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PubMed1992

Accelerated decay of the cell bound C4b2a complex by serum of patients with membranoproliferative glomerulonephritis and acute poststreptococcal glomerulonephritis.

Serum from patients with membranoproliferative glomerulonephritis (MPGN) and acute poststreptococcal glomerulonephritis (APSGN) accelerated the decay of the cell bound C4b2a (C42) and C4b hemolytic activity relative to pooled normal human serum (pNHS) after 5 min incubation at 30 degrees C in EDTA-GVB. The accelerated decay of the C42 hemolytic activity was heat stable (56 degrees C 30 min) and was inhibited by monoclonal antibody against human C4 binding protein (MoAb:C4BP) or C4 binding protein (C4BP) depleted serum. C4 nephritic factor (C4NeF) was employed to stabilize the labile classical pathway C3 convertase C42 complex. Serum from patients with MPGN and APSGN reduced the C4NeF stabilizing activity. Sera from 32 of 46 patients with MPGN and all of 7 patients with APSGN reduced the C42 hemolytic activity relative to 50 normal human serum (NHS) after 5 min incubation at 30 degrees C in EDTA-GVB, and there was no relationship with the serum concentration of C4BP. In vivo, accelerated decay of C42 convertase might interfere with the clearing and processing mechanism of circulating immune complexes (IC) by reducing deposition of C3b on the IC lattice.

Acute Disease↗

PubMed1976

Immune complex nephritis in Schistosoma mansoni-infected mice.

Swiss outbred mice infected with 80-100 cercariae of Schistosoma mansoni developed in 60% of the cases a wide range of glomerular lesions involving mainly the mesangium. The lesions were associated with the presence of granular deposits of murine immunoglobulins and C3, suggesting an immune complex mechanism. In addition, nephritic glomeruli in about 20% of the cases could be stained by a specific rabbit antischistosoma serum after removal of excess host immunoglobulins. The presence of circulating immune complexes in the serum of infected animals was suggested by the increased molecular weight of circulating C3. The onset of the immunopathologic lesions appeared to be related to duration, intensity and type of infection. Single-sex parasite infection, in fact, led to significant reduction of glomerular lesions.

Animals↗

PubMed1992

Autoantibody to the alternative pathway C3/C5 convertase and its anti-idiotypic response. A study in affinity.

In an effort to understand the development and control of autoantibody production, we studied the affinity of autoantibody to the alternative pathway C3/C5 convertase (C3 nephritic factor (C3NeF)) and its autoanti-idiotypic antibodies, Ab2 alpha and Ab2 beta. These were isolated and purified from newborns, normal adults, and patients with membranoproliferative glomerulonephritis. In all cases, both IgG and IgM C3NeF were available for study. The affinity of IgG and IgM C3NeF for their natural Ag (10(8) liters/mol) as well as for the internal image of that Ag displayed on Ab2 beta was high (10(10) liters/mol). Furthermore, the affinity of IgG C3NeF was nearly 100-fold higher in patients than in newborns, whereas there were no significant changes with IgM C3NeF. By contrast, there were not differences in the affinity of IgG Ab2 alpha (which does not display any likeness to the native Ag) from normal adults and patients to any C3NeF isolate. There was, however, a progressive increase in affinity between both Ab2 alpha preparations and IgG C3NeF from newborns, adult normal subjects, and patients, implying an alteration in C3NeF to account for the changes in affinity. These data suggest that Ag-driven affinity maturation occurs with autoantibody but may not occur within the idiotypic network. These data also indicate that as autoantibody affinity matures, it appears to modify its idiotype, perhaps in an effort towards autoregulation.

Adult↗

PubMed1985

Immunological monitoring of plasma exchange in primary IgA nephropathy.

