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PubMed1979

Further evidence for the antibody nature of C3 nephritic factor (C3NeF).

C3 nephritic factor (C3NeF), found in the sera of some patients with membranoproliferative glomerulonephritis, has been shown to be composed of two heavy and two light chains, like IgG; in addition it shares antigenic determinants with IgG. Purified C3NeF binds to the amplification convertase of complement, C3b,Bb, and thereby prevents decay of its C3-cleaving potential. The capability of C3NeF to bind to C3b,Bb was used as a means for purifying C3NeF to homogeneity. The investigation described in this report suggests that binding of C3NeF to C3b,Bb occurs via the Fab portion of the molecule. Pepsin treatment of eight C3NeF preparations resulted in an average loss of 76% of C3NeF functional activity. Papain treatment induced a loss of approximately 90%. The decrease in functional activity could be attributed to the accelerated rate of dissociation of 125I-F(ab')2 and 125I-Fab fragments from stabilized cell-bound C3b,Bb. The dissociation rate of 125I-F(ab')2 from C3b,Bb was comparable with the decay of the functional activity of C3b,Bb stabilized by F(ab')2 or Fab fragments of C3NeF. Although these results suggest that the stabilizing activity of C3NeF is mediated by the Fab portion of the molecule, it was found that the Fc portion also contributes to its functional activity.

Antibodies↗
PubMed1979

Renal transplantation for patients with type I and type II membranoproliferative glomerulonephritis: serial complement and nephritic factor measurements and the problem of recurrence of disease.

Fourteen patients with membranoproliferative glomerulonephritis as their original kidney disease received 16 renal allografts. All 14 patients are alive, 11 currently have functioning allografts, and one graft was lost to recurrence of membranoproliferative glomerulonephritis. Originally depressed serum complement (C3) concentrations returned to normal soon after transplantation in those patients with no clinical evidence of recurrence. Two patients with type II membranoproliferative glomerulonephritis had recurrence of disease. Nephritic factor (C3NeF) was high in both these patients before they received their transplants and was absent soon thereafter. However, abnormally high levels were again detected in their course. The one recurrence of type I membranoproliferative glomerulonephritis was associated with depressed C3, Clq, C4 and factor B but without C3NeF activity. Despite warnings of "high risks/ and "high mortality" associated with renal transplants in patients with membranoproliferative glomerulonephritis, we, because of these results and a review of the literature, continue to recommend renal transplants from both living related (LRD) and cadaver (CAD) donors in otherwise suitable patients who have renal failure due to membranoproliferative glomerulonephritis.

Adolescent↗
PubMed1990

Production of IgG and IgM autoantibody to the alternative pathway C3 convertase in normal individuals and patients with membranoproliferative glomerulonephritis.

To understand the origin of autoantibody production, we studied the ontogeny of antibody to the alternative pathway C3 convertase (C3 nephritic factor or C3NeF). Peripheral blood mononuclear cells from newborns, normal adults, and patients with membranoproliferative glomerulonephritis produced IgM and IgG C3NeF after culture for 14 days with pokeweed mitogen. Both IgM and IgG moieties appear to have the same paratope and are able to inhibit each other's binding and function. The affinity constant for each of the C3NeF molecules was moderately high (10(8) liters/mol) and there appeared to be little difference between the Ka values for the IgG and the IgM autoantibodies or between Ka values for autoantibodies isolated from newborns, adults, and patients. These data, then, indicate that the ability to produce C3NeF autoantibody is present from the time of birth in normal individuals. The high affinity of these autoantibodies under normal conditions suggests that C3NeF may play a more important physiological role than previously anticipated.

Antibody Formation↗
PubMed1979

Hereditary angio-oedema and C3 nephritic factor--HL-A study.

