Aristolochic acid as a causative factor in a case of Chinese herbal nephropathy.
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Aristolochia↗
Biomedical subjects
Charles D Pusey
Publications and source records attributed to Charles D Pusey.
Immunology of anti-glomerular basement membrane disease.
Anti-glomerular basement membrane disease is a form of autoimmune glomerulonephritis often accompanied by lung haemorrhage. It is characterized by circulating and deposited antibodies that bind basement membrane components in the glomerulus and lung alveolus. Since early descriptions of the deposition of immunoglobulin on the glomerular basement membrane, work has focused on the binding properties of the autoantibodies, and this has led to the identification of the autoantigen as the non-collagenous region of the alpha 3 chain of type IV collagen. Despite being thought of as a prototypic antibody mediated autoimmune disease, it is becoming apparent that both humoral and cellular immune mechanisms act in concert to initiate and perpetuate disease. Recent data have shed light on the molecular pathogenesis of anti-glomerular basement membrane disease and provided a more complete framework on which to build our understanding of autoimmune renal disease. This should lead to novel approaches to immunotherapy for patients with glomerulonephritis.
Anti-Glomerular Basement Membrane Disease↗
Anti-CD8 monoclonal antibody therapy is effective in the prevention and treatment of experimental autoimmune glomerulonephritis.
Experimental autoimmune glomerulonephritis (EAG), which is an animal model of Goodpasture's disease, can be induced in Wistar Kyoto rats by a single injection of rat glomerular basement membrane (GBM) in adjuvant. EAG is characterized by circulating and deposited anti-GBM antibodies, focal necrotizing glomerulonephritis with crescent formation, and glomerular infiltration by T cells and macrophages. Our hypothesis was that T cell-mediated immunity, in addition to humoral immunity, was necessary for the development of crescentic nephritis in this model. To investigate the role of CD8+ T cells in the pathogenesis of EAG, the in vivo effects of an anti-CD8 monoclonal antibody (OX8) were examined, with administration starting at the time of immunization (prevention) or 2 wk after immunization, when glomerular abnormalities were first detected (treatment). When administered intraperitoneally at 5 mg/kg, three times per week, from week 0 to week 4 (prevention), OX8 completely inhibited the development of albuminuria, deposits of fibrin in the glomeruli, glomerular and interstitial abnormalities, the influx of CD8+ T cells and macrophages, and glomerular expression of granzyme B and inducible nitric oxide synthase. Circulating anti-GBM antibody levels were not reduced, but there was a reduction in the intensity of antibody deposition on the GBM. When administered at the same dose from week 2 to week 4 (treatment), OX8 greatly reduced the severity of EAG; in particular, the formation of crescents was prevented. These studies demonstrate that anti-CD8 monoclonal antibody therapy is effective in both the prevention and treatment of EAG. They confirm the importance of T cell-mediated immunity in the pathogenesis of this model of Goodpasture's disease. Similar therapeutic approaches may be worth investigating in human crescentic glomerulonephritis.
Albuminuria↗
Interleukin-11 attenuates nephrotoxic nephritis in Wistar Kyoto rats.
Interleukin-11 (IL-11) is a multifuctional cytokine with anti-inflammatory activity. The effect of IL-11 was studied in an experimental model of necrotizing glomerulonephritis induced in Wistar Kyoto rats by an injection of anti-glomerular basement membrane antibody (nephrotoxic serum). Intraperitoneal injection was chosen as the route of IL-11 administration in all experiments. In experiment 1, recombinant human IL-11 (1360 microg) was given 2 h before nephrotoxic serum, then once daily until day 6. In experiment 2, a lower dose of IL-11 (800 microg/d) was used. Rats were treated either with IL-11 400 microg twice daily intraperitoneally or with 800 microg once daily intraperitoneally for 6 d. In experiment 3, the lower dose of IL-11 was given 2 h before nephrotoxic serum, then twice daily until day 2. In experiment 1, IL-11 significantly reduced proteinuria (13.2 +/- 3.3 versus 63.2 +/- 4.3 mg/24 h), fibrinoid necrosis (0.58 +/- 0.08 versus 1.52 +/- 0.06 quadrants/glomerular cross section [gcs]), macrophage infiltration (ED1-positive cells, 24.4 +/- 1.8 versus 39.3 +/- 1.9 cells/gcs), apoptosis (1.11 +/- 0.1 versus 2.39 +/- 0.2 apoptotic bodies/gcs), and proliferating cell nuclear antigen-positive cells (24.4 +/- 2.0 versus 37.3 +/- 2.3 cells/gcs). Inducible nitric oxide synthase-positive cells were significantly increased (3.1 +/- 0.3 versus 2.0 +/- 0.2 cells/gcs). In experiment 2, a lower dose of IL-11 significantly reduced proteinuria and fibrinoid necrosis. Macrophage infiltration was similar in treated and control groups, although the number of sialoadhesin-positive macrophages (ED3+) was significantly reduced in the IL-11-treated rats. In experiment 3, quantitative competitive reverse transcriptase-polymerase chain reaction showed that the mRNA ratio of IL-1 beta/beta-actin in the treated rats was reduced compared with controls. By the use of probes designed from mouse IL-11 receptor alpha-chain sequence, it was also shown that rat mesangial cells and macrophages expressed IL-11 receptor alpha-chain, demonstrating that they were capable of responding to IL-11. In this model of necrotizing glomerulonephritis, high-dose IL-11 treatment markedly reduced both proteinuria and fibrinoid necrosis. At the lower dose, there was a reduction in glomerular injury and macrophage sialoadhesin expression, but without an alteration of macrophage numbers, suggesting that IL-11 may be acting in part to reduce macrophage activation.
