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PubMed1979

Recurrence of dense deposits in transplanted kidney: II. Serum complement and nephritic factor profiles.

Dense deposit disease of the kidney is a rare form of chronic glomerulonephritis frequently associated with serum complement abnormalities (low C3 levels) and a circulating C3 convertase activator of the alternative pathway, the C3 nephritic factor (NF). Eleven patients with end-stage dense deposit disease underwent kidney transplantation. Of the 11, 7 had pretransplant low C3 and NF. In the posttransplant period, persisting low C3 levels were associated with persisting NF, although not quantitatively so. The original glomerular lesion recurred in the graft within 6 months in 9 of 11. Of these 9, 2 had no complement abnormalities either prior to or after transplantation. Pretransplant complement abnormalities were rapidly corrected in 4 of 7 patients whether or not recurrence of the original lesion occurred. Thus, serum complement profiles before and after transplantation are neither predictive nor indicative of recurrence.

Complement C3↗
PubMed1987

Bactericidal capacity against Neisseria meningitidis of normal human serum and sera with functional deficiencies of the third and eight complement factor.

The bactericidal capacity of serum with C3 deficiency secondary to circulating C3 nephritic factor, serum with C8 deficiency and normal human serum were assessed in vitro against Neisseria meningitidis groups A-C. Normal human serum and C8-deficient serum, originating from a 28-year-old male with two episodes of meningococcal meningitis, showed significant bactericidal capacity against meningococci groups A and B. Against group C meningococci the C8-deficient serum revealed significant bactericidal capacity, whereas normal human serum showed no bactericidal effect. Serum with C3 deficiency, obtained from a 16-year-old female with two episodes of meningococaemia, showed no bactericial effect against meningococci groups A-C. Incubation of normal human serum and C8-deficient serum with isolated nephritic factor resulted in C3 depletion and abolished the bactericidal effect.

Adolescent↗
PubMed2002

Management of membranoproliferative glomerulonephritis type II with plasmapheresis.

Membranoproliferative glomerulonephritis type II (MPGN II) is a rare kidney disease identified microscopically by electron-dense deposits surrounded by complement component C3 in glomerular basement membranes. MPGN II usually leads to renal failure, and patients with MPGN II experience a high rate of recurrence following renal transplantation. No treatment modalities have been proven successful if recurrence does occur. The sera of most patients with MPGN II contain complement C3 nephritic factor (C3NF), an IgG autoantibody directed against C3 convertase (C3bBb) that results in constitutive breakdown of C3. C3NF may be important in the pathogenesis of the disease. Since C3NF is IgG, we predicted that C3NF could be removed from the serum through plasmapheresis. We describe the use of long-term plasmapheresis to maintain good renal function in a 15-year-old girl with rapidly progressive recurrent MPGN II. After 73 plasmapheresis procedures over 63 weeks, her serum creatinine remained stable, and her creatinine clearance trended upward. Serial biopsies of the transplanted kidney demonstrated persistent MPGN II but no development of tubular atrophy. During the course of therapy, serum C3NF activity decreased; furthermore, C3NF activity was detected in the removed plasma. We have shown that plasmapheresis is a safe and effective method for delaying the onset of chronic renal failure in recurrent MPGN II. The efficacy may be due to the removal of serum C3NF.

Adolescent↗
PubMed1986

Production of nephritic factor of the alternative complement pathway by Epstein Barr virus-transformed B cell lines derived from a patient with membranoproliferative glomerulonephritis.

