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PubMedDate not supplied

An IgG autoantibody which inactivates C1-inhibitor.

Antibodies are considered to play a specific pathogenic role in certain disease states such as myasthenia gravis, Graves' disease and autoimmune haemolytic anaemia. Autoantibodies which interfere with the function of enzyme cascade systems have also been described in diseases such as acquired haemophilia (anti-factor VIII antibodies) and glomerulonephritis (C3 nephritic factor). The identification of these autoantibodies is crucial to an understanding of the aetiology of such diseases and is also of importance in revealing the inter-relationships of the immune system with other biological pathways. This is the first report of an immunoglobulin G (IgG) autoantibody reactive with C1-inhibitor (C1-Inh), a pivotal inhibitor of the inflammatory response which is known to inactivate proteins of the complement, kinin, fibrinolytic and 'contact phase' systems. This autoantibody was isolated from a patient with a novel variant of acquired angioedema and C1-Inh dysfunction. This finding highlights the involvement of the immune system in the pathogenesis of disorders characterized by the presence of dysfunctional inflammatory response proteins.

Autoantibodies↗

PubMed1977

[Hyperacute rejection of an HL-A identical renal allograft (author's transl)].

Hyperacute renal allograft rejection is described in a patient suffering from mesangio-proliferative glomerulonephritis. The transplanted kidney was HL-A identical and the direct cytotoxic cross-match between the recipient's serum and donor lymphocytes was negative. Intrarenal consumption of C 3, but not of C 1 q, C 4, total haemolytic complement, IgG or Igm was demonstrated. Immunofluorescence studies exhibited dense granular deposits of C 3, but not of IgG, IgM C 1q or C 4. These findings together with the observation of beta 1 C-beta 1A converting activity in the patient's serum, raised the possibility that the alternative pathway of complement activation induced by nephritic factor could have operated in this case. Further studies will be necessary to clarify the question whether hyperacute rejection of renal allografts is only antibody mediated or not.

Acute Disease↗

PubMed1980

The interaction of C5 with C3b in free solution: a sufficient condition for cleavage by a fluid phase C3/C5 convertase.

We have measured the interactions of C3b with C5 in free solution under conditions that favor detecting weak binding interactions (high C3b and low C5 concentrations and low ionic strength). When a mixture of 125I-C5 (2 X 10(-8) M) and unlabeled C3b (3.8 x 10(-5) M) was ultracentrifuged in a sucrose gradient, virtually all of the C5 sedimented to the position of a 13 to 14S complex. In contrast, a sedimentation rate for C5 of 9S was obtained in the absence of C3b. The ability to bind C5 was observed to be a property of C3b since native C3 was unable to bind C5. It was also found that beta 1H by itself could inhibit the binding of C5 to cell-bound C3b. From inhibition studies, we estimate that the association constant for the C3b-C5 interaction is on the order of 2 x 10(6) M-1 in a low ionic strength buffer (mu = 0.06) and 5-fold weaker at physiologic ionic strength. C5 bound to C3b in free solution was cleaved by nephritic factor-stabilized fluid phase C3bB. C5 activation did not occur on omitting C3b. We conclude that the ability to bind C5 is a property of C3b molecules whether surface bound or in free solution and that when C5 is bound in either fashion, it can be cleaved by a fluid phase C3/C5 convertase.

Animals↗

PubMedDate not supplied

[The activation of the complement system in various connective tissue diseases].