Plasma exchange (PE) has recently been proposed for primary immunoglobulin (Ig)-A nephropathy (PIgAGN) with progressive course. To develop suitable guidelines for PE in these cases, the authors evaluated the clinical usefulness of some immunological parameters in five patients with PIgAGN treated with PE combined with immunosuppressive drugs and small doses of corticosteroids. These parameters included the levels of IgA-containing immune complexes (IgAIC) by a specific conglutinin assay, the function of the mononuclear phagocyte system (MPS) by the in vivo clearance of IgG-sensitized erythrocytes, and complement activation as determined by C3d measurement. HLA types were also determined. Three patients had an acute nephritic syndrome with a rapidly progressive course, one of them showing sclerotic histologic changes. The two other cases had a relentless progression toward renal failure. In the patient with sclerotic PIgAGN, the MPS function was normal and the IgAIC and C3d levels were low throughout the treatment. In the other four cases, the high IgAIC and C3d levels and the MPS dysfunction found before treatment markedly improved after several PEs. The immunological parameters remained normal during the post-PE follow-up in two cases with acute nephritic syndrome and rapidly progressive course, but worsened again in two cases with a relentless course, particularly in one who possessed the B8/DR3 HLA type. Immunological monitoring including IgAIC, C3d, and MPS function is proposed, in addition to histological and clinical evaluation, as a guideline for PE in PIgAGN with evolving course.

Adolescent↗

PubMed1984

Circulating immune complexes and complement breakdown product C3d in glomerulonephritis and kidney transplantation.

Circulating immune complexes (CIC) and the complement breakdown product C3d were measured in 81 patients with glomerulonephritis (GN), 28 patients with early and 25 patients with long-term renal transplants. CIC were measured by a Clq-binding assay and C3d by a double-decker rocket immunoelectrophoresis. In patients with GN, CIC were detected in 19 and elevated C3d levels found in 45 patients. The highest levels of C3d were found in patients with membranoproliferative GN type I and II, diffuse sclerosing GN and GN secondary to SLE and Wegener's granulomatosis. No relationship was found between CIC and C3d, and the combination of CIC with C3d measurements did not help to characterize 'nephritogenic' CIC. C3d was frequently elevated in patients with impaired renal function which may reflect an inflammatory 'nephritic' process, but may also be due to a reduced renal elimination. Furthermore C3d was frequently elevated in patients with improving or decreasing renal function, and in patients with heavy proteinuria. Longitudinal studies of renal transplant patients suggested that immunosuppressive treatment decreased the C3d level. Patients with early renal transplants had elevated C3d levels that normalized during the first month after successful transplantation. CIC and elevated C3d were not related to onset of acute rejection episodes in early transplant patients nor to late renal graft failure.

Antigen-Antibody Complex↗

PubMed1973

Hypocomplementemia of membranoproliferative nephritis. Dependence of the nephritic factor reaction on properdin factor B.

Membranoproliferative nephritis in children is frequently associated with a hypocomplementemia produced at least in part by C3 breakdown mediated by a circulating anticomplementary factor known as C3 nephritic factor (C3NeF). C3 breakdown by this factor in vitro requires the presence of a pseudoglobulin cofactor and magnesium. The present study provides evidence that properdin factor B (C3 proactivator) is activated in the nephritic factor reaction and is the direct mediator of C3 breakdown by C3NeF. Depletion of factor B from mixtures of normal human serum (NHS) and plasma from a patient with membranoproliferative nephritis (MPP), either by heating or by immune equivalence absorption, blocks C3 breakdown by C3NeF. Addition of purified factor B to these mixtures restores the anticomplementary effect. When purified factor B is added to mixtures of MPP and purified C3, breakdown also occurs. Associated with the C3 breakdown is a change in the electrophoretic mobility of factor B from the beta to the gamma position, a shift which has been associated with cleavage activation of the molecule. Further, serum factor B levels are often low in patients with membranoproliferative nephritis and bear a rough inverse correlation with C3NeF levels. It thus appears that factor B is the previously described heat-labile C3NeF cofactor. Whether the C3NeF reaction proceeds via a pathway comparable to that activated by the cobra venom factor or via that activated by zymosan or inulin cannot be determined from the present data.

Absorption↗

PubMed1976

Formation in the presence of C3 nephritic factor (C3NeF) of an alternative pathway C3 convertase containing uncleaved B.

C3 nephritic factor (C3NeF) interacts with native C3 and B in the absence of D to generate a C3 convertase containing an uncleaved form of B. Dose response studies with C3NeF and B, respectively, revealed incremental C3 inactivation without loss of B. These findings are in agreement with the previous isolation from such reaction mixtures of a 10S complex containing haemolytically inactive C3 and active B and manifesting C3 convertase activity. Functional contamination of C3 with C3b was negated by demonstrating that pretreatment of C3 with C3bINA had no effect on its subsequent interaction with B and C3NeF to generate C3 convertase activity, while pretreatment of C3b eliminated its effective interaction with B and C3NeF. Relatively higher concentrations of C3bINA present during interaction of C3, B and C3NeF suppressed C3 inactivation, indicating its dependence on amplification by utilization of the initial C3b generated. Trace quantities of D were not found by functional analyses of C3, B and C3NeF and pretreatment of these proteins with a concentration of DFP sufficient to suppress D activity had no effect on their effective interaction. The introduction of D to mixtures of C3NeF, B, and C3 resulted in B clevage and more efficient expression of C3 convertase function as defined by a reduced requirement for C3NeF.