Animals↗
Oral administration of glomerular basement membrane prevents the development of experimental autoimmune glomerulonephritis in the WKY rat.
Experimental autoimmune glomerulonephritis (EAG), an animal model of Goodpasture's disease, can be induced in Wistar Kyoto (WKY) rats by a single injection of collagenase-solubilized rat glomerular basement membrane (GBM) in adjuvant. EAG is characterized by circulating and deposited anti-GBM antibodies, accompanied by focal necrotizing glomerulonephritis with crescent formation. The inhibitory effect of orally administered antigens has been reported in various animal models of autoimmunity but not in EAG in the rat. The effects of feeding rat GBM by gavage, at total doses of 0.5, 2.5, or 5 mg, before immunization were examined. A dose-dependent effect was observed on the development of EAG. A dose of 0.5 mg of GBM had no effect on disease, 2.5 mg resulted in a moderate reduction in the severity of nephritis but no change in anti-GBM antibody production, and 5 mg resulted in a marked reduction in circulating and deposited anti-GBM antibodies, albuminuria, deposits of fibrin in the glomeruli, severity of glomerular abnormalities, and numbers of infiltrating T cells and macrophages. Animals that were fed 5 mg of GBM showed a significant reduction in IgG2a but not IgG1, anti-GBM antibody levels, suggesting downregulation of Th1 responses. There was also a dose-dependent reduction in the proliferative responses of splenic T cells from treated animals to GBM antigen in vitro. These results clearly demonstrate that mucosal tolerance can be induced by oral administration of GBM antigen and that this approach is effective in preventing EAG.
Administration, Oral↗
In Goodpasture's disease, CD4(+) T cells escape thymic deletion and are reactive with the autoantigen alpha3(IV)NC1.
Goodpasture's disease is characterized by rapidly progressive glomerulonephritis and pulmonary hemorrhage, in association with circulating and deposited anti-glomerular basement membrane antibodies that recognize the alpha3 chain of type IV collagen [alpha3(IV)NC1] (known as the Goodpasture antigen). Unlike many other autoimmune diseases, recurrences are rare. In experimental models and human studies, both humoral and cellular mechanisms have been demonstrated to be involved in disease pathogenesis. However, there are few data on the characteristics of the autoreactive T cells or the mechanisms of tolerance to the autoantigen in human patients. It was demonstrated, using immunohistochemical analyses and reverse transcription-PCR, that the Goodpasture antigen is expressed in normal human thymus. Using limiting dilution analyses, the frequencies of circulating autoreactive T cells in patients and control subjects were assessed. During acute disease, there were increased frequencies of CD4(+) T cells reactive with alpha3(IV)NC1 (ranging from 1:6300 to 1:65,000), which decreased with time. There was a significant difference between patients during their acute disease phase and control subjects with respect to the frequency index for alpha3(IV)NC1-specific CD4(+) T cells (P < 0.05, Mann Whitney U test). The decrease in autoreactive CD4(+) T-cell numbers during recovery may be the reason why recurrences are infrequent and may explain the loss of pathogenic autoantibodies with time, because of a lack of T-cell help.
Acute Disease↗
Careers in academic medicine: the clinician scientist scheme.
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Academic Medical Centers↗
Rapidly progressive glomerulonephritis: current and evolving treatment strategies.
Rapidly progressive glomerulonephritis (RPGN) must be diagnosed and treated quickly to prevent irreversible organ injury. The commonest cause of RPGN is anti-neutrophil cytoplasm antibody (ANCA) associated small vessel vasculitis, and the most severe is anti-glomerular basement membrane (GBM) antibody disease. In this review we address pathogenesis, diagnosis, treatment and outcome in these two entities, with emphasis on novel therapies.
Anti-Glomerular Basement Membrane Disease↗