Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0033687 (proteinuria)
 24,015 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To identify the immunologic mechanisms that influence susceptibility to GN, we compared the severity of accelerated anti-glomerular basement membrane (GBM) nephritis between Lewis (LEW) and Brown Norway (BN) rats and analyzed differences in their immune responses to the nephritogenic immunoglobulin. Lewis (LEW) rats preimmunized with sheep IgG developed proliferative GN with marked proteinuria [peak protein excretion (mean +/- SEM) = 85.3 +/- 15.3 mg/24 hr; normal = 6.4 +/- 0.8 mg/24 hr] after receiving a subnephritogenic dose of sheep anti-rat GBM antiserum. Identically treated Brown Norway (BN) rats, on the other hand, had minimal renal pathology and minimal proteinuria (peak protein excretion = 22.6 +/- 3.1 mg/24 hr; normal = 13.0 +/- 0.6 mg/24 hr). Serum titers of rat anti-sheep IgG isotypes and intraglomerular binding of sheep IgG, rat IgG, and rat complement (C3) were comparable in both strains. In contrast, only LEW rats developed a strong cellular immune response to sheep IgG represented by intrarenal T lymphocyte (OX19+) and monocyte (ED1+) accumulation [LEW vs. BN (mean +/- SEM): OX19+ = 0.60 +/- 0.10 vs. 0.14 +/- 0.01 cells/glomerulus, control = 0.02 +/- 0.01; ED1+ = 4.0 +/- 0.4 vs. 1.0 +/- 0.2 cells/glom., control = 0.8 +/- 0.3] and a significant cutaneous delayed-type hypersensitivity (DTH) reaction [LEW versus BN (mean +/- SEM): delta ear thickness = 0.22 +/- 0.02 vs. 0.05 +/- 0.03 mm; control = 0.04 +/- 0.02 mm]. Upon rechallenge with sheep IgG in vitro, LEW splenocytes expressed a T helper 1 (Th1) cytokine pattern (IFN gamma and IL-2 mRNA, but little IL-4 mRNA) which is associated with delayed-type hypersensitivity reactions. BN splenocytes, on the other hand, expressed IL-4 in addition to IL-2 and IFN gamma mRNA that is consistent with an undifferentiated (Th0) cytokine profile. These studies suggest that humoral immunity to heterologous immunoglobulin planted in the kidney is not sufficient for full expression of accelerated anti-GBM nephritis, and that additional cellular immune mechanisms are required. We conclude that susceptibility to accelerated anti-GBM nephritis is strongly influenced by the host's propensity to mount a Th1-type response and DTH reaction to the disease-inciting immunoglobulin.
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PMID:Immunologic determinants of susceptibility to experimental glomerulonephritis: role of cellular immunity. 906 95

The role of immunoglobulin (Ig) and complement as mediators of Heymann nephritis (HN) has been questioned by recent studies showing that HN can be induced in a C6-deficient rat that cannot assemble the membrane attack complex of complement. Also, the severity of HN can be reduced by therapy directed at CD8+ T cells, which has no effect on antibody (Ab) production or immune deposits. To identify whether T cells may contribute to the glomerular injury of active HN in Lewis rats, the mononuclear infiltrate and cytokine mRNA in glomeruli and kidney interstitium were examined. Groups of Lewis rats immunized with Fx1A in CFA developed HN, and were compared to controls that received CFA only. Proteinuria, the marker of glomerular filtration barrier dysfunction, was absent at four weeks but present at eight weeks in HN. Serum anti-Fx1A Ab and glomerular Ig were present in HN at both time points. Immunoperoxidase staining with monoclonal Abs identified, at eight weeks, a glomerular infiltrate of CD4+ and CD8+ T cells, and macrophages, but not NK cells. Semiquantitative RT-PCR of isolated glomeruli at eight weeks demonstrated expression of cytokine mRNA for Th1 CD4+ cells (IFN-gamma and TNF-beta/LT, but not IL-2), cytotoxic CD8+ T cells (granzyme A and perforin), and macrophages (TNF-alpha and IL-10), but not Th2 CD4+ cells (no increase in IL-4, IL-5 and IL-6). At eight weeks, the cellular infiltrate and pattern of cellular activation in glomeruli was different to that in renal cortex. In the cortical infiltrate CD8+ cells were a lesser component, and NK cells were increased, as were CD4+ cells and macrophages. RT-PCR identified increased cytokine mRNA for macrophages, Th1 and Th2 cells, but not cytotoxic effector T cells. At four weeks, T cells including CD4+ and CD8+ cells were identified in the isolated glomeruli of rats with HN, but there was no increase in cytokine mRNA expression. There was no infiltrate or increase in cytokine mRNA detected in renal cortex at four weeks. Anti-Fx1A Ab's and glomerular deposition of Ig develop many weeks before the onset of proteinuria, when there is only a small cellular infiltrate present. The progressive development of infiltrates of activated T cells, principally Th1 and cytotoxic effector cells, and macrophages, within glomeruli is coincident with the development of proteinuria. These findings raise the possibility that these cells contribute to the mediation of the glomerular injury and proteinuria of HN.
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PMID:Role of T cells in the mediation of Heymann nephritis. ii. Identification of Th1 and cytotoxic cells in glomeruli. 908 71

A case in which the enterotoxins of Staphylococcus aureus may have served as bacterial superantigens is presented. This 71-year-old man developed proteinuria and renal dysfunction after contacting pneumonia caused by methicillin-resistant Staphylococcus aureus (MRSA), coagulase type II. The infection occurred after surgery for recurrent lung cancer. Staphylococcus enterotoxins B, C, and TSST-1 were detected from the bacillus. Ten days after the onset of pneumonia, proteinuria was noted; urinary protein was as high as 1.8 g/day. The serum creatinine was elevated from 1.0 mg/dl to 3.7 mg/dl. Several immunological reactions were detected; the serum levels of IgG and IgA were increased, and the selective usage of T-cell receptor V beta (TCRV beta) was observed. Serum levels of IL-1 beta, IL-2, IL-6, IL-8, IL-12, and tumor necrosis factor alpha (TNF alpha) were also elevated. Examination of the renal biopsy specimen by light microscopy showed minor to mild mesangial proliferative glomerulonephritis. Immunofluorescence microscopy demonstrated the deposition of IgG, IgA, and C3, mainly along the capillary walls. Electron microscopy revealed electron dense deposits, mainly in the subepithelial areas, and injury to the glomerular basement membrane. When the pneumonia improved following antibiotic therapy, the renal function also improved, and proteinuria decreased. The levels of immunoglobulins and the usage of TCRV beta also decreased. Because staphylococcus enterotoxins act as superantigens, we believe this to be a typical case of superantigen-related glomerulonephritis.
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PMID:A case of superantigen-related glomerulonephritis after methicillin-resistant Staphylococcus aureus (MRSA) infection. 940 16

Chronic graft-vs-host disease (GvH), induced by injection of DBA/2 lymphocytes into (C57BL/6 x DBA/2)F1 hybrids, is a murine model for lupus nephritis, associated with a Th2-dependent polyclonal B cell activation. The development of glomerulosclerosis in this model is preceded by a glomerular influx of LFA-1+ T cells. We investigated whether exposure to bacterial superantigen would modulate the course of this autoimmune syndrome. Injection of the bacterial superantigen staphylococcal enterotoxin B (SEB) in mice has been shown to induce the activation of TcRVbeta8+ T cells. Within 2 weeks after GvH induction, mice were injected twice with 20 microg of SEB and the following parameters were examined: cytokine and Ig profile, proteinuria and renal pathology. The second SEB injection induced in GvH mice an increased release of both interferon-gamma (IFN-gamma) and interleukin-10 (IL-10) as compared with control F1 mice. No differences were observed in IL-2 production. SEB-treated GvH mice demonstrated a delayed onset of proteinuria. Histological analysis of the kidney showed that SEB-challenged GvH mice displayed significantly more interstitial inflammation and mesangial proliferation together with more IgG2a deposits in glomeruli than non-injected GvH mice. From these results, we conclude that GvH mice are more responsive to SEB in terms of cytokine production and that bacterial infection can modulate the course of this renal disease from a membranous to a more proliferative type of nephropathy.
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PMID:T cell subsets in experimental lupus nephritis: modulation by bacterial superantigen. 1004 39

Previous study suggested that MRL-lpr/lpr mice treated with tamoxifen (TAM) had less severe proteinuria, reduced serum titre of anti-dsDNA autoantibodies and an increased survival rate. To investigate further the regulatory mechanisms of TAM on MRL-lpr/lpr female mice, a total dose of 200 microg per mice (5.5 mg/kg) was given every 2 weeks subcutaneously, while the control mice were injected with oil only. After being treated with TAM four times, the mice were killed and cellular functions were evaluated. The TAM-treated groups had smaller sized spleen and lymph nodes. Flow cytometric analysis of splenocytes had a significantly lower percentage of cell number of T cells and double negative T cells (CD4- CD8- T cells). There was no difference in cytokine production (interleukin (IL)-2, IL-4, IL-5, IL-10 and interferon-gamma (IFN-gamma)) from splenocytes stimulated with concanavalin A (Con A) or cytokines (IL-6) secreted by peritoneal exudate cells when stimulated with lipopolysaccharide (LPS). However, IL-2 from lymph node cells was significantly higher on TAM-treated mice. Finally, splenocytes or purified T cells stimulated with anti-CD3 antibody plus cross-linking immunoglobulin G (IgG) of the TAM-treated group had higher 3H-incorporation of proliferation assay compared with that of control groups. In vitro study further demonstrated that IL-2-activated proliferation of lymph node double negative (DN) T cells can be inhibited by TAM treatment in a dose-dependent manner. Our finding demonstrated that TAM may potentially influence T cells and modulate the immune function, which offers a novel approach to explore the feasibility of hormone therapy for autoimmune diseases.
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PMID:Tamoxifen alleviates disease severity and decreases double negative T cells in autoimmune MRL-lpr/lpr mice. 1080 66

IL-18 (formerly known as IFN-gamma-inducing factor) enhances Th1 responses via effects that are thought to be dependent on and synergistic with IL-12. The potential for IL-18 to exert IL-12-independent effects in delayed-type hypersensitivity (DTH) responses was studied in a model of Th1-directed, DTH-mediated crescentic glomerulonephritis induced by planting an Ag in glomeruli of sensitized mice as well as in cutaneous DTH. Sensitized genetically normal (IL-12(+/+)) mice developed proteinuria and crescentic glomerulonephritis with a glomerular influx of DTH effectors (CD4(+) T cells, macrophages, and fibrin deposition) in response to the planted glomerular Ag. IL-12p40-deficient (IL-12(-/-)) mice showed significant reductions in crescent formation, proteinuria, and glomerular DTH effectors. Administration of IL-18 to IL-12(-/-) mice restored the development of histological (including effectors of DTH) and functional glomerular injury in IL-12(-/-) mice to levels equivalent to those in IL-12(+/+) mice. IL-18 administration to IL-12(-/-) mice increased glomerular ICAM-1 protein expression, but did not restore Ag-stimulated splenocyte IFN-gamma, GM-CSF, IL-2, or TNF-alpha production. Sensitized IL-12(+/+) mice also developed cutaneous DTH following intradermal challenge with the nephritogenic Ag. Cutaneous DTH was inhibited in IL-12(-/-) mice, but was restored by administration of IL-18. IL-12(+/+) mice given IL-18 developed augmented injury, with enhanced glomerular and cutaneous DTH, demonstrating the synergistic effects of IL-18 and IL-12 in DTH responses. These studies demonstrate that even in the absence of IL-12, IL-18 can induce in vivo DTH responses and up-regulate ICAM-1 without inducing IFN-gamma, GM-CSF, or TNF-alpha production.
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PMID:IL-18 has IL-12-independent effects in delayed-type hypersensitivity: studies in cell-mediated crescentic glomerulonephritis. 1103 8

A peptide based on complementarity-determining region (CDR)-1 of a monoclonal murine anti-DNA Ab that bears the common idiotype, 16/6Id, was synthesized and characterized. The peptide, designated pCDR1, was found to be an immunodominant T-cell epitope in BALB/c mice. The CDR1-based peptide was shown to be capable of inhibiting the in vivo priming of BALB/c mice immunized with the peptide or with the whole anti-DNA 16/6Id(+) mAbs of either mouse or human origin. We show here that administration of pCDR1 (weekly, i.v., 100 microgram/mouse) in aqueous solution for 5 weeks starting at the time of disease induction with the human 16/6Id prevented the development of clinical manifestations of experimental systemic lupus erythematosus (SLE). Further, 10 weekly injections of pCDR1 to BALB/c mice with an established experimental SLE down-regulated clinical manifestations of SLE (e.g., anti-DNA auto-Abs, leukopenia, proteinuria, immune complex deposits in the kidneys) in the treated mice. Prevention of SLE induction was shown to be associated mainly with a decrease in the levels of IL-2, INFgamma, and the proinflammatory cytokine TNFalpha. On the other hand, the secretion of the immunosuppressive cytokine TGFbeta was elevated. Amelioration of the clinical manifestations of an already established experimental SLE correlated with a dramatic decrease in TNFalpha secretion, elevated levels of TGFbeta, and immunomodulation of the Th1 and Th2 type cytokines to levels close to those observed in healthy mice.
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PMID:The mechanism by which a peptide based on complementarity-determining region-1 of a pathogenic anti-DNA auto-Ab ameliorates experimental systemic lupus erythematosus. 1115 9

Bilaterally nephrectomized Lewis recipients of Fisher 344 (F344) kidney allografts, treated with CyA (1.5 mg/kg/day x 10), develop progressive changes of chronic rejection. Treated F344-to-F344 acted as isograft controls. Proteinuria was determined sequentially. Grafts were harvested 8, 12 and 16 weeks after transplantation (n = 9/group/time period). Infiltrating host cells and their products were assessed in chronically rejecting grafts by histology and immunostaining using mAbs for monocyte/macrophages, T-cells, ICAM-1, LFA-1 and cytokines. For in vitro binding studies, snap-frozen sections of transplanted kidneys were incubated with monocytes/macrophages and lymphocytes isolated from peripheral blood (PBL) of naive animals. For in vivo migration studies, naive cell populations were labeled with Bis-Benzamide and transferred i.v. to grafted animals at weeks 8, 12 and 16 (n = 3/group); grafts were harvested 24 h later and cell localization assessed under immunofluorescence. Increasing numbers of ED1 + monocytes/macrophages in allografted kidneys peaked at 16 weeks, localizing preferentially in glomeruli, where IL-1, IL-6 and TNF-alpha expression had also become intense and correlated with progressive glomerulosclerosis. Binding studies corroborated these results. In vitro, a few monocytes/macrophages bound to glomeruli and vessels at 8 weeks; by 12 weeks, binding to glomeruli was high (72% of cells). In vivo, large numbers of transferred labelled monocytes/macrophages were found in kidney allografts at 12 weeks (23%, isografts; < 7%, P < 0.01). In contrast T cells (primarily CD4+) were a consistent feature in allografts elevated as compared to isografts and correlating with in vitro and in vivo binding patterns; associated cytokines included IL-2, IFN- and TNF-alpha. Functional data followed these results: urine protein excretion by allograft recipients increased from baseline at 8 weeks (12 mg/day) to > 50 mg/day at 16 weeks at which point animals were beginning to die of renal failure; proteinuria in isografted rats did not increase during this time period. These results suggest that monocyte/macrophage and CD4+ T cells and their products are important in chronic kidney allograft rejection, contributing to the progressive sclerosis and fibrosis.
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PMID:Host leukocytes and their products in chronic kidney allograft rejection in rats. 1127 Dec 42

To investigate, whether T lymphocytes alone are sufficient to induce glomerulonephritis, a model in SCID mice was developed. Conditions for the generation and exclusive glomerular targeting of crosslinked ovalbumin (OVA) polymers and a series of OVA-specific T-cell clones and lines were established. Only a well-defined subfraction of OVA polymers exclusively targeted to the glomerular mesangium without causing local alteration in the absence of IgG. From numerous T-cell preparations spanning different Th-1/-2 profiles one T-helper cell clone characterized by ELISPOT assay as pure Th-1 (IFN-gamma and IL-2) induced nephritislike pathology. Histological examination at days 1, 2, 5, and 21 showed major infiltrates in proximal tubular regions (PTR) at day 5 accompanied by significant proteinuria. No injury was observed after deposition of irrelevant antigen or injection of other T-cell preparations. Detailed histological analysis revealed that Th-1 cell numbers peaked early in glomeruli (2.1 +/- 0.6 vs 0/gcs). Macrophages, however, were hardly detectable in glomeruli (0.5 +/- 0.3/gcs) at this time, while they formed the major constituent of the PTR infiltrates at day 5 (83 +/- 1). These data in a new SCID nephritis model indicate that memory Th-1 cells together with localized antigen presenting cells trigger nephritis.
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PMID:CD4+ T cells recognizing specific antigen deposited in glomeruli cause glomerulonephritis-like kidney injury. 1216 77

Two peptides based on the complementarity-determining regions (CDR) 1 and 3 (pCDR1 and pCDR3) of a murine monoclonal anti-DNA autoantibody that expresses the common idiotype 16/6Id were shown to down-regulate systemic lupus erythematosus (SLE)-associated T cell responses and to prevent the development of clinical symptoms in the SLE-prone mice, (NZB x NZW)F(1). In the present study the ability of the CDR-based peptides to treat an already established disease was tested. Mice were given 10 weekly injections of peptides either i.v. or s.c. The treatment led to a moderate reduction in the anti-DNA autoantibody titer, and a significant decrease in proteinuria and kidney pathology. The CDR-based peptides affected the pathogenic isotypes (IgG2a and IgG3) of the anti-DNA antibodies in the serum and in immune complexes in the kidneys. Both peptides mitigated disease manifestations and prolonged the survival of mice that were treated starting at the age of 7 months when full-blown disease was already developed. Furthermore, some beneficial effects of treatment with the CDR-based peptides could be adoptively transferred to diseased recipients. A reduction in the secretion of IL-2, IFN-gamma, IL-4 and IL-10 was detected in supernatants of splenocytes of the treated mice. In contrast, treatment up-regulated the immunosuppresive cytokine-transforming growth factor-beta. Thus the ameliorating effect of the CDR-based peptides on SLE manifestations is at least partially via the immunomodulation of the cytokine profile.
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PMID:Peptides based on the complementarity-determining regions of a pathogenic autoantibody mitigate lupus manifestations of (NZB x NZW)F1 mice via active suppression. 1257 50


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