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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↗
PubMed1981

Autolytic fragmentation of complement components C3 and C4 under denaturing conditions, a property shared with alpha 2-macroglobulin.

The alpha polypeptide chain of the complement protein C3 splits into two fragments of 74 000 and 46 000 apparent mol.wt. under certain conditions used to prepare the protein for SDS (sodium dodecyl sulphate)/polyacrylamide-gel electrophoresis. The cleavage reaction occurs over a wide range of temperatures and from pH 4.6 to 10.6 in the presence of denaturants such as urea, SDS and guanidine hydrochloride. It is also induced by heat-denaturation of C3 in the absence of chemical denaturants. The reaction occurs only with haemolytically active C3, and is not observed with hydroxylamine-inactivated C3 or with C3b. A similar cleavage of the alpha-chain of complement component C4 occurs under the same conditions, forming fragments of 53 000 and 41 000 apparent mol.wt. This reaction is again specific for haemolytically active C4, and does not occur with C4b or hydroxylamine-inactivated C4. The complement component C5, although structurally similar to C3 and C4, does not undergo a reaction of this type. The characteristics of the denaturation-induced cleavage of C3 and C4 match those described for the 'heat-induced' cleavage of alpha 2-macroglobulin [Harpel, Hayes & Hugli (1979) J. Biol. Chem. 254, 8669-8678]. Cleavage of alpha 2-macroglobulin is also specific for the active form of the protein, and does not occur with chemically inactivated or proteinase-cleaved forms. The unusual conditions and specificity of the peptide-bond cleavage in all three proteins suggest that it is an autolytic process rather than being the result of trace proteinase contamination. The active forms of C3, C4 and alpha 2-macroglobulin have the transient ability to form covalent bonds after activation. The autolytic cleavage reaction is likely to be related to the covalent-bond-forming reactions of these proteins.

Complement C3↗
PubMed2004

Isolation and characterization of complement component C3 from Atlantic cod (Gadus morhua L.) and Atlantic halibut (Hippoglossus hippoglossus L.).

Complement component C3 was isolated from the plasma of cod (Gadus morhua L.) and halibut (Hippoglossus hippoglossus L.). Fast protein liquid chromatography (FPLC) techniques, involving ion exchange and gel filtration columns, were used. The purified proteins were analysed by SDS-PAGE which showed a two-chain structure, alpha- and beta-chains, as seen in higher vertebrates. Both proteins had intra-chain thioesters located within their alpha-chains and N-terminal amino acid sequencing confirmed their identity with reference to known C3 amino acid sequences from other species. Specific antibodies were prepared against cod and halibut C3 and tested in Western blotting on sera and purified C3. The proteolytic fragmentation of C3 was tested with trypsin, pepsin, papain and the extracellular product (ECP) from the bacterium Aeromonas salmonicida ssp. achromogenes (Asa). Both trypsin and papain were successful in cleaving C3 whereas pepsin and ECP had no effect. Carbohydrate moieties were detected in the alpha- and beta-chains of cod and halibut C3 and N-linked oligosaccharides were removed from the C3 with PNGase treatment, revealing a difference in C3 glycosylation between the two species.

Amino Acid Sequence↗
PubMed1975

Plasma amino acids and protein levels in chronic renal failure and changes caused by oral supplements of essential amino acids.

1. Plasma amino acids and six proteins have been measured in patients with chronic renal failure receiving low protein diets before and after oral supplementation with essential amino acids. 2. All the patients on low protein diets had a lower percentage of essential amino acids in their plasma than normal subjects but after supplementation, plasma levels increased significantly with minimal increase in non-essential amino acids or urea nitrogen. 3. Mean levels of plasma transferrin, complement C3 and globulin Gc were lower and plasma prealbumin higher in patients than in normal subjects. Plasma complement C4 and albumin were not different from normal. 4. Seven out of nine patients who tolerated the supplementation showed a significant increase in plasma transferrin, prealbumin and complement C3 but not in complement C4, globulin Gc or albumin. 5. Correlations between the percentage of essential amino acids and each of plasma transferrin, prealbumin and complement C3 and also between several of the plasma proteins further substantiate their value in the assessment of dietary intake in chronic renal failure. 6. The value of amino acid supplementation on low protein diets in chronic renal failure is discussed in relation to these observations.

