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

We established a T cell line, MV1, specific for rat vascular smooth muscle antigen from the regional lymph nodes of immunized MRL/Mp-+/+ mice. Adoptive transfer of MV1 T cells induced vasculitis lesions in the lungs of the syngeneic recipient mice pre-treated with cyclophosphamide. Flow cytometric analysis showed that MV1 was a CD4+ T cell line. The T cells proliferated in the presence of the vascular smooth muscle antigen and mitomycin C-treated syngeneic spleen cells. The cross experiments using an ovalbumin-specific T cell line demonstrated that MV1 was specific for vascular smooth muscle antigen. The antigen-specific proliferation of MV1 was CD4-dependent, which was consistent with the flow cytometric analysis. In addition, MV1 T cells, upon activation with anti-CD3 antibody or antigen-specific activation, killed A20.2J mouse B lymphoma cells. MV1 T cells also killed a CD95 (Fas)-transfected T lymphoma line, but not its parental Fas-negative cell line. These findings indicate that MV1 T cells killed target cells via a Fas ligand (FasL)/Fas pathway. The cytotoxicity of MV1 T cells may play an important role in the development of vasculitis in this model. Although the antigenic epitopes of MV1 and the lung specificity of vasculitis remain to be clarified, MV1-induced vasculitis should serve as an experimental model of human pulmonary vasculitis.
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PMID:A vascular smooth muscle-specific CD4+ T cell line that induces pulmonary vasculitis in MRL-+/+ mice. 869 25

A defect in apoptotic signal transmission through CD95 is an essential genetic mechanism for lymphoproliferation and autoimmunities in lpr or gld mice. However, disease manifestations are largely affected by the host genetic background. To identify and map such host genes modifying lpr gene effect, ie, the lpr modifier (Lprm) genes, 82 MRL/lpr x (MRL/lpr x C3H/lpr) F1 mice were subjected to immunopathological and genetical analyses. High-grade vasculitis and glomerulonephritis among backcross mice were observed in separate groups of mice. Microsatellite analysis revealed that there were two host genes affecting the occurrence of vasculitis, Lprm1 (chromosome 4) and Lprm2 (chromosome 3). A recessive MRL allele at Lprm1 enhanced vasculitis to occur in both sexes, whereas that of Lprm2 inhibited its development selectively in females. Genotype combinations of these two genes explained the severity of vasculitis in crosses of MRL/lpr and C3H/lpr mice and also the vasculitis-prone recombinant inbred strain McH5/lpr. A recessive MRL allele at Lprm3 (chromosome 14) suppressed glomerulonephritis. The weight of the spleen was increased by a recessive MRL allele at Lprm4 (chromosome 5) yielding a logarithm of odds score of 2.02 in a quantitative trait locus analysis. In contrast, the weight of axillary lymph nodes was increased by a recessive MRL allele at a locus on chromosome 2, but its presence was not supported by the quantitative trait locus analysis. The titer of anti-dsDNA autoantibody was controlled by the locus Lprm5 on chromosome 16, which had an logarithm of odds score of 3.41. Possible candidate genes for Lprm genes deduced from their map locations are discussed and compared with the autoimmunity genes reported thus far. In conclusion, autoimmune disease manifestations by the lpr mutation are affected by multiple host genes separately.
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PMID:Host modifier genes affect mouse autoimmunity induced by the lpr gene. 940 30

