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Results for “complement C3 inhibitor”

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PubMed2000

Pro-inflammatory cytokines induce the transcription factors C/EBPbeta and C/EBPdelta in astrocytes.

The transcription factors CCAAT/enhancer binding protein (C/EBP)-beta and -delta are key regulators for the expression of the acute phase genes in the liver, such as complement component C3 and antichymotrypsin. In the brain, these acute phase proteins are produced in response to pro-inflammatory cytokines by the reactive astrocytes, in particular those surrounding the amyloid plaques of Alzheimer's disease brains. Here we show that lipopolysaccharides (LPS), IL-1beta, and TNFalpha induce the expression of the c/ebpbeta and -delta genes in mouse primary astrocytes. This induction precedes the expression of the acute phase genes coding for the complement component C3 and the mouse homologue of antichymotrypsin. The induction of these two acute phase genes by LPS is blocked by cycloheximide, whereas this protein synthesis inhibitor does not affect the expression of the c/ebp genes. Altogether, our data support a role as immediate-early genes for c/ebpbeta and -delta, whose expression is induced by pro-inflammatory cytokines in mouse cortical astrocytes. In the liver, these transcription factors are known to play an important role in inflammation and energy metabolism regulation. Therefore, C/EBPbeta and -delta could be pivotal transcription factors involved in brain inflammation, in addition to their previously demonstrated role in brain glycogen metabolism regulation (Cardinaux and Magistretti. J Neurosci 16:919-929, 1996).

Animals↗

PubMed1972

Ontogeny of the human complement system: in vitro biosynthesis of individual complement components by fetal tissues.

The human fetal liver is capable of synthesizing the biologically active form of the second (C2) and fourth (C4) components of complement as early as 8 wk after conception, and the inhibitor of C1 (C1 INH) as early as 11 wk after conception. Biologically active C3 was produced in vitro by fetal liver obtained at 14 wk gestation. These conclusions were based on the observations that isolated fetal livers produced biologically active C2, C3, C4, and C1 INH, that this production was temperature dependent and reversibly inhibited by well-known inhibitors of protein synthesis, and that (14)C-labeled amino acids were incorporated into proteins immunochemically identical with these proteins. The data suggested that a large mononuclear cell was the cell type in the fetal liver that synthesized C2 and C4.

Amino Acids↗

PubMed1976

Activation of the alternative pathway of complement in childhood acute lymphoblastic leukemia.

Sequential studies in children with acute lymphoblastic leukemia have demonstrated that at diagnosis or relapse there is defective utilization of complement by the alternative pathway. Thus, the sera of 17/18 patients fail to completely consume C3 to C9 when incubated with zymosan or cobra venom factor (CoF). This underutilization is due to a specific inhibitor of C3 activation which has been partially isolated. By remission, the inhibotor disappears and the CoF and zymosan assays return to normal. In addition, serum levels of C3 and factor B are elevated at the time of diagnosis or relapse but fall to below 3 S.D. from the mean in nearly 60 per cent of the cases during induction therapy. Similarly, serum C4 levels which are normal at diagnosis fall to less that 3 S.D. from the mean in 7/12 cases during treatment. Low C3 levels correlate well with factor B values, suggesting that if C3 to C9 are utilized after the inhibitor has been eliminated, such utilization occurs primarily through the alternative pathway. Presumably, as illustrated by the low C4 levels, this activity is mediated by the ampliciation loop of the alternative pathway involving classical pathway generation of C3b.

Child↗

PubMed1981

Cleavage of C3 by neutral proteases from granulocytes in pleural empyema.

The possibility of direct inactivation of C3 by granular enzymes from polymorphonuclear leukocytes (PMNLs) in pleural empyema was examined. As a group, pleural empyema from 10 patients with purulent effusions and a positive bacteriologic culture cleaved significantly more 125I-labeled C3 bound to Sepharose (18.4% +/- 7.3%) than did 19 sterile pleural effusions (2.4% +/- 0.9%; P less than 0.001) and sonicates from bacterial strains commonly found in empyema (1.4% +/- 0.2%). Granular enzymes from 7 X 10(6) PMNLs cleaved 78.5% of 125I-labeled C3 bound to Sepharose. When proteolysis of 125I-labeled C3 after incubation with pleural empyema or PMNL granular enzymes was examined with polyacrylamide gel electrophoresis, breakdown products were similar. Granulocyte elastase-like activity was detected in four samples of pleural empyema. Granulocyte elastase inhibitors, as well as 10% human serum, effectively suppressed cleavage of C3 and elastase-like activity. In pleural empyemas, granula enzymes from PMNLs, especially elastase, apparently contribute to low complement-mediated opsonic activity by direct inactivation of C3.

