Lymphocyte-independent pathways underlie the pathogenesis of murine cytomegalovirus-associated secondary hemophagocytic lymphohistiocytosis (original) (raw)
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Clinical and Experimental Immunology, 2018
Haemophagocytic lymphohistiocytosis (HLH) constitutes a spectrum of immunological disorders characterized by uncontrolled immune activation and key symptoms such as fever, splenomegaly, pancytopenia, haemophagocytosis, hyperferritinaemia and hepatitis. In genetic or primary HLH, hyperactivated CD8 1 T cells are the main drivers of pathology. However, in acquired secondary HLH, the role of lymphocytes remains vague. In the present study the involvement of lymphocytes in the pathogenesis of a cytomegalovirus-induced model of secondary HLH was explored. We have previously reported CD8 1 T cells to be redundant in this model, and therefore focused on CD4 1 helper and regulatory T cells. CD4 1 T cells were activated markedly and skewed towards a proinflammatory T helper type 1 transcription profile in mice displaying a severe and complete HLH phenotype. Counter to expectations, regulatory T cells were not reduced in numbers and were, in fact, more activated. Therapeutic strategies targeting CD25 high hyperactivated T cells were ineffective to alleviate disease, indicating that T cell hyperactivation is not a pathogenic factor in cytomegalovirus-induced murine HLH. Moreover, even though T cells were essential in controlling viral proliferation, CD4 1 T cells, in addition to CD8 1 T cells, were dispensable in the development of the HLH-like syndrome. In fact, no T or B cells were required for induction and propagation of HLH disease, as evidenced by the occurrence of cytomegalovirus-associated HLH in severe combined immunodeficient (SCID) mice. These data suggest that lymphocyte-independent mechanisms can underlie virus-associated secondary HLH, accentuating a clear distinction with primary HLH.
Virology Journal, 2017
Background: Hemophagocytic lymphohistiocytosis (HLH) is a rare immunological disorder caused by unbridled activation of T cells and macrophages, culminating in a life-threatening cytokine storm. A genetic and acquired subtype are distinguished, termed primary and secondary HLH, respectively. Clinical manifestations of both forms are frequently preceded by a viral infection, predominantly with herpesviruses. The exact role of the viral infection in the development of the hemophagocytic syndrome remains to be further elucidated. Methods: We utilized a recently developed murine model of cytomegalovirus-associated secondary HLH and dissected the respective contributions of lytic viral replication and immunopathology in its pathogenesis. Results: HLH-like disease only developed in cytomegalovirus-susceptible mouse strains unable to clear the virus, but the severity of symptoms was not correlated to the infectious viral titer. Lytic viral replication and sustained viremia played an essential part in the pathogenesis since abortive viral infection was insufficient to induce a fullblown HLH-like syndrome. Nonetheless, a limited set of symptoms, in particular anemia, thrombocytopenia and elevated levels of soluble CD25, appeared less dependent of the viral replication but rather mediated by the host's immune response, as corroborated by immunosuppressive treatment of infected mice with dexamethasone. Conclusion: Both virus-mediated pathology and immunopathology cooperate in the pathogenesis of full-blown virus-associated secondary HLH and are closely entangled. A certain level of viremia appears necessary to elicit the characteristic HLH-like symptoms in the model.
Journal of immunology (Baltimore, Md. : 1950), 2016
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 als...
How Viruses Contribute to the Pathogenesis of Hemophagocytic Lymphohistiocytosis
Frontiers in Immunology, 2017
Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening, hyperinflammatory syndrome, characterized by the uncontrolled activation of macrophages and T cells, eliciting key symptoms such as persistent fever, hepatosplenomegaly, pancytopenia, hemophagocytosis, hyperferritinemia, and coagulopathy. Viral infections are frequently implicated in the onset of active HLH episodes, both in primary, genetic HLH as in the secondary, acquired form. Infections with herpesviruses such as Epstein-Barr virus and cytomegalovirus are the most common. In autoimmune diseases, a link between viral infections and autoreactive immune responses has been recognized for a considerable time. However, the mechanisms by which viruses contribute to HLH pathogenesis remain to be clarified. In this viewpoint, different factors that may come into play are discussed. Viruses, particularly larger DNA viruses such as herpesviruses, are potent modulators of the immune response. By evading immune recognition, interfering with cytokine balances and inhibiting apoptotic pathways, viruses may increase the host's susceptibility to HLH development. In particular cases, a direct connection between the viral infection and inhibition of natural killer cell or T cell cytotoxicity was reported, indicating that viruses may create immunological deficiencies reminiscent of primary HLH.
The Journal of allergy and clinical immunology, 2016
Hemophagocytic lymphohistiocytosis (HLH) is a severe inflammatory condition driven by excessive CD8(+) T-cell activation. HLH occurs as both acquired and familial hemophagocytic lymphohistiocytosis (FHL) forms. In both conditions, a sterile or infectious trigger is required for disease initiation, which then becomes self-sustaining and life-threatening. Recent studies have attributed the key distal event to excessive IFN-γ production; however, the proximal events driving immune dysregulation have remained undefined. We sought to investigate the role of regulatory T (Treg) cells in the pathophysiology of experimental FHL. Because mutation in perforin is a common cause of FHL, we used an experimental FHL mouse model in which disease in perforin-deficient mice is triggered by lymphocytic choriomeningitis virus (LCMV). We assessed Treg and CD8(+) T-cell homeostasis and activation during the changing systemic conditions in the mice. In addition, human blood samples were collected and ana...