A knowledge of the complement system in patients with collagen diseases is of interest as it may serve to indicate the existence of activity or non-activity in these diseases. We have studied the existence or non-existence of the activity of the complement system through evaluation of the levels of C3, as well as the implicated mechanism of the classical or alternate pathways through the measure of C'4 and C'3 proactivator components. Quantitation of complement components was obtained by electroimmunodiffusion, employing specific antiserum. From the results obtained, we observed that the complement activity in patients with SLE, the classic pathway was affected more (7 patients of the 24 studied), than the alternate pathway (3 patients). However, in those patients affected by sclerodermia, there seems to be an equal incidence of the activation of complement through both pathways (2 patients with activation through each way). Also of interest is the existence of a patient with SLE and another affected by sclerodermia in which a selective reduction of C'3 was observed. This observation suggests the possible existence of a selective destruction, perhaps mediated through a factor type such as the nephritic factor. However, there may exist other patients of whom we have already commented on, with a parallel reduction in the three components which suggests a change in the synthesis or in the simultaneous activation in both of the pathways. When realizing the comparative studies of the state in which the immunoglobulins (IgG, IgA and IgM) and complement components are to be found, the conclusion is that there is no significative correlation between the two. This is particularly interesting as it assumes the necessity of knowing the state of the complement and not only of the immunoglobulin, in order to know the state of activity in which the process is.

Complement C3↗

PubMed1978

[Recurrence of intramembraneous glomerulonephritis in 2 consecutive kidney transplantations].

A case of dense intramembranous deposit disease, partial lipodystrophy, hypocomplementemia, and nephritic factor-like activity in the serum is presented. Recurrence of underlying renal disease was noted in two consecutive renal allografts. The first transplant was lost 7 months after implantation, chronic renal rejection being an additional cause of graft failure. A favourable clinical course, however, was observed after the second renal transplantation. 22 months after surgery, the patient was fully rehabilitated and transplant function only slightly reduced despite electron microscopic evidence of typical dense intramembranous deposit lesions. Low C3-serum complement and normal C4-serum complement levels were constant findings throughout observation time. The case supports the assumption that patients with dense intramembranous deposit disease should not be excluded from renal transplantation As shown in the literature, maintenance of satisfactory graft function is usually obtained for a long period of time despite recurrence of original disease.

Adult↗

PubMed1993

Immunohistochemical localization of C3d fragment of complement and S-protein (vitronectin) in normal and diseased human kidneys: association with the C5b-9 complex and vitronectin receptor.

The localization of C3d, a fragment produced by C3 activation and S-protein (vitronectin), a regulatory factor of C5b-9, was studied immunohistochemically in normal human kidney and renal biopsies from patients with several types of glomerulonephritis. Immunofluorescent staining of the normal kidneys showed that C3d was present along the glomerular basement membrane (GBM), tubular basement membrane (TBM) and arterioles, and that S-protein was present in the GBM, mesangium, TBM, and arterioles. Immunoelectron microscopy of isolated basement membranes showed that C3d was localized exclusively on the epithelial side of the GBM, and that S-protein was present along both the epithelial and endothelial sides. In nephritic tissues, glomerular staining of C3d, C5b-9, and S-protein was increased when compared with that in normal tissues. S-protein, frequently co-localized with C3d and C5b-9 neoantigen, was intensely positive in the immune deposits of glomerular capillaries and the mesangial area, overlapping the background staining of GBM and mesangial matrix. S-protein and its receptor were occasionally co-localized in the glomeruli. These findings indicate that C3d and S-protein are normally present in the glomeruli. Co-staining of C3d, C5b-9 neoantigen, and S-protein within the immune deposits of nephritic kidneys suggests in situ binding of S-protein to locally-formed C5b-9 complex, or merely co-distribution of S-protein with the complex, rather than trapping of large molecular SC5b-9 complex from the circulation.

Complement C3d↗

PubMed1993

Analysis of clinical and laboratory profile in Indian childhood systemic lupus erythematosus and its comparison with SLE in adults.

Data on the clinical and laboratory profiles of 83 children with SLE have been analysed and compared with data on 187 adults with the disease. The clinical features of childhood SLE are similar to those seen in adults, although clinical and laboratory parameters reflect propensity to a more severe form of the disease in the juvenile age group. However, in comparison to descriptions of childhood lupus from developed countries, in India the female-to-male ratio in this age group parallels that in adults. Renal involvement is noted to be more common, whereas gastro-intestinal and haematological abnormalities are less common. Interestingly, leucopenia, lymphopenia and nephritic type of renal involvement are commonly seen in boys with SLE, but these features are non-existent in men.

