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Pediatric Nephrology

, Volume 34, Issue 8, pp 1311–1323 | Cite as

Autoimmune abnormalities of the alternative complement pathway in membranoproliferative glomerulonephritis and C3 glomerulopathy

  • Marina NorisEmail author
  • Roberta Donadelli
  • Giuseppe Remuzzi
Review

Abstract

Membranoproliferative glomerulonephritis (MPGN) is a rare chronic kidney disease associated with complement activation. Recent immunofluorescence-based classification distinguishes between immune complex (IC)-mediated MPGN, with glomerular IgG and C3 deposits, and C3 glomerulopathies (C3G), with predominant C3 deposits. Genetic and autoimmune abnormalities causing hyperactivation of the complement alternative pathway have been found as frequently in patients with immune complex-associated MPGN (IC-MPGN) as in those with C3G. In the last decade, there have been great advances in research into the autoimmune causes of IC-MPGN and C3G. The complement-activating autoantibodies called C3-nephritic factors (C3NeFs), which are present in 40–80% of patients, form a heterogeneous group of autoantibodies that stabilise the C3 convertase or the C5 convertase of the alternative pathway or both. A few patients, mainly with IC-MPGN, carry autoantibodies directed against the two components of the alternative pathway C3 convertase, factors B and C3b. Finally, autoantibodies against factor H, the main regulator of the alternative pathway, have been reported in a small proportion of patients with IC-MPGN or C3G. The identification of distinct pathogenetic patterns leading to kidney injury and of targets in the complement cascade may pave the way for tailored therapies for IC-MPGN and C3G, with specific complement inhibitors in the development pipeline.

Keywords

Membranoproliferative glomerulonephritis C3 glomerulopathy Complement Alternative pathway Autoantibodies Nephritic factor 

Introduction

Membranoproliferative glomerulonephritis (MPGN) is a chronic proteinuric nephropathy that can occur at any age, both in children and adults [1].

The disease may present with asymptomatic hematuria and proteinuria, or acute nephritic syndrome, nephrotic syndrome, chronic kidney disease or even as glomerulonephritis rapidly progressing to end stage renal disease (ESRD). The high variability of clinical presentation and course is likely caused by differences in the pathogenesis and timing of diagnosis (which is based on a kidney biopsy) relative to the clinical course [2].

The pattern of glomerular injury as observed using light microscopy typically includes thickening of the capillary wall, with the appearance at silver staining of a double contour, owing to the formation of a new layer of glomerular basement membrane (GBM) beneath the endothelium, and mesangial expansion due to increased matrix deposition and mesangial hypercellularity [3].

Classification and pathogenesis

Previously, based on electron microscopy localisation of electron-dense deposits relative to the glomerular basement membrane, MPGN was classified as MPGN type I, [4] with subendothelial electron-dense deposits, MPGN type II (or dense deposit disease, DDD), with intramembranous highly electron-dense deposits [5], and MPGN type III, with both subendothelial and subepithelial deposits [6].

This historical classification has recently been replaced with a classification based on the composition of the glomerular deposits as analysed by immunofluorescence [7, 8] (Fig. 1). Those cases in which glomerular immune deposits show substantial immunoglobulin staining accompanying C3 staining are classified as immune complex-associated MPGN (IC-MPGN) and would identify forms secondary to malignancies, infections or autoimmune diseases [8]. The above conditions are characterised by persistent antigenemia and the formation of antigen-antibody immune complexes that initiate the classical pathway of complement, resulting in the deposition of immune complexes and C3 activation fragments in the glomerulus. However, in a fraction of IC-MPGN cases, an underlying cause cannot be identified [9, 10].
Fig. 1

Schematic representation of membranoproliferative glomerulonephritis (MPGN) reclassification based on immunofluorescence findings

Those cases characterised by predominant glomerular C3 staining (C3c staining ≥ 2 orders of magnitude more than any other immune reactants) are called C3 glomerulopathies (C3G). On the basis of the quality of the deposits seen in glomeruli by electron microscopy, C3G is further divided into DDD with distinctive highly electron-dense osmiophilic deposits that are typically found within the glomerular basement membrane and also occur in the mesangium, and C3 glomerulonephritis (C3GN), with mesangial, intramembranous, subendothelial and sometimes subepithelial deposits [11, 12]. The term C3G is also used to define mesangial and endocapillary proliferative patterns different from MPGN or even nonspecific alterations sharing C3-dominant glomerular staining [11].

Dysregulation of the alternative pathway of complement has been proposed as the primary cause of C3G and may be associated with a broad spectrum of autoantibodies, like C3 nephritic factors (C3NeFs) or autoantibodies against complement components and regulators, and with complement gene abnormalities [2].

However, acquired and genetic abnormalities in the alternative pathway of complement have been found as frequently in patients with IC-MPGN as in those with C3G [9, 13]. These findings indicate that the two diseases may have more commonalities than previously recognised, with dysregulation of the complement alternative pathway playing a main pathogenetic role.

In IC-MPGN and C3G, kidney histology changes are the result of the transfer of circulating immune complexes and complement activation products through the fenestrated glomerular endothelial cells to the subendothelium and mesangium. This immune material triggers an influx of leukocytes that damage the capillary walls by the release of cytokines and proteases, leading to proteinuria and hematuria. This phase is followed by a reparative reaction with formation of a second layer of basement membrane and mesangial expansion [3].