Adult↗
PubMed2006

The complement component C3 plays a critical role in both Th1 and Th2 responses to antigen.

BACKGROUND: Complement component C3 is synthesized by keratinocytes and is activated after skin injury. C3 is also synthesized by peritoneal macrophages, which are activated by the adjuvant alum. OBJECTIVE: We sought to investigate the role of C3 in inciting allergic skin Inflammation and systemic immune responses after epicutaneous sensitization or intraperitoneal sensitization with antigen. METHODS: C3-deficient (C3-/-) mice and wild-type (WT) control animals were subjected to epicutaneous sensitization with the antigen ovalbumin (OVA) on shaved and tape-stripped skin or intraperitoneal immunization with OVA in alum. RESULTS: Skin Infiltration by eosinophils and expression of mRNA encoding the TH2 cytokines IL-4 and IL-5 in OVA-sensitized skin sites was impaired in C3-/- mice. Splenocytes from epicutaneously sensitized C3-/- mice secreted less IL-4, IL-5, IL-13, and IFN-gamma in response to OVA stimulation than splenocytes from WT control animals. The defect in cytokine secretion by splenocytes was also observed after intraperitoneal immunization of C3-/- mice. C3-/- mice had impaired IgG1, IgG2a, and IgE antibody responses after both epicutaneous and intraperitoneal immunization. The defect in cytokine secretion of C3-/- mice was not due to defective proliferation to antigen, was not observed after anti-CD3 stimulation, and was corrected by the addition of purified C3 protein. CONCLUSION: These results suggest that C3 plays an important role in both the TH1 and TH2 response to antigen in vivo. CLINICAL IMPLICATIONS: The complement pathway might be a potential target in the therapy of allergic diseases.

Administration, Cutaneous↗
PubMed1994

The fractionation of human plasma proteins. II. The purification of human complement proteins C3, C3u, and C5 by application of affinity chromatography.

We have devised a purification scheme for human complement proteins C3, C3u, and C5. Affinity chromatography is employed to isolate each of these three proteins in a highly purified form. Typical yields were 910, 30, and 53 mg for C3, C3u, and C5, respectively, from 3 liters of human plasma. These yields reflect 31 and 32% recoveries for C3 and C5, respectively. The major advantages of this protocol over other published procedures are the application of affinity chromatography to yield high quality purified complement components, and the fact that the purification of C3, C3u, and C5 is part of a broader scheme designed for the isolation of over 20 plasma proteins from a single batch of plasma.

Blood Proteins↗
PubMed1981

Mouse complement components C3 and C4. Characterization of their messenger RNA and molecular cloning of complementary DNA for C3.

Mouse liver mRNA species which direct the cell-free synthesis of pro-C3 and pro-C4 polypeptides with an apparent molecular weight of 175,000 and 190,000, respectively, were shown to sediment faster than 28 S. By electrophoresis in a denaturing gel the mRNA for C3 was determined to contain approximately 7,500 ribonucleotides. cDNA was synthesized from size-fractionated mouse liver mRNA and cloned in the plasmid pBR 322. Among the cDNA clones recovered three were identified as being complementary to portions of the mRNA for C3.

Animals↗
PubMed2005

IgG naturally occurring antibodies stabilize and promote the generation of the alternative complement pathway C3 convertase.

