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Mouse Cytomegalovirus Infection in BALB/c Mice Resembles Virus-Associated Secondary Hemophagocytic Lymphohistiocytosis and Shows a Pathogenesis Distinct from Primary Hemophagocytic Lymphohistiocytosis.
Brisse, Ellen; Imbrechts, Maya; Put, Karen; Avau, Anneleen; Mitera, Tania; Berghmans, Nele; Rutgeerts, Omer; Waer, Mark; Ninivaggi, Marisa; Kelchtermans, Hilde; Boon, Louis; Snoeck, Robert; Wouters, Carine H; Andrei, Graciela; Matthys, Patrick.
Afiliação
  • Brisse E; Laboratory of Immunobiology, Rega Institute, University of Leuven, 3000 Leuven, Belgium;
  • Imbrechts M; Laboratory of Immunobiology, Rega Institute, University of Leuven, 3000 Leuven, Belgium;
  • Put K; Laboratory of Immunobiology, Rega Institute, University of Leuven, 3000 Leuven, Belgium;
  • Avau A; Laboratory of Immunobiology, Rega Institute, University of Leuven, 3000 Leuven, Belgium;
  • Mitera T; Laboratory of Immunobiology, Rega Institute, University of Leuven, 3000 Leuven, Belgium;
  • Berghmans N; Laboratory of Molecular Immunology, Rega Institute, University of Leuven, 3000 Leuven, Belgium;
  • Rutgeerts O; Laboratory of Experimental Transplantation, University of Leuven, 3000 Leuven, Belgium;
  • Waer M; Laboratory of Experimental Transplantation, University of Leuven, 3000 Leuven, Belgium;
  • Ninivaggi M; Synapse BV, Cardiovascular Research Institute Maastricht School for Cardiovascular Diseases, Maastricht University, 6229 Maastricht, the Netherlands;
  • Kelchtermans H; Synapse BV, Cardiovascular Research Institute Maastricht School for Cardiovascular Diseases, Maastricht University, 6229 Maastricht, the Netherlands;
  • Boon L; Epirus Biopharmaceuticals Netherlands, 3584 Utrecht, the Netherlands;
  • Snoeck R; Laboratory of Virology and Chemotherapy, Rega Institute, University of Leuven, 3000 Leuven, Belgium; and.
  • Wouters CH; Laboratory of Pediatric Immunology, University Hospital Gasthuisberg, University of Leuven, 3000 Leuven, Belgium.
  • Andrei G; Laboratory of Virology and Chemotherapy, Rega Institute, University of Leuven, 3000 Leuven, Belgium; and.
  • Matthys P; Laboratory of Immunobiology, Rega Institute, University of Leuven, 3000 Leuven, Belgium; patrick.matthys@kuleuven.be.
J Immunol ; 196(7): 3124-34, 2016 Apr 01.
Article em En | MEDLINE | ID: mdl-26903481
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 ß-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.
Assuntos

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Muromegalovirus / Infecções por Herpesviridae / Linfo-Histiocitose Hemofagocítica Tipo de estudo: Diagnostic_studies / Etiology_studies / Guideline / Prognostic_studies / Risk_factors_studies Limite: Animals Idioma: En Ano de publicação: 2016 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Muromegalovirus / Infecções por Herpesviridae / Linfo-Histiocitose Hemofagocítica Tipo de estudo: Diagnostic_studies / Etiology_studies / Guideline / Prognostic_studies / Risk_factors_studies Limite: Animals Idioma: En Ano de publicação: 2016 Tipo de documento: Article