The role of the Fas/FasL system in ANCA-associated vasculitis is unclear. We therefore assessed levels of soluble Fas (sFas) in sera and Fas expression on mononuclear cells from patients with ANCA-positive vasculitis and compared the results with those found in other rheumatic diseases. Serum levels of sFas were determined by ELISA. The ANCA-positive vasculitis patients studied included 29 at onset, 17 in first remission while on therapy, and 12 in quiescence. For comparison, 10 patients with Sjogren's syndrome (SS), 14 patients with systemic lupus erythematosus (SLE), 29 patients with rheumatoid arthritis (RA), 7 patients on dialysis (DP), and 26 healthy controls (HC) were studied. In addition, Fas expression in mononuclear cells was examined at the mRNA level using reverse transcriptase (RT)-PCR in 6 vasculitis patients at onset and in first remission. The expression of CD95 on the surface of leukocytes was determined by flow cytometry in 6 vasculitis patients at onset of the disease, in 6 patients in clinical remission, and in 6 HC. Expression of Fas and FasL in renal biopsy specimens was studied using immunohistochemistry. Patients with vasculitis had high sFas levels irrespective of disease phase. Both vasculitis patients and patients with RA and SLE had significantly increased sFas levels compared with healthy controls. All patient groups had sFas levels, which correlated with raised serum creatinine values. However, the sFas levels in vasculitis patients in first remission and in quiescence were increased despite a lower serum creatinine compared with onset. Some of the vasculitis patients showed an increased mRNA expression of Fas in mononuclear cells after treatment, suggesting that Fas production fluctuates with the intensity of the disease. The expression of CD95 on leukocytes was slightly decreased in vasculitis patients compared to healthy controls. No alterations of Fas and FasL expression were seen in renal biopsy specimens. These results show that ANCA-positive vasculitis patients have high sFas levels and that the levels remain elevated even in clinical remission. The findings indicate that perturbations in the Fas/Fas ligand system may play a role in the disease process in ANCA vasculitis.
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PMID:Serum sFAS levels are elevated in ANCA-positive vasculitis compared with other autoimmune diseases. 1214 96

The etiology of rheumatoid arthritis (RA) remains unknown; however, recent studies have suggested a central role of the vascular endothelium in RA pathogenesis. The immune complex (IC)-mediated vasculitis is typical for RA. The studies reported herein were undertaken to determine 1) whether IC isolated from plasma of patients with RA are capable of inducing expression of ICAM-1/CD54 and Fas antigen/CD95 on the endothelial cell (EC) in vitro, 2) whether the capacity to induce expression of this phenotypic markers of EC activation is determined by the size or by the composition of the IC. The concentrations of IC were chosen to be within the range for IC levels in plasma. We have shown that all IC-containing samples (n = 8) significantly and in a dose-dependent manner increased level of ICAM-1 expression on the EC. In selected experiments EC were incubated with IC in the presence of complement. The presence of serum containing active complement components resulted in further up-regulation of ICAM-1 expression only in 4 of 8 cases, independently on the ability of IC to fix complement. Additionally, we have found that all IC samples significantly and in a dose-dependent manner induced the marked increase in CD95 expression on the EC. Furthermore, the levels of augmented expression of CD95 correlated with the levels of CD54 expression stimulated by the same IC-containing samples. We have demonstrated that these levels of stimulated expression of ICAM-1 as well as levels of Fas antigen expression negatively correlated with percentage amounts of IgM in total protein concentration of IC and directly correlated with IgG content in comparison to IgM in the structure of this IC. Our results show that IC stimulate ECs to express ICAM-1 and CD95, all of which have been implicated in the pathogenesis of rheumatic disease. The studies reported herein provide further information regarding to inflammatory potential of IC in RA.
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PMID:Influence of Immune Complexes on Expression of CD54 and CD95 on the Surface of Endothelial Cells of ECV-304 Line. 1268 82

The pathogenesis of vasculitis is complex and is yet to be fully elucidated, although it is known that inflammatory cells play a major role. Dysregulation of apoptosis and defective clearance of inflammatory cells could lead to the persistence of inflammation and excessive tissue injury. In this study we aimed to investigate Fas (CD95) and apoptosis on peripheral blood (PB) neutrophil and lymphocytes in Henoch-Schonlein purpura, both in the acute phase and after resolution to determine the role of apoptosis in this self-limited vasculitis. Leukocytoclastic vasculitis presenting with Henoch-Schonlein purpura (HSP) was diagnosed according to ACR 1990 criteria and confirmed by skin biopsy. Thirty-seven patients (22 boys, 15 girls) aged 2.5-17 years (9 +/- 3.3) were enrolled in the study. Expression of CD95 and apoptosis were investigated by the annexin/PI method on peripheral blood neutrophils and lymphocytes in both the acute and the resolution phases of the disease. The mean neutrophil and lymphocyte CD95 expression was 65.4 +/- 37.6% and 33.3 +/- 7.3%, respectively, in the acute stage and 62.8 +/- 44.2% and 41 +/- 20%, respectively, in the resolution ( P > 0.05). The percentage of apoptotic peripheral blood neutrophils and lymphocytes as determined by annexin positivity was 13.3 +/- 11.31% and 8.6 +/- 9.5%, respectively, during the acute phase and 4.6 +/- 3.4% and 3.1 +/- 3.1%, respectively, in the resolution (P = 0.002, P = 0.008). These results suggest that increased apoptotic process in the immune effector cells in the acute phase of the disease may play an important role in the early control of inflammatory response and repair in leukocytoclastic vasculitis, thereby contributing to the self-limited nature of the disease.
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PMID:The role of apoptosis in childhood Henoch-Schonlein purpura. 1457 87

