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)

The human CR1 was genetically engineered by site directed mutagenesis into a truncated form which was secreted from transfected Chinese hamster ovary cells. This soluble recombinant CR1 (sCR1) was purified from the supernatants of the Chinese hamster ovary cells cultured in a hollow fiber bioreactor. sCR1 inhibits the C3 and C5 convertases of the classical and the alternative pathways in vitro. The ability of sCR1 to inhibit the immune complex-mediated inflammation in vivo was tested in a rat reversed passive Arthus reaction model. Administration of sCR1 at the dermal sites reduced the Arthus vasculitis in a dose-dependent manner as judged by both gross and microscopic examination, as well as by immunohistologic localization of C3 and C5b-9 neoantigen deposits. These data suggest that sCR1 inhibits the Arthus reaction by interrupting the activation of the C cascade, hence limiting the detrimental immune complex-induced tissue damage in vivo.
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PMID:Recombinant soluble human complement receptor type 1 inhibits inflammation in the reversed passive arthus reaction in rats. 182 90

We investigated whether a decreased complement receptor expression or function of monocytes isolated from peripheral blood of 52 patients with rheumatoid arthritis (RA) and rheumatoid vasculitis (RV) could account for the previously observed diminished degradation of immune complexes by monocytes of patients with RA and RV. On average, monocytes from all patients expressed significantly less CR1, and degraded significantly less AC3b when compared with monocytes of healthy controls. In addition, monocytes from RV patients degraded significantly less AC3b when compared with monocytes from patients with RA. The expression of both CR1 and CR3 on monocytes of RV patients was lower compared with RA patients but this difference was only significant for CR3. No differences were found between AC3b degradation and the expression of CR1 and CR3 between patients with active and inactive RA. Using linear discriminant analysis on the variables AC3b, CR1 and CR3, 94% of the patients could be classified correctly as healthy controls, RA or RV, suggesting a true multi-variate relationship between these parameters and patients groups. Our results suggest that the diminished capacity of monocytes from RA patients to degrade AC3b is due partly to a decreased expression of CR1 and CR3.
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PMID:Degradation of aggregates of activated C3 (C3b) by monocytes of patients with rheumatoid arthritis is related to vasculitis. 214 58

This study reports the quantitative analysis of complement receptor (CR1) molecules on erythrocyte surface, the amount of immunoglobulin-containing material (IgG-IC and IgA1-IM) on the erythrocyte surface, and the concentrations of circulating immune complexes (IgG-CIC and IgA-CIC); also reported are the HLA phenotypes of 44 patients affected by various forms of glomerulonephritis (including 20 primary IgA nephropathy, 11 membranous glomerulonephritis, 9 lupus nephritis and 4 renal vasculitis). Erythrocyte CR1 molecules were found to be decreased (P less than 0.02) and erythrocyte IgG-IC were less than in controls (P less than 0.025) in lupus nephritis patients, whereas IgG-CIC were significantly greater (P less than 0.02). In patients affected by primary IgA nephropathy, mean erythrocyte CR1 concentrations were significantly decreased (P less than 0.02). Patients with impaired renal function had mean erythrocyte CR1 values significantly greater than those with normal renal function (P less than 0.002). Immunoglobulin-containing material on the erythrocyte surface was not significantly increased, whereas the serum concentrations of both IgA-CIC and IgG-CIC were significantly increased (P less than 0.02). In membranous nephropathy erythrocyte CR1 molecules were quantitatively similar to control data and no increase in CIC was observed. Conversely, erythrocyte IgG-IC were significantly increased (P less than 0.01). No significant relationship among erythrocyte CR1 molecules, erythrocyte surface-associated immunoglobulins, CIC, and HLA phenotype was observed in any patient group.
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PMID:Complement receptor (CR1) and IgG or IgA on erythrocytes and in circulating immune complexes in patients with glomerulonephritis. 212 61

Expression of the C3b/C4b receptor (CR1) on erythrocytes is decreased in patients with systemic lupus erythematosus (SLE) compared to normal individuals, and the CR1 antigen is absent from podocytes in severe diffuse proliferate nephritis of SLE. In the present study, we examined the relationship between the number of CR1 on erythrocytes and the occurrence and severity of SLE nephritis, and assessed the expression of CR1 on erythrocytes and the occurrence and severity of SLE nephritis, and assessed the expression of CR1 on erythrocytes in non-SLE nephritis and other systemic inflammatory diseases by measuring the binding of 125I-labeled rabbit F(ab')2 and murine monoclonal IgG anti-CR1 antibodies to erythrocytes of normal individuals and patients in a French population. The number of binding sites for monoclonal anti-CR1 antibody on erythrocytes of 116 normal individuals was 743 +/- 22 (mean +/- SEM) with a range of 169-1,333, and the frequency distribution of this number in the population was bimodal. In 112 patients with SLE, the mean number of CR1 sites on erythrocytes was decreased to 62% of the mean for normal individuals (p less than 0.001). No correlation was found between CR1 expression on erythrocytes and the presence or immunohistopathological type of glomerulonephritis in biopsy specimens from these patients. The mean number of CR1 on erythrocytes of 29 patients with non-SLE glomerulonephritis was slightly decreased to 89% of the normal mean (p greater than 0.05), which could not be attributed to glomerular immune complex disease or vasculitis.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Decreased expression of C3b receptor (CR1) on erythrocytes of patients with systemic lupus erythematosus contrasts with its normal expression in other systemic diseases and does not correlate with the occurrence or severity of SLE nephritis. 294 97

