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Acute Primary Infection with Mouse Cytomegalovirus Represents a Natural Animal Model for Virus-Associated Secondary Hemophagocytic Lymphohistiocytosis

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Hemophagocytic lymphohistiocytosis (HLH) is a complex, life-threatening immune disorder, characterized by systemic inflammation, an out-of-control cytokine storm and widespread organ damage. In contrast to primary HLH, secondary HLH occurs without any known mutation in granule-mediated cytotoxicity, in a context of infections, malignancies or autoimmune/autoinflammatory disorders. Both subtypes are generally precipitated by an infectious agent, predominantly a member of the Herpesviridae. Exploiting this knowledge, we created an animal model for virus-associated secondary HLH by administering mouse cytomegalovirus (MCMV) to immunocompetent wild-type mice. Infected 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. Additionally, mice developed lymphadenopathy, coagulopathy, liver dysfunction and hypercytokinemia. Strikingly, MCMV-infected interferon (IFN)-gamma-deficient mice were more prone to develop HLH-like symptoms, challenging the major pathogenic role attributed to IFN-gamma in most mouse models of primary HLH. As secondary HLH is known to occur in patients with primary infection or reactivation of human cytomegalovirus, our research demonstrates MCMV infection of wild-type mice as a promising natural model with utility for elucidating the poorly understood pathogenesis of secondary HLH and exploring novel treatment options.
Tijdschrift: JOURNAL OF CLINICAL IMMUNOLOGY
ISSN: 0271-9142
Volume: 34
Pagina's: S170 - S170
Jaar van publicatie:2014