Nephritic factor of the alternative complement pathway (C3NeF) is an IgG autoantibody which binds to and stabilizes the C3 convertase (C3bBb) enzyme, and which has been detected mainly in sera from patients with membranoproliferative glomerulonephritis (MPGN) and partial lipodystrophy. To study the production of C3NeF, mononuclear cells isolated from the peripheral blood of patients with MPGN and C3NeF activity in their sera were infected with Epstein Barr virus (EBV) to establish active B lymphocyte cell lines. By using a modified C3NeF screening assay, we detected C3NeF activity in the supernatant of a B cell line derived from a patient with MPGN Type II, but in none of the supernatants of B cell lines derived from normal individuals. C3NeF-positive supernatants were investigated for their ability to conserve classical or alternative pathway C3 convertase activity by using EAC3bBb and EAC4b2a stabilization assays. C3NeF-positive supernatants stabilized the C3bBb convertase activity, but not the C4b2a convertase activity. Studies of the supernatants, using anti-human IgG affinity columns, showed that the C3NeF activity was in the IgG fraction; furthermore, C3NeF antibody agglutinated sheep erythrocytes coated with C3bBb, but not with C3b alone. On gel electrophoresis, both heavy and light chains of the C3NeF were comparable in size to that of normal human IgG molecules. We conclude that C3NeF, produced in vitro by EBV-transformed B cell lines derived from a patient with MPGN Type II, is functionally identical to the conventional C3NeF in serum. In vitro preparation of homogeneous NeF(s) should greatly facilitate the studies of the role of these autoantibodies in complement dysmetabolism.

B-Lymphocytes↗
PubMed2006

Deletion of Lys224 in regulatory domain 4 of Factor H reveals a novel pathomechanism for dense deposit disease (MPGN II).

We report a novel pathomechanism for membranoproliferative glomerulonephritis type II (MPGN II) caused by a mutant Factor H protein expressed in the plasma. Genetic analyses of two patients revealed deletion of a single Lys residue (K224) located within the complement regulatory region in domain 4 of Factor H. This deletion resulted in defective complement control: mutant protein purified from the plasma of patients showed severely reduced cofactor and decay-accelerating activity, as well as reduced binding to the central complement component C3b. However, cell-binding activity of the mutant protein was normal and comparable to wild-type Factor H. The patients are daughters of consanguineous parents. As both patients but also their healthy mother were positive for C3 nephritic factor, the mutant Factor H protein is considered relevant for unrestricted activation of the disease-causing activation of the alternative complement pathway. Replacement of functional Factor H by fresh frozen plasma (10-15 ml/kg/14 days) was well tolerated, prevented so far disease progression in both patients, and is in the long run expected to preserve kidney function.

Amino Acid Sequence↗
PubMedDate not supplied

Selective C3 deficiency due to C3 nephritic factor in an apparently healthy girl.

Routine laboratory investigations performed on the serum of an 8-year-old girl examined because of a moderate degree of iron-deficiency anemia showed a markedly reduced C3 level. More detailed complement studies revealed a selective C3 deficiency, as indicated by the almost undetectable C3 concentration tested by both hemolytic and immunochemical assays and by the normal or slightly reduced levels of all the other complement components. The hemolytic activity of the serum was restored by the addition of partially purified C3 component. The isolated C3 deficiency could be attributed to the presence of a C3-cleaving activity in the serum of the propositus. This activity was identified as C3 nephritic factor (C3NeF) since it was heat-stable, was absorbed by Cowan I strain of Staphylococcus aureus and was-eluted in the IgG fraction after DEAE-chromatography of the serum. The levels of H and I factors of the alternative pathway in the serum of the propositus and of C3 in the serum samples of her parents and two siblings were found to be within the normal range. The previous clinical history of the girl and the follow-up for a period of approximately 5 years showed that she was apparently healthy and did not reveal clinical and/or laboratory evidence of glomerulonephritis, lipodystrophy or repeated bacterial infections usually associated with the presence of C3NeF in the serum.

Anemia, Hypochromic↗
PubMed1989

A properdin dependent nephritic factor slowly activating C3, C5, and C9 in membranoproliferative glomerulonephritis, types I and III.