We investigated the capacity of monocytes to degrade soluble aggregates of IgG in vitro in the absence (Fc receptor [FcR] mediated) and presence of complement (FcR and C3 receptor mediated). Adherent monocytes from 33 patients with active rheumatoid arthritis (RA) and rheumatoid vasculitis, 32 patients with inactive RA alone, and 20 healthy controls were incubated with 125I-aggregated IgG (125I-AIgG) of restricted size with or without fresh serum. Normal monocytes degraded 9.8% of 125I-AIgG via FcR alone and the presence of complement enhanced degradation to 2.7%. Degradation of 125I-AIgG via FcR from patients without active RA suggested a depressed function of FcR. The maximal amount of 125I-AIgG which was bound by monocytes from patients with inactive and active RA, however, was increased compared to normals, suggesting a defect in intracellular processing in patients with RA. The degradation of 125I-AIgG in the presence of complement was also significantly depressed for both groups of patients. The monocytes from the patients also had decreased numbers of C3b receptors (CR1). Since CR1 are involved in the enhanced uptake of immune complexes bearing complement, the depressed capacity of monocytes from patients with RA to degrade 125I-AIgG in vitro may be caused both by a diminished uptake as well as a diminished capacity to degrade soluble AIgG.
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PMID:Diminished uptake and degradation of soluble aggregates of IgG by monocytes of patients with rheumatoid arthritis and vasculitis. 366 74

Complement factor I deficiency is known to be associated with recurrent pyogenic infections. The patient described here had recurrent attacks of otitis, sinusitis, and bronchopneumonia since childhood. At the age of 24 years, he had an acute episode of systemic vasculitis with purpura, but no nephritis. A factor I deficiency was diagnosed when he was 36 years old. Because of the uncontrolled activation of the alternative pathway of complement, several other components were depleted, in particular C3, which explained the predisposition for pyogenic infections. A progressive loss of renal function accompanied by proteinuria and hematuria started after the age of 40 years. Renal biopsy showed a focal segmental glomerulonephritis (GN) with glomerular deposits of immunoglobulins and complement C3 and C4 fragments. The glomerular podocytes showed an almost complete loss of complement receptor 1 (CR1; CD35). The expression of CR1 was very low on erythrocytes, as well. Thus, CR1, the most efficient cell-bound cofactor for the inactivation of C4b/C3b by factor I, appears to be consumed when factor I is missing. Although this is the first report of factor I deficiency associated with GN, it is unlikely that the development of the nephritis was fortuitous because GN has been found in many other diseases characterized by uncontrolled activation of the alternative pathway.
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PMID:Glomerulonephritis in a patient with complement factor I deficiency. 1035 6

Proteinase 3 (PR3), which is also called myeloblastin, the target autoantigen for antineutrophil cytoplasmic antibodies (ANCA) in Wegener's granulomatosis, is a serine proteinase stored in azurophil granules of human neutrophils. We have previously shown that, in contrast to elastase or myeloperoxidase, PR3 is also expressed at the plasma membrane of a subset of unactivated neutrophils and that a high proportion of neutrophils expressing membrane PR3 is a risk factor for vasculitis. The present study demonstrates that the association of PR3 with the plasma membrane is not an ionic interaction and seems to be covalent. Fractionation of neutrophils shows that, besides the azurophil granules, PR3 could be detected both in specific granules and in the plasma membrane-enriched fraction containing secretory vesicles, whereas elastase and myeloperoxidase were exclusively located in azurophil granules. Electron microscopy confirms that PR3 is present along with CR1 in secretory vesicles as well as in some specific granules. In neutrophils stimulated with an increasing dose of FMLP, membrane PR3 expression increased with the degranulation of secretory vesicles, followed by specific granules, and culminated after azurophil granules mobilization. The presence of a readily plasma membrane-mobilizable pool of PR3 contained in the secretory vesicles might play a relevant role in the pathophysiological mechanisms of ANCA-associated vasculitis.
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PMID:Presence of proteinase 3 in secretory vesicles: evidence of a novel, highly mobilizable intracellular pool distinct from azurophil granules. 1049 22

CR1 and CR2 expression is decreased by approximately 50% on B cells of patients with systemic lupus erythematosus (SLE). Expression is also decreased in the MRL/lpr murine model of SLE prior to the development of clinical disease, suggesting that this alteration may play a role in pathogenesis. To determine whether the decrease in receptor levels affects the development of SLE, we analyzed MRL/lpr mice in which CR1/CR2 expression was altered by gene targeting. Mice from each cohort (Cr2+/+, Cr2+/-, and Cr2-/-) were analyzed biweekly for the development of proteinuria and autoantibodies. Kidneys were examined at 12 and 16 weeks for evidence of immune complex deposition and renal disease. Deficiency of CR1/CR2 did not affect survival or development of renal disease as measured by proteinuria. Mice deficient in CR1/CR2 had significantly lower levels of IgG3 rheumatoid factor (RF) and total serum IgG3, suggesting a specific defect in production of IgG3 in response to endogenous autoantigens. Since IgG3 RF has been associated with the development of vasculitis in this model, we examined the mice for alterations in development of this clinical manifestation. Although there was no difference in the development of ear necrosis among the three groups, renal arteritis was not identified in any of the Cr2+/- mice, whereas it was present in 20% of the Cr2+/- and 40% of the Cr2+/+ mice. Finally, significantly higher levels of IgA were seen in the glomeruli of Cr2+/- mice compared to Cr2+/- or Cr2+/+ mice, suggesting that CR1/CR2 are involved in either the regulation of IgA production or the clearance of IgA immune complexes. Together these data support the concept that alterations in CR1/CR2 expression or function affect the regulation of autoantibody production and/or clearance and may have clinical consequences.
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PMID:CR1/CR2 deficiency alters IgG3 autoantibody production and IgA glomerular deposition in the MRL/lpr model of SLE. 1529 81