Adult↗

PubMedDate not supplied

Complement receptors and regulatory proteins in human atherosclerotic lesions.

Complement activation in human atherosclerotic lesions is indicated by the presence of C5b-9 terminal complexes. By using monoclonal antibodies to the complement C3b receptor (CR1) and the iC3b receptor (CR3), it was observed that approximately 20% of the cells in complicated human carotid lesions express CR1 and CR3 antigens. One to five percent of complement receptor-positive cells stained for smooth muscle cell-specific myosin, and the remainder were determined to be predominantly macrophages, based on their reactivity to anti-LeuM3 (CD14) monoclonal antibody. No C3dg receptor (CR2)-positive cells were observed in any of the eight lesions examined. The complement regulatory glycoprotein decay accelerating factor (DAF) was widely distributed extracellularly, in addition to being present on 20% to 60% of the total cell population. Factor H, a plasma protein that regulates alternative pathway C3 convertase formation, was observed extracellularly in 70% of the lesions examined. C1 inhibitor was present in a few plaque specimens, was relatively sparse, and appeared largely cell associated. Terminal C5b-9 complement complexes were pervasive in all lesions. Both the complement regulatory proteins and the activation products were limited to the area of lesion involvement and were absent from normal arterial wall. The results demonstrate that molecules involved in complement regulation and complement ligand binding are present in atherosclerotic lesions, where they may function to modulate the activities of complement.

Arteriosclerosis↗

PubMed1989

Halogenation and proteolysis of complement component C3 on Salmonella typhimurium during phagocytosis by human neutrophils.

We examined the fate of C component C3 on the surface of Salmonella typhimurium during ingestion by human neutrophils. Initial experiments showed that C3 fragments and C3-acceptor complexes were the major serum ligands which were surface iodinated by canine myeloperoxidase on serum-incubated rough and smooth isolates of S. typhimurium. In contrast, labeled C3 was not identified when the same organisms were ingested by neutrophils in the presence of 125I-Na, a situation previously shown to iodinate particulate targets via the neutrophil myeloperoxidase-halide-H2O2 system. Pretreatment of neutrophils before phagocytosis with the lipid-soluble protease inhibitor diisopropylfluorophosphate (DFP), but not with other protease inhibitors (p-nitrophenylguanidinobenzoate, leupeptin, pepstatin), substantially blocked proteolysis of 125I-C3 on S. typhimurium strain RG108 during ingestion by neutrophils. Purification of neutrophil phagosomes containing S. typhimurium-bearing 125I-C3 showed that DFP but no other protease inhibitors blocked proteolysis of 125I-C3 within phagosomes. Iodinated C3-acceptor complexes were identified by immunoprecipitation from the detergent-insoluble fraction of phagosomes prepared from DFP-treated cells ingesting S. typhimurium in the presence of 125I-Na. These results show that C3 fragments on the surface of S. typhimurium are the major serum ligands which are halogenated and degraded by proteolysis during phagocytosis by human neutrophils, and suggest that the majority of proteolysis on the ingested target occurs within the neutrophil phagosome.

Adsorption↗

PubMed2000

[The complement system: an old story or target of new therapeutic approaches?].

The complement system is a multifactorial protein cascade system which is essentially involved in the early unspecific immune response. Its major function is the activation of cellular defense mechanisms, opsonisation of foreign particles and the destruction of target cells. While the impact of the different complement components for bacterial elimination still remains controversial, overwhelming activation of the complement cascade, however, can induce life threatening tissue damage due to the effective cytotoxic properties. In the last years a variety of studies demonstrated beneficial, organ protective effects of complement modulation in models of severe inflammation. Attempts to control the complement system include the application of endogenous complement inhibitors e.g. C1-inhibitor (C1-INH) or the administration of recombinant complement receptors such as the soluble complement receptor 1 (rsCR1). Moreover antibodies against key proteins (C3, C5), against their activation products (C5a) or against complement receptor 3 (CR3, CD18/11b) mediated adhesion of leukocytes to the vascular endothelium, represent effective options of complement modulation. Besides this, insertion of membrane bound human complement regulators (DAF- CD55, MCP- CD46 or CD59) into xenogenic donor organs has proven effectiveness to prevent xenograft rejection. The described interventions protected from severe organ damage in various animal models of sepsis, myocardial and intestinal ischaemia-reperfusion injury, ARDS, nephritis, and xenograft rejection. With respect to recent clinical data, complement inhibition could represent a useful therapeutic strategy to control overwhelming inflammation. Own experiments demonstrated protective effects of complement modulation with C1 INH and rsCR1 in a model of complement induced pulmonary injury. With respect to sufficient host defense, however, the use of complement inhibitors must be considered carefully.