In one family of twenty-four members hereditary angio-oedema was present in the family for six generations. The protein C1 esterase inactivator found in nine patients proved to be non-active in a functional test. Another anomaly found in the complementary system was labelled C3 nephritic factor without any renal, or other clinical symptoms. Study of HL-A haplotypes did not show any linkage with the loci A, B and C. Hereditary angio-oedema is a disease arising from a specific defect in the inactivator of the C1 esterase (C1 INA) which is a regulating component of the complement system (Donaldson & Evans, 1963). This system is of current interest because of its interaction with other mechanisms of inflammation. Moreover, some links have been discovered recently between HL-A and hereditary defects of complement. This paper reports new findings in a family with hereditary angio-oedema.

Angioedema↗
PubMed1978

Identification of nephritic factor as an immunoglobulin.

C3 nephritic factor (C3NeF) activity in sera from three patients with mesangiocapillary glomerulonephritis, one of whom had partial lipodystrophy, was found on chromatography to be associated with fractions containing IgG and no other detectable proteins. Immunoadsorption of IgG from these fractions with a highly purified anti-IgG removed the C3NeF, and the IgG, eluted after combination with the anti-IgG, retained C3NeF activity. In each case the isolated IgG with C3NeF activity was found to contain more than one subclass of IgG and both kappa and lambda chains, indicating that the immunoglobulin comprising C3NeF in these patients is heterogeneous and not monoclonal. The identification of C3NeF as an immunoglobulin suggests that it may be an autoantibody against antigenic determinants of complement components present in the C3 convertase of the alternative pathway.

Chromatography, Ion Exchange↗
PubMed1977

Mesangial proliferative glomerulonephritis with irregular intramembranous deposits. Another variant of hypocoplementemic nephritis.

Two patients with a persistent mesangial proliferative glomerulonephritis and reduced serum C3 levels have been followed for six and 10 years. Both have had a mild course with normal renal function and spontaneous morphologic improvement. Levels of the fourth component (C4) and second component (C2) of complement, and properdin factor B have been normal; the third component (C3) of complement nephritic factor has not been detected. Ultrastructurally, irregular intramembranous electron-dense deposits are present, primarily within the lamina densa. These deposits are separated by varying lengths of normal-appearing glomerular basement membrane. Intramembranous and subendothelial electron-lucent areas, containing vesicles, are also seen. Subendothelial deposits, mesangial interposition, splitting of the glomerular basement membrane and ribbon-like intramembranous deposits are not found. The disease in these patients was clinically indistinguishable at onset from mrmbranoproliferative glomerulonephritis (MPGN). The possibility of a variant with mild clinical course, no progression and spontaneous morphologic improvement is important in planning and assessing treatment programs in this disease group.

Adolescent↗
PubMed1976

Host resistance to lipopolysaccharides in the pathogenesis of multiple sclerosis and membranoproliferative glomerulonephritis.

Host resistance against bacterial lipopolysaccharides (L.P.S.) and especially against its toxic part lipid A has earlier been demonstrated in biological assays. In this paper an aryl-esterase is shown to be associated with alfa-1-lipoprotein (ArE) and is probably responsible for the detoxification of L.P.S. in man. Furthermore C3 is shown to be activitated by L.P.S. From these facts it is suggested that ArE performs the initial degradation of L.P.S. followed by complement activation and trapping of the L.P.S.--complement complex in the reticuloendothelial system. It is postulated that a deficient host response against L.P.S. can be the triggering mechanism in multiple sclerosis due to the lack of ArE in myelin, and that an infectious-agent/L.P.S. syndrome can activate latent infections in connection with a severe hyperreactivity to L.P.S. Preliminary investigations in patients with membranoproliferative glomerulonephritis have shown low levels of ArE in serum. This change, together with the low C3 values in these patients, may result in deficient L.P.S. detoxification and it is suggested that L.P.S. are at least partly responsible for the production of C3 nephritic factor.

Antigen-Antibody Complex↗
PubMed1990

Determination of C3 nephritic factor activity by a microassay based on the peroxidase-like activity of the heme group.