The IgG fraction of serum from patients with membranoproliferative glomerulonephritis (MPGN) types I and III was found to contain a nephritic factor (NFI/III) which differed from that usually present in MPGN type II and partial lipodystrophy (NFII) in that it converts C5 and C9 as well as C3, is dependent on properdin for its activity, and requires an incubation period of several hours rather than 30 min for its demonstration. C3 conversion occurred in the absence of an intact classical pathway. This nephritic factor was found in patients with reduced serum levels of terminal components and its activity, like that of the nephritic factor in MPGN type II, correlated with the serum C3 level indicating that these nephritic factors play a large role in producing hypocomplementemia. Although potentially nephritogenic because of its ability to activate the terminal pathway, the presence of this nephritic factor did not clearly correlate with clinical course.

Complement Activation↗
PubMed1983

Meningococcal meningitis associated with persistent hypocomplementaemia due to circulating C3 nephritic factor.

Two teenage patients who presented with meningococcal meningitis were found to have persistently low C3 levels even after recovery. This was accompanied by circulating C3 nephritic factor, which persisted for more than 12 months in each case. Neither patient had evidence of partial lipodystrophy or of glomerulonephritis initially, although one patient subsequently developed mesangioproliferative glomerulonephritis following a second admission with pneumococcal pneumonia. It is possible that the generation of the nephritic factor was initiated during the presenting illness.

Adolescent↗
PubMedDate not supplied

Complement activation in acute glomerulonephritis in children.

Serial determinations of complement components (C1q, C4, C3, C5 and factor B) were performed in 32 children with acute glomerulonephritis. Low levels of C3 were found in 30 patients and low levels of C5 in 26. The findings of reduced C1q and/or C4 levels (25 patients) in the first days of the disease suggest activation of the classical pathway. Depressed Factor B levels were found rarely (4 patients). In all patients, the presence of a C3 splitting activity and/of a C3 nephritic factor-like activity was investigated. Both activities were demonstrated in 7 patients whereas in another patient, only C3 splitting activity was noted. A disappearance of both activities was observed in all patients. In 3 patients tested, the C3 nephritic factor-like activity was heat-labile and was therefore not related to true C3 nephritic factor. Both pathways are implicated in the early phases of the disease but continued C3 depression is probably through alternate pathway.

Acute Disease↗
PubMed1979

The complement system in pediatric renal disease.

A brief review of the classical and the alternative pathways of complement activation is presented. Clinically, according to the complement system, we can divide the children with glomerulonephritis into two groups, normocomplementemic and hypocomplementemic. In addition, inherited complement deficiencies can be identified associated with renal diseases. We discuss the three possible sources of complement in urine, although more control studies are necessary in patients with different causes of proteinuria in order to define the clinical significance of complementuria. The immunohistological results of glomerular nephritic biopsy material by the fluorescence antibody technique is analyzed with respect to clinical diagnosis and evaluation of the treatment. The nature of C3NeF as an antibody to factor B-C3 complex is demonstrated by different groups and in different diseases. Finally, the presence of a receptor for complement in the glomerulus, is explained in human disease by the deposition of immune complexes into the renal glomeruli.

Antigen-Antibody Complex↗
PubMed1979

Modulation of the properdin amplification loop in membranoproliferative and other forms of glomerulonephritis.

The mean serum concentrations of C3b inactivator (C3bINA) and beta1H globulin were measured in eighty-six sera (thirty-five membranoproliferative, thirteen membranous, thirty-one focal and seven minimal change) taken from seventy-five patients with histologically diagnosed glomerulonephritis. In none of the four groups of sera did the mean concentrations of both these proteins differ significantly from the mean levels in a group of fifty normal sera. However, in the membranoproliferative group, the mean level of C3bINA, but not beta1H, was significantly lower in the nephritic factor positive than in the nephritic factor negative group. When the eighty-six sera were considered together, serum concentrations of C3bINA and beta1H correlated with levels of C3, factor B, properdin and C4. When the membranoproliferative group was considered separately, C3bINA levels correlated with levels of C3, factor B, properdin and C4 and beta1H correlated with C3 and factor B, but not properdin or C4 in the nephritic factor negative group, but no such correlations were observed in the nephritic factor positive group. The significance of these findings is discussed in the light of current thoughts on the mechanisms of modulation of the alternative pathway.

Beta-Globulins↗