Complement Inactivator Proteins↗

PubMed2002

Detection of serine proteases in extracts of the domestic mite Blomia tropicalis.

Previous studies have shown that the domestic mites Dennatophagoides pteronyssinus and D. farinae contain allergens with serine protease activity. These proteolytic allergens include trypsin, chymotrypsin, elastase, kallikrein, and C3/C5 convertase. However, it is not known whether the domestic mite Blomia tropicalis shares with other mite species the serine protease activities. The enzymatic activity present in extracts obtained from food-free B. tropicalis was investigated using specific substrates and inhibitors. Based upon the concentration response and inhibition profiles, and the digestion of specific substrates our data demonstrate that extracts from B. tropicalis exhibit several serine-protease-like activities. The enzyme activities detected in the B. tropicalis extracts are trypsin, elastase, chymotrypsin, kallikrein, C3/C5 convertase, and mast cell protease. Our results also demonstrate that kallikrein and C3/C5 convertase-like activities were not significantly affected by the alpha1-antiprotease, a naturally occurring serine protease inhibitor which protects lung mucosa from the enzymatic action. These data strongly suggest that the Echymyopodidae mite B. tropicalis shares at least five serine proteases with members of other mite families, the Glycyphagidae and Pyroglyphidae. In addition, our data demonstrate the potential use of biochemical methods to detect serine proteases for evaluation of mite growth in viitro, or to detect environmental exposures to these enzymes.

Animals↗

PubMed2003

Complement activation following optic nerve crush in the adult rat.

Activation of the complement cascade following peripheral nerve axotomy and following traumatic brain injury has been demonstrated in previous studies. This study investigates the temporal pattern of microglia/macrophages and complement activation following axotomy of sensory CNS neurons, using a standardized experimental crush injury of the optic nerve in adult rats. Numerous ED1-labeled macrophages were found at the lesion site and distal to the injury at 7 days post injury (dpi). Complement C3-mRNA was upregulated 2-28 days post lesion, indicating local synthesis of complement in the optic nerve. Furthermore, increased immunoreactivity (IR) for the end product of the complement cascade, the membrane attack complex (MAC), was detected along disintegrating axons co-labeled with anti-neurofilament distal to the injury. Double-labeling for microglia show MAC-immunoreactivity expressed in their immediate vicinity, indicating a key role of microglia/macrophages in complement activation. The complement regulator Clusterin was upregulated in astrocytes at the lesion site as well as in the distal portion of the injured optic nerve, suggesting activation of a defense response to endogenous complement attack. A crush injury of the optic nerve leads to complement activation at the site of lesion and along the distal portion of the nerve, as well as upregulation of the complement inhibitor Clusterin at least in astrocytes. Reactive microglial cells seem to have a key role in complement activation as a local source of C3. We suggest that the balance between complement activation and their regulators may have impact on axonal degeneration following optic nerve injury.

Animals↗

PubMed1997

[On phenotype and genotype features of serum and erythrocyte proteins in occupation-related bronchopulmonary pathology].

Electrophoresis and isoelectric focusing assessed distribution of phenotypic and gene frequency for 7 highly polymorphic proteins in 163 patients having occupational chronic bronchitis, pneumoconiosis and bronchial asthma. Phenotypic frequency studies, when compared to the reference group, revealed significant differences in the following parameters: proteinase inhibitor, 3rd component of complement, transferrin, serum blood-group specific component, phosphoglucomutase of RBC. Gene frequency studies revealed the significant differences in 3rd component of complement (C3), transferrin (Tf) and phosphoglucomutase of RBC (PGM): the patients demonstrated increased amounts of C3 F, Tf C3 and PGM 2b alleles. The results could be used for individual forecasting the risk of occupational diseases and for choosing the individual prophylactics.

Anion Exchange Protein 1, Erythrocyte↗

PubMed1989

Biosynthesis of complement factor H by human umbilical vein endothelial cells. Regulation by T cell growth factor and IFN-gamma.

