Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0042384 (vasculitis)
 20,525 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Arterial smooth muscle cells (SMC) express major histocompatibility complex (MHC) class II antigens in experimental vasculitis and in the human atherosclerotic plaque. We have therefore studied the regulation of expression of MHC antigens in cultured human arterial SMC, using immunofluorescence, radioimmunoprecipitation and a quantitative cell-surface immunoradiometric assay. SMC expressed class I, but not class II, antigens on their cell surfaces under basal conditions. Treatment of SMC with recombinant or natural interferon-gamma (IFN-gamma) induced expression of class II antigens in the following order of intensity, DR greater than DP greater than DQ. HLA-DR protein in SMC showed the same MW as that synthesized by B-lymphoblastoid cells. Antibodies to IFN-gamma blocked all HLA-DR-inducing activity in mixed leucocyte reaction (MLR) supernatants and PHA-stimulated peripheral blood mononuclear cell (PBMC)-conditioned media, indicating that IFN-gamma is the only lymphokine secreted under these conditions that is capable of de novo induction of HLA-DR expression in SMC. Treatment of SMC with recombinant human tumour necrosis factor-alpha (TNF) or lymphotoxin (LT) did not per se induce class II antigen expression. However, both TNF and LT substantially enhanced IFN-gamma-induced expression of HLA-DQ while decreasing that of HLA-DP. TNF, but not LT, increased HLA-DR expression. Also, in dermal fibroblasts, IFN-gamma-induced HLA-DP expression was significantly inhibited in the presence of TNF. These data demonstrate that TNF and LT differentially modulate IFN-gamma-induced MHC antigen expression in mesenchymal cells. The fact that SMC can express MHC class II antigens suggests that this cell type may serve as an accessory cell in the initiation of the immune response.
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PMID:MHC class II antigen expression in human vascular smooth muscle cells is induced by interferon-gamma and modulated by tumour necrosis factor and lymphotoxin. 210 84

Antibodies that bind to endothelial cells have been identified in patients with diverse forms of vasculitis and thrombosis. Sera from patients with systemic lupus erythematosus contain both complement-fixing antibodies and immune complexes that bind to cultured endothelial cells. Sera from patients with heparin-associated thrombocytopenia and thrombosis contain antibodies that react with heparin bound to the endothelium and cross-react with heparan sulfate synthesized by endothelial cells. Children with Kawasaki syndrome may develop cytolytic IgM antibodies that recognize surface antigens induced on endothelial cells by interferon-gamma, interleukin 1, and tumor necrosis factor. The presence of alloantibodies to tissue-restricted polymorphic antigens expressed by endothelial cells is frequently associated with thrombotic microvascular injury and hyperacute allograft rejection. Binding of antibodies and immune complexes to endothelial cells in vitro initiates platelet adherence, production of tissue factor, and secretion of plasminogen activator inhibitor. Antibody-mediated endothelial cell injury may play a role in other vascular disorders of unknown cause.
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PMID:Disorders associated with antibodies to endothelial cells. 266 9

Blocking the CD28-B7 T cell costimulatory pathway with the fusion protein CTLA4Ig inhibits alloimmune responses in vitro and in vivo and induces tolerance to cardiac allografts in mice and rats, but the mechanisms mediating the tolerant state in vivo are unknown. Here, we report the effects and potential mechanisms of CTLA4Ig in the rat renal allograft model. LEW rats were nephrectomized and received renal allografts from major histocompatibility complex-incompatible WF rats. While all untreated and control immunoglobulin (Ig)-treated animals acutely rejected their allografts and died, 86% of rats that received a single injection of CTLA4Ig on day 2 after transplantation had prolonged survival (> 60-100 days) with preserved renal function. By contrast, only 29% of animals that received CTLA4Ig on the day of engraftment had prolonged survival. Long-term survivors (> 100 days) exhibited donor-specific tolerance, accepting donor-matched WF but acutely rejecting third-party BN cardiac allografts. Immunohistological analysis of grafts sampled at 1 week after transplantation showed that both control and CTLA4Ig-treated animals had mononuclear cell infiltrates, with a higher percentage of CD4+ cells in the CTLA4Ig-treated group. However, while this was associated with vasculitis and tubulitis in control grafts, there was no evidence of tissue injury in CTLA4Ig-treated animals. The immune response leading to graft rejection in control animals was characterized by expression of the T helper (Th) type 1 cytokines interleukin (IL)-2 and interferon-gamma. In contrast, the persistent CD4+ infiltrate without graft rejection in CTLA4Ig-treated animals was associated with increased staining for the Th2-related cytokines IL-4 and IL-10. Furthermore, grafts from CTLA4Ig-treated animals had marked upregulation of intragraft staining for IgG1, but not IgG2a or IgG2b. Administration of rIL-2 to CTLA4Ig-treated animals restored allograft rejection in 50% of animals tested. These results confirm that blockade of the CD28-B7 pathway after alloantigenic challenge induces donor-specific acceptance of vascularized organ allografts, and indicates in this model that CTLA4Ig inhibits Th1 but spares Th2 cytokines in vivo.
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PMID:CD28-B7 blockade after alloantigenic challenge in vivo inhibits Th1 cytokines but spares Th2. 753 98