We report a modification of a method for measuring the C3 nephritic factor, using the peroxidase activity of the heme group. This modification increases the sensitivity of the method, approximately seven-fold when NEF activities are measured in U/mL. It is less time-consuming and it allows the simultaneous testing of a larger number of samples, simplifying the screening of sera and ensuring an easy and simple test for the detection of NEF in purification processes as well as in in vitro production. The method could also be useful in other hemolytic assays.

Biological Assay↗
PubMed1992

On the origin of C3 nephritic factor (antibody to the alternative pathway C3 convertase): evidence for the Adam and Eve concept of autoantibody production.

The antibody to the alternative pathway C3 convertase, designated C3 nephritic factor or C3NeF, is an autoantibody that is produced in everyone from the time of birth. The elaboration of C3NeF utilizes germline V-region genes which undergo antigen-driven affinity maturation, resulting in an autoantibody that is produced in large amounts with high affinity and narrow specificity. Our data also suggest that under normal conditions, the idiotypic network may play an important part in the control of this autoantibody. Further, a defect in the network with loss of control or inappropriate stimulation may be an underlying mechanism in the unrestricted production of C3NeF in patients with membranoproliferative glomerulonephritis.

Adult↗
PubMed1978

Membranoproliferative glomerulonephritis (MPGN type I) and dense deposit disease (DDD) in children.

A review of the histologic findings in 27 patients originally classified as having some form of membranoproliferative glomerulonephritis (MPGN) revealed 13 with MPGN Type I and 14 with dense deposit disease (DDD). In all 14 cases where electron microscopy was performed, the histologic diagnosis was confirmed. In nine cases the diagnosis of DDD was easily made in histologic sections on the basis of ribbon-like, brightly PAS positive thickening of the GBM, without "splitting" and with relatively slight mesangial proliferation. However, in five cases the picture closely resembled MPGN Type I, with hypercellularity, "splitting" and only focal ribbon-like thickening of the GBM, which required oil immersion for recognition. There was no correlation between the serum C3 levels and the morphologic diagnosis: nine (4 MPGN Type I, 5DDD) had persistently low C3 levels, two (1 MPGN Tye I, 1DDD) were normocomplementemic, and in 16, the C3 levels varied. C3 levels increased with time in nearly all patients. The clinical course was similar in patients with MPGN Type I and DDD. Significant correlations between the rate of development of renal failure and sex, age of onset, nephrotic syndrome or therapy could not be made. The five year survival rate was 87%; 12 developed renal insufficiency by five years. Although morphologically distinct, these findings suggest that DDD is clinically indistinguishable from MPGN Type I.

Cell Membrane↗
PubMed1977

Complement activation in semisolid media: insolubilization of alternative pathway convertases in agar gels with C3 nephritic factor-containing sera.

It was previously shown that when normal human serum and purified properdin or serum containing nephritic factor were allowed to diffuse toward each other in agar, a stainable precipitin line formed only in the presence of an intact alternative pathway. In the present study we have shown that when guinea pig erythrocytes were incorporated in agar and normal human serum was allowed to diffuse toward C3 nephritic factor-containing serum, a line of hemolysis appeared that coincided with the stainable line. The line of hemolysis only formed in the presence of C3, factor B and Mg++, as does the properdin or C3 nephritic factor-induced stainable line. When C2-deficient serum was incorporated in agar with guinea pig erythrocytes and serum samples containing nephritic factor were applied in wells, rings of lysis developed, the areas of which correlated significantly with nephritic factor activity. When partially purified nephritic factor (contaminated only with IgG) or serum containing nephritic factor was subjected to electrophoresis in agar-guinea pig erythrocyte gels and overlaid with normal human serum, bands of lysis developed that required factor B and C3. Lysis of guinea pig erythrocytes in this system appears to be due to insolubilization of alternative pathway convertases with activation of the membrane attack unit C5-C9.

Complement C3↗