Adolescent↗

PubMed1995

Complement system promotes transfer of immune complex across glomerular filtration barrier.

BACKGROUND: The solubilizing effect of complement (C) on immune complexes (IC) in the fluid phase is well known, however effects on tissue-deposited IC have not been analyzed in detail. We studied the influence of C depletion on the movement of IC across the glomerular basement membrane in a rat model of passive in situ IC nephritis. EXPERIMENTAL DESIGN: The left kidneys of intact rats, rats given cobra venom factor (C-depleted) or rats given anti-polymorphonuclear granulocyte antiserum (PMN-depleted) were perfused with cationized ferritin (electron-dense tracer antigen), followed by intravenous injection of rabbit anti-ferritin antibody 15 minutes later. The glomerular distribution of rabbit IgG (antibody) and rat C3 was visualized by immunogold staining. RESULTS: In intact, nephritic rats (non C-depleted), the distribution of antigen, antibody, and C3 (IC) was mainly subendothelial 2 and 6 hours after antibody injection, at 24 hours about 75% and by 48 hours virtually all 3 IC components were localized on the subepithelial side of the glomerular basement membrane in all glomeruli. In C-depleted rats, the distribution of IC was as in intact rats, up to 6 hours. At 24 hours, two patterns of IC distribution within individual glomeruli could be distinguished. About 2/3 of the capillary wall area revealed a distribution similar to the C-intact animals; however in 1/3 of the capillary wall area, IC was still predominantly subendothelial at 24 hours. By 48 hours, some accumulation in the lamina densa was noted. At day 7, some IC was still subendothelial, in limited areas, even though serum C3 level had returned to 60% of normal. On the other hand, the distribution of IC in polymorphonuclear leukocyte-depleted, C-intact rats, showed no difference to that in control nephritic rats. Proteinuria was significantly decreased in both C-depleted rats and polymorphonuclear leukocyte-depleted rats. Thus, enhanced glomerular permeability itself does not guarantee complete, rapid IC movement. CONCLUSIONS: The C system promotes effective transfer of IC across the glomerular basement membrane, probably due to the solubilizing effect of C on IC lattices.

Animals↗

PubMed1991

Complement and monocytes are essential for provoking glomerular injury in passive Heymann nephritis in rats. Terminal complement components are not the sole mediators of proteinuria.

Complement but not polymorphonuclear granulocytes (PMN) causes glomerular injury in passive Heymann nephritis in rats. We have now identified monocytes as another important mediator in this model. Passive Heymann nephritis was induced in Wistar rats by intravenous injection of sheep anti-rat Fx1A antiserum. Four groups (all receiving anti-rat Fx1A antiserum) were studied: (a) rats given normal sheep globulin (nephritic controls), (b) rats given sheep anti-rat PMN globulin (PMN-depleted), (c) rats given sheep anti-rat monocyte globulin (monocyte-depleted), (d) rats injected with cobra venom factor (complement-depleted). In vitro specificity controls for anti-cell antisera were made by cytotoxicity tests and inhibition of phagocytosis. In vivo specificity controls were performed in heterologous Masugi nephritis (PMN-dependent) and accelerated Masugi nephritis (monocyte-dependent). Complement and monocyte depletion significantly delayed the onset of proteinuria (p less than 0.001 versus nephritic controls on day 5), PMN depletion had no significant effect. Monocyte infiltration was seen in control nephritic rats, but monocyte depletion prevented this influx. In the monocyte-depleted group, no differences in glomerular deposition of C3, C9, and C5b-9 were seen in comparison to the nephritic control rats. Serum C3 levels were comparable in groups a, b, and c, the complement system was biologically active in the monocyte depleted-group (c), and the amount of anti-Fx1A antibody bound was the same in all groups. This shows that, besides complement, monocytes are required for induction of renal damage in passive Heymann nephritis. The concept of a sole role for complement in glomerular immune injury involving subepithelial immune deposits should be reconsidered.

