Lupus, C3 nephritic factor and partial lipodystrophy.
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Adult↗
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Nucleotide sequence of a human autoantibody to the alternative pathway C3/C5 convertase (C3NeF).
The production of autoantibodies to the alternative pathway C3/C5 convertase or C3 Nephritic Factor (C3NeF) is one characteristic of membranoproliferative glomerulonephritis. The complete nucleotide sequences of the heavy and light chain variable regions of an IgG C3NeF produced by an EBV transformed B cell line derived from a patient with membranoproliferative glomerulonephritis were determined. The VH and VL gene segments used by this C3NeF are extensively mutated suggesting that antigenic selection and affinity maturation may occur during the generation of these autoantibodies.
Amino Acid Sequence↗
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↗
Activation of the classic complement pathway in patients with the C3 nephritic factor.
5 patients, including 4 with partial lipodystrophy and 1 with dense deposit disease (type II mesangiocapillary glomerulonephritis; MCGN), had positive C3 nephritic factor assays by both a crossed-gel immunoelectrophoretic and a magnesium-dependent hemolytic assay. One or more early classic complement component was significantly decreased in the serum from each patient. The titer of the C3 nephritic factor did not correlate with the presence of dense intramembranous deposits or with the severity of the renal disease. One patient with partial lipodystrophy had ultrastructural evidence suggesting transformation from type I to type II MCGN. These findings do not support a strict separation of MCGN into subtypes according to current criteria.
Adolescent↗
Idiopathic mesangiocapillary glomerulonephritis. Comparison of types I and II in children and adults and long-term prognosis.
Of 104 patients with idiopathic mesangiocapillary glomerulonephritis studied for at least two years, 69 patients had type I disease and 35 had type II. Forty-five patients were children, and 59 were adults. Type II mesangiocapillary glomerulonephritis was more common in children than in adults, but no other clinical feature distinguished the two types at onset. Complement studies revealed that patients with type II had lower serum C3 concentrations and more frequently showed C3-splitting activity (C3 nephritic factor) in the serum. Children had hypertension or a lowered glomerular filtration rate less frequently at onset than did adults, but children had a higher incidence of a hematuric onset; C3 nephritic factor was also more frequent in the children. During a follow-up period of two to 21 years (mean eight years), only seven patients (five with type I and two with type II) showed clinical remission, whereas 38 percent of patients with type I and 49 percent of patients with type II died or required dialysis; a further 23 percent of patients with type I and 16 percent of patients with type II had continuing disease and reduced glomerular filtration rate. Only the presence and persistence of a nephrotic syndrome in type I predicted renal failure. In both types, the presence of sclerosis or crescents in the initial renal biopsy specimen was associated with a poorer prognosis, but no other feature was of major prognostic value.
Adolescent↗
[Cold-induced urticaria with activity of C3 nephritic factor].
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Child↗
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↗
Complement and glomerular disease - a natural history study.
Over a 5-year period we have performed sequential measurements of a range of complement components in 127 patients. Each had a well-characterised glomerular lesion and there was no evidence of an underlying connective tissue disorder. In 17 patients with varied histopathology, who did not have C3 nephritic factor, there was a persisting complement defect which was present during remission in the patients we were able to study. The finding of such defects is consistent with the thesis that primary complement system abnormalities predispose to the development of glomerular lesions. Interestingly, these abnormalities did not influence the prognosis of our patients. In 12 other cases without C3 nephritic factor, complement levels were below the normal range when the glomerular lesion was active but returned to it in remission; these were secondary changes. We showed by discriminant analysis that some circulating complement component levels, assessed in relation to each other and without reference to a statistically derived 'normal' range, discriminated between histological subgroups and had prognostic significance as well. These patterns could not be distinguished until the data were stored and analysed by computer.
Analysis of Variance↗
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↗
[Partial lipodystrophy with osteomyelitis].
A case with partial lipodystrophy and osteomyelitis is presented. Low C3 levels due to C3 nephritic factor may have contributed to the development of osteomyelitis.
Adolescent↗
A novel ELISA assay for the detection of C3 nephritic factor.
We have developed an ELISA procedure for the detection of C3 nephritic factor (C3NeF), in which wells are coated with a fixed concentration of 2 micrograms C3b per well, and subsequently reacted with B and D. The presence of increasing concentrations of NiCl2 showed a NiCl2 concentration-dependent generation of C3bBb and very little solid-phase bound C3bBb was generated with MgCl2. The formation of solid-phase C3bBb in the presence of an optimal concentration of 1 mM NiCl2, was time-dependent and plateau values were reached after 30 min at 37 degrees C. IgG purified from the serum of a patient with membranoproliferative glomerulonephritis (MPGN) type II containing C3NeF stabilizing activity was bound to the C3bBb generated on microwells in a dose-dependent manner whereas normal IgG exhibited only minor reactivity. C3NeF activity was measured using the ELISA method in patients with MPGN type II (n = 15) and other diseases (n = 17) and in normal controls (n = 15). Most of the patients with MPGN type II exhibited positive C3NeF at various levels, while two of the disease controls showed only slight reactivities. C3NeF titers measured by this new ELISA procedure correlated well with previously described hemolytic assays (r = 0.617, p < 0.01).
