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

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

Eleven of 204 children with nephrotic syndrome had thrombotic complications: arterial thrombosis in five, venous thrombosis in four, and pulmonary embolism in two. Fifty-one episodes of thromboembolism were recognized in 116 adult patients with nephrotic syndrome. Despite the lower incidence, thromboembolic complications tended to be more severe in children. In vitro indices of hemostasis and clinical evidence of thromboembolic complications were compared in children and adults. Antithrombin III concentrations and activities were abnormal in seven of 10 children, but in only two of 32 adults. In both groups, alpha 2-macroglobulin was elevated, but more markedly so in children. No evidence for circulating granulocyte-derived proteases (elastase/antielastase complexes) was noted in either group. Protein C was significantly elevated in children with nephrotic syndrome, but was normal in adults. Children also differed from adults with nephrotic syndrome in laboratory evidence of subthreshold disseminated intravascular coagulation (i.e., elevated soluble fibrinogen monomeric complexes and fibrin degradation products) and indicators of in vivo platelet activation (elevated beta-thromboglobulin). The more severe coagulation abnormalities in children may be linked to the more pronounced hypoalbuminemia.
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PMID:Hemostasis and thromboembolism in children with nephrotic syndrome: differences from adults. 358 1

Thirty eight patients with Crohn's disease and 30 patients with ulcerative colitis have been assessed using the technique of faecal excretion of 111Indium granulocytes to quantify precisely acute inflammatory activity. At the time of each faecal granulocyte measurement the serum concentration of the acute phase protein C-reactive protein and the erythrocyte sedimentation rate were estimated. C-reactive protein concentration was significantly higher in Crohn's disease than ulcerative colitis both overall and particularly in relation to given levels of granulocyte excretion. No such distinction was observed between the erythrocyte sedimentation rates in the two diseases. The present findings show that the acute phase response differs significantly between Crohn's disease and ulcerative colitis. Patients with ulcerative colitis may be constitutionally different from those with Crohn's disease and unable to mount a major acute phase response to their own disease.
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PMID:Differing acute phase responses in Crohn's disease and ulcerative colitis. 373 90

The direct effects of IL-10 on the proliferation and lymphokine production of human peripheral blood T cells and CD4+ T cell clones representing the Th0, Th1-like, and Th2-like Th cell subsets were investigated in the absence of professional APC. IL-10 partially inhibited the proliferative responses of CD4+ human T cell clones induced by anti-CD2 or anti-CD3 mAb cross-linked on CD32 (Fc gamma RII)-transfected mouse L cells. Transfection of ICAM-1 or LFA-3 in CD32+ L cells resulted in enhanced proliferative responses of CD4+ T cell clones after activation by anti-CD3 mAb, whereas transfection of B7 in CD32+ L cells enhanced proliferative responses of CD4+ T cell clones after activation by anti-CD2 mAb. In addition, B7 expression on CD32+ L cells was required for activation of small resting T cells by anti-CD3 or anti-CD2 mAb. IL-10 inhibited the proliferation of T cell clones induced by anti-CD2 or anti-CD3 mAb on CD32+ L cells expressing these accessory molecules, indicating that interactions of LFA-3, ICAM-1, and B7 with their ligands on T cells did not overcome the inhibitory effects of IL-10. Inhibition of proliferation of T cell clones by IL-10 was in all instances completely neutralized by relatively low concentrations of IL-2, whereas IL-4 was ineffective. IL-10 did not affect the expression of the TCR/CD3 complex, CD2, LFA-1, CD28, or IL-2R alpha- or beta-chains, nor did it inhibit the induction of the latter two molecules on T cells after activation. Inhibition of proliferation was found to be the result of specific inhibition of IL-2 production by the responding T cell subsets, which occurred at the mRNA level. The production and mRNA levels of IL-4, IL-5, IFN-gamma, and granulocyte/macrophage-CSF were not affected by IL-10. Taken together, these results indicate that IL-10/IL-10R interaction on CD4+ T cell clones and peripheral blood T cells results in signaling pathways that specifically interfere with activation processes leading to IL-2 production. These direct inhibitory effects on IL-2 production by activated T cells may contribute to the general immunosuppressive activities of IL-10.
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PMID:Direct effects of IL-10 on subsets of human CD4+ T cell clones and resting T cells. Specific inhibition of IL-2 production and proliferation. 768 12

