Significance of C3 nephritic factor (C3NeF) in non-hypocomplementaemic serum with membranoproliferative glomerulonephritis (MPGN)

Abstract

SUMMARYC3NeF is an autoantibody of C3 convertase (C3bBb) and is often detected in the serum of hypocomptcmentitemic MPGN patients. Serum samples from 104 non-hypocomplementaemic MPGN patients (C3NeF) were studied. C3NeF, whieh eannot activate the alternative pathway, was found in the sera of 6 patients. We examined the C3NeF in purified IgG from five of the nonhypocomplementaemic serum samples (non-hypo C3NcF) and four hypocomplementacmic scrum samples (hypocomplcmcntaemic C3NeF) to determine why C3NeF does not induce C3 splitting and hypocomplcmcntaemia. Purified IgG from non-hypo C3NeF stabilized EAC4b3bBb cells in a manner similar to IgG from hypocomplementaemie C3NeF in EDTA gelatin veronal buffer. However, the non-hypo C3NeF IgG did not stabilize C3 convertase (EAC4b3bBb eells) in the presence of control proteins (factors H and 1). whereas the hypocomplementaemie C3NeF IgG did. The C3NeF in the hypoeomplementaemic serum displayed two characteristics: (i) inhibition of intrinsic decay of Ce convertase (C3bBb); and (ii) inhibition of extrinsic decay by factors H and I. Although the C3NeF in the non-hypocomplementaemic sera did inhibit the intrinsic decay in a manner similar to the hypocomplementaemie C3NeF IgG. il did nol inhibit the extrinsic decay. Due lo the different characteristics of hypocomplementaemic C3NeF and non-hypo C3NeF in the serum samples, the non-hypo C3NeF did not activate C3. Therefore, we conclude that C3NeF exhibits a heterogeneity which is very important in relation to the pathogenesis of MPGN.

Membranoproliferative glomerulonephritis with C3NeF and genetic complement dysregulation

“…It has been suggested that C3NeF antibodies have different characteristics, depending of their target epitope on the AP convertase. Ohi et al showed that in vitro C3NeF isolated from hypocomplementemic patients both stabilizes the enzyme, prolonging its half time life, and inhibits the action of the control proteins FH and FI, whereas the stabilizing activity of C3NeF of non-hypocomplementemic patients is inhibited in the presence of FH or FI [9]. In the last scenario, C3NeF may represent the factor that precipitates the disease in individuals with heterozygous mutations of AP regulatory proteins.…”

“…Most frequently, AP dysregulation is linked to the presence of C3 nephritic factor (C3NeF), an autoantibody stabilizing the AP C3 convertase, and causing activation of plasma C3 despite normal level of complement regulators [9]. C3NeF is detected in about 80% and 40% of patients with DDD, and either MPGNI or MPGNC3, respectively [6][7][8].…”

Autoantibodies to complement components in C3 glomerulopathy and atypical hemolytic uremic syndrome

“…Some C3Nefs require the presence of properdin, others are properdinindependent [15,16]. All C3Nefs prevent the natural intrinsic decay of C3bBb [14,17], but the stabilized convertases are variously resistant against extrinsic decay mediated by factor H, CR1 or DAF [18][19][20][21][22]. Stabilization of the C3bBb convertase by C3Nef results in higher and prolonged activity, C3 and C5 consumption and activation of the terminal pathway [16,17].…”

Membranoproliferative Glomerulonephritis, Dense Deposit Disease, and Cryoglobulinemic Glomerulonephritis

“…3 The presence or absence of C3Nef therefore does not have clinical prognostic significance and does not independently predict recurrence of disease in allograft kidneys. [4][5][6] Likewise, C3 levels in serum also have no significant prognostic importance. Mutations in regulatory proteins of the alternative pathway also can lead to overactivity of C3 and DDD.…”