Complement C3 Nephritic Factor↗
Hypocomplementaemia in a newborn caused by transplacental passage of maternal autoantibody with C3 nephritic factor (C3 NeF) activity.
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Autoantibodies↗
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↗
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↗
Herpes gestationis associated with the C3 nephritic factor.
Herpes gestationis (HG) is a rare, blistering disease of pregnancy and the puerperium that has immunologic findings of C3 with or without IgG deposited in a linear, band-like distribution along the dermoepidermal basement membrane zone (BMZ). A circulating IgG factor has been demonstrated that will fix complement by the classic pathway in vitro. This study involves a patient who had classic HG with C3 at the BMZ, and who had a circulating factor with activity via the alternative complement pathway similar to the previously described C3 nephritic factor found in patients with partial lipodystrophy, systemic lupus erythematosus, and membranoproliferative glomerulonephritis. Like the C3 nephritic factor, the activity was detected in IgG fractions of serum samples.
Adult↗
Outcome of idiopathic membranoproliferative glomerulonephritis in children. Arbeitsgemeinschaft Pädiatrische Nephrologie.
The aim of this multicentre study was to analyse the long-term outcome of idiopathic membranoproliferative glomerulonephritis (MPGN) according to histological type and to the presence of C3 nephritic factor. Fifty patients aged 2-14 years at the onset of the study were followed over 2-20 years; 26 patients had MPGN type I, 17 had type II and 7 had type III. Treatment was variable. At the last observation, 30 patients had reached terminal and four pre-terminal renal failure. The median survival probability until renal death was 15.3, 8.7 and 15.9 years for disease types I, II and III respectively (difference between MPGN types I + III versus type II: p = 0.013). The presence of an initial nephrotic syndrome was associated with a more rapid progression (p = 0.018). C3 nephritic factor was of no prognostic value. We conclude that the outcome of MPGN mainly depends on the histological type observed.
Adolescent↗
Barraquer-Simons lipodystrophy, Raynaud's phenomenon and cutaneous vasculitis.
We report a 32-year-old man who presented with a 2-year history of unexplained weight loss and symptoms of Raynaud's phenomenon. Clinical examination and investigations were consistent with a diagnosis of acquired partial lipodystrophy (Barraquer-Simons disease). This patient also exhibited an associated cutaneous vasculitis and peripheral perniotic changes. He had normal renal function and glucose tolerance and no immunological abnormality has been detected in his serum to date. The absence of C3-nephritic factor in the presence of overt lipodystrophy suggests that there may be another factor or immunological mediator responsible for the subcutaneous changes seen in patients with lipodystrophy.
Adult↗
C3 nephritic factor and mesangiocapillary glomerulonephritis.
The association of a C3 splitting activity, known as C3 nephritic factor (C3NeF), with mesangiocapillary glomerulonephritis (MCGN), especially MCGN type II, has long been known. Several forms of C3NeF are now recognised, the main one being an IgG which acts as an autoantibody binding to factor H, a normally occurring component of the complement system. Complement is in a continuous state of activation with inbuilt checks and controls, and factor H plays a very important part in the controlling mechanisms by preventing the overwhelming activation of complement at the stage of C3 conversion. C3NeF binds to factor H, thus preventing its inhibitory action, and allowing complement activation to proceed with, in vivo, the well-known consequences in MCGN of very low serum levels of C3. The question naturally arose whether C3NeF causes MCGN. Complex relationships between MCGN, C3NeF and partial lipodystrophy, also characterised by C3NeF and hypocomplementaemia, but preceding the development of MCGN, suggest that hypocomplementaemia predisposes to MCGN. Another possibility is that C3NeF acts directly within glomeruli to cause local complement activation and ensuing damage. Neither possibility could be resolved, but some recent observations have restimulated interest in a possible causative role for C3NeF in MCGN. First, factor H deficiency, by mechanisms other than blocking by C3NeF, in animals and man is associated with MCGN. Second, adipocytes, now known themselves to produce complement system proteins, are lysed in vitro by C3NeF, thus suggesting a mechanism for partial lipodystrophy. By analogy, the C3NeF may produce glomerular damage, as glomerular cells produce complement components.
Adolescent↗