The present studies were initiated to characterize a 150-kDa molecule with inhibitory activity for C3bBb formation, which is present in human umbilical vein endothelial cells (HUVEC). Therefore, human endothelial culture supernatants (HECS) were analyzed for the presence of human complement factor H by ELISA. It was found that H was present in HECS. An immunoblot analysis of affinity purified H from HECS showed that the size of HUVEC H was identical to that of plasma H. The mean production of H by HUVEC of first passage cultures was 40 ng/10(6) cells/day. The synthesis of HUVEC H was fully inhibitable by the addition of cycloheximide to the cultures, suggesting that H is de novo synthesized. Additional evidence for de novo synthesis was obtained by using biosynthetic labeling with [35S] methionine, immunoprecipitation, and SDS-PAGE. It was demonstrated that, indeed, HUVEC produce and secrete factor H. Two forms of the protein were identified, the 150-kDa form and also a 45-kDa form, both forms have been identified in plasma. The functional activity of HUVEC H is identical to that of plasma H. IFN-gamma induced enhanced synthesis of H by HUVEC, whereas it had no effect on C3 synthesis. Supernatant from stimulated PBMC, T cell growth factor, enhanced synthesis of both H and C3. The present studies indicate that H is produced by HU-VEC and that H may function as an inhibitor of complement activation at the endothelial cell level and, thereby, together with molecules like decay accelerating factor and membrane cofactor protein, may influence resistance of endothelial cells to complement mediated damage.

Binding, Competitive↗

PubMed2006

Pharmacological evidence for activation of phospholipid and small GTP binding protein signalling cascades by Nod factors.

The effects of lipo-chitin oligosaccharide Nod factors (NodNGR[S] from Rhizobium sp. NGR234) on root hair deformation in Vigna unguiculata (L.) Walp. were studied using pharmacological agents to mimic and/or inhibit their action. It was hypothesised that the rearrangement of the cytoskeleton seen during Nod factor induced root hair deformation is modulated by protein kinase C, monomeric G proteins of the Rho superfamily and the location and amount of phosphatidylinositol 3-phosphates (PI3Ps). This hypothesis is supported by the following observations. The protein kinase C activators, 12-deoxyphorbol 13-acetate (DPA) and diacylglycerol kinase inhibitor 1, stimulated root hair deformation to a level similar to that seen with Nod factors or mastoparan, whereas the inhibitor Gö 6976 inhibited root hair deformations induced by NodNGR[S], mastoparan, DPA and diacylglycerol kinase inhibitor 1. The Ras antagonists mevastatin and sulindac sulphide, and the Rho antagonist exoenzyme C3 toxin from Clostridium botulinum all inhibited Nod factor stimulated root hair deformation. Pasteurella multocida toxin activates Rho and stimulated root hair deformation, this stimulation was inhibited by both neomycin and exoenzyme C3 toxin. The PI3 kinase inhibitors, wortmannin and LY-294002 attenuated Nod factor induced root hair deformation. These studies were complemented with actin immunoprecipitations of root hair enriched microsomal membrane preparations from V. unguiculata which pulled down small GTP binding proteins. Root hair deformation is an important early stage in the formation of nitrogen fixing nodules and this study highlights that these processes may depend on signalling cascades involving phospholipids and small GTP binding proteins.

Actins↗

PubMed2000

A recombinant soluble chimeric complement inhibitor composed of human CD46 and CD55 reduces acute cardiac tissue injury in models of pig-to-human heart transplantation.

BACKGROUND: Inasmuch as complement plays a critical role in many pathological processes and in xenograft rejection, efficient complement inhibitors are of great interest. Because the membrane-associated complement inhibitors are very effective, recombinant soluble molecules have been generated. METHODS: We tested the efficacy of complement activation blocker-2 (CAB-2), a recombinant soluble chimeric protein derived from human decay accelerating factor (DAF, CD55) and membrane cofactor protein (MCP, CD46), in two models of pig-to-human xenotransplantation in which tissue injury is complement mediated. The in vitro model consisted of porcine aortic endothelial cells and human serum, and the ex vivo model consisted of a porcine heart perfused with human blood. RESULTS: In vitro, addition of CAB-2 to serum inhibited cytotoxicity and the deposition of C4b and iC3b on the endothelial cells. Ex vivo, addition of CAB-2 to human blood prolonged organ survival from 17.3 +/- 6.4 min in controls to 108 +/- 55.6 min with 910 nM (100 microg/ml) CAB-2 and 219.8 +/- 62.7 min with 1820 nM (200 microg/ml) CAB-2. CAB-2 also retarded the onset of increased coronary vascular resistance. The complement activity of the perfusate was reduced by CAB-2, as was the generation of C3a and SC5b-9. The myocardial tissues had similar deposition of IgG, IgM, and Clq; however, CAB-2 reduced the deposition of C3, C4, and C9. Hearts surviving >240 min demonstrated trace to no deposition of C9 and normal histologic architecture. CONCLUSION: These results indicate that CAB-2 can function as an inhibitor of complement activation and markedly reduce tissue injury in models of pig-to-human xenotransplantation and thus may represent a useful therapeutic agent for xenotransplantation and other complement-mediated conditions.

