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*
Department of Medicine, Section of Nephrology, University of Chicago, Chicago, IL 60637;
Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21205; and
Department of Medicine, Division of Rheumatology, University of Colorado Health Sciences Center, Denver, CO 80262
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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To prevent injury of self tissue, complement is regulated by both plasma and cell membrane-associated proteins (4). A focal point of regulation is at the level of the C3/C5 convertases of both pathways. This occurs in humans via the action of the plasma proteins, factor H and C4-binding protein, and the cell membrane proteins, complement receptor 1, decay-accelerating factor, and membrane cofactor protein, all members of the regulators of complement activation gene family (5). These proteins inhibit C3/C5 convertases by accelerating their intrinsic decay and/or by acting as a factor I cofactor for the cleavage and inactivation of C3b and C4b. The related rodent protein, CR1-related gene/protein y (Crry),3 has combined decay-accelerating and factor I cofactor activity for C3b and C4b (6, 7).
Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by the loss of tolerance to self Ags and the production of autoAbs. Many autoAbs display typical features of Ag-specific responses in that they are of the IgG isotype, react with multiple independent sites on an Ag, have undergone somatic mutation, and have high affinity for Ag. The complement system is believed to be centrally involved in the pathogenesis of human SLE. Complement is systemically consumed, and, as a reflection of this, complement levels are typically decreased, especially in patients with active glomerulonephritis (GN) (8, 9). Deposition of C3 activation fragments and other complement components in damaged tissues, such as the glomerulus and skin, suggests that this consumption is pathogenic and centrally involved in inflammatory injury.
Other observations regarding human SLE illustrate that the situation is more complex. For instance, an SLE-like syndrome, withloss of tolerance manifested by high levels of autoAbs, is frequently found in patients with inherited complete deficiencies of early classical pathway components such as C1 (C1q or C1r/C1s), C2, or C4 (10). This also appears to be the case in mice with C1q deficiency (11). Although the reasons for loss of tolerance are not understood, and the renal disease in these patients and mice may be less severe (12, 13), these observations have cast some doubt on the importance of complement activation for some of the disease manifestations of SLE.
To gain insight into the specific pathophysiologic mechanisms underlying SLE and to identify candidate genes that might be important in human SLE, a number of murine models of SLE have been studied (14, 15, 16, 17). One of the best characterized is the MRL/lpr strain. MRL/lpr mice differ from the lupus-prone congenic MRL+ strain by the nearly complete absence of the membrane Fas protein (18), necessary for apoptosis, which is due to a retroviral insertion in the fas gene (19).
MRL/lpr mice develop a severe proliferative GN. The evolution of disease recapitulates findings in humans, with mesangial proliferative GN early in disease and diffuse proliferative and crescentic GN later in the course. Ultimately, glomerulosclerosis and renal failure occur in the terminal phase of disease (20). In both humans and mice with SLE, the finding of C3 and C5b-9 in association with glomerular immune deposits (21, 22) and the observations that nephritogenic Abs typically are complement-fixing IgG Abs (23) support the concept that complement contributes to tissue damage and GN in human and mouse models of SLE.