Cytokine & growth factor reviews, 2014
Hemophagocytic lymphohistiocytosis (HLH) comprises a group of life-threatening immune disorders classified into primary or secondary HLH. The former is caused by mutations in genes involved in granule-mediated cytotoxicity, the latter occurs in a context of infections, malignancies or autoimmune/autoinflammatory disorders. Both are characterized by systemic inflammation, severe cytokine storms and immune-mediated organ damage. Despite recent advances, the pathogenesis of HLH remains incompletely understood. Animal models resembling different subtypes of HLH are therefore of great value to study this disease and to uncover novel treatment strategies. In this review, all known animal models of HLH will be discussed, highlighting findings on cell types, cytokines and signaling pathways involved in disease pathogenesis and extrapolating therapeutic implications for the human situation.
Archives of Virology, 2000
Salivary gland-derived murine cytomegalovirus (SGV) infections of mice have been widely used as models of human cytomegalovirus infections and in the study of CMV biology. Still, many aspects of SGV pathogenesis are not clearly defined. Fatal and non-fatal SGV infections were investigated to characterize pathogenetic correlates of mortality and to assess the role of the immune response in disease progression. Suppression of immune responses was observed in both lethal and sublethal infections. Depletion of immune cell populations in spleen, however, correlated with severe CMV-induced hepatitis and mortality. In addition, T cell depletion studies indicated a requirement for this immune cell subset in control of liver damage and survival of infected mice. Examination of cytokine responses revealed a previously undescribed shock-like syndrome in lethally-infected mice characterized by high levels of tumor necrosis factor ␣ and interferon ␥. Furthermore, the sites of tumor necrosis factor ␣ gene induction did not strictly correlate with either viral load or the sites of tissue damage during infection. Taken together, these findings define the pathogenetic progression of disease as it relates to disease outcome and suggests that organ-specific differences in cytokine induction play a significant role in the late stages of acute lethal MCMV infections.
Antiviral T Cell Response Triggers Cytomegalovirus Hepatitis in Mice
Journal of Virology, 2012
One common sign of human cytomegalovirus infection is altered liver function. Murine cytomegalovirus strain v70 induces a rapid and severe hepatitis in immunocompetent mice that requires the presence of T cells in order to develop. v70 exhibits approximately 10-fold-greater virulence than the commonly used strain K181, resulting in a more severe, sustained, and lethal hepatitis but not dramatically higher viral replication levels. Hepatitis and death are markedly delayed in immunodeficient SCID compared to immunocompetent BALB/c mice. Transfer of BALB/c splenocytes to SCID mice conferred rapid disease following infection, and depletion of either CD4 or CD8 T cells in BALB/c mice reduced virus-induced hepatitis. The frequency of CD8 T cells producing gamma interferon and tumor necrosis factor in response to viral antigen was higher in settings where more severe disease occurred. Thus, virus-specific effector CD8 T cells appear to contribute to lethal virus-induced hepatitis, contrasting their protective role during sublethal infection. This study reveals how protection and disease during cytomegalovirus infection depend on viral strain and dose, as well as the quality of the T cell response.
British Journal of Haematology, 2016
Haemophagocytic lymphohistiocytosis (HLH) comprises a heterogeneous spectrum of hyperinflammatory conditions that are inherited (primary HLH) or acquired in a context of infections, malignancies or autoimmune/autoinflammatory disorders (secondary HLH). Genetic defects in the cytotoxic machinery of natural killer and CD8 + T cells underlie primary HLH, with residual cytotoxicity determining disease severity. Improved sequencing techniques have expanded the range of causal mutations and have redefined many cases of secondary HLH as primary HLH and vice versa, blurring the distinction between both subtypes. These insights allow HLH to be conceptualized as a threshold disease, in which interplay between various genetic and environmental factors causes progressive inflammation into a critical point, beyond which uncontrolled activation of immune cells and excessive cytokine production give rise to the cardinal symptoms of HLH. Various pathogenic pathways may thus converge to a common end stage of fulminant HLH.
Blood, 2004
Hemophagocytic lymphohistiocytosis (HLH) is a rare disorder with familial and acquired forms. The familial form is associated with mutations in the perforin gene and both forms are associated with severe defects in lymphocyte cytotoxic function. We examined perforin-deficient mice as a model of HLH in order to gain insight into this poorly understood disorder. While these mice do not spontaneously develop HLH-like symptoms, we found that they manifest all of the features of HLH after infection with lymphocytic cho-riomeningitic virus (LCMV). Following LCMV infection, perforin-deficient mice develop fever, splenomegaly, pancytopenia, hypertriglyceridemia, hypofibrinogenemia, and elevation of multiple serum cytokine levels, and hemophagocytosis is evident in many tissues. Investigation into how this phenotype develops has revealed that CD8 ؉ T cells, but not natural killer (NK) cells, are necessary for the development of this disorder. Cytokine neutralization studies have revealed that interferon gamma (IFN␥) is uniquely es-sential as well. Finally, the excessive amount of IFN␥ seen in affected mice appears to be driven by increased antigen presentation to CD8 ؉ T cells. These studies provide insight into the pathophysiology of HLH, and provide new targets for specific therapeutic intervention in this fatal disorder. (Blood. 2004;104: 735-743)