Acute primary infection with mouse cytomegalovirus represents a natural animal model for virus-associated secondary hemophagocytic lymphohistiocytosis

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.status: publishe

Venous thrombotic events in psoriasis patients : a systematic review with meta-analysis

Background: Psoriasis is a chronic inflammatory skin disease associated with numerous comorbidities. Psoriasis has been linked to an increased risk of metabolic syndrome and atherosclerotic arterial disease. Inflammatory conditions are known to increase the risk of venous thromboembolism (VTE), a frequent cause of morbidity and mortality. However, the relationship between psoriasis and VTE has received little attention and existing studies have shown conflicting results. Objectives: This systematic review aims to perform a meta-analysis on VTE in psoriasis patients. Methods: We conducted a systematic electronic search of the incidence of VTE (pulmonary embolism [PE], deep venous thrombosis [DVT] and/or retinal vein occlusion [RVO]) in psoriasis patients on PubMed, Web of Science, Embase and Cochrane (specifics: see ). Only English literature and full manuscripts were included; abstracts were excluded. Pooled risk ratio and 95% confidence interval were calculated using Review Manager. Results: Seven articles were included. Each study separately indicated a correlation between psoriasis and VTE after adjustment for several clinical parameters. The confounders included in the adjustment differed between studies, but all included adjustment for age, gender and comorbidities. A meta-analysis of the unadjusted data of the five studies that reported raw data on number of VTE events and patient follow-up (person-years) showed a pooled risk ratio for VTE and psoriasis of 1.29 (95% CI: 0.92-1.81). The statistical heterogeneity was high with I (2) of 97%. Conclusions: Published data adjusted for key confounders demonstrate in general a significantly increased prevalence of VTE in psoriasis patients. Both psoriasis severity and number of confounders assessed seem to have an impact on this correlation. In this review, we pooled unadjusted data of the studies and we found a non-significant increased risk for VTE in psoriasis patients compared to healthy controls. This discrepancy suggests that psoriasis severity, age, gender or comorbidities may influence the risk of VTE in subgroups of the psoriasis population. Future research to identify subgroups at risk for VTE is warranted. Key messages The included studies reported an increased risk of VTE, DVT, PE and RVO in psoriasis patients. A meta-analysis was performed on five studies that reported raw data and showed that the pooled risk ratio for VTE in psoriasis patients overall was increased, however not significantly, compared to healthy controls. Further research to pinpoint psoriasis subgroups at risk (e.g. severe psoriasis patients, younger age, associated comorbidities) of developing VTE is warranted

Mouse cytomegalovirus infection in BALB/c mice resembles virus-associated secondary hemophagocytic lymphohistiocytosis (HLH) and shows a pathogenesis distinct from primary HLH

Hemophagocytic lymphohistiocytosis (HLH) comprises a group of life-threatening disorders classified into primary or secondary HLH. The former is caused by genetic defects in granule-mediated cytotoxicity, the latter occurs without a known genetic predisposition in underlying infections, malignancies or autoimmune and autoinflammatory syndromes. Both subtypes are characterized by systemic inflammation, hypercytokinemia and widespread organ damage, mediated by aberrantly activated CD8+ T cells and histiocytes. Despite recent advances, the pathogenesis of HLH remains incompletely understood. Since HLH is often precipitated by a viral infection, predominantly with Herpesviridae, we established an animal model for virus-associated secondary HLH by administering the β-herpesvirus mouse cytomegalovirus (MCMV) to wild-type BALB/c mice. Infected mice displayed the clinicopathologic features of HLH: fever, pancytopenia, hemophagocytosis, hyperferritinemia and elevated serum levels of soluble CD25. Systemic inflammation was reflected in the activated profile of CD8+ T cells and histiocytes in different organs, and in the development of a cytokine storm. Notably, IFN γ levels were the most highly elevated. Nonetheless, MCMV-infected IFN γ-deficient mice developed the aforementioned HLH-like symptoms, suggesting a redundancy of IFN γ in the pathogenesis of our model. In fact, MCMV-infected IFN γ-deficient mice displayed a more complete spectrum of HLH, including splenomegaly, coagulopathy and decreased NK cell cytotoxicity. These data indicate a regulatory role for IFN-γ in our model of secondary HLH, as opposed to its major pathogenic role in primary HLH mouse models. Therefore, caution is warranted when extrapolating treatment strategies from primary to secondary HLH, particularly now a clinical trial has started using anti-IFN-γ therapy in primary HLH patients.status: accepte

A microfluidic platform for single B-cell isolation to rapidly discover human monoclonal antibodies

status: accepte

Lytic viral replication and immunopathology in a cytomegalovirus-induced mouse model of secondary hemophagocytic lymphohistiocytosis

Abstract 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 full-blown 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

Identification of cytokine cell sources in a new mouse model of systemic juvenile idiopathic arthritis highlights innate immunity of this disorder

Objective Systemic juvenile idiopathic arthritis (sJIA) is a rheumatic childhood disease, with distinctive systemic inflammatory features and a typical cytokine profile. The etiology of sJIA is largely unknown. Here, we aimed to elucidate the role of specific cell populations and cytokines in the pathogenesis, by means of a new mouse model of sJIA relying on the injection of complete Freund’s adjuvant (CFA) in interferon-gamma deficient (IFN-g KO) mice. Wild type (WT) mice developed a minor inflammation, indicating that IFN-g provides protection in the disease process. Methods Cytokine mRNA levels were analyzed in organs and purified immune cell populations of CFA-challenged IFN-g KO and WT mice. Cytokine antagonists and cell depleting antibodies were administered to mice. Clinical, laboratory and immune features of sJIA were evaluated. Results In the diseased IFN-g KO mice, elevated expression of IL 1β, IL-6, IL-17 and IL-22 were found in lymph nodes and – remarkably - also in lung tissue. Gamma-delta T cells were a major cell source for IL-17, and anti-IL-17 antibodies abrogated the disease. In the non-diseased WT mice, expression of IFN-g was almost exclusively found in NK, NKT and gamma-delta T cells. Transient neutralization of IFN-g as well as depletion of NK cells in WT mice both resulted in a fulminant sJIA-like disease. Conclusion These data pinpoint innate immune cells and non-lymphoid organs as important sources of cytokines in CFA-induced animal models. The results also demonstrate that NK cells provide a regulatory function in the pathogenesis of sJIA, by production of IFN-g.status: publishe

Lymphocyte-independent pathways underlie the pathogenesis of murine cytomegalovirus-associated secondary haemophagocytic lymphohistiocytosis

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 CD8T 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 CD8T cells to be redundant in this model, and therefore focused on CD4helper and regulatory T cells. CD4T 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 CD25hyperactivated 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, CD4T cells, in addition to CD8T 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.status: publishe