The deposition of circulating immune reactants in blood vessels, an important event in the pathogenesis of certain types of vasculitis, requires an increase in permeability in the endothelial monolayer. An in vitro model to examine the integrity of endothelial cell monolayers and their response to inflammatory mediators has been developed. Human umbilical vein endothelial cells were grown to confluence on an FITC-labelled matrix and monolayer integrity was assessed by the exclusion of a 125I-anti-FITC antibody. Alteration in endothelial monolayer permeability was associated with an increase in uptake of 125I-anti-FITC antibody, expressed as a percentage of the maximal uptake of antibody on to FITC-matrix from which endothelial cells had been stripped. We determined the effects on endothelial monolayer permeability of acute agonists (thrombin and histamine), cytokines (tumour necrosis factor-alpha (TNF-alpha), interferon-gamma (IFN-gamma), IL-1 and IL-4) and combinations of acute agonists and cytokines. Addition of thrombin in concentrations ranging from 0.5 to 15 U/ml led to an increased uptake of 125I-anti-FITC antibody from 2% to 15% relative to unstimulated endothelium. For other agonists and cytokines the increases in permeability were: (i) histamine (50-400 pmol/ml) increased uptake 5-22%; (ii) TNF (12.5-100 ng/ml) increased uptake 2-12%; (iii) IFN-gamma (125-250 U/ml) increased uptake 1.5-3%. IL-1 beta (50-100 U/ml) and IL-4 (50-100 U/ml) had no effect. Synergistic interactions on endothelial monolayer permeability were seen with the following combinations: (i) IL-4 (100 U/ml) and TNF (12.5 ng/ml) uptake 11%; (ii) IL-4 (100 U/ml) and IFN-gamma (125 U/ml) uptake 6.5%; (iii) TNF (12.5 ng/ml) and IFN-gamma (125 ng/ml) uptake 7%; (iv) thrombin (0.5 U/ml) and histamine (50 pmol/ml) uptake 13.5%; and (v) TNF (12.5 ng/ml) and thrombin (0.5 U/ml) uptake 8.5%. These observations suggest that interactions between cytokines and acute inflammatory mediators such as thrombin and histamine may be important in determining whether immune complexes are deposited in vessel walls. This model system may now be useful for the further investigation in vitro of the mechanisms involved in the pathogenesis of immune complex-mediated vascular damage.
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PMID:Combinations of low concentrations of cytokines and acute agonists synergize in increasing the permeability of endothelial monolayers. 842 96

Human T-cell lymphotropic virus type I (HTLV-I) is known to cause adult T-cell leukemia/T-cell lymphoma and tropical spastic paraparesis/HTLV-I-associated myelopathy. Recent seroepidemiologic, clinical, and virologic studies indicate that the virus is also related to a certain type of uveitis, which has been classified as uveitis without defined etiologies or idiopathic uveitis. According to the seroepidemiologic survey, the seroprevalence of HTLV-I in patients with idiopathic uveitis was significantly higher than that of two control groups, that is, patients with uveitis with defined etiologies and patients with nonuveitic ocular diseases. Clinically, the uveitis seen in HTLV-I carriers is characterized by moderate to severe cellular infiltration in the eye and by moderate retinal vasculitis, and the intraocular inflammation responds well to corticosteroid therapy. Interestingly, 25% of female patients with the disease had a previous history of Graves disease with hyperthyroidisms. The following virologic, molecular biologic findings suggest that cytokines produced by HTLV-I-infected T cells in the eye play the central role in the pathogenic mechanisms of the uveitis: (a) the virus load in the peripheral blood monocytes analyzed by the quantitative polymerase chain reaction methods was significantly greater in patients with the uveitis than in asymptomatic carriers, (b) the proviral DNA of HTLV-I and the gene expression of the virus at the mRNA level was detected in the infiltrating cells from the eyes of the patients, (c) the virus particles were detected by electron-microscopic examination in the T-cell clones established from the intraocular fluid of the patients, and (d) the HTLV-I-infected T cells produced a variety of cytokines without any stimuli, such as interleukin (IL)-1 alpha, IL-2, IL-3, IL-6, IL-8, IL-10, tumor necrosis factor alpha, interferon-gamma, and granulocyte-macrophage colony-stimulating factor. Based on the seroepidemiologic, clinical, and virologic data, the uveitis seen in HTLV-I carriers is considered to be a distinct clinical entity related to HTLV-I infection, and the disease is designated as HTLV-I uveitis.
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PMID:HTLV-I uveitis. 879 4