Animals↗

PubMed1980

[Uremic hemolytic syndrome in the adult. A study of four cases (author's transl)].

Four cases of the uremic-hemolytic syndrome in the adult are presented. One of them was associated with the presence of the Australia antigen in the plasma. Another had recurrent and familial characteristics associated with the ingestion of oral contraceptives and exhibited a persistent activation of the C3 fraction and the presence of C3NeF (nephritic factor). The two remaining cases were associated with the post partum. Three patients have received sodium heparin continuously, two of which (post partum uremic-hemolytic syndrome) recovered the renal function. A third case, with recurrent uremic-hemolytic syndrome, presented an improvement of the renal function under heparin treatment after the first episode of the disease, but not after the second. Two patients are included in a program of periodic hemodyalisis. The mechanisms by which infections, ingestion of oral contraceptives or post partum can produce an intravascular coagulation syndrome or immunitary disorders are analyzed, both phenomena being interrelated and apparently playing an important role in the pathogenesis of the uremic-hemolytic syndrome.

Adolescent↗

PubMed1991

Tubulointerstitial nephritis during the heterologous phase of nephrotoxic serum nephritis.

This study was designed to characterize the immunopathology of acute tubulointerstitial disease in nephrotoxic serum nephritis in nonsensitized rats. Groups of Lewis rats were studied at 12 time periods ranging from 10 min to 28 days after nephrotoxic serum injection. Nephritic rats developed interstitial nephritis during the acute heterologous phase of renal injury. Coincident with the focal deposition of nephrotoxic antibodies along tubular basement membranes at 24 h, an influx of polymorphonuclear cells and macrophages was evident. The most prominent infiltrate, present between days 3 and 7, was dominated by macrophages with smaller numbers of lymphocytes that were mainly cytotoxic T cells. Dual-labeling studies demonstrated the colocalization of linear tubular basement membrane deposits of the nephrotoxic antibody with focal clusters of interstitial lymphohemopoietic cells. Increased complement deposition was not evident along the tubular basement membranes; moreover, C3 depletion with cobra venom factor failed to attenuate the interstitial inflammation. During the late autologous phase of glomerulonephritis, tubular basement membrane deposits of rat IgG did not appear and the interstitial disease resolved. The results of this study demonstrate that the heterologous phase of nephrotoxic serum nephritis is an antibody-mediated disease directed against the basement membranes not only of the glomeruli but also of some tubules. Antibody deposition is followed by an acute influx of phagocytic cells to both regions of the kidney. These cells may play an important role in the genesis of acute interstitial injury and chronic interstitial fibrosis associated with antiglomerular basement membrane nephritis.

Albuminuria↗

PubMed1976

Mesangiocapillary glomerulonephritis with dense "deposits" in the basement membranes of the kidney.

Amongst 125 patients with mesangiocapillary glomerulonephritis (MCGN), 19 showed continuous intramembranous dense "deposits" (IDD). Most were children or young adults. Two patients had partial lipodystrophy. Eleven had a consistently low plasma concentration of C3; only three, however, had an initial low plasma concentration of C4, which rose and then remained normal in two. Tests for the C3 nephritic factor were positive in thirteen patients, and plasma C1q was normal in 8 out of 11 cases investigated. Ten out of twelve (seven of them with low plasma C3) showed C3 deposition by immunofluorescence in the glomerular tuft. This was also demonstrated in some instances in Bowman's capsule and tubular basement membranes. Stains for IgG, IgA, C4 and C1q were negative in all, whereas stains for IgM and fibrin were weakly positive in the glomeruli of three and eight cases repectively. Eight patients went into terminal renal failure over an average of thirty-three months and required hemodialysis or transplantation. MCGN with IDD is an uncommon pattern of renal response to injury, which involves activation of the alternate pathway of the complement system and has a poor short term prognosis. The association with partial lipodystrophy and C3-splitting activity suggests a primary complement abnormality.