Complement C3↗

PubMed1975

Properdin- and nephritic factor-dependent C3 convertases: requirement of native C3 for enzyme formation and the function of bound C3b as properdin receptor.

Two complex enzymes were assembled that both converted C3 to C3b, one consisting of activated properdin (P), native C3, proactivator (PA) and proactivator convertase (PAase), and the other of nephritic factor (NF) and the same three cofactors. By maintaining a critical concentration of PAase, the P-C3 convertase and the NF-C3 convertase were shown to function efficiently without formation of the C3b-feedback enzyme. The former two enzymes are distinct from the C3b-dependent C3 convertase in that they utilize native C3 instead of C3b and PA in an apparently uncleaved form. The P- and NF-C3 convertase express maximal activity within approximately 10 min at 37 degrees C and decay with a half-life of 35 min at 37 degrees C, which is in contradistinction to the reported lability of the C3b-feedback enzyme. P- and NF-C3 convertases are inhibited by their product C3b, which may constitute a heretofore unknown control of the alternative pathway. A direct physical interaction of P with native C3 and C3b was demonstrated by agglutination of C3b-bearing erythrocytes and by agglutination inhibition. Bound C3b thus constitutes the only known receptor of P and may fulfill an important localizing function for P and the P-C3 convertase in vivo. Although P and NF form functionally similar enzymes, they act independently of each other and are apparently immunochemically unrelated proteins.

Absorption↗

PubMed1976

C3 nephritic factor (C3NeF): stabilization of fluid phase and cell-bound alternative pathway convertase.

C3 nephritic factor (C3NeF) defined by the capacity of nephritic serum and its fractions to initiate loss of the B antigen of C3 in normal serum was purified from the serum of three different donors and shown to function by stabilization of membrane-bound and fluid phase alternative pathway C3 convertase. C3NeF converts cell-bound C3B sites in a dose-related manner to CEB(NeF) sites, which exhibit an approximate 10-fold increase in half-life. The linear relationship between the C3NeF input and the residual hemolytic sites on EAC43B present after incubation for 20 min at 30 degrees C, during which labile C3B sites have decayed, indicates that the number of residual C3B sites is directly related to the dose of C3NeF. The capacity of C3NeF to stabilize the C3B convertase in a temperature- and dose-dependent manner, which is independent of binding or consumption of C3NeF, in a fluid phase reaction mixture of 125I-B, 131I-C3 and D permits isolation of a 10S complex containing radiolabeled C3 and B and exhibiting C3, convertase activity on an exogenous C3 source. Thus, the stabilizing effect of C3NeF is not limited to membrane-bound C3B but is also sufficient to permit recovery of a fluid phase C3 convertase formed during the interaction of C3, B, and D.

Binding Sites↗

PubMedDate not supplied

Inducible nitric oxide synthase induction in Thy 1 glomerulonephritis is complement and reactive oxygen species dependent.