In this review, we will make an overview of the known and emerging evidence regarding the nature and pathogenetic role of autoimmune drivers of complement alternative pathway dysregulation in IC-MPGN and C3G.

The complement system

The complement system is involved in innate and adaptive immunity and consists of more than 30 soluble and cell-bound proteins that participate in three activation pathways: the classical, alternative and mannose-binding lectin pathways [14]. The classical and lectin pathways are triggered by the recognition of pathogens or damaged cell surfaces by antibodies or recognition molecules, respectively (Fig. 2), and result in the generation of the classical/lectin pathway C3 convertase complex (C4bC2a), which cleaves C3 into the anaphylatoxin C3a and C3b. C3b deposits on the surface of target cells and binds receptors on leukocytes, initiating phagocytosis [14, 15]. The alternative pathway is continuously activated by the spontaneous hydrolysis (“tick-over”) of the thioester bond in C3, generating C3(H2O). The binding of C3(H2O) to factor B (FB), followed by cleavage of FB to Bb by factor D (FD), forms the initiation alternative pathway C3 convertase C3(H2O)Bb in the fluid phase, which cleaves C3 and forms small amounts of C3b. C3b associates with FB, and the subsequent FB cleavage by FD leads to the formation of the amplification C3 convertase complex C3bBb, both in the fluid phase and on activating surfaces [14], which cleaves more C3 molecules to C3a and C3b (Fig. 2). As C3b generated by all the three pathways can form the amplification C3bBb convertase of the alternative pathway, the latter is a powerful amplification loop for the entire complement system.
Fig. 2

The three-complement activation pathways. MBL, mannose-binding lectin; MASP, MBL-associated serine proteases; FP, properdin; C3(H2O)Bb, alternative pathway initiation convertase; FD, complement factor D; FB, complement factor B; sC5b-9, soluble terminal complement complex; MAC, terminal membrane attack complex; C1-inh, C1 inhibitor, inactivates C1r and C1s, MASP-1 and MASP-2; FH, complement factor H, binds C3b, exerts cofactor activity for factor I-mediated C3b cleavage, prevents the formation of the alternative pathway C3 convertase and destabilises (decay-accelerating activity) the alternative pathway C3 and C5 convertases; THBD, thrombomodulin, promotes degradation of C3a and C5a and increases FH cofactor activity; MCP, membrane cofactor protein, exerts cofactor activity for factor I-mediated C3b cleavage; DAF, decay-accelerating factor, has decay-accelerating activity on C3/C5 convertases of the classical and alternative pathway; C4bp, C4b-binding protein, binds to C4b and has decay-accelerating activity for the classical/lectin pathway C3 convertase and cofactor activity for factor I-mediated C4b cleavage; FI, complement factor I, it degrades C3b and C4b aided by cofactors; Vn, vitronectin; Cl, clusterin, bind soluble forming C5b-7 complex to produce soluble C5b-9 (sC5b-9) complexes; CD59, protectin, prevents C5b-9 formation

The association of another C3b molecule with C3 convertases (C4bC2a or C3bBb) leads to the formation of C5 convertases of the classical/lectin (C4bC2aC3b) and alternative (C3bBbC3b) pathways, which cleave C5 into C5a and C5b. The C3 convertase of the alternative pathway is stabilised by the plasma protein properdin, which binds to the complex [16], and also facilitates the switch of the C3 convertase to C5 convertase [17]. The complement cascade culminates in the activation of the terminal complement pathway, in which C5b binds C6 and C7 to form C5b-7, which inserts itself into a cell membrane and by binding with C8 and several molecules of C9 forms the terminal membrane attack complex (C5b-9), causing cell lysis (Fig. 2).

Because of the central role of the alternative pathway in the effector functions of the complement cascade, in physiological conditions, its activity is kept under strict control by fluid phase and membrane-bound regulatory proteins, such as complement factor H (FH), complement factor I (FI), membrane cofactor protein (MCP), complement receptor 1 (CR1), decay-accelerating factor (DAF), thrombomodulin (THBD) and CD59 (Fig. 2) to prevent damage to self tissues and cells [14]. Regulatory proteins inactivate C3b (FI) or foster FI-dependent C3b inactivation (cofactor activity, FH, MCP and CR1), accelerate the dissociation of the C3 and C5 convertases (decay-accelerating activity, FH, DAF and CR1) and inhibit the association of C9 with C5b-8 to prevent C5b-9 formation (CD59) in cell membranes (Fig. 2). The anticoagulant endothelial transmembrane protein THBD contributes to complement regulation by increasing FH cofactor activity and by promoting the inactivation of C3a and C5a by thrombin actable fibrinolysis inhibitor [14, 18].

The formation of the membrane attack complex is also controlled by the two soluble regulators, vitronectin and clusterin, which bind to neo formed C5b-7 complexes in plasma. Once formed, soluble C5b-7/clusterin/vitronectin complexes bind with C8 and C9 to produce soluble C5b-9 complexes (sC5b-9) [19, 20] that cannot insert into cell membrane (Fig. 2).

