title: Mouse Cytomegalovirus Infection in BALB/c Mice Resembles Virus-Associated Secondary Hemophagocytic Lymphohistiocytosis and Shows a Pathogenesis Distinct from Primary Hemophagocytic Lymphohistiocytosis.
abstract: 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 β-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-γ, a key pathogenic cytokine in models of primary HLH, were the highest. Nevertheless, murine CMV-infected IFN-γ-deficient mice still developed the aforementioned HLH-like symptoms. In fact, IFN-γ-deficient mice displayed a more complete spectrum of HLH, including splenomegaly, coagulopathy, and decreased NK cell cytotoxicity, indicating a regulatory role for IFN-γ in the pathogenesis of virus-associated secondary HLH as opposed to its central pathogenic role in primary HLH.
authors.affiliation: Laboratory of Immunobiology, Rega Institute, University of Leuven, 3000 Leuven, Belgium;
authors.forename: Ellen
authors.initials: E
authors.lastname: Brisse
authors.affiliation: Laboratory of Immunobiology, Rega Institute, University of Leuven, 3000 Leuven, Belgium;
authors.forename: Maya
authors.initials: M
authors.lastname: Imbrechts
authors.affiliation: Laboratory of Immunobiology, Rega Institute, University of Leuven, 3000 Leuven, Belgium;
authors.forename: Karen
authors.initials: K
authors.lastname: Put
authors.affiliation: Laboratory of Immunobiology, Rega Institute, University of Leuven, 3000 Leuven, Belgium;
authors.forename: Anneleen
authors.initials: A
authors.lastname: Avau
authors.affiliation: Laboratory of Immunobiology, Rega Institute, University of Leuven, 3000 Leuven, Belgium;
authors.forename: Tania
authors.initials: T
authors.lastname: Mitera
authors.affiliation: Laboratory of Molecular Immunology, Rega Institute, University of Leuven, 3000 Leuven, Belgium;
authors.forename: Nele
authors.initials: N
authors.lastname: Berghmans
authors.affiliation: Laboratory of Experimental Transplantation, University of Leuven, 3000 Leuven, Belgium;
authors.forename: Omer
authors.initials: O
authors.lastname: Rutgeerts
authors.affiliation: Laboratory of Experimental Transplantation, University of Leuven, 3000 Leuven, Belgium;
authors.forename: Mark
authors.initials: M
authors.lastname: Waer
authors.affiliation: Synapse BV, Cardiovascular Research Institute Maastricht School for Cardiovascular Diseases, Maastricht University, 6229 Maastricht, the Netherlands;
authors.forename: Marisa
authors.initials: M
authors.lastname: Ninivaggi
authors.affiliation: Synapse BV, Cardiovascular Research Institute Maastricht School for Cardiovascular Diseases, Maastricht University, 6229 Maastricht, the Netherlands;
authors.forename: Hilde
authors.initials: H
authors.lastname: Kelchtermans
authors.affiliation: Epirus Biopharmaceuticals Netherlands, 3584 Utrecht, the Netherlands;
authors.forename: Louis
authors.initials: L
authors.lastname: Boon
authors.affiliation: Laboratory of Virology and Chemotherapy, Rega Institute, University of Leuven, 3000 Leuven, Belgium; and.
authors.forename: Robert
authors.initials: R
authors.lastname: Snoeck
authors.affiliation: Laboratory of Pediatric Immunology, University Hospital Gasthuisberg, University of Leuven, 3000 Leuven, Belgium.
authors.forename: Carine H
authors.initials: CH
authors.lastname: Wouters
authors.affiliation: Laboratory of Virology and Chemotherapy, Rega Institute, University of Leuven, 3000 Leuven, Belgium; and.
authors.forename: Graciela
authors.initials: G
authors.lastname: Andrei
authors.affiliation: Laboratory of Immunobiology, Rega Institute, University of Leuven, 3000 Leuven, Belgium; patrick.matthys@kuleuven.be.
authors.forename: Patrick
authors.initials: P
authors.lastname: Matthys
mesh_terms: D000818:Animals; D015415:Biomarkers; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D003602:Cytotoxicity, Immunologic; D004195:Disease Models, Animal; D006566:Herpesviridae Infections / Q000150:complications* / Q000821:virology; D006644:Histiocytes / Q000276:immunology / Q000378:metabolism; D007371:Interferon-gamma / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D007694:Killer Cells, Natural / Q000276:immunology / Q000378:metabolism; D008099:Liver / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000821:virology; D051359:Lymphohistiocytosis, Hemophagocytic / Q000175:diagnosis / Q000209:etiology* / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D018146:Muromegalovirus / Q000502:physiology*; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism
chemical_list: D015415:Biomarkers; D016207:Cytokines; D007371:Interferon-gamma