Thy 1 glomerulonephritis (GN) is a rat model of complement-dependent immune mesangial injury with induced glomerular nitric oxide (NO) synthesis. To examine mechanisms of inducible nitric oxide synthase (iNOS) induction, we studied the effects of treatment with the antioxidant N-acetyl-cysteine (NAC) and soluble complement receptor 1 (sCR1). Thy 1 GN was induced by intravenous anti-Thy 1 antibody. Glomeruli were isolated and kidney tissue taken from 30 min to 24 h after induction. Nitrite (NO-2) synthesis, luminol chemiluminescence for reactive oxygen species (ROS), and iNOS and cytokine mRNA were assayed in isolated glomeruli. Mesangial injury (mesangiolysis) and leucocyte infiltration were quantitated on tissue sections. NAC (i.p. 1,000 mg/kg, 1 h prior to anti-Thy 1) reduced glomerular NO-2 synthesis (3.5 +/- 0.66 vs. untreated 8.2 +/- 1.1, p = 0.02), and iNOS mRNA expression, and abolished enhanced chemiluminescence. In vitro incubation of nephritic glomeruli with 20 mM NAC also suppressed nitrite production (4.7 +/- 0.8 vs. untreated 12.2 +/- 0. 7 nmol NO-2/2,000 glomeruli/48 h, p = 0.003), and chemiluminescence. In NAC-treated animals, neutrophil infiltration (0.5 +/- 0 vs. untreated 9.6 +/- 1.6 glomerulus, p = 0.0005), and macrophage infiltration (1.7 +/- 0.4 vs. untreated 12.0 +/- 0.1, p = 0.006) were abolished, and mesangiolysis was significantly reduced (45.9 +/- 1.3 vs. untreated 34.4 +/- 2.1 cells/glomerulus, p = 0.009). NAC did not inhibit anti-Thy 1 antibody deposition. C1q was unaffected, but C3 was reduced. sCR1 treatment prevented iNOS mRNA induction, the enhanced chemiluminescence, and the neutrophil infiltration at 1 h. IL-1beta and TNFalpha mRNAs were not affected by either NAC or sCR1. These results show that NAC inhibits iNOS induction and NO synthesis in this model, and suppresses ROS synthesis and injury. They suggest that complement-dependent ROS generation is the critical initiating event that follows fixation of anti-Thy 1 antibody.

Acetylcysteine↗

PubMed1984

Reduction of phagocyte adherence by nephritic sera: relation to complement activation.

Phagocytes isolated from either normal donors or from patients with poststreptococcal (P-SGN), lupus erythematosus (SLE-GN), or membranoproliferative (MPGN) glomerulonephritis showed normal adherence to glass (PAg) after incubation in normal human serum (NHS), but was reduced after incubation in patient serum. Low PAg was the consequence of incubation of normal phagocytes with the earliest available sera from all 22 P-SGN patients, 28 of 37 SLE-GN patients, 19 of 25 patients with MPGN type I, all 10 with types II and III, and all 5 with nephritis associated with chronic bacteremia. Low C3 and decreased PAg were related by regression analysis in sera from patients with P-SGN (P less than 0.001), SLE-GN (P less than 0.005), and MPGN (P less than 0.001) type I. In patients with P-SGN and one patient with nephritis associated with chronic bacteremia, complement levels and PAg returned to normal in parallel with clinical improvement. In vitro, PAg was reduced by NHS treated with either zymosan or bovine serum albumin (BSA)-anti-BSA complexes but neither BSA-anti-BSA complexes or zymosan, previously incubated in NHS, reduced PAg. PAg was normal in serum deficient in C4 or C5 unless treated with zymosan.

Adult↗

PubMedDate not supplied

Proinflammatory effects in experimental mesangial proliferative glomerulonephritis of the immunosuppressive agent SDZ RAD, a rapamycin derivative.

BACKGROUND/AIM: The new immunosuppressant SDZ RAD, a rapamycin derivative, inhibits growth factor driven cell proliferation. SDZ RAD designed for transplantation may also be a candidate agent to treat inflammatory kidney diseases. Therefore, we investigated the effects of SDZ RAD in two different animal models of glomerulonephritis, in anti- Thy1.1 nephritis and in acute puromycin aminonucleoside (PAN) nephrosis. METHODS: Eighty-seven male Wistar rats were investigated. Anti-Thy1.1 nephritis: healthy rats (n = 9), SDZ RAD-treated healthy rats (n = 6), nephritic rats (n = 9), SDZ RAD placebo treated nephritic rats (n = 6), SDZ RAD-pretreated nephritic rats (n = 9), and early (n = 6) as well as delayed (n = 6) SDZ RAD-posttreated nephritic rats. PAN nephrosis: healthy rats (n = 6), SDZ RAD-treated healthy rats (n = 6), nephritic rats (n = 12), and SDZ RAD-pretreated nephritic rats (n = 12). In a separate study, 12 male Sprague-Dawley rats were analyzed in anti-Thy1.1 nephritis: healthy rats (n = 3), nephritic rats (n = 3) and pretreated nephritic rats (n = 6). SDZ RAD and SDZ RAD placebo were given at single doses of 2.5 mg/kg body weight per day by gavage. The experiments lasted until days +2 and +9 after induction of anti-Thy1. 1 nephritis and until day +13 in the case of PAN nephrosis. RESULTS: In anti-Thy1.1 nephritis, SDZ RAD demonstrated marked proinflammatory effects in a time-dependent manner, as reflected by severe focal damage to glomerular histology including inhibition of mesangial cell proliferation, reduction of creatinine clearance, and increase in plasma creatinine levels as well as proteinuria. Almost identical results were obtained in both rat strains. In contrary, SDZ RAD ameliorated significantly the development of PAN nephrosis. Animals pretreated by this agent showed a significant reduction of proteinuria and of glomerular invasion of monocytes/macrophages. CONCLUSION: Some caution is warranted for the use of SDZ RAD in inflammatory glomerular diseases, since it accentuated glomerular damage induced by anti-Thy1.1 antibodies.

Animals↗

PubMed1999

Effect of renovascular hypertension on experimental glomerulonephritis in rats.

Systemic hypertension is a major risk factor that determines the rate of progression of kidney disease. The underlying mechanisms, however, are incompletely understood. To gain insight into these mechanisms, the present study was undertaken to characterize the effects of renovascular hypertension on the course of anti-thymocyte antibody-induced glomerulonephritis. Glomerulonephritis was induced in rats 6 weeks after the initiation of two-kidney, one-clip hypertension, when blood pressure was already increased. Structure and function of the clipped and the nonclipped kidney were examined 5 days later. Glomerular filtration rate (GFR) was measured by inulin clearance. The induction of nephritis did not alter the blood pressure in either hypertensive rats or normotensive controls. Albuminuria increased slightly in normotensive rats after the induction of nephritis, whereas no significant differences were found between hypertensive rats with or without nephritis. No significant differences were found for the GFR values of normotensive controls and nephritic animals or for values in the clipped kidney with or without nephritis. However, the GFR of the nonclipped kidney was significantly reduced in nephritic animals as compared with all other groups. Morphologic evaluation revealed that hypertensive rats with nephritis exhibited a combination of characteristics of nephritis and hypertensive glomerular injury. Histologic findings of nephritis, such as glomerular binding of rabbit IgG and glomerular proliferation and mesangial matrix expansion, were similar after the induction of nephritis in controls and in the clipped and nonclipped kidneys of hypertensive animals. However, intraglomerular microaneurysms were significantly more often found in the non-clipped kidneys after the induction of nephritis. Hypertension-induced deterioration of glomerular function was not associated with marked morphologic deterioration but rather with a combination of the characteristics of nephritis and hypertensive glomerular injury.

Albuminuria↗

PubMed1996

Decrease of glomerular disialogangliosides in puromycin nephrosis of the rat.

Puromycin aminonucleoside nephrosis (PAN) is a model for human minimal change nephropathy induced in rats by injection of puromycin. In PAN, defective sialylation of a major sialoprotein of podocytes, podocalyxin, has been demonstrated and the consequent decrease of anionic charge suggested as a causative factor for increased glomerular permeability and proteinuria. Whether defective sialylation is a general feature of PAN affecting also glomerular glycosphingolipids is not known. We have shown that rat glomeruli are rich in disialogangliosides GD3 and O-acetyl GD3, the functions of which are not known. Here, we made a sequential analysis of the glomerular gangliosides, especially of GD3 and its O-acetyl derivative in acute PAN using immunohistochemical and biochemical techniques and compared the results with another rat model of glomerular disease, Heymann nephritis. The prominent immunohistochemical finding was the almost total disappearance of glomerular O-acetyl GD3 and a substantial decrease of its precursor GD3 peaking at 10 days after injection of puromycin. Segmental areas lacking these gangliosides remained in glomeruli still at 30 days after injection. The response was dose dependent. Semiquantitative analysis by thin layer chromatograms showed that O-acetyl GD3 was decreased by 41% already at 3 days and by 60% at 10 days after injection of puromycin. Also GD3, the immediate precursor of O-acetyl GD3, was decreased by 20 and 19%, respectively, at 3 and 10 days after injection. At 3 days after injection, overt proteinuria had not started. At these times, no other changes were observed in the glomerular gangliosides. The decrease of glomerular GD3 and O-acetyl GD3 indicates a decrease of GD3 synthase activity and perhaps of O-acetyltransferase activity in PAN nephrosis. As these changes preceded the overt proteinuria, they may have a causal relationship to it. In the glomeruli of Heymann nephritic rats, no similar changes were seen, suggesting that the sialylation defect is not due to proteinuria but is a consequence of targeted puromycin action on cells.

Albuminuria↗