Churg-Strauss syndrome (CSS) is a rare form of systemic vasculitis occurring in patients with asthma. The cause of CSS is unknown, and yet little data are available regarding its pathogenesis. The presence of a marked tissue- and blood-eosinophilia, as well as secretory products of eosinophils in blood and tissues, implicates a pathogenetic role of eosinophil granulocytes. Prolonged survival of eosinophils due to inhibition of CD95-mediated apoptosis by soluble CD95 seems to contribute to eosinophilia in CSS. Although the mechanisms involved in eosinophil-activation in CSS have not been elucidated, recent data suggest a possible role of T lymphocytes secreting eosinophil-activating cytokines. This review describes the current insights into the pathogenesis of CSS in the light of its putative nature as a type 2 granulomatous disease. Recent clinical, experimental and epidemiologic data regarding the possible role of inflammatory cells and their secretory products, anti neutrophil cytoplasm antibodies (ANCA), epidemiologic factors and anti-asthma treatments are summarized.
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PMID:Update on the pathogenesis of Churg-Strauss syndrome. 1474 Apr 30

Dendritic cells (DC) genetically engineered to express Fas (CD95) ligand (FasL-DC) have been proposed as immunotherapeutic tools to induce tolerance to allografts. However, we and others recently showed that FasL-DC elicit a vigorous inflammatory response involving granulocytes and can promote Th1-type CD4+ and cytotoxic CD8+ T lymphocytes. This prompted us to evaluate the pathology induced by intravenous injection of FasL-DC in mice. We observed that FasL-DC obtained after retroviral gene transfer of bone marrow precursors derived from Fas-deficient C57Bl/6 mice induce massive pulmonary inflammation and pleuritis one day after a single intravenous injection in C57Bl/6 mice. Two months later, all mice presented granulomatous vasculitis of small to medium sized vessels, alveolar haemorrhage and pleuritis. In these lesions, apoptotic bodies were found in large number. Anti-neutrophilic cytoplasmic and anti-myeloperoxidase autoantibodies were not detected. This study documents that intravenous injection of FasL-DC causes severe lung granulomatous vasculitis. This new animal model for vasculitis is inducible, highly reproducible and shares many features with human Wegener granulomatosis. This model may be an appropriate tool to further investigate the pathogenesis of vasculitis and test new therapeutic strategies. Moreover, our findings highlight the potential severe complications of FasL-DC-based immunotherapy.
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PMID:Dendritic cells overexpressing Fas-ligand induce pulmonary vasculitis in mice. 1519 46

Autoimmune disorders are induced by various environmental and occupational substances. Among the most typical factors involving these substances, it is well known that silica exposure causes not only pulmonary fibrosis known as silicosis, but also induces autoimmune diseases such as rheumatoid arthritis known as Caplan's syndrome, systemic sclerosis, systemic lupus erythematosus, and anti-neutrophil cytoplasmic autoantibody (ANCA)-related vasculitis/nephritis. To investigate the immunological effects of silica, a focus on the occurrence of autoimmune dysfunction may clarify these autoimmune diseases and develop effective tools for observing silicosis patients (SIL). In this review, our investigation concerns the autoantibodies found in SIL, alteration of CD95/Fas and related molecules in SIL, case-oriented and in vitro analyses of silica-induced activation of responder and regulatory T cells, and supposed mechanisms of reduction of CD4+25+FoxP3+ regulatory T cells (T(reg)) in SIL. Further studies are required to investigate Th17 and the interaction with T(reg) in SIL to understand the cellular and molecular mechanisms of environmental and occupational autoimmune disorders.
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PMID:Environmental factors producing autoimmune dysregulation--chronic activation of T cells caused by silica exposure. 2222 3