Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.21.69 (APC)
 16,337 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Latent infection of vascular cells with herpes-viruses may play a pathogenic role in the development of human atherosclerosis. In a previous study, we found that cultured human umbilical vein endothelial cells (HUVECs) infected with herpes simplex virus 1 (HSV-1) became procoagulant, exemplified both by their enhanced assembly of the prothrombinase complex and by their inability to reduce adhesion of platelets. We now report two further procoagulant consequences of endothelial HSV infection: loss of surface thrombomodulin (TM) activity and induction of synthesis of tissue factor. Within 4 hr of infection of HUVECs, TM activity measured by thrombin-dependent protein C activation declined 21 +/- 3% (P less than 0.05) and by 18 hr, 48 +/- 5% (P less than 0.001). Similar significant TM decrements accompanied infection of bovine aortic endothelial cells. Identical TM loss was induced with HSV-2 infection but not with adenovirus infection. Decreased surface expression of TM antigen (measured by the specific binding of a polyclonal antibody to bovine TM) closely paralleled the loss of TM activity. As examined by Northern blotting, these losses apparently reflected rapid onset (within 4 hr of HSV infection) loss of mRNA for TM. In contrast, HSV infection induced a viral-dose-dependent increase in synthesis of tissue factor protein, adding to the procoagulant state. The results indicate that loss of endothelial protein-synthetic capacity is not a universal effect of HSV infection. We suggest that the procoagulant state induced by reduction in TM activity and amplified tissue factor activity accompanying HSV infection of endothelium could contribute to deposition of thrombi on atherosclerotic plaques and to the "coagulant-necrosis" state that characterizes HSV-infected mucocutaneous lesions.
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PMID:Infection of vascular endothelial cells with herpes simplex virus enhances tissue factor activity and reduces thrombomodulin expression. 216 19

Atherosclerotic lesions have been reported to contain herpes simplex virus (HSV) genomic material. This and other evidence suggests that latent viral infection may be an atherogenic trigger. Moreover, active HSV lesions manifest histologically marked fibrin deposition in microvessels. Our laboratory tested in vitro whether HSV infection would cause human umbilical vein endothelial cells to become procoagulant and attract inflammatory cells. Early infection of human endothelial cells with HSV-1 alters the surface conformation as detected by merocyanine 540 staining. The efficiency of prothrombinase complex assembly increases, resulting in a two- to threefold accelerated rate of thrombin generation on the cell surface of virally infected endothelium. HSV infection of endothelium results in a marked increase in thrombin-induced platelet adhesion with a concomitant decrease in prostacyclin secretion in response to thrombin. Viral infection enhances coagulation by decreasing endothelial thrombomodulin expression and subsequent activation of protein C. Viral infection also induces tissue factor in human endothelial cells within 4 hours of infection. Not only does the endothelial monolayer become procoagulant when infected with HSV, it also becomes a more adherent surface for granulocytes. Resting and stimulated granulocyte adherence is enhanced twofold on virally infected endothelium. Enhanced adhesion is accompanied by excessive granulocyte-mediated lysis of 51Cr-labeled HSV-infected endothelium and endothelial cell detachment from its substrate. Exaggerated endothelial detachment correlated with poor binding of infected endothelial cells to substratum matrix proteins. Resuspended virus-infected cells bound significantly less well to tissue culture containers coated with fibronectin, laminin, and type IV collagen. HSV-infected endothelium alters the anticoagulant properties of the endothelium causing it to become procoagulant.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Proinflammatory and procoagulant effects of herpes simplex infection on human endothelium. 219 Jun 48

Lymphotoxin alpha-deficient (LTalpha-/-) mice, which lack lymph nodes and possess a disorganized spleen, develop dysfunctional CD8+ T cells upon HSV infection and readily succumb to herpes encephalitis. Such mice do develop apparently normal peptide-specific CD8+ T cell responses, as measured by MHC class I tetramer staining, but the majority of cells fail to become cytotoxic or express peptide-induced IFN-gamma production. In the present study, we demonstrate that functional defects of CD8+ T cells in LTalpha-/- mice can be largely rectified by the administration of plasmid DNA encoding CCR7 ligands before HSV infection. Treated mutant mice developed increased peptide-specific cytotoxic responses, enhanced numbers of CD8+ T cells capable of producing IFN-gamma, as well as improved resistance to HSV challenge. The corrective effect of chemokine treatment appeared to result from improved dendritic cell-mediated Ag presentation. Thus, a major consequence of the treatment was an increase in splenic dendritic cell number in CCR7 ligand-treated LTalpha-/- mice with such splenocyte populations showing improved APC activity in vitro. Our results document that functional defects of CD8+ T cells can be corrected, and indicate the value of plasmid vector encoding appropriate chemokines to achieve such immunotherapy.
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PMID:Plasmid DNA encoding CCR7 ligands compensate for dysfunctional CD8+ T cell responses by effects on dendritic cells. 1156 71

Professional APC play a central role in generating antiviral CD8(+) CTL immunity. However, the fate of such APC following interaction with these same CTL remains poorly understood. We have shown previously that prolonged Ag presentation persists in the presence of a strong CTL response following HSV infection. In this study, we examined the mechanism of survival of APC in vivo when presenting an immunodominant determinant from HSV. We show that transferred peptide-labeled dendritic cells were eliminated from draining lymph nodes in the presence of HSV-specific CTL. Maturation of dendritic cells with LPS or anti-CD40 before injection protected against CTL lysis in vivo. Furthermore, endogenous APC could be eliminated from draining lymph nodes early after HSV infection by adoptive transfer of HSV-specific CTL, yet the cotransfer of significant virus-specific CD4(+) T cell help promoted prolonged Ag presentation. This suggests that Th cells may assist in prolonging class I-restricted Ag presentation, potentially enhancing CTL recruitment and allowing more efficient T cell priming.
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PMID:CD4+ T cells can protect APC from CTL-mediated elimination. 1675 82

Ag presentation within the regional lymph node is crucial for the initiation of CD8+ T cell responses following viral infection. The magnitude and quality of the CD8+ T cell response are regulated by the interplay between the size of the APC population and duration of Ag presentation. To understand how these parameters are finely regulated during an immune response, we have investigated the dynamics of Ag presentation in influenza A virus and HSV-1 infection. In both infections, APC production was calculated to occur over the first few days of infection, after which there was slow exponential decay over a period of up to 2 wk. This production rate is most likely determined by the Ag availability and recruitment and/or maturation rate of dendritic cells. APC production was found to closely parallel lymph node cell recruitment in both infections. This was greatest in the first 6 h of infection for HSV and over the second and third day for influenza. In HSV infection, the peak production also coincides with peak viral levels. By contrast, in influenza infection, APC production ceased between the third and fourth day despite the presence of high levels of virus until 5 days after infection. These analyses demonstrate that two quite different self-limiting infections generate the APC necessary to drive T cell responses early in infection at different rates. Understanding how such contrasting kinetics of Ag presentation impacts on the growth and size of developing protective T cell populations has important implications for the design of vaccines and immunotherapies.
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PMID:Kinetics of major histocompatibility class I antigen presentation in acute infection. 1912 33