Normal human IgG contains naturally occurring anti-C3 antibodies (anti-C3 NAbs) that have been proposed to regulate complement amplification. Here, we report a novel procedure for anti-C3 NAb purification. Pooled human IgG was fractionated on a DEAE column prior to affinity chromatography on IgG and then on C3. Anti-C3 NAbs co-purified with anti-F(ab')2 NAbs. In a refined protocol, IgG fractions were absorbed on Fc, F(ab')2, and C3, which allowed to isolate the directly accessible NAbs and to remove IgG hinge-region-specific NAbs. Since a substantial fraction of total anti-C3 NAbs in whole IgG pre-existed as complexes, IgG that did not bind to the three affinity columns was treated with urea and the affinity chromatography repeated to collect the dissociated NAbs. The urea-accessible anti-F(ab')2 NAbs were rather pure but anti-C3 NAbs yet contained substantial amounts of anti-F(ab')2 NAbs. Anti-C3 NAbs showed up to 400-fold and anti-F(ab')2 NAbs, up to 30-fold enrichment as compared to pooled normal human IgG. Anti-C3 NAb preparations exhibited nephritic factor activity that was up to 60 times stronger than that of total IgG from a patient with membranoproliferative glomerulonephritis type 2. In addition, anti-C3 NAbs promoted C3 convertase generation, when added to the convertase precursor or during convertase assembly, suggesting a non-nephritic-factor mechanism. Factors H and I reduced the overall level of activity but had no influence on the NAb dose-response curve meaning that NAbs did not interfere with factor H binding. Convertase promoting activity during assembly correlated with the content of anti-C3 NAbs in NAb complexes. In conclusion, anti-C3 NAbs associated with framework-specific anti-idiotypic NAbs stabilize C3 convertase and promote its generation but their activity is compensated for in whole IgG.

Antibodies, Anti-Idiotypic↗
PubMed2000

Detection of two variants of complement component C3 in C3-deficient guinea pigs distinguished by the absence and presence of a thiolester.

The complement system is an essential part of the innate defense, and C3 is an integral part of this powerful system. In previously identified complement C3 deficient guinea pigs only approx. 5% of the normal serum C3 level is detectable. No differences were found between in vitro C3 protein synthesis and C3 mRNA levels of cells from C3-deficient and wild-type animals and the amino acid sequences of both C3 proteins are identical as deduced from cDNA sequencing. Previously, the principal inability to form a C3 thiolester was discussed as a possible reason for this C3-deficiency. Here we report the isolation of two functionally different C3 species from the C3-deficient animals. Only one of these C3 proteins exhibits normal hemolytic activity and contains a thiolester group. The second C3 species is exclusively present in C3-deficient animals and lacks a thiolester, explaining its failure to express hemolytic activity. The presence of a second C3 species lacking a thiolester structure only in C3-deficient animals indicates that the stability of the thiolester may play a role in C3 deficiency. However further analysis of the in vitro stability of the thiolesters of C3 from normal and C3-deficient guinea pigs revealed no differences. A decreased in vivo thiolester stability might lead to the presence of C3 with and without a thiolester or alternatively the expression of two isoforms of C3 in these animals. Considering the central role of C3 in host defense, the mechanisms of C3 thiolester formation require further analysis.

Animals↗
PubMed1985

Human complement component C3: cDNA coding sequence and derived primary structure.

The complete cDNA coding sequence and derived amino acid sequence of human complement component C3 are presented. The encoded precursor molecule contains a signal peptide of 22 amino acid residues, the beta chain (645 residues), and the alpha chain (992 residues). The two chains are joined by four arginine residues not present in the mature protein. Several functionally important sites have been localized, such as the thiolester site, the cleavage site liberating the anaphylatoxin, and two sites of cleavage by the serine protease factor I, as well as a peptide fragment with leukocyte mobilizing activity. At least two carbohydrate attachment sites, one on each chain, have been identified. Human C3 has 79% identity to mouse C3 at the nucleotide level and 77% identity at the amino acid level. The protease alpha 2-macroglobulin and complement component C4 show considerable homology to C3, suggesting that the three proteins have evolved from a common ancestor.

Amino Acid Sequence↗
PubMed1990

Antagonism of estrogen- and antiestrogen-induced uterine complement component C3 expression by ICI 164,384.

The uterus of the immature rat synthesizes and secretes complement component C3 in response to estradiol treatment. This response occurs in the uterine epithelial cells and is also stimulated by several antiestrogens including tamoxifen and LY117018. The administration of a new antiestrogen ICI 164,384 blocked the estradiol as well as the antiestrogen-stimulated increases in uterine weight, epithelial cell height, C3 synthesis and C3 mRNA. ICI 164,384 demonstrated no agonist properties in terms of epithelial cell response as determined by C3 expression.

Animals↗