In patients with IC-MPGN or C3G, perturbation of the balance between complement activators and regulators results in dysregulation of the complement alternative pathway, mainly in the fluid phase, as demonstrated by C3 consumption and the formation of complement activation products in the circulation [2, 9, 21], which are delivered to the kidney and accumulate in the glomerular tuft.

C3 nephritic factors, a heterogenous group of antibodies

A complement-activating factor was first described in 1969 in the serum of patients with glomerulonephritis, which specifically cleaved C3 [22]. It was later clarified that the C3-activating effect of serum is due to heterogenous IgG and IgM autoantibodies called C3NeFs [23], which are present in 40–50% of patients with IC-MPGN and in 45–80% of patients with C3G (40–50% in C3GN and 70–80% of patients with DDD, Table 1) [9, 13, 34].
Table 1

Antibodies activating the complement system in IC-MPGN and C3G

Autoantibodies

Epitopes

Effect

Frequency

References

C3NeF

Different target neoepitopes on alternative pathway C3 convertase (C3bBb)

Stabilisation of C3bBb by preventing spontaneous decay and/or accelerated decay by FH, DAF or CR1

40–50% IC-MPGN

40–50% C3GN

70–80% DDD

[9, 13]

C5NeF

Different target neoepitopes on alternative pathway C5 convertase (C3bBbC3b)

Stabilisation of C3bBbC3b

2 cases

22/39 C3GN

7/20 DDD

[24, 25]

C4NeF

Different epitopes on classical/lectin C3 convertase (C4bC2a) or/and C5 convertase (C4bC2aC3b)

Stabilisation of C4bC2a/C4bC2aC3b by preventing both spontaneous and the C4b-binding protein, CR1 or DAF-mediated decay

1/13 C3G

5/168 C3G

[26, 27]

Anti-FB/C3b

Native FB and Bb fragment in the C3bBb complex

Stabilisation of C3bBb against decay; inhibition of C3bBbC3b activation

1 DDD

3/32 DDD

5/23 IC-MPGN

2/118 C3G

[28, 29, 30]

C3b

1/23 IC-MPGN

2/118 C3G

[30]

FB and C3b

1 DDD, 1 MPGN

4/23 IC-MPGN

1/118 C3G

[30, 31]

Anti-factor H

Amino-terminal complement regulatory domain of FH

Unpaired fluid phase FH-mediated complement regulation

1 IC-MPGN, 1 DDD

1/32 DDD

5 IC-MPGN

11 C3GN

1 DDD

[28, 32, 33]

C3NeFs bind to neoepitopes of the assembled alternative pathway C3 convertase (C3bBb) and stabilise both the fluid phase and the cell-bound C3 convertase complex [35] increasing its half-life from a few seconds to minutes or even hours [35, 36]. C3NeFs bound to the C3 convertase may inhibit interaction with the complement regulators FH, CR1 and DAF and prevent their decay-accelerating activity [37, 38, 39].

The traditional test for detecting C3NeF activity is the hemolytic assay (HA) (Fig. 3a), based on the evaluation of the hemolysis by terminal membrane attack complex of sensitised sheep red cells carrying alternative pathway C3 convertase sites. The degree of hemolysis is dependent on the amount of C3b deposited on the cells, in turn dependent on the amount of C3 convertase stabilised by C3NeFs.
Fig. 3

Published hemolytic assays of nephritic factors. a The traditional assay of C3NeF. Sheep erythrocytes sensitised with rabbit anti-sheep erythrocyte antibody (EA) are treated with normal human serum (NHS) and C2 and C3 (EAC4b3b erythrocytes). C3bBb enzyme is then preformed on EAC4b3b cells by incubation with FB and FD (EAC3bBb erythrocytes). The C3 convertase is allowed to decay for different periods of time in the presence of patient or control IgG or serum with or without the complement inhibitors FH, DAF or CR1. Complement-mediated hemolysis is then induced through the addition of rat serum and measured by optical density (OD) at 410 nm. b Modified hemolytic assay of C3NeF from [28]. Sheep erythrocytes (e) are coated with C3b (EAC3b) by exposure to FB-partially inactivated/FH-depleted serum, followed by the formation of alternative pathway C3 convertase with FB and FD in the absence or in the presence of properdin (EAC3bBb(P)). c Simplified hemolytic assay of C3NeF [25]. Sheep erythrocytes (e) in alternative pathway buffer are incubated with a mixture of patient and normal human serum to form the C3 convertase (EAC3bBb) followed by rat serum to induce hemolysis. d Hemolytic assay of C5NeF [25]. Antibody-sensitised sheep erythrocytes (EA) are incubated with FB- and FH-depleted serum containing a C5 inhibitor (C5 inh), then resuspended in alternative pathway buffer and incubated with FB and FD and patient or control IgG. Lysis is induced by adding human C3-depleted serum (R3 serum). e Hemolytic assay of C5NeF [24]. EAC4b3b sheep erythrocytes are incubated with FB, FD and properdin (P) to form the alternative pathway C5 convertase (EAC3bBbP-C3b), followed by patient or control IgG, decay and rat serum induced hemolysis

Sensitised erythrocytes bearing C4b and C3b (EAC4b3b) are prepared using sheep erythrocytes treated with anti-sheep erythrocyte antibody and normal human serum, followed by incubation with C2 and C3. C3bBb enzyme is then preformed on EAC4b3b cells through incubation with FB and FD (EAC3bBb) [40, 41]. The C3 convertase is allowed to decay for different periods of time in the presence of patient or control IgG and with or without complement regulators. Complement-mediated hemolysis is then induced through the addition of rat serum to provide C5 and the other terminal complement components, and the released haemoglobin is measured by optical density at 410 nm [42, 43] (Fig. 3a). Under these experimental conditions, hemolysis due to residual convertase activity is minimal with control IgG (5–10% of hemolysis) but is increased in samples incubated with C3NeFs [44].