Animals↗

PubMed2001

Tears contain the complement regulator CD59 as well as decay-accelerating factor (DAF).

Previous studies have shown that DAF (or CD55), a cell surface inhibitor of autologous C3 activation, is present in tears and that > 90% of the C3 convertase regulatory activity in tear fluid resides in this protein (Lass JH et al., Invest Ophth Vis Sci 1990; 31:1136-48). This study investigated whether (i) the membrane cofactor protein (MCP or CD46), an additional factor that regulates C3 activation, and (ii) the membrane inhibitor of reactive lysis (MIRL or CD59), a cell surface regulator that acts to prevent formation of the membrane attack complex, are also present in tears, and if so, are functional. Two-site immunoradiometric assays showed that MCP is present in tears at low levels (42 + 8 ng/ml, n = 8) while CD59 is present at levels (222 + 78 ng/ml, n = 14) comparable to those of DAF (325 + 289 ng/ml, n = 12). The concentrations of CD59 (i) were increased two-fold or more in closed eye tears, and (ii) were decreased in reflex tears. Western blotting showed that CD59 protein in tears migrates with an apparent mol. wt similar to membrane CD59 protein. Phenyl-Sepharose adsorption and Triton X-114 partitioning of tear CD59 as well as of tear DAF however, showed that both proteins are devoid of GPI anchors. Assays using cobra venom factor-activated human serum and guinea pig erythrocytes showed that CD59 is functionally active in inhibiting autologous C5b-9-mediated lysis and, under constitutive conditions, accounts for > 85% of the C9 inhibitory activity in tear fluid.

CD55 Antigens↗

PubMed2006

Surface protease of Treponema denticola hydrolyzes C3 and influences function of polymorphonuclear leukocytes.

Treponema denticola is a dominant microorganism in human periodontal lesions. One of the major virulence factors of this microorganism is its chymotrypsin-like surface protease, dentilisin. The purpose of this study was to evaluate the effect of dentilisin on human polymorphonuclear leukocytes (PMNs). We used chemiluminescence to assess production of O(-)(2) by PMNs against T. denticola ATCC 35405 and dentilisin-deficient mutant K1. T. denticola ATCC 35405 induced production of O(-)(2), whereas dentilisin-deficient K1 did not. We found that chymostatin, a protease inhibitor, strongly reduced the ability of T. denticola ATCC 35405 to induce production of, O(-)(2), whereas K1 was relatively unaffected. We also used Immunoblot and ELISA to evaluate the activation of complement by this microorganism in relation to PMNs. T. denticola ATCC 35405 hydrolyzed the alpha-chain of C3, producing iC3b. Furthermore, strain ATCC 35405 induced a larger release of MMP-9 from PMNs than strain K1. Dentilisin activated PMNs via complement pathways and may play a role in establishing periodontal lesions.

Bacterial Proteins↗

PubMed1983

Complement activation and impaired capacity to solubilize immune complexes or to prevent their formation in essential mixed cryoglobulinemia.