To study the effects of continuous complement pathway blockade in the immunological and pathological events that occur in experimental lupus nephritis, we created transgenic mice expressing soluble Crry (sCrry) directed by the broadly active and heavy metal-inducible metallothionein (MT)-I promoter (24). In these transgenic mice, Crry mRNA was widely distributed, including in liver, brain, lung, and kidney (25, 26). In the latter, it was widely expressed both in glomeruli and tubules. This Crry transgenic line was then bred into MRL/lpr mice, and the clinical and pathological events occurring with complement inhibition were studied.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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MRL/lpr mice were purchased from The Jackson Laboratory (Bar Harbor, ME). Crry transgenic mice were originally produced on an outbred CD-1 background (25). For these studies, mice derived from a single founder were backcrossed into MRL/lpr mice until the eighth and ninth generations, retaining <0.4% of CD-1 genes. The presence of the Crry transgene was determined by PCR and confirmed by serum ELISA, as described previously, because normal mice do not have circulating sCrry (25). In all cases, littermate controls bred contemporaneously, which lacked the Crry transgene, were used. A total of 196 mice (89 transgene positive and 107 transgene negative) was studied. Forty-two mice (22 transgene positive and 20 transgene negative) from the ninth generation were used in a survival study, while 154 mice (67 transgene positive and 87 transgene negative) from the eighth and ninth generations were sacrificed at 18, 21, or 24 wk of age, and kidneys were analyzed for pathological changes. Serum and urine samples were collected once per month from all mice. If an animal died before its intended sacrifice data, the most recently obtained serum and urine sample was used in analyses.
To stimulate the MT-I promoter and increase systemic and renal sCrry levels (25), selected animals were fed zinc (25 mM ZnSO4 in drinking water) after weaning. For every variable considered in this study, zinc feeding had no effect in transgene-negative animals compared with littermate controls not fed zinc. Hence, all data from transgene-negative animals were pooled for these analyses.
Measurements from sera and urine
Blood urea nitrogen (BUN) and urinary creatinine concentrations were detected with a Beckman Autoanalyzer (Beckman Coulter, Fullerton, CA). Urinary albumin concentration was measured by ELISA (Bethyl Laboratories, Montgomery, TX), as described previously (27). Urinary albumin was normalized to creatinine excretion and presented as milligrams of albumin per milligram of creatinine. Albumin excretion in normal mice is <0.025 mg/mg creatinine.
Complement activity was measured by a previously described assay in which C3 deposition on zymosan, a potent activator of the alternative pathway, was assessed by flow cytometry (6, 28). Because of the concern that complement activity declines with time in wild-type MRL/lpr mice, reflecting disease activity and complement consumption, a separate group of F13 animals was studied at 10 wk of age for these analyses. Transgene-positive animals were compared with littermate transgene-negative animals handled identically.
For detection of anti-dsDNA autoAbs from serum, 96-well plates were coated with methylated BSA (Sigma-Aldrich, St. Louis, MO), followed by calf thymus dsDNA (Sigma-Aldrich). After blocking with 1% BSA, serial dilutions of sera were plated for 2 h at room temperature. A standard curve was prepared with a mAb to dsDNA and ssDNA (1D12; kindly provided by B. Kotzin, University of Colorado Health Sciences Center, Denver, CO). Dilutions of MRL/lpr sera obtained from 3-mo-old mice were used as an internal control to control for interplate variability. A mAb specific only for ssDNA (H4330 from B. Kotzin) was used as a control to ensure that no ssDNA reactivity was present on the plate. After washing, bound IgG anti-dsDNA was detected with HRP-labeled goat anti-mouse IgG (Kirkegaard & Perry Laboratories, Gaithersburg, MD) and ABTS peroxidase substrate, and the OD at 405/490 nm was determined. The amounts of anti-dsDNA Abs present were quantified by plotting against the standard curve, and values are expressed in relative units.
For detection of IgG or IgG3 rheumatoid factors (RF), 96-well plates were coated with rabbit IgG or mouse IgG2a (Sigma-Aldrich), respectively. After blocking with 1% BSA, serial dilutions of sera were plated for 1 h at room temperature. Control sera from a B6/lpr mouse with known high titers of RF and from a 3-mo-old MRL/lpr mouse were plated as internal controls to control for interplate variability. After washing, bound RF were detected with HRP-labeled goat anti-mouse IgG (Fc fragment specific; Jackson ImmunoResearch Laboratories, West Grove, PA) or goat anti-mouse IgG3 (Caltag Laboratories, Burlingame, CA) and ABTS peroxidase substrate, and the OD405/490 was determined.
