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PubMed1996

Chronic complement C3 gene expression in the CNS of transgenic mice with astrocyte-targeted interleukin-6 expression.

Both cytokines and complement are thought to play significant, but poorly understood roles, in the pathogenesis of a variety of neurodegenerative diseases. In this study, we examined the expression of C3, the central component of complement, in the brains of transgenic mice with constitutive astrocyte expression of the proinflammatory cytokine, interleukin-6 (IL-6). Immunohistochemistry studies demonstrated elevated deposition of C3 in the brains of transgenic animals compared with normal animals. Northern blot analysis of mRNA from brain and other tissues demonstrated an age-related increase in C3 gene expression only in the brains of transgenic animals, indicative of local synthesis. In situ hybridization studies revealed coincidence between C3 and IL-6 transgene expression, as well as areas of neuronal and white matter damage observed in cerebellum and hind brain. Furthermore, C3 mRNA expression was observed in ependymal cells, perivascular mononuclear cells, endothelial cells, and scattered cells throughout the white matter and the brain stem. The overlap in C3 mRNA expression with areas of pathology suggests that complement may contribute to the inflammation and cellular injury observed in this model. The transgenic mice used in these studies provide a novel and valuable tool for examining the role of complement in central nervous system pathobiology.

Animals↗
PubMed1985

Identification and characterization of a variant of the third component of complement (C3) in rainbow trout (Salmo gairdneri) serum.

A rainbow trout serum protein that is cross-reactive with the third complement component of rainbow trout (C3-1) was purified to homogeneity and its structural and functional properties compared with those of C3-1. This protein (termed C3-related protein: C3-2) bears a close structural resemblance to C3-1, although C3-2 apparently shows no hemolytic activity. Like C3-1, C3-2 consists of two disulfide-linked polypeptide chains (128,000 alpha and 72,000 beta) and retains the unique thiol ester site in the alpha-chain. C3-2 shares some antigenicity with C3-1, but it also displays distinctive antigenic determinants of its own. Comparison of tryptic peptide maps revealed that about 20% of the peptides was specific to either C3-1 or C3-2, and about 80% of the peptides were common to both proteins. Amino acid compositions of the alpha- and beta-chains of C3-2 were similar to those of C3-1. Furthermore, amino acid sequence analysis of the NH2 termini of the alpha- and beta-chains of C3-2 revealed a high degree of homology with those of C3-1, 24 of 26 residues in the alpha-chain and all 20 in the beta-chain of C3-2 were identical with those found in C3-1. Both C3-1 and C3-2 were detected in all the adult rainbow trout tested and in first generation offspring randomly bred from them.

Alleles↗
PubMed1985

Sequential serum complement (C3) and immunoglobulin levels in shock/trauma patients developing acute fulminant systemic sepsis.

The complement system has been implicated in the physiopathology of septic shock. Since infection is a major cause of death in trauma patients, we examined daily serum C3 and immunoglobulin levels in all victims of major trauma during a 3-month interval. Sixteen patients developed acute systemic sepsis 3-15 days after admission. For all variables the lowest values occurred shortly after hospital admission, during or just after fluid resuscitation. Thereafter, the serum C3 and immunoglobulin concentrations gradually returned to the normal ranges, despite the onset of fulminant systemic sepsis. Except for IgM, the occurrence of hypotension during sepsis did not affect the recovery patterns of the measured variables. In the five patients experiencing hypotension, serum IgM dropped transiently but resumed its normalization trend after the restoration of adequate perfusion pressure. In the three nonsurvivors there was no reduction in the serum C3 or immunoglobulin levels prior to death. These data do not support a role for C3 or the immunoglobulins in the pathogenesis of acute fulminant clinical sepsis. On the contrary, the behavior of these substances during severe sepsis is more consistent with protective host defense functions.

Acute Disease↗
PubMed1986

Platelet-associated immunoglobulins IgG, IgM, IgA and complement C3 in immune and nonimmune thrombocytopenic disorders.