Leukocytes release lysosomal proteases and reactive oxygen species in response to various stimuli that damage the adjacent endothelial cells. We investigated the effects of granulocyte lysosomal proteases (granulocyte elastase [GE] and cathepsin G [CG] and/or hydrogen peroxide (H2O2) on thrombomodulin (TM) activity of endothelial cells. We wished to determine whether the activated leukocytes damage the nonthrombogenic systems of endothelial cells. When cultured human umbilical vein endothelial cells (HUVECs) were incubated with GE, TM activity of the cells (as judged by the protein C activation capacity) decreased to about 10% of control with the concomitant increase of immunoreactive TM concentration in the conditioned media. CG also decreased TM activity to about 20% of control with the concomitant increase in immunoreactive TM concentration in the conditioned media. The GE- or CG-induced inactivation of TM was not observed in the presence of alpha 1-proteinase inhibitor. Immunoblot analysis showed that CG cleaved purified TM to yield one major fragment with an M(r) of 43,000; TM activity of this fragment was about 10% of the control activity. When purified TM was incubated with GE, TM activity decreased to 10% of control, and no detectable band was found on immunoblotting, suggesting that CG and GE cleave TM into inactive fragments and that GE degrades the epitope structure of TM. Although H2O2 (1.0 mmol/L) enhanced chromium 51 release from prelabeled HUVECs after 30 minutes of incubation, it decreased TM activity only slightly.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Granulocyte proteases and hydrogen peroxide synergistically inactivate thrombomodulin of endothelial cells in vitro. 820 Dec 66

Polymorphonuclear neutrophils (PMN) have long been thought to be short-lived, terminally differentiated cells incapable of synthesizing significant levels of protein, with their primary function being phagocytosis and the release of cytotoxic compounds. More recently, it has been demonstrated that PMN can produce a number of functionally diverse substances, including IL-1, IL-6, and IL-8. Although PMN express class I MHC Ag, it has not been definitely demonstrated that they can synthesize and express class II Ag. This would suggest that, although PMN can indirectly assist in the induction of an immune response through production of cytokines, they are incapable of acting as APC for CD4+ Th cells. We show that, in the presence of a defined medium (AIM V), human serum, and granulocyte-CSF, nearly 100% of isolated PMN can survive for up to 2 days in vitro. We also show that PMN express MHC class II when present as bystander cells in a monocyte/T cell Ag presentation assay for 44 h. In addition, granulocyte/macrophage CSF (GM-CSF), IFN-gamma, and IL-3 can induce class II on pure cultures of PMN, with GM-CSF appearing to be the most potent of the three cytokines. Furthermore, induction of class II on PMN is distinctly donor dependent, with PMN from some donors repeatedly showing very high, and others very low, induction of class II when treated with GM-CSF. Their potential to express class II suggests that PMN could play a significant role in immunoregulation and disease pathogenesis. The variation in class II induction on PMN from individual donors might explain previous failures to detect class II induction on PMN and could be a factor in the varied susceptibility of different individuals to autoimmune and inflammatory disorders such as the production of antibodies to PMN cytoplasmic components.
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PMID:Induction of MHC class II on human polymorphonuclear neutrophils by granulocyte/macrophage colony-stimulating factor, IFN-gamma, and IL-3. 833 42

Erythropoietin (EPO) therapy in hemodialysis patients may be associated with an enhanced risk of vascular access and extracorporeal thrombosis. Assessment of blood coagulation and fibrinolysis was performed monthly on a group of 21 hemodialysis patients treated with EPO, and on four iron-deficient hemodialysis patients treated with iron dextran infusions alone. Seventeen of the EPO treated patients were also monitored after withdrawal of EPO to allow hemoglobin to fall to pre-EPO levels, and 16 of these patients during a second subsequent phase of EPO therapy with EPO administered using the alternative route (subcutaneous/intravenous) from the first phase of treatment. Ten untreated hemodialysis patients with intrinsically high hemoglobins were studied as controls. EPO was associated with significant increases in the endothelial product Factor VIII von Willebrand factor antigen (FVIIIvWFAg), and plasma fibrinogen, to levels comparable to those observed in the untreated control patients. Both FVIIIvWFAg and fibrinogen remained significantly elevated when EPO was withdrawn. Whole blood platelet aggregation (spontaneous, collagen, and ADP-induced) also increased following EPO, collagen and ADP-induced aggregation, increasing further when EPO was withdrawn. Transient but significant changes occurred in plasma measures of thrombin-antithrombin III complex, prostacyclin stimulating factor, and protein C during the first EPO treatment phase, and also thrombin-antithrombin III complex during the second treatment phase, all favoring a tendency to thrombosis. D-dimer increased significantly following EPO withdrawal. Erythrocyte deformability, and granulocyte aggregation did not change. There was no effect of route of EPO administration (subcutaneous or intravenous) or EPO dose on any of these parameters.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Effect of erythropoietin therapy and withdrawal on blood coagulation and fibrinolysis in hemodialysis patients. 835 60

Murine epidermis contains two leukocyte populations: Langerhans cells (LC), which are APC of dendritic cell (DC) lineage, and dendritic epidermal T cells (DETC), which are members of the tissue-type gamma delta T cell family. Despite close physical approximation in vivo, the extent to which LC and DETC affect each other's function has remained unknown. We addressed this question using the long term DC line XS52 and the gamma delta T cell line 7-17, both of which were established from mouse epidermis, and both of which retain important features of the resident populations from which they were derived. XS52 DC proliferated maximally when cocultured with gamma-irradiated 7-17 DETC. They also proliferated in response to culture supernatants collected from anti-CD3- or Con A-activated 7-17 DETC, but not from nonstimulated DETC. In both systems, DETC-induced XS52 DC growth was inhibited partially (up to 70%) by Abs against granulocyte/macrophage CSF (GM-CSF) or CD115 (CSF-1 receptor) and nearly completely (up to 90%) by both together. Among 28 tested cytokines, only GM-CSF, CSF-1, IL-4, and IL-13 promoted XS52 DC growth significantly. Anti-IL-4 failed to inhibit DETC-induced XS52 cell growth, and IL-4 was not detectable in DETC supernatants. Thus, we conclude that GM-CSF and CSF-1 (and perhaps IL-13) account for the DC growth-promoting activity secreted by DETC. These results suggest that during coculture, XS52 DC activate 7-17 DETC to secrete both GM-CSF and CSF-1. In fact, when cultured with XS52 DC, 7-17 DETC also elevated their expression of the gamma c receptor and acquired proliferative responsiveness to their own growth factor IL-15. We propose that LC and DETC in situ may interact with each other in a similar manner, thereby regulating their residence and function.
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PMID:Cytokine-mediated communication between dendritic epidermal T cells and Langerhans cells. In vitro studies using cell lines. 875 35

Human peripheral blood contains a small subpopulation of immature dendritic cells (iDC) distinguished from circulating monocytes by their low expression of CD14. We utilized leukapheresis and countercurrent centrifugal elutriation to obtain myeloid origin mononuclear cell (MOMC) fractions of monocytes and iDC for study. These subpopulations were ultrastructurally and immunophenotypically similar before culture. After a 20- to 96-h culture either alone, with recombinant human granulocyte-monocyte CSF, or with endotoxin, greater up-regulation of costimulatory molecule expression was observed among iDC than among monocytes, and only iDC expressed the activation molecule CD83. Treatment with rhIL-4 caused many MOMC to develop morphologic properties of dendritic cells within 96 h, but costimulatory molecule up-regulation and CD14 down-regulation were heterogeneous, and CD83 expression was infrequent. In contrast, calcium ionophore (CI) treatment induced rapid and consistent effects in MOMC from both healthy volunteers and cancer patients, including down-regulated CD14 expression, acquisition of dendritic cell morphologic properties, up-regulated MHC and costimulatory molecule expression, and de novo CD83 expression. Many such effects occurred within 20 h of treatment. CI treatment activated purified CD14+ monocytes and also enhanced the spontaneous activation of purified CD14-/dim iDC in culture. Unfractionated MOMC, purified monocytes, and purified iDC displayed equivalently enhanced T cell-sensitizing efficiency following CI treatment. CD4+ T cell sensitization to keyhole limpet hemocyanin and CD8+ T cell sensitization to MART-1 melanoma-associated peptide were achieved in a single culture stimulation. Therefore, circulating monocytes and iDC can be induced by CI to manifest properties of activated DC, providing large numbers of efficient, nontransformed autologous APC for T cell sensitization strategies.
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PMID:Calcium ionophore-treated peripheral blood monocytes and dendritic cells rapidly display characteristics of activated dendritic cells. 937 70

There is now compelling evidence that intradermal vaccination with an efficacious adjuvanted antigen triggers a series of coordinated responses characterized initially by the rapid mobilization and recruitment of granulocytes to the lung. Activation of effector cells of the innate immune system is intended to provide surveillance and temporary protective cover at vulnerable mucosal sites while both T and B cell precursors, as well as haematopoietic progenitor cells, are undergoing dramatic reductions in numbers during the first 2-4 days post-vaccination. Some of these events recapitulate those seen after infection with a pathogen. Initial decreases in cell numbers in the thymus and bone marrow (BM) are followed by rapid increases in cellular proliferation in these organs, probably in response to peripheral signals. Vaccine-induced cell death (by apoptosis) in the thymus may provide one of many stimuli needed to up-regulate BM production of progenitor cells, and cells of the B, myeloid and monocytic lineages so that depleted peripheral compartments are replenished. Reconstitution of the latter cell population is critical in ensuring sufficient numbers of APC are generated to deal with extraneous antigen resulting from either vaccination or proliferation of a pathogen. Ultimately, these APC, as effector cells of the innate immune system, must provide pattern recognition of dangerous pathogens and serve to activate appropriate T cell responses. Vaccination not only educates both the innate and adaptive arms of the immune response but also more interestingly, appears to regulate subsequent innate immune responses following exposure to a lethal challenge dose of bacteria. Under these conditions, the rate of loss of BM precursors is greatly attenuated in mice previously vaccinated with adjuvanted antigen compared to unvaccinated controls or mice that had received only antigen. Mice intradermally vaccinated with adjuvanted antigen also displayed increased rates of granulocyte and monocyte recruitment in the lung and spleen. These events occurred very rapidly within 12-36 h of challenge and may be crucial in providing complete protection in vaccinated mice against a challenge dose that was otherwise lethal for unvaccinated controls. Therefore, an important characteristic of an efficacious intradermal vaccine may be the ability to deplete T and B precursors in the thymus and BM lymphoid compartments followed by increased rates of haematopoiesis to re-supply peripheral requirements for granulocytes/monocytes, and T and B cells. Adaptive immunity elicited by intradermal vaccination is, therefore, dependent upon prior activation of the innate immune system.
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PMID:Skin delivery of a hybrid liposome/ISCOM vaccine implicates a role for adjuvants in rapid modulation of inflammatory cells involved in innate immunity before the enhancement of adaptive immune responses. 968 68


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