats:sup>\u2212\/\u2212<\/jats:sup>Prf1<jats:sup>\u2212\/\u2212<\/jats:sup> mice were infected with lymphocytic choriomeningitis virus (LCMV), and HLH immunopathologic features, including survival, weight loss, cytopenias, cytokine profiles, and immune cell phenotypes, were assessed. Mixed bone marrow chimeras were created to determine the immune cell\u2013intrinsic role of IFN\u03b3 receptor signaling. CD8+ T cell depletion and interleukin\u201033 (IL\u201033)\/ST2 blockade were performed using monoclonal antibodies.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>LCMV infection of IFN\u03b3<jats:sup>\u2212\/\u2212<\/jats:sup>Prf1<jats:sup>\u2212\/\u2212<\/jats:sup> mice resulted in severe HLH\u2010like disease. CD8+ T cells and the IL\u201033\/ST2 axis remained essential mediators of disease; however, IFN\u03b3\u2010independent HLH immunopathology correlated with a 10\u201315\u2010fold increase in neutrophilia (<jats:italic>P<\/jats:italic> &lt; 0.001) and an altered cytokine milieu dominated by IL\u20106, IL\u20101\u03b2, and granulocyte\u2013macrophage colony\u2010stimulating factor (GM\u2010CSF) (<jats:italic>P<\/jats:italic> &lt; 0.05). Furthermore, IFN\u03b3 regulated CD8+ T cell expression of GM\u2010CSF and neutrophil survival.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>IFN\u03b3 is not necessary for the development of fulminant HLH, requiring physicians to consider case\u2010by\u2010case treatment strategies. Use of therapies that target upstream activators of CD8+ T cells, such as IL\u201033\/ST2 signaling, may be more universally applicable treatment options that ameliorate both IFN\u03b3\u2010dependent and \u2010independent manifestations of HLH\/MAS.<\/jats:p><\/jats:sec>","DOI":"10.1002\/art.41076","type":"journal-article","created":{"date-parts":[[2019,8,10]],"date-time":"2019-08-10T00:48:37Z","timestamp":1565398117000},"page":"335-347","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":41,"title":["Genetic Deficiency of Interferon\u2010\u03b3 Reveals Interferon\u2010\u03b3\u2013Independent Manifestations of Murine Hemophagocytic Lymphohistiocytosis"],"prefix":"10.1002","volume":"72","author":[{"given":"Thomas N.","family":"Burn","sequence":"first","affiliation":[{"name":"Perelman School of Medicine at the University of Pennsylvania and Children\u2019s Hospital of Philadelphia  Philadelphia 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