The complement profile, the immune complex solubilizing capacity (ICSC), the immune complex precipitation inhibition capacity (ICPIC), the presence of cryoprecipitable material, and the presence of immune-aggregate- and non-immune-aggregate mediated C1q-binding activity was assessed in serum samples from 23 patients suffering from essential mixed cryoglobulinemia (EMC). No correlation between the levels of cryoglobulins and the clinical activity of EMC was found. The mean C1q-binding activity in EMC serum samples was abnormally elevated 28 +/- 29% (mean +/- SD). In six out of eight serum samples that contained C1q-binding material, evidence was obtained that such material was of the complexed immunoglobulin G (IgG) type. Among the levels of C1q, C1r, C2, C4, C3, C5, C6, C1-inhibitor, C3d, B, I, H, as well as the total hemolytic activity and the activity of the alternative pathway of the complement, the mean serum concentrations of C1, C2, and C4 and in consequence the mean total hemolytic activity were significantly reduced, whereas the mean levels of C3d were significantly elevated in the EMC serum samples. The capacity of the 23 EMC serum samples to solubilize preformed immune precipitates from bovine serum albumin (BSA) and rabbit anti-BSA antibodies as well as their capacity to prevent the formation of the precipitable form of such complexes was analyzed. Compared to the ICSC and the ICPIC of 30 normal human sera, the ICSC and the ICPIC of EMC serum samples were reduced to 57 +/- 24% and 38 +/- 33%, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed1990

Interferon-mediated transcriptional and post-transcriptional modulation of complement gene expression in human monocytes.

The addition of lymphoblastoid interferon alpha, fibroblast interferon beta and recombinant interferon gamma to in vitro monocyte cultures produced dose-dependent increases in transcription rates of the genes encoding the second component of complement (C2), factor B (B) and C1 inhibitor, and the abundance of their respective mRNA. Interferon gamma was the most effective at stimulating transcription of the C1-inhibitor gene whereas interferons alpha and beta were more effective at increasing the transcription of the C2 and B genes. Transcription of the C3 gene was reduced by interferon gamma. None of these cytokines altered the level of transcription of the actin gene. Interferon-induced changes in the levels of transcription of the C2, B and C1-inhibitor genes occurred rapidly, with significant changes occurring within 30 min of exposure to these cytokines. Within 4 h of removal of the interferons from the culture fluid, the level of transcription of the C1-inhibitor, C2, B and C3 genes returned to control values, as did abundance of C2, B and C3 mRNA. However, the abundance of C1-inhibitor mRNA remained elevated in interferon-gamma-treated monocytes. Combinations of interferons produced less than additive effects on the stimulation of the transcription of C2, B and C1-inhibitor genes, whereas measurements of C1-inhibitor mRNA and B mRNA showed that interferon gamma acted synergistically with interferon gamma to increase the abundance of the mRNA. Their effects on C2 mRNA abundance were less than additive. The half-lives of C1-inhibitor, C2, B and C3 mRNA were not altered by interferon alpha, whereas interferon gamma shortened the half-life of C2 mRNA by approximately 50%, and prolonged the half-lives of B and C1-inhibitor mRNA approximately twofold and fivefold, respectively. The half-life of C3 mRNA was unaltered by either interferon. These results show that the large increase in C1-inhibitor synthesis which occurs in interferon-gamma-treated monocytes, is due to a combination of increased transcription and increased C1-inhibitor mRNA stability. They also suggest that the synergistic effects of interferon alpha together with interferon gamma on C1-inhibitor and factor B synthesis is also dependent upon increased transcription and increased mRNA stability.

Complement C1 Inactivator Proteins↗

PubMed2001

Complement component C3 is not required for full expression of immune complex glomerulonephritis in MRL/lpr mice.

Complement activation and tissue deposition of complement fragments occur during disease progression in lupus nephritis. Genetic deficiency of some complement components (e.g., Factor B) and infusion of complement inhibitors (e.g., Crry, anti-C5 Ab) protect against inflammatory renal disease. Paradoxically, genetic deficiencies of early components of the classical complement pathway (e.g., C1q, C4, and C2) are associated with an increased incidence of lupus in humans and lupus-like disease in murine knockout strains. Complement protein C3 is the converging point for activation of all three complement pathways and thus plays a critical role in biologic processes mediated by complement activation. To define the role of C3 in lupus nephritis, mice rendered C3 deficient by targeted deletion were backcrossed for eight generations to MRL/lpr mice, a mouse strain that spontaneously develops lupus-like disease. We derived homozygous knockout (C3(-/-)), heterozygous (C3(+/-)), and C3 wild-type (C3(+/+)) MRL/lpr mice. Serum levels of autoantibodies and circulating immune complexes were similar among the three groups. However, there was earlier and significantly greater albuminuria in the C3(-/-) mice compared with the other two groups. Glomerular IgG deposition was also significantly greater in the C3(-/-) mice than in the other two groups, although overall pathologic renal scores were similar. These results indicate that C3 and/or activation of C3 is not required for full expression of immune complex renal disease in MRL/lpr mice and may in fact play a beneficial role via clearance of immune complexes.

Albuminuria↗