A two-stage radioactive antiglobulin test--using unlabelled antisera specific for IgG, IgA, IgM and C3 followed by binding of 125I-staphylococcal protein A--was applied to determine platelet-associated immunoglobulins (PAIg) and complement (PAC3) in thrombocytopenias of various etiologies. One hundred and one patients with immune thrombocytopenia (chronic autoimmune, 48; acute autoimmune, 37; Evans syndrome, nine; connective tissue diseases, seven) and 20 patients with presumed nonimmune thrombocytopenia (bone marrow aplasia or malignancy, six; septicemia, five; hypersplenism, five; cirrhosis of liver, three; others, one) were studied. Increased levels of PAIg/C3 were found in 76% of patients with immune thrombocytopenia. PAIgG was raised in 66%, PAIgM in 57%, PAIgA in 44%, and PAC3 in 29%. Isolated elevation of PAIgG and of PAIgM was found in four and three cases, respectively; PAIgA and PAC3 were elevated in one case each. PAIgG was associated with PAIgM in 56%, with PAIgA in 34%, and with PAC3 in 27%. Both patients with Evans' syndrome and patients with connective tissue diseases had significantly higher PAIgM levels than the other patients with immune thrombocytopenia. In patients with nonimmune thrombocytopenia, increased rates of PAIg/C3 were also encountered. Positive test results were found in 88% (PAIgG 88%, PAIgM 47%, PAIgA 35%, and PAC3 24%). In immune-mediated thrombocytopenia, we observed a significant inverse correlation between platelet counts and PAIgG, PAIgA, and PAC3, but not with PAIgM. In contrast, no such correlation was found in patients with nonimmune thrombocytopenia. Our data indicate that the evaluation of neither parameter alone nor the combination of PAIg/C3 will discriminate between immune and nonimmune thrombocytopenia. Preferential coating with certain immunoglobulins, however, may be present in some subgroups of immune thrombocytopenias.

Blood Platelets↗
PubMed1998

Molecular genetics of the complement C3 convertases in lower vertebrates.

Evolution of the two gene families of the complement system involved in the formation of the C3 convertases, B/C2 and C3/C4/C5, was studied at the cDNA level in lower vertebrates. Cyclostomes, the most primitive extant vertebrates, seem to possess only one member each of these families, indicating that gene duplication between B and C2 or among C3, C4 and C5 occurred in the lineage of jawed vertebrates. Typical C3 and C4 cDNAs were identified in both amphibian (Xenopus) and teleost (medaka fish), locating the C3/C4 gene duplication before the divergence of ray-finned fish and lobe-finned fish. On the other hand, typical B cDNA was identified in Xenopus, whereas teleost counterparts from three species all showed intermediate character between B and C2, suggesting the possibility that the B/C2 gene duplication occurred in the tetrapod lineage. Genetic linkage between these two family genes within the MHC was observed in Xenopus but not in medaka fish.

Animals↗
PubMed1975

Interactions of the third component of complement (C3) with cross-linked dextran. II. Demonstration of an alternate pathway activation as binding mechanism of C3 to cross-linked dextran.

In previous investigations we could show that incubation of cross-linked dextran (Sephadex) with normal human serum results in the binding of the third component of complement to the Sephadex beads. In this paper, data are presented which demonstrate that not only human but also guinea pig C3 reacts with Sephadex and that this binding is due to an alternate pathway of C3 activation. This conclusion was drawn, since a) C3 is bound also from guinea pig serum with total deficiency of C4, b) the reaction can be completely blocked by EDTA but only diminished by EGTA and c) the reaction turned out to be temperature dependent with an optimum at 37 degrees C and could be abolished by diluting the serum more than 1:16. The ability of cross-linked dextran to activate C3 via the alternate pathway seems to be due to conformational changes, since in our experiments soluble dextran of the same source was found to be ineffective in this respect. Implications from these findings and possible applications are discussed.

Animals↗
PubMed1993

Complement C3 gene expression and regulation in human glomerular epithelial cells.

Extra-hepatic synthesis of complement is thought to mediate local tissue inflammatory injury. To investigate this phenomenon in the glomerular epithelial cell (GEