Mice with targeted deletion of fibrinogen‐like protein 2 (fgl2) spontaneously developed autoimmune glomerulonephritis with increasing age, as did wild‐type recipients reconstituted with fgl2−/− bone marrow. These data implicate FGL2 as an important immunoregulatory molecule and led us to identify the underlying mechanisms. Deficiency of FGL2, produced by CD4+CD25+ regulatory T cells (Treg), resulted in increased T cell proliferation to lectins and alloantigens, T helper 1 (Th1) polarization, and increased numbers of antibody‐producing B cells following immunization with T‐independent antigens. Dendritic cells (DC) were more abundant in fgl2−/− mice and had increased expression of CD80 and MHCII following LPS stimulation. Treg cells were also more abundant in fgl2−/− mice, but their suppressive activity was significantly impaired. Antibody to FGL2 completely inhibited Treg cell activity in vitro. FGL2 inhibited DC maturation and induced apoptosis of B cells through binding to the low affinity FcγRIIB receptor. Collectively, these data suggest that FGL2 contributes to Treg cell activity and inhibits the development of autoimmune disease. This work was supported in part by grants from the Heart and Stroke Foundation of Canada and the Canadian Institutes for Health Research.
contributed equally to this work. Conflict of interest:The authors have declared that no conflict of interest exists. Nonstandard abbreviations used: tissue factor (TF); murine hepatitis virus type 3 (MHV-3); postcoitus (pc); alanine aminotransferase (ALT); hepatitis B surface antigen (HBsAg); hepatitis B e-antigen (HBeAg); hepatitis B viral capsid (HBcAg); severe acute respiratory syndrome (SARS).
contributed equally to this work. Conflict of interest:The authors have declared that no conflict of interest exists. Nonstandard abbreviations used: tissue factor (TF); murine hepatitis virus type 3 (MHV-3); postcoitus (pc); alanine aminotransferase (ALT); hepatitis B surface antigen (HBsAg); hepatitis B e-antigen (HBeAg); hepatitis B viral capsid (HBcAg); severe acute respiratory syndrome (SARS).
A new SARS animal model was established by inoculating SARS coronavirus (SARS-CoV) into rhesus macaques (Macaca mulatta) through the nasal cavity. Pathological pulmonary changes were successively detected on days 5-60 after virus inoculation. All eight animals showed a transient fever 2-3 days after inoculation. Immunological, molecular biological, and pathological studies support the establishment of this SARS animal model. Firstly, SARS-CoV-specific IgGs were detected in the sera of macaques from 11 to 60 days after inoculation. Secondly, SARS-CoV RNA could be detected in pharyngeal swab samples using nested RT-PCR in all infected animals from 5 days after virus inoculation. Finally, histopathological changes of interstitial pneumonia were found in the lungs during the 60 days after viral inoculation: these changes were less marked at later time points, indicating that an active healing process together with resolution of an acute inflammatory response was taking place in these animals. This animal model should provide insight into the mechanisms of SARS-CoV-related pulmonary disease and greatly facilitate the development of vaccines and therapeutics against SARS.
Fibrinogen-like protein 2 (FGL2) is a multifunctional protein, which has been implicated in the pathogenesis of allograft and xenograft rejection. Previously, FGL2 was shown to inhibit maturation of BM-derived DC and T-cell proliferation. The mechanism of the immunosuppressive activity of FGL2 remains poorly elucidated. Here, we focus on identification of FGL2-specific receptor(s) and their ability to modulate APC activity and allograft survival. Using flow cytometry and surface plasmon resonance analysis, we show that FGL2 binds specifically to Fc gamma receptor (FccR)IIB and FccRIII receptors, which are expressed on the surface of APC, including B lymphocytes, macrophages and DC. Antibody to FccRIIB and FccRIII, or deficiency of these receptors, abrogated FGL2 binding. IntroductionFibrinogen-like protein 2 (FGL2), also known as fibroleukin, was first cloned from cytotoxic T lymphocytes and was classified as a member of the fibrinogen superfamily due to its homology (36%) with fibrinogen b and g chains [1]. Predicted as a type II transmembrane glycoprotein [2], cell membraneassociated FGL2 was shown to exhibit novel prothrombinase activity when associated with cell membranes/phospholipid vesicles [3,4], which has been implicated in the pathogenesis of à These authors contributed equally to this study.Correspondence: Dr. Gary Levy e-mail: glfgl2@attglobal.net DOI 10.1002/eji.200838338 Eur. J. Immunol. 2008. 38: 3114- [7]. The procoagulant activity was shown to depend on the serine 89 at the linear N terminal domain of FGL2 [4].The C terminal globular portion of FGL2 lacks the prothrombinase activity and contains a classical fibrinogen-related domain (FRED), which has been suggested to possess immunomodulatory activity based on several lines of evidence. First, other fibrinogen superfamily members including fibrinogen [8] Results Recombinant FcFGL2 protein binds to APCRecombinant FcFGL2 was generated and purified as described in the Materials and methods. The molecular size of the recombinant proteins was examined by SDS-PAGE, silver staining and Western blotting. FcFGL2 had a molecular weight of approximately 440 kDa under non-reducing conditions, which was confirmed by gel filtration (data not shown), and 110 kDa under reducing conditions (Fig. 1A). These data suggested that FcFGL2 exists as a tetramer, consistent with previous reports [13,21]. The Fc tag had a molecular size of 64 kDa under non-reducing conditions and 33 kDa under reducing conditions, suggesting that Fc is dimeric. Biotinylated FcFGL2 bound to the RAW264.7 cells (mouse macrophage cell lines), BMDC, the B-cell line A20 (which expresses only one Fcg receptor, FcgRIIB), thioglycolate-elicited peritoneal exudates cells (495% macrophages) from C57BL/6J mice, but FcFGL2 did not bind to the B-cell line A20IIA1.6, which does not express FcgRIIB (Fig. 1B) [22]. EL4 cells (a mouse T-cell line) did not bind FcFGL2 (data not shown). As expected, the Fc tag protein alone failed to bind to any of these cells and thus, Fc provided an appropriate negativ...
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