Induction of monocyte procoagulant activity by murine hepatitis virus type 3 parallels disease susceptibility in mice.

Abstract

The in vitro induction of procoagulant activity (PCA) in murine peripheral blood mononuclear cells (PBM) by murine hepatitis virus type 3 (MHV-3) correlates with the disease susceptibility in three strains of mice. PBM from BALB/c mice, a strain in which MHV-3 infection results in fatal acute fulminant hepatitis, responds to the virus with a robust PCA response, whereas PBM from C3H/St mice, a strain which develops mild acute hepatitis followed by chronic hepatitis, only exhibit a modest PCA response. In contrast, PBM from A/J mice, a strain fully resistant to MHV-3, generate no increase in PCA above control levels. The induction phase of MHV-3 PCA is rapid, with an increase within 1-1.5 h, with maximum activity at 18h, and it precedes MHV-3 replication in either 17 CL1 cells, a fully permissive cell line, or in monocytes from these strains of mice. The PCA response of BALB/c PBM exceeds the response to any other known stimulus. No induction occurs upon direct stimulation of monocytes by MHV-3, but in the presence of lymphocyte collaboration, the PCA response is observed first at a lymphocyte:monocyte ratio of 2:1 and reaches a maximum as the lymphocyte:monocyte ratio approaches 4:1. This response appears to provide a functional marker for susceptibility to MHV-3 infection in inbred strains of mice and could be important in the pathogenesis of MHV-3-induced disease.

The novel CD4+CD25+ regulatory T cell effector molecule fibrinogen-like protein 2 contributes to the outcome of murine fulminant viral hepatitis #

“…It should be noted that macrophages from A/J mice can produce FGL2 to interferon gamma in vitro, yet do not generate FGL2 to MHV-3 in vivo. [31][32][33] Taken together, the data demonstrate that production of FGL2 is tightly regulated and supports the important role of Treg-expressed FGL2 in the pathogenesis of MHV-3-induced FH. The mechanism by which FGL2 mediates its immunosuppressive activity is currently under intensive investigation.…”

Targeted Deletion of fgl2 Leads to Impaired Regulatory T Cell Activity and Development of Autoimmune Glomerulonephritis

“…These proteins have been shown to exhibit coagulant and angiogenic activity, as well as immunoregulatory activity (1,2,30). Similar to other members of the fibrinogen superfamily, our laboratory has recently discovered (19) that FGL2 inhibits murine DC maturation and adaptive T cell immune responses, in addition to its role in innate immunity through its ability to activate the coagulation system (7)(8)(9)(10)(11)(12)(13)(14)(15).…”

“…FGL2 was first cloned from human CTLs, and its protein structure deduced from the nucleotide sequence showed a high degree of homology to fibrinogen ␤ and ␥ subunits (3). FGL2 has been shown to play an important role in innate immunity as an immune coagulant expressed by activated reticuloendothelial cells (macrophages and endothelial cells) (4 -6) and has been implicated in the pathogenesis of several inflammatory disorders, including viral hepatitis (7)(8)(9)(10), allo-and xenograft rejection (11)(12)(13), and cytokine induced fetal loss (14,15). In a previous report (13), we showed that Ab to FGL2 ameliorated allograft rejection.…”

Fibrinogen Stimulates Macrophage Chemokine Secretion Through Toll-Like Receptor 4

“…Accordingly, injury, infection, and (auto)immunity are associated with extravascular fibrin(ogen) (3)(4)(5)(6).…”