{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T20:59:19Z","timestamp":1789419559829,"version":"build-2803163510"},"reference-count":65,"publisher":"Oxford University Press (OUP)","issue":"7","license":[{"start":{"date-parts":[[2016,4,1]],"date-time":"2016-04-01T00:00:00Z","timestamp":1459468800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2016,4,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening immunological disorder that is characterized by systemic inflammation, widespread organ damage, and hypercytokinemia. Primary HLH is caused by mutations in granule-mediated cytotoxicity, whereas secondary HLH occurs, without a known genetic background, in a context of infections, malignancies, or autoimmune and autoinflammatory disorders. Clinical manifestations of both HLH subtypes are often precipitated by a viral infection, predominantly with Herpesviridae. Exploiting this knowledge, we established an animal model of virus-associated secondary HLH by infecting immunocompetent wild-type mice with the \u03b2-herpesvirus murine CMV. C57BL\/6 mice developed a mild inflammatory phenotype, whereas BALB\/c mice displayed the clinicopathologic features of HLH, as set forth in the Histiocyte Society diagnostic guidelines: fever, cytopenia, hemophagocytosis, hyperferritinemia, and elevated serum levels of soluble CD25. BALB\/c mice also developed lymphadenopathy, liver dysfunction, and decreased NK cell numbers. Lymphoid and myeloid cells were in a hyperactivated state. Nonetheless, depletion of CD8+ T cells could not inhibit or cure the HLH-like syndrome, highlighting a first dissimilarity from mouse models of primary HLH. Immune cell hyperactivation in BALB\/c mice was accompanied by a cytokine storm. Notably, plasma levels of IFN-\u03b3, a key pathogenic cytokine in models of primary HLH, were the highest. Nevertheless, murine CMV\u2013infected IFN-\u03b3\u2013deficient mice still developed the aforementioned HLH-like symptoms. In fact, IFN-\u03b3\u2013deficient mice displayed a more complete spectrum of HLH, including splenomegaly, coagulopathy, and decreased NK cell cytotoxicity, indicating a regulatory role for IFN-\u03b3 in the pathogenesis of virus-associated secondary HLH as opposed to its central pathogenic role in primary HLH.<\/jats:p>","DOI":"10.4049\/jimmunol.1501035","type":"journal-article","created":{"date-parts":[[2016,2,23]],"date-time":"2016-02-23T04:13:29Z","timestamp":1456200809000},"page":"3124-3134","source":"Crossref","is-referenced-by-count":43,"title":["Mouse Cytomegalovirus Infection in BALB\/c Mice Resembles Virus-Associated Secondary Hemophagocytic Lymphohistiocytosis and Shows a Pathogenesis Distinct from Primary Hemophagocytic Lymphohistiocytosis"],"prefix":"10.1093","volume":"196","author":[{"given":"Ellen","family":"Brisse","sequence":"first","affiliation":[{"name":"Laboratory of Immunobiology, Rega Institute, University of Leuven , 3000 Leuven ,","place":["Belgium"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maya","family":"Imbrechts","sequence":"additional","affiliation":[{"name":"Laboratory of Immunobiology, Rega Institute, University of Leuven , 3000 Leuven ,","place":["Belgium"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karen","family":"Put","sequence":"additional","affiliation":[{"name":"Laboratory of Immunobiology, Rega Institute, University of Leuven , 3000 Leuven ,","place":["Belgium"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anneleen","family":"Avau","sequence":"additional","affiliation":[{"name":"Laboratory of Immunobiology, Rega Institute, University of Leuven , 3000 Leuven ,","place":["Belgium"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tania","family":"Mitera","sequence":"additional","affiliation":[{"name":"Laboratory of Immunobiology, Rega Institute, University of Leuven , 3000 Leuven ,","place":["Belgium"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nele","family":"Berghmans","sequence":"additional","affiliation":[{"name":"Laboratory of Molecular Immunology, Rega Institute, University of Leuven , 3000 Leuven ,","place":["Belgium"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Omer","family":"Rutgeerts","sequence":"additional","affiliation":[{"name":"Laboratory of Experimental Transplantation, University of Leuven , 3000 Leuven ,","place":["Belgium"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark","family":"Waer","sequence":"additional","affiliation":[{"name":"Laboratory of Experimental Transplantation, University of Leuven , 3000 Leuven ,","place":["Belgium"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marisa","family":"Ninivaggi","sequence":"additional","affiliation":[{"name":"Synapse BV, Cardiovascular Research Institute Maastricht School for Cardiovascular Diseases, Maastricht University , 6229 Maastricht ,","place":["the Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hilde","family":"Kelchtermans","sequence":"additional","affiliation":[{"name":"Synapse BV, Cardiovascular Research Institute Maastricht School for Cardiovascular Diseases, Maastricht University , 6229 Maastricht ,","place":["the Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Louis","family":"Boon","sequence":"additional","affiliation":[{"name":"Epirus Biopharmaceuticals Netherlands , 3584 Utrecht ,","place":["the Netherlands"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert","family":"Snoeck","sequence":"additional","affiliation":[{"name":"Laboratory of Virology and Chemotherapy, Rega Institute, University of Leuven , 3000 Leuven ,","place":["Belgium"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carine H","family":"Wouters","sequence":"additional","affiliation":[{"name":"Laboratory of Pediatric Immunology, University Hospital Gasthuisberg, University of Leuven , 3000 Leuven ,","place":["Belgium"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Graciela","family":"Andrei","sequence":"additional","affiliation":[{"name":"Laboratory of Virology and Chemotherapy, Rega Institute, University of Leuven , 3000 Leuven ,","place":["Belgium"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Patrick","family":"Matthys","sequence":"additional","affiliation":[{"name":"Laboratory of Immunobiology, Rega Institute, University of Leuven , 3000 Leuven ,","place":["Belgium"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2016,4,1]]},"reference":[{"key":"2025030702152244500_r1","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1007\/s00431-006-0258-1","article-title":"Familial and acquired hemophagocytic lymphohistiocytosis","volume":"166","author":"Janka","year":"2007","journal-title":"Eur. 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