C3NeF-stabilised C3 convertase continuously cleaves C3 to C3b, leading to chronic complement activation and low C3 levels, which are frequently observed in IC-MPGN and C3G patients that carry C3NeFs (C3NeF+) [9]. In some C3NeF+ patients, C3 consumption is accompanied by low serum C5 and elevated plasma sC5b-9 levels, also suggesting stabilisation of the alternative pathway C5 convertase (C3bBbC3b) [24, 45]. However, the presence of C3NeF is not always associated with C5 consumption and complement terminal pathway activation [46, 47]. In addition, C3NeF activity was also found in some MPGN patients with normal C3 levels. Purified IgGs from patients with normal C3 inhibited spontaneous alternative pathway C3 convertase decay but not decay mediated by FH, while IgG from hypocomplementemic patients inhibited both spontaneous and FH-accelerated decay [48].

The pathogenetic role of C3NeFs in IC-MPGN and C3G has long been debated [2, 49]. C3NeF activity, as measured by the hemolytic assay, correlates poorly with C3 levels, fluctuates in patients over time and does not correlate with disease activity [50, 51, 52]. In a long-term follow-up study in children with idiopathic MPGN, C3 levels remained normal throughout the observation period in six C3NeF+ patients [50], and there was no significant difference in renal survival probability in patients with or without C3NeF activity. In addition, C3NeF activity has been reported with other diseases, including partial lipodystrophy [53], and more rarely in post-streptococcal glomerulonephritis, systemic lupus erythematosus and meningococcal meningitis [54, 55, 56] and even in healthy subjects [57]. In a family with MPGN and partial lipodystrophy, C3NeF was found in all members with lipodystrophy but it did not segregate with the renal phenotype, and C3NeF activity was found in asymptomatic family members of patients with DDD [49].

All the above uncertainties are likely due to the fact that C3NeFs are heterogeneous autoantibodies, which we here collectively refer to as nephritic factors (NeFs). NeFs may have different target epitopes and induce the activation of the complement alternative pathway cascade through different molecular mechanisms that cannot be evidenced by the traditional hemolytic assays, which only evaluates the degree of complement-mediated erythrocyte lysis. In addition, few laboratories measure NeFs, and methods are different and lack appropriate quality control. International efforts are underway, coordinated by the Committee for the Standardisation and Quality Assessment of Complement Measurements of the International Complement Society (https://www.complement.org/committee), to establish standardised and reproducible NeF tests.

Clarification of the heterogeneous nature of NeFs and their diverse impact on complement alternative pathway abnormalities in C3G has come from recent studies describing new functional tests (Figs. 3 and 4). Modified hemolytic assays were set up using sheep erythrocytes directly coated with C3b through exposure to FB-partially inactivated/FH-depleted serum, followed by the formation of alternative pathway C3 convertase with FB and FD in the absence or in the presence of properdin. The decay and subsequent hemolysis were then conducted as in the traditional test [28] (Fig. 3b). Of 32 patients with DDD, 69% had C3 convertase-stabilising IgGs in the test without properdin, while IgGs from three additional patients had a stabilising effect only on properdin-containing C3 convertase. The latter finding confirms previous reports suggesting the existence of properdin-dependent C3NeFs [45]. When mixed with control serum, serum from most patients who were positive in the above tests formed C3 activation fragments, indicating that the stabilised C3 convertase complex maintained its enzymatic activity [28].
Fig. 4

Published biochemical assays of nephritic factors [25]. COS and COS-P: C3 convertase stabilisation ELISAs. Alternative pathway C3 convertase (C3bBb) is formed in the presence of serum or purified IgGs with FB and FD on C3b-coated wells in the absence (COS) or in the presence (COS-P) of properdin (P). The complex is allowed to decay with or without the complement inhibitors FH, DAF or CR1, and then residual Bb is detected by ELISA. COIg: C3NeF-binding ELISA. Alternative pathway C3 convertase is preformed adding FB, FD and P to C3b-coated microwells, followed by incubation with patient IgG. Bound IgG are detected by ELISA using horseradish peroxidase-conjugated (HRP) anti-human IgG. FPC: C3NeF fluid phase C3 cleavage assay. A mixture of patient serum and NHS is incubated in alternative pathway buffer. C3 cleavage products are detected by Western blot

In a Spanish cohort of 101 patients with DDD, MPGN type I or III (likely including patients with IC-MPGN and C3GN) or, rarely, other renal pathologies, and proven alternative pathway activation, C3NeF activity was analysed using five assays [25]: C3 convertase stabilisation ELISAs in which C3 convertase was formed with FB and FD on C3b-coated wells in the presence of patient serum or purified IgGs, in the absence (COS, Fig. 4) or in the presence (COS-P, Fig. 4) of properdin; C3NeF-binding ELISA (COIg, Fig. 4), which measured the binding of patient IgG to C3 convertase preformed on ELISA plates; C3NeF fluid phase C3 cleavage assay that detected the cleavage of C3 by patient serum (FPC, Fig. 4); and a simplified C3NeF hemolysis assay with sheep erythrocytes in alternative pathway buffer incubated with a mixture of patient and normal human serum followed by rat serum to induce hemolysis (Fig. 3c). The ELISA assay for convertase stabilisation with properdin (COS-P) was the most sensitive and detected C3NeF in 36% of patients [25], confirming the observation by Zhang et al. [28] that some C3NeFs need properdin to carry out their stabilising activity. Most C3NeFs also blocked accelerated decay of the C3 convertase through FH, DAF or CR1, but subsets of C3NeFs failed to inhibit FH-mediated and/or CR1-mediated and/or DAF-mediated decay. The authors hypothesised that C3NeFs that do not affect the decay-accelerating activity of either FH or the other regulators may be less pathogenetic in vivo [25]. No C3NeF+ sera bound directly to C3b, FB and Bb indicating that C3NeF interacted with neoepitopes in the convertase complex and not with the isolated C3 convertase proteins or fragments [25]. Finally, four C3NeF+ samples were also tested in a hemolytic assay modified to investigate the activity of the alternative pathway C5 convertase (Fig. 3d) and two samples were found to also enhance/stabilise the C5 convertase (C5NeF, Table 1) [25]. These data are in line with old reports in the literature that described a nephritic factor of the terminal pathway that converted C3 slowly, activated the terminal pathway and was properdin-dependent in a few patients with acute post-streptococcal glomerulonephritis or MPGN [45, 47, 58].

Evidence of the existence of C5NeF was supported by a large study by Marinozzi et al. [24]. The authors, by studying a cohort of 59 patients with C3G, identified a subgroup of patients that carried circulating autoantibodies stabilising the alternative pathway C5 convertase (Table 1). The assay (Fig. 3e) was based on the hemolysis of C3b-coated sheep erythrocytes and followed the same experimental procedure as that conventionally used for the screening of C3NeF [43], with the exception that the convertase was formed in the presence of properdin, which is instrumental to the arrangement of the alternative pathway C5 convertase on cell surfaces [17].

In the report by Marinozzi et al. [24], patients with C3G could be grouped into four subsets based on the results of testing for the presence of C3 convertase- and C5 convertase-stabilising antibodies: 29% of patients had antibodies that only stabilised the C3 convertase (C3NeF); in 10% of patients, the antibodies stabilised the C5 convertase (C5NeF) but not the C3 convertase; while 39% of patients had antibodies stabilising both the C3 and the C5 convertases. Only 22% of patients were negative in both assays. The presence of different type of NeFs correlated with complement parameters in serum and plasma. Thus, C3 serum levels were lower in patients positive for C3NeF and/or C5NeF, compared with patients who were negative. Plasma sC5b-9 levels were higher in C5NeF-positive than in C5NeF-negative patients and the activity of patients’ IgG to stabilise the C5 convertase correlated with plasma sC5b-9 levels [24].

Notably, autoantibodies that stabilise the C5 convertase were more frequently present in patients with C3GN than in patients with DDD [24], suggesting that DDD-related antibodies mainly affect the C3 convertase, and on the contrary, C3GN-associated autoantibodies target both the C3 and C5 convertase. These results have some limitations, since about half of patients lacked electron microscopy examination and the distinction between C3GN and DDD was only made based on light microscopy. In addition, patients with IC-MPGN were not included in the study.

Despite these limitations, the data from Marinozzi et al. [24] provided important insights into possible pathogenetic mechanisms underlying the different abnormalities in the complement profiles of patients with C3GN and DDD. In previous studies, levels of sC5b-9 were significantly elevated in plasma from C3GN patients but not in DDD patients, indicating greater terminal pathway activation in C3GN vs. DDD [46]. This trend was confirmed by a more recent report based on unsupervised cluster analysis, showing that patients with DDD fall into a cluster (cluster 3) characterised by a high prevalence of C3NeF, low serum C3, but with plasma sC5b-9 levels that are significantly lower than in clusters 1 and 2, which mainly included patients with C3GN and IC-MPGN, respectively [21].

The hypothesis of DDD and C3GN as diseases of C3 or C5 convertase activation, respectively, is challenged by results of mass spectrometry analysis in kidney biopsies that revealed the presence of components of the terminal complement pathway (C5, C6, C7, C8 and C9) in glomeruli from patients with C3GN but also from patients with DDD [59, 60]. The terminal complement regulators clusterin and vitronectin, which form the sC5b-9 complex (Fig. 2), were uniformly detected in glomeruli of patients with either C3GN or DDD [59, 60], indicating that circulating sC5b-9 is sequestered in the glomeruli in both subgroups of C3G patients. Altogether, the above evidence would suggest that despite a lower prevalence of C5NeF and lower levels of plasma sC5b-9 in DDD than in C3GN, fluid phase terminal complement activation may play a role in the accumulation of glomerular complement deposits as well as in glomerular lesions in DDD. At variance with findings in C3GN and DDD, terminal complement components were rarely identified in IC-MPGN glomerular deposits [60] which mainly contained immunoglobulins, C3 and C4. This difference cannot be explained based on the prevalence of C3NeFs or on sC5b-9 levels, which are quite comparable between patients with IC-MPGN and C3G [9].

The above discrepancies highlight the need for further studies on the molecular mechanisms underlying complement activation by NeFs.

Finally, the reports on patients with IC-MPGN, C3GN or DDD carrying both C3NeF and heterozygous mutations in complement regulatory genes [9, 13, 61] and the association of specific variants and haplotypes in CFH, MCP and C3 genes with IC-MPGN, C3GN or DDD [13, 62] indicate that a combination of acquired and genetic factors is needed to determine the specific pattern of complement dysregulation and the types of glomerular lesions.

C4 nephritic factor

IgG antibodies that recognise the C3 convertase of the classical/lectin pathways (C4bC2a) were first reported in a patient with post-infectious glomerulonephritis [63] and in patients with systemic lupus erythematosus [64] and were termed C4 nephritic factors (C4NeFs, Table 1). These antibodies prolong the half-life of the C4bC2a convertase by preventing both the spontaneous and C4b-binding protein-, CR1- or DAF-mediated decay [38, 65] and enhance C3 and C5 cleavage. C4NeFs have also been shown to prevent inactivation of C4b by FI [65].

Subsequent studies detected C4NeFs in patients with MPGN [66, 67]. In a large cohort of 100 hypocomplementemic MPGN patients, C4NeFs were identified in 19 patients [67]. Interestingly, about 50% of C4NeF+ patients were also C3NeF+. Patients both C3NeF+ and C4NeF+ showed a more severe decrease in circulating C3 and C5 and terminal components C6 and C9 than patients who were either C3NeF+ or C4NeF+, suggesting an additive or synergistic effect of the two classes of complement-activating antibodies [67]. The latter report predated the immunofluorescence-based classification of MPGN; however, intense glomerular C3 deposits without glomerular immunoglobulin staining were observed in a subset of C4NeF+ patients [67], suggesting a possible association between C4NeFs and C3G. This possibility was confirmed by two more recent studies that identified C4NeFs in 1 of 13 [26] and in 5 of 168 [27] patients with C3G. Consistent with previous reports, C4NeF antibodies isolated from C3G patients stabilised the C4bC2a complex and prevented CR1-, DAF- and C4 binding protein-mediated decay [26, 27]. Notably, in five of six patients, no risk factors for complement dysregulation other than C4NeF could be identified, since C3NeFs were negative and no complement gene abnormalities were found. That triggering of classical/lectin complement pathways can lead to C3G is consistent with the relationship of post-infectious glomerulonephritis (PIGN) and C3G. Post-infectious glomerulonephritis is initiated by glomerular immune complex depositions following an infection. In the majority of cases, the disease is reversible, but in some cases, there is an evolution into a persistent glomerulonephritis characterised by glomerular C3 deposits without immunoglobulins [68, 69]. In these atypical cases of PIGN, the presence of acquired or genetic risk factors could predispose [55, 69, 70] to a switch from classical/lectin pathway-driven PIGN to a chronic alternative pathway-driven process.

However, the pathological significance of autoantibodies stabilising the classical/lectin pathway convertase in C3G and why particular patients develop C4NeFs remains to be clarified.

Anti-factor B and C3b autoantibodies

Autoantibodies targeting the two components of the alternative pathway C3 convertase, C3b and FB (Table 1), have been reported in association with both IC-MPGN and C3G. An anti-FB autoantibody identified in a patient with DDD, who was negative for C3NeF, bound both to native factor B in serum and to Bb in the C3bBb convertase [29]. The antibody stabilised the C3bBb convertase against spontaneous and FH-mediated decay, resulting in increased C3 cleavage. However, unlike NeFs, the anti-FB antibody inhibited the activation of C5 convertase and prevented complement-mediated rabbit erythrocyte lysis in vitro [29]. In two other C3NeF-negative patients, one with DDD and one with MPGN, combined FB and C3b autoantibodies, have been described [31]. As in the previous report, the FB antibodies recognised the native FB protein [31]. The addition of IgGs isolated from both patients to normal human serum or to an in vitro-assembled C3 convertase resulted in increased release of Ba and C3a cleavage products, compared with control IgGs [31], indicating that the autoantibodies enhance C3 convertase activity. More recently, Marinozzi et al. [30] screened a cohort of 141 patients with IC-MPGN and C3G and identified seven patients with anti-FB IgGs, three patients with anti-C3b IgGs and five patients with both anti-FB and anti-C3b autoantibodies [30]. Interestingly, 10 of these 15 patients were diagnosed with IC-MPGN and 43% of the studied IC-MPGN patients were positive for anti-FB and/or anti-C3b antibodies, which highlights the link between IC-MPGN and the complement alternative pathway. Anti-FB antibodies recognised the intact FB protein, consistent with previous data [29, 31], as well as the Bb fragment but not the Ba cleavage product. Purified IgG from patients positive for anti-FB or anti-C3b antibodies bound to the alternative pathway C3 convertase in vitro enhanced its assembly and stabilised the complex [30]. However, only 4 of 15 autoantibodies increased the activity of C3/C5 convertases assembled on sheep erythrocytes. In line with data from Chen et al. [31], the incubation of anti-FB IgGs from six patients with normal human serum caused the release of higher amounts of Bb and C3a fragments compared with IgGs from healthy donors, indicating fluid phase activation of the alternative pathway, but did not enhance the generation of sC5b-9 [30]. The latter finding is consistent with massive C3 staining and negative C5b-9 staining in kidney biopsies of anti-FB antibody-positive patients [30], suggesting that these antibodies primarily act at the C3 convertase level without substantially influencing the terminal pathway. Finally, IgGs from patients with anti-C3b antibodies decreased the capacity of C3b to bind CR1, a complement regulator that is highly expressed by podocytes but did not perturb binding to FH [30]. The association between anti-FB and anti-C3b antibodies and complement alternative pathway activation was confirmed in vivo by finding higher than normal plasma Bb levels in all 15 patients with anti-FB and/or anti-C3b antibodies [30]. The origin of these autoantibodies remains unknown, although an association with infective events was hypothesised, based on the clinical history of infection in half of the patients with anti-FB/C3b antibodies.

However, the presence of anti-FB and anti-C3b antibodies correlated poorly with clinical phenotype. The outcomes of patients were heterogenous, ranging from minor urinary abnormalities to nephrotic syndrome with varying degrees of renal impairment to ESRD [30]. Two of three patients experienced recurrence after renal transplantation. At present, there is no proof that anti-FB and anti-C3b antibodies play a causative role in IC-MPGN and C3G. They may be formed secondarily to increased amounts of complement cleavage products in the circulation of patients due to a primary hit and/or other genetic or acquired predisposing factors. In this regard, anti-FB autoantibodies were reported by Zhang et al. in three DDD patients who were also positive for C3NeFs [28].

Factor H autoantibodies

A monoclonal anti-FH “mini autoantibody” consisting of lambda light chain dimer was first described more than 25 years ago in a patient with MPGN [71]. FH protein comprises 20 short consensus repeats (SCRs) and regulates complement alternative pathway both in fluid phase and on cell surfaces. The amino-terminal SCRs 1–4 contain the complement regulatory domain, while the central (SCRs 6–8) and C-terminus (SCRs 19–20) repeats are responsible for FH binding to glycosaminoglycans on cells [72]. The anti-FH “mini autoantibody” was found in the MPGN patient, bound to SCR3 in the N-terminal complement regulatory domain, and caused uncontrolled activation of the alternative pathway and C3 consumption when added to normal human serum [73].

Subsequently, IgGs targeting FH were reported in a few patients with MPGN type I reminiscent of IC-MPGN [32, 74] or C3G [28, 32, 75, 76] (Table 1). Functional studies performed in three patients revealed that the antibodies predominantly bound the FH N-terminal domain [32, 77]. The IgGs isolated from a patient with DDD and monoclonal gammopathy inhibited fluid phase cofactor activity of FH for C3b degradation by FI [77].

A more recent report [33] described anti-FH antibodies in 17 patients, 5 with IC-MPGN, 11 with C3GN and one with DDD, representing 11% of a French cohort. Through epitope mapping, the N-terminal domain of FH was identified as the major binding site of the autoantibodies [33]. Consistently, IgGs isolated from three patients inhibited the fluid phase FI cofactor activity of FH but did not affect the FH regulatory activity on cell surfaces in a sheep erythrocyte lysis assay [33]. Notably, IgGs isolated from about 60% of IC-MPGN and C3G patients with anti-FH autoantibodies did not cause any defect in FH function in vitro [33]. In addition, the IC-MPGN/C3G-associated antibodies showed a weak binding avidity for FH and did not form stable circulating complexes in vivo [33].

The above findings are at variance with anti-FH autoantibodies that are found in about 10% of patients with aHUS. Indeed aHUS-associated anti-FH antibodies mainly target the C-terminal region of FH [76] and prevent FH-mediated cell surface protection from complement activation. In about 30% of cases, the antibodies also bind to the middle part and the N-terminus of FH and perturb both fluid phase and cell surface complement control [49]. In addition, aHUS-associated antibodies form stable circulating immune complexes and their presence correlated with low FH levels and with disease activity [78].

Taken together, these data indicate that in IC-MPGN and C3G the anti-FH antibodies have smaller functional effects than, and distinct pathogenetic consequences from, those associated with aHUS. Thirty to 40% of patients with C3G and anti-FH antibodies were also C3NeF+ [28, 32, 33, 74, 75, 76, 77]. It is plausible that antibodies to FH, by impairing fluid phase FH-mediated complement regulation, and C3NeFs, by stabilising the C3 convertase, play a synergistic role in mediating complement dysregulation in these patients.

The cause of anti-FH antibody formation in IC-MPGN and C3G remains undefined. Patients with IC-MPGN/C3G and anti-FH antibodies do not have the homozygous deletion of the CFHR1 gene [32, 33], which is frequently associated with anti-FH antibodies in aHUS. As the high degree of homology between FH and FHR1 is important for the generation of antibodies against FH C-terminus in aHUS [79], the lack of FHR1 deficiency might explain the different epitope specificity of IC-MPGN/C3G-associated anti-FH antibodies compared with aHUS-associated anti-FH antibodies.

Interestingly, a monoclonal gammopathy—defined as clonal proliferation of lymphocytes or plasma cells leading to the production of circulating monoclonal immunoglobulin [80]—was observed in the first reported patient with a monoclonal anti-FH “mini autoantibody” [73] and also in about 50% of adult patients who developed anti-FH autoantibodies [33, 75, 76, 77]. The finding that the anti-FH autoantibodies isolated from these patients had the same light chain as the monoclonal Ig suggested that the anti-FH reactivity can be caused by the monoclonal immunoglobulin [33]. Thus, monoclonal gammopathies may favour the production of either a light chain directed against FH or complete anti-FH IgGs. Screening for the presence of monoclonal gammopathy is suggested for adult patients with IC-MPGN or C3G and anti-FH autoantibodies.

Conclusions and therapeutic perspectives

Over the last decade, great advances have been made in the investigation into the autoimmune causes of IC-MPGN and C3G (summarised in Table 1).

It is now clear that C3NeFs belong to a heterogeneous group of autoantibodies (NeFs). NeFs may stabilise either C3 convertase or C5 convertase or both and/or prevent their accelerated decay through regulators of the complement alternative pathway. Some NeFs need properdin to exert their stabilising activity. Other NeFs stabilise the classical/lectin pathway C3 convertase. Most studies have been done on NeFs isolated from patients with C3G, and there is little data about the nature and mechanism of action of NeFs from patients with IC-MPGN. In addition, there is a poor correlation between the available functional data on NeFs and the composition of complement glomerular deposits. Further studies are needed to clarify the exact molecular mechanisms through which the different NeFs activate complement and induce different patterns of glomerular injury. Whether NeFs are primary causes or consequences and/or amplifiers of the disease is another open issue that requires further investigation.

Anti-FB and/or anti-C3b antibodies have been reported in a small number of patients, mainly with IC-MPGN. At variance with C3NeFs and C5NeF that only recognise neoepitopes in the C3 or C5 convertase complexes, the anti-FB and anti-C3b antibodies also bind to the isolated target proteins. In addition, the anti-FB antibodies stabilise the C3 convertase but inhibit the activation of C5 convertase.

Finally, anti-FH autoantibodies predominantly targeting the FH N-terminal domain and inhibiting fluid phase cofactor activity of FH have been reported both in IC-MPGN and C3G.

The heterogeneity of NeFs and the combined presence of NeFs with other complement-activating autoantibodies or with genetic complement variants in several patients with IC-MPGN or C3G highlight the multifactorial nature of the pathogenesis underlying these diseases.

An optimal disease-directed treatment for IC-MPGN and C3G patients has not been established. Therapies targeting the immune cells that produce autoantibodies, including steroids and the humanised monoclonal anti-CD20 antibody rituximab, did not consistently reduce the activity of C3NeF and gave limited and inconsistent clinical results [81, 82, 83]. A retrospective study suggested the effectiveness of mycophenolate mofetil in C3G patients with C3NeF [84], but these results should be confirmed in prospective studies.

Emerging knowledge on the molecular mechanisms by which NeFs and the other autoantibodies induce complement activation leading to kidney injury, along with an accurate analysis of complement profile, may help designing therapies with complement inhibitors already in clinical use or in the development pipeline, which are tailored to the specific defect. For instance, FD or FB inhibitors that target the alternative pathway C3 convertase [85] may be effective in patients carrying NeFs and other autoantibodies that activate complement mainly at C3 level. On the other hand, patients with NeFs inducing activation of the terminal complement pathway could benefit from the anti-C5 monoclonal antibody eculizumab [82, 86].

Notes

Acknowledgements

This work was partially supported by Fondazione ART per la Ricerca sui Trapianti ART ONLUS (Milano, Italy), The Kidneeds Foundation (Iowa City, Iowa) and by a grant from Ministero della Salute (RF-2016-02361720, Italy). We wish to thank Kerstin Mierke for revising English grammar and style.

Compliance with ethical standards

Conflict of interest

Marina Noris has received honoraria from Alexion Pharmaceuticals for giving lectures and participating in advisory boards. None of these activities have had any influence on the results or interpretation in this article. GR has consultancy agreements with AbbVie*, Alexion Pharmaceuticals*, Bayer Healthcare*, Reata Pharmaceuticals*, Novartis Pharma*, AstraZeneca*, Otsuka Pharmaceutical Europe* and Concert Pharmaceuticals*.

*No personal remuneration is accepted, and compensations are paid to his institution for research and educational activities. The other authors declare no conflict of interest.

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Copyright information

© IPNA 2018

Authors and Affiliations

  • Marina Noris
    • 1
    Email author
  • Roberta Donadelli
    • 1
  • Giuseppe Remuzzi
    • 1
    • 2
    • 3
  1. 1.IRCCS - Istituto di Ricerche Farmacologiche “Mario Negri”Clinical Research Center for Rare Diseases “Aldo e Cele Daccò”BergamoItaly
  2. 2.Department of Biomedical and Clinical SciencesUniversity of MilanMilanItaly
  3. 3.Unit of Nephrology and DialysisAzienda Ospedaliera Papa Giovanni XXIIIBergamoItaly

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