Mercuric chloride (HgCl2) induces a T cell-dependent autoimmune syndrome in Brown-Norway (BN) rats characterized by a humoral response, tissue injury with an accumulation of CD8+ and CD4+ T cells, and an increase in tissue IL-4 mRNA and serum IgE suggesting Th2 cell activation. In other models of autoimmune disease, CD8+ cells act in both anti- and pro-inflammatory capacities, suggesting that functionally distinct CD8+ populations exist in vivo. The effect of treatment with OX8, a depleting anti-CD8 MoAb, on the initiation of HgCl2-induced autoimmunity was assessed in two experiments in a total of 20 BN rats, and compared with 20 animals treated with a control MoAb or PBS. OX8 significantly depleted peripheral blood CD8+ lymphocytes, had no effect on HgCl2-induced anti-collagen or myeloperoxidase antibodies, nor on the incidence or severity of caecal vasculitis. The severity of HgCl2-induced arthritis was significantly reduced in OX8-treated animals; median peak score reduced from 7.5 to 3.0 (experiment 1) and from 7.0 to 4 (experiment 2) (P = 0.009, Mann-Whitney U-test). OX8 treatment also exacerbated the early rise in HgCl2-induced IgE and induced a significant rise in plasma interferon-gamma (IFN-gamma), suggesting that CD8+ cells may have a regulatory influence on Th cell populations. These data provide direct evidence that CD8+ cells may act in a proinflammatory capacity in both this model of autoimmunity and the pathogenesis of inflammatory arthritis.
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PMID:Anti-CD8 treatment reduces the severity of inflammatory arthritis, but not vasculitis, in mercuric chloride-induced autoimmunity. 891 74

Production of the third and fourth components of complement (C3, C4) by smooth muscle cells was investigated by using normal human aortic smooth muscle cells (AoSMC), human smooth muscle cell line (G402) and vascular smooth muscle cells obtained from human umbilical cord vein (UVSMC). AoSMC spontaneously produced both C3 and C4 at 15 ng/10(6) cells/72 hr and 22 ng/10(6) cells/72 hr, respectively, and both were enhanced by interferon-gamma (IFN-gamma). Although phorbol 12-myristate 13-acetate (PMA) and tumour necrosis factor-alpha (TNF-alpha) enhanced C3 production, C4 production was reduced by these agents. On the other hand, G402 produced C4 but not C3 in a dose-dependent manner when cultured with IFN-gamma. UVSMC produced only a small amount of C3 and C4 compared with AoSMC or G402. C3 and C4 produced by AoSMC were confirmed to be identical with their human serum counterparts as determined by sodium dodecyl sulphate-polyacrylamide gel electrophoresis and measurement of haemolytic activity. Northern blotting analysis showed that the expression of mRNA of C3 and C4 was enhanced by TNF-alpha and IFN-gamma, respectively, in AoSMC. Our findings suggest the importance of smooth muscle cells as a source of components of complement in vascular diseases including vasculitis.
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PMID:Production of the third and fourth component of complement (C3, C4) by smooth muscle cells. 894 12

The level of interferon-gamma (IFN-gamma) in pleural fluid has been reported to be increased in pleural tuberculosis. Nevertheless, its diagnostic value has not yet been well-established, and immunocompromised patients have not previously been evaluated. The aim of this study was to determine the value of the IFN-gamma level in pleural fluid for diagnosing tuberculous pleurisy in immunocompetent and immunocompromised patients. Three hundred and eighty eight consecutive patients were studied prospectively (73 with tuberculous pleural effusions, including nine with concurrent human immunodeficiency virus (HIV) infection and one after liver transplantation, and 315 with nontuberculous effusions). IFN-gamma was measured by radioimmunoassay. The sensitivity of the test, using a 3.7 U.mL-1 cut-off point, was 0.99 (95% confidence interval (95% CI) 0.93-1.00) and the specificity was 0.98 (95% CI 0.96-1.00). The sensitivity of the test did not differ in HIV-positive and HIV-negative patients. Patients with lymphoma, vasculitis or vascular connective tissue disease did not have abnormal IFN-gamma values. In conclusion, the level of interferon-gamma in pleural fluid is a very good diagnostic marker of tuberculous pleural effusion, even in immunocompromised patients.
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PMID:Interferon-gamma in 388 immunocompromised and immunocompetent patients for diagnosing pleural tuberculosis. 898 Sep 81

Granulomatous inflammatory lesions are a major histopathological feature of a wide spectrum of human infectious and autoimmune diseases. Experimental autoimmune thyroiditis (EAT) with granulomatous histopathological features can be induced by mouse thyroglobulin (MTg)-sensitized spleen cells activated in vitro with MTg and anti-interleukin-2 receptor (anti-IL-2R), anti-IL-2, or anti-interferon-gamma (anti-IFN-gamma) monoclonal antibody (MAb). These studies suggested that IFN-gamma-producing T cells requiring IL-2 for growth may negatively regulate activation of granulomatous EAT effector cells. As IL-12 promotes activation of IFN-gamma-producing Th1 cells, the present study was undertaken to determine the role of IL-12 in activation of effector cells for granulomatous EAT. MTg-sensitized cells activated in vitro with MTg, anti-IL2R MAb, and IL-12 induced severe, destructive granulomatous thyroiditis with neutrophil inflammation, fibrin deposition, and necrosis. Many glands ultimately underwent atrophy and became fibrotic; some also showed fibrinoid necrosis and a mixed inflammatory cell infiltration of blood vessel walls indicative of a necrotizing vasculitis. Induction of severe granulomatous EAT by IL-12 required MTg in vitro and was unrelated to the IL-12-induced increase in IFN-gamma production. IL-12 markedly increased IFN-gamma production but did not induce a shift to a Th1-dominant phenotype, as other Th1 and Th2 cytokines were generally unaffected and both Th1 and Th2 cytokines were expressed in recipient thyroids. Addition of IL-12 or neutralization by anti-IL-12 at various times indicated that IL-12 exerted its primary effects in the final 24 hours of the 72-hour culture and was not required in recipient mice. Cells cultured with anti-IL-12, MTg, and anti-IL2R MAb transferred mild lymphocytic EAT but little or no granulomatous EAT. Thus, IL-12 profoundly regulates the in vitro activation of effector cells that induce histologically distinct autoimmune inflammatory lesions in the thyroid.
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PMID:Interleukin-12 promotes activation of effector cells that induce a severe destructive granulomatous form of murine experimental autoimmune thyroiditis. 958 3

Inflammation of the arterial wall in giant cell arteritis induces a series of structural changes, including the formation of new vasa vasorum. To study the regulation of neoangiogenesis in giant cell arteritis, temporal arteries were examined for the extent and localization of microvessel generation and for the production of angiogenic factors. In normal arteries, vasa vasorum were restricted to the adventitia, but in inflamed arteries, capillaries emerged in the media and the intima. These capillaries displayed a distinct topography with a circumferential arrangement in the external one-third of the intima. Neovascularization was closely correlated with the formation of lumen-obstructing intima, the fragmentation of the internal elastic lamina, and the presence of multinucleated giant cells. Comparison of tissue cytokine transcription in temporal arteries of giant cell arteritis patients with and without up-regulated neoangiogenesis identified interferon-gamma and vascular endothelial growth factor but not fibroblast growth factor-2 as mediators associated with vasa vasorum proliferation. Giant cells and CD68-positive macrophages at the media-intima junction were found to be the major cellular sources of vascular endothelial growth factor. These data demonstrate that formation of new vasa vasorum in vasculitis is regulated by inflammatory cells and not by arterial wall cells, raising the possibility that it represents a primary disease mechanism and not a secondary hypoxia-induced event. Increased neovascularization in interferon-gamma-rich arteries suggests that the formation of new vasa vasorum is determined by the nature of the immune response in the arterial wall, possibly resulting from the generation and functional activity of multinucleated giant cells.
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PMID:Formation of new vasa vasorum in vasculitis. Production of angiogenic cytokines by multinucleated giant cells. 1048 34


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