Adolescent↗

PubMed1974

A serum factor in chronic hypocomplementemic hephritis distinct from immunoglobulins and activating the alternate pathway of complement.

Nephritic factor (C3NeF) has been isolated from plasma of patients with hypocomplementemic chronic glomerulonephritis (HCG) by ion exchange and molecular sieve chromatography. This material was further treated with solidified anti-Ig antiserum. The purified material failed to react with antiserum to human IgG, IgG3, Fab, Fc, and kappa and lambda chains, but retained full C3NeF activity. The nonidentity of C3NeF with IgG was further demonstrated by Ouchterlony analysis using anti-IgG and anti-C3NeF. Isolated C3NeF was found to be a protein with a sedimentation coefficient of 7S and a mol wt of 150,000 daltons, which on microzone electrophoresis and gel electrophoresis at pH 8.6 behaved as a gamma-globulin. C3NeF is not a C1q precipitin and does not activate the classical complement pathway. Unlike cobra venom factor, it failed to enter into a complex with C3 proactivator (C3PA) when incubated with normal human serum (NHS) and then subjected to sucrose density gradient ultracentrifugation. The action of isolated C3NeF on C3 requires C3PA, C3PA convertase (C3PAse), and properdin (P). Similarly, C3PA conversion by C3NeF requires P, C3PAse, and C3. Total hemolytic activity was lost by incubation of 64 microg of C3NeF/1 ml NHS at 37 degrees C for 30 min. Both C3a and C5a anaphylatoxin could be generated by C3NeF in serum previously depleted of anaphylatoxin inactivator. Anti-C3NeF was found to detect an antigen in all NHS tested. Treatment of NHS with solidified anti-C3NeF caused impairment of the alternate complement pathway. It failed to sustain lysis of glutathione-treated human erythrocytes initiated by inulin. It is conceivable that the normal serum constituent which is removed by anti-C3NeF constitutes the inactive precursor of C3NeF, and a heretofore unrecognized component of the alternate pathway.

Adsorption↗

PubMed1976

Nephritic factor: its structure and function and its relationship to initiating factor of the alternative pathway.

Nephritic factor (NF) has a molecular weight of 170,000 and is composed of two disulfide-linked 85,000-dalton chains. NF assembles the fluid phase C3 convertase from Factors B and D, C3, and magnesium by physically incorporating itself into the enzyme complex. NF exerts its stabilizing effect on the cell-bound C3/C5 convertase, EC3b,B, by physically associating itself with this complex. On decay of the cell-bound enzyme NF is released into the fluid phase and retains its binding and stabilizing potential. Its activity is resistant to diisopropylfluorophosphate treatment. Because NF causes agglutination of EC3b,B, it must be endowed with more than one binding site.

Binding Sites↗

PubMed1987

C4 nephritic factor in a patient with chronic glomerulonephritis.

C4 nephritic factor (C4NeF) was found in the serum of a patient with chronic glomerulonephritis, whose C3 level was quite low (less than 1% of normal). C4NeF prevented the intrinsic decay of C4b2a enzyme and prolonged the half life of the C4b2a from several minutes to more than 1 h in the solid and fluid phase. The C4NeF activity was associated with a protein fraction immunochemically identified as the IgG3 subclass and it bound specifically to the EAC142 cells. In addition, the patient's serum contained C3-cleaving activity, probably C4b2a, C4NeF complex, which may have lowered the level of C3 in the patient's serum. Spontaneously, the titer of C4NeF decreased, while the level of C3 increased.

Chronic Disease↗

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↗