For detection of total IgG in the serum, 96-well plates were coated
with goat anti-mouse 
(Southern Biotechnology Associates,
Birmingham, AL). After blocking with 1% BSA, serial dilutions of sera
were plated for 1 h at room temperature. A standard curve was
prepared with mouse IgG (Southern Biotechnology Associates). Control
serum from a 3-mo-old MRL/lpr mouse was used as an internal
control to control for interplate variability. After washing, bound IgG
was detected with HRP-labeled goat anti-mouse IgG (Fc fragment
specific; Jackson ImmunoResearch Laboratories) and ABTS peroxidase
substrate, and the OD405/490 was determined. The
amounts of IgG present were quantified by plotting against the standard
curve, and values were expressed in milligrams per milliliter.
Measurements from tissue
Groups of animals were sacrificed at 18, 21, and 24 wk of age. Kidneys were removed, divided into sections snap frozen for immunofluorescence (IF) microscopy, and fixed in 10% buffered formalin for light microscopic evaluation. Spleens were removed from all animals and weighed.
Cryostat sections (4 µm) were processed for direct IF microscopy using FITC-conjugated Abs to mouse C3 and IgG (Cappel Laboratories, Durham, NC) (29). At least 30 glomeruli from each animal were examined by an observer blinded to the origin of the specimens, and a semiquantitative score of staining intensity and distribution from 0 to 4+ was given, as previously detailed (27).
For light microscopy, 4-µm sections stained with periodic acid Schiff were provided as coded slides to a renal pathologist (M. Haas), who was blinded to the origin of each section. For each slide, the extent of GN was graded in a semiquantitative (0–4+) manner according to the schema of Passwell et al. (30). In addition, the fraction of total glomeruli containing cellular or fibrocellular crescents and the fraction showing sclerosis and/or hyalinosis were also determined for each animal.
Statistical analyses
All data are expressed as mean ± SEM and were analyzed using Minitab (State College, PA) and Stata (College Station, TX) software. When a single transgenic group was compared with its littermate control, two-sample t or Wilcoxon rank-sum tests were used for parametric and nonparametric data, respectively. Survival curves were analyzed by the nonparametric Kaplan-Meier method. For multiple comparisons, one-way ANOVA followed by Tukey’s pairwise comparisons were used. Potential relationships between variables were examined by Pearson product moment correlation coefficient.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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To examine spontaneous mortality occurring over time in the
MRL/lpr lupus strain, 42 mice were studied (22 transgene
positive and 20 transgene negative). In this group of studies, all
animals were fed zinc in drinking water after weaning; in the Crry
transgenic animals, this resulted in stimulation of the MT-I promoter,
thereby increasing sCrry levels. As shown in Fig. 1
, Crry transgenic animals had prolonged
survival compared with littermate animals lacking the transgene
(p < 0.01), demonstrating that chronic
complement inhibition with sCrry confers a survival advantage to
MRL/lpr mice.
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To determine whether chronic complement inhibition affects renal
disease in MRL/lpr mice, the following experiments were
performed. A total of 154 mice was studied, of which 67 had the
Crry transgene and 87 were littermate animals lacking the
Crry transgene; some mice from each group were fed zinc in
drinking water to increase sCrry levels. To evaluate renal function and
histology at different times, animals were scheduled for sacrifice at
18, 21, or 24 wk of age. As shown in Fig. 2, MRL/lpr mice lacking the
Crry transgene developed renal failure over time, which was
prevented by complement inhibition with sCrry. Furthermore, at the time
of sacrifice or before spontaneous death, 11 of 67 (16.4%)
transgene-positive animals had BUN values >50 mg/dl compared with 37
of 87 (42.5%) of transgene-negative animals (p
= 0.001). Thus, complement inhibition with sCrry protects against the
development of impaired renal function.
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Crry transgenic animals did not appear to die from renal failure, as
preterminal BUN values in this group were 46.6 ± 9 mg/dl
(n = 9), and no animal had BUN values >100 mg/dl. In
contrast, control MRL/lpr mice lacking the Crry
transgene developed renal failure before spontaneous death with BUN
values of 122 ± 29 mg/dl (n = 16;
p = 0.024 vs Crry transgenic animals). There was no
difference in the mean time from serum acquisition and death in the two
groups of animals (2.6 ± 0.5 and 2.5 ± 0.3 wk in
transgene-positive and transgene-negative animals, respectively).
Furthermore, if the animals that died were removed from the analysis
shown in Fig. 2, the statistically significant differences between the
24-wk-old animals remained. Thus, complement inhibition with sCrry
protects MRL/lpr animals from renal failure, which may
translate into a survival advantage. Those animals in the Crry
transgenic group that died spontaneously appeared to do so from
manifestations other than renal failure.
To formally assess glomerular functional abnormalities, urinary albumin
was measured. As shown in Fig. 3, albuminuria was decreased in those Crry transgenic animals in which
sCrry levels were increased by zinc feeding, illustrating that
complement inhibition effectively reduces this measure of renal
disease.
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To examine the autoimmune phenotype in MRL/lpr mice,
serological markers of disease were measured. For these studies, there
was no difference within groups whether animals were fed zinc or not;
as such, data shown were pooled. There were no differences in the
levels of total IgG, anti-dsDNA Ab, or IgG and IgG3 RF in Crry
transgenic MRL/lpr mice compared with their littermate
transgene-negative controls (Table I).
Furthermore, there was no correlation between any of these serological
measures and clinical indices of renal disease. Spleen weights were
also measured in animals. There were no differences between
MRL/lpr animals with and without the Crry
transgene at 18, 21, and 24 wk of age (Table II). Thus, complement inhibition with
sCrry does not appear to affect the underlying autoimmunity in
MRL/lpr mice, as can occur with complete complement protein
deficiencies of early classical pathway components (31, 32).
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sCrry levels were also measured in animals we studied for renal disease manifestations. sCrry levels were increased in 24-wk-old animals fed zinc compared with those not (22.7 ± 2.6 and 18.4 ± 1.3 µg/ml, respectively), although these were not statistically different. Furthermore, sCrry levels in serum did not correlate with renal functional measures, which might reflect that locally produced sCrry in kidney was more important in limiting renal disease.
Pathologic findings
As expected in the setting of complement inhibition with sCrry,
there was less C3 deposition in the glomeruli of Crry transgenic mice
compared with transgene-negative control mice (Table III and Fig. 4). In contrast to the reduction in C3
deposition, IgG deposition in glomeruli was unchanged with sCrry
overexpression (Fig. 5). Correspondent to
the reduced BUN levels, GN and glomerulosclerosis were also reduced by
sCrry overexpression in all groups, although there was no statistically
significant difference by our scoring system (Table IV and Fig. 6).
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examines animals with C3
staining scores 
2.5. As expected, a significantly greater number of
animals without the Crry transgene had high C3 staining,
which was associated with renal failure. In contrast, none of the 15
Crry transgenic animals with a C3 staining score 2.5 developed renal
failure. Because Crry acts as a factor I cofactor to inactivate C3b, it
may be that this C3 observed in these Crry transgenic mice is
inactivated C3b, which bears no relationship to disease measures.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Despite the clear effect on renal disease as measured by BUN and albuminuria, we did not find an alteration in histological measures of GN. A dissociation between clinical and pathological disease measures in lupus nephritis can occur in humans (33). The pathological measures of glomerular disease used in this study do seem to be valid measurements, as BUN levels and pathological variables were strongly correlated (p < 0.001 in all cases). Our findings most likely can be explained by informative censoring (34), as clinical features of disease were collected on all animals, while the analysis of pathological variables could not be performed on the animals that died before their scheduled time of sacrifice. Of these animals that died spontaneously, the nine Crry transgenic animals had only mildly elevated BUN levels. In contrast, the 16 transgene-negative animals that died spontaneously did so with severe renal failure, with average BUN values of 122 mg/dl obtained within 4 wk of their death. The modest increases in mean pathological scores between 18 and 24 wk of age, particularly for the transgene-negative animals, support the notion that the more severely involved animals were lost from analysis between these two time points.
Similar to our findings in the nephrotoxic serum nephritis model
(25), we noted an apparent dose response between the level
of complement inhibition and disease manifestations in
MRL/lpr mice. Transgenic animals in which sCrry was
maximally stimulated with zinc feeding had BUN levels that were nearly
normal and albuminuria reduced by a factor of 3 compared with
MRL/lpr animals without the transgene and those with the
transgene not fed zinc. These results support that the observed effects
were truly due to complement inhibition. However, there was a
discrepancy between sCrry levels and disease outcome measures. We
believe that sCrry produced locally in kidneys of Crry transgenic
animals may be important in protecting against renal disease
(35) and is not reflected in serum levels. Second, as
transgenic animals not zinc supplemented developed renal disease and a
declining glomerular filtration rate, it is likely that there was
impaired sCrry elimination. This is supported by the increase in
average sCrry levels from 7.7 µg/ml in 10-wk-old animals to 18.4
µg/ml in 24-wk-old animals, a time frame in which glomerular
filtration rate (as estimated by BUN levels and illustrated in Fig. 2)
declined by 50%. An additional interesting finding was the correlation
between C3 staining and clinical outcomes in animals without the
Crry transgene, but the discrepancy between these two
measures in mice with the transgene. This suggests that even in those
transgenic animals in which C3 was activated, it was subsequently
inactivated by factor I using sCrry present in glomeruli as
cofactor.
The spontaneous mortality that occurs in MRL/lpr animals has traditionally been considered to occur from renal failure (20). Yet, this conclusion came into question from studies by Lloyd et al. (36) with MRL/lpr mice with targeted deficiency of ICAM-1. Their results suggested that pulmonary disease led to mortality in MRL/lpr mice; this was delayed in ICAM-1-deficient animals. Despite their improved survival, ICAM-1-deficient animals did not have an alteration in histological manifestations of GN or proteinuria. In our study, MRL/lpr animals without the transgene that died spontaneously clearly did so with renal failure; whether this was the proximate cause of their deaths could not be ascertained. In contrast, transgene-positive animals that died did not have renal functional impairment, suggesting that they died from another cause such as pulmonary failure, which was not affected by inhibition of the complement system.
The role for complement activation in SLE and lupus nephritis has largely been supported by circumstantial evidence such as the findings of systemic complement consumption and local deposition in relevant tissue sites. Recent mouse studies have extended these to more formal proof for the involvement of complement. Wang et al. (37) treated the New Zealand Black/New Zealand White F1 lupus mouse strain with anti-C5 mAb and noted an improvement in survival and a reduction in proteinuria. Studies by Watanabe et al. (38) showed that factor B-deficient MRL/lpr mice were protected from GN. In addition to showing a role for the complement system in lupus GN, these illustrated that the alternative pathway amplification loop is relevant in this immune complex-mediated disease. Our data confirm and extend these two studies to include a detailed examination of the effect of complement inhibition on renal function over time. The studies with anti-C5 mAb (37, 39) have led to clinical trials of anti-C5 mAbs in human SLE and other diseases.
There are distinct advantages to the use of Crry transgenic mice as in these studies. Complement inhibition by sCrry is continuous and relatively constant. The level of complement inhibition we achieved in these studies was significant but not complete. The MT-I promoter is widely active and results in relatively high renal expression of the transgene (24). Therefore, in these animals there was also locally produced sCrry, which may not be reflected in sera measures of complement activity. In particular, the high tubular expression of the Crry transgene, which leads to significant release of biologically active sCrry in tubular lumina (25), constitutes a significant benefit because C3 convertase regulators are normally absent at this site (40, 41, 42, 43) and tubular injury is clearly important in progressive glomerular diseases. Success in these studies supports the design of similar genetic strategies in humans, such as the use of renal-specific promoters directing the production of complement inhibitors (44).
Inhibition of the complement system is not without its potential risks. By and large these drawbacks have been identified from observations made on human subjects with complement deficiencies and include susceptibility to autoimmune disease, impaired immune complex processing, and predisposition to infectious illnesses. With the generation of mice with targeted deficiencies of individual complement proteins, such abnormalities have also been observed in animals with comparable defects (11, 27, 45). In line with this, it is important for us to comment on the recent observations made by the Gilkeson laboratory on MRL/lpr mice with complete deficiencies of factor B or C3 (38, 46). Paradoxically, lupus mice with factor B deficiency were protected from renal disease, while those with C3 deficiency had worsened renal disease. One conceivable explanation for these data relates to the need for C3 (and C4) to clear glomerular immune complexes (27). Because of this, C3-deficient MRL/lpr animals had considerably more immune deposits in glomeruli, which could interact with Fc receptors on inflammatory cells (46, 47).
In contrast, the use of sCrry is well tolerated, as shown by our findings described in this study, as well as those involving Crry transgenic mice with serum sickness and MRL+ mice with the Crry transgene (our unpublished observations). Specifically, there is no impairment in immune complex processing, as happens in mice or humans with complete complement protein deficiencies. Furthermore, there is no apparent propensity to infection or spontaneous autoimmune disease. This illustrates the advantages of using Crry transgenic mice, in which some beneficial complement function is present compared with the total absence of complement activity in knockout animals. In addition, there is no analogous complement deficiency that can mirror the effects of Crry, as this protein is a multifaceted complement inhibitor with activity toward C3 and C4 in the alternative and classical pathway C3 convertases (6, 7, 48).
In summary, in this study, we have shown that MRL/lpr lupus mice expressing the potent C3 convertase regulator Crry as a soluble protein were protected from renal disease and its attendant mortality. The level of systemic expression of sCrry was moderate and led to significant, but not complete, complement inhibition. Local production of sCrry occurred in kidney and may not have been reflected in this measure of complement inhibition. Thus, our findings suggest that complement inhibition at the level of C3 convertases will be well tolerated in clinical practice. This is particularly relevant, as human complement inhibitors with activity profiles comparable with rodent sCrry are in clinical studies (49, 50, 51, 52).
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Richard J. Quigg, Department of Medicine, Section of Nephrology, University of Chicago, 5841 South Maryland Avenue, MC5100, Chicago, IL 60637. E-mail address: rquigg{at}medicine.uchicago.edu
3 Abbreviations used in this paper: Crry, CR1-related gene/protein y; BUN, blood urea nitrogen; GN, glomerulonephritis; IF, immunofluorescence; MT, metallothionein; RF, rheumatoid factor; sCrry, soluble Crry; SLE, systemic lupus erythematosus.
Received for publication October 15, 2001. Accepted for publication January 23, 2002.
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M. Nangaku Complement Regulatory Proteins: Are They Important in Disease? J. Am. Soc. Nephrol., September 1, 2003; 14(9): 2411 - 2413. [Full Text] [PDF]
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L. Bao, M. Haas, D. M. Kraus, B. K. Hack, J. K. Rakstang, V. M. Holers, and R. J. Quigg Administration of a Soluble Recombinant Complement C3 Inhibitor Protects Against Renal Disease in MRL/lpr Mice J. Am. Soc. Nephrol., March 1, 2003; 14(3): 670 - 679. [Abstract] [Full Text] [PDF]
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) had significantly improved survival
(p < 0.01) compared with littermate
MRL/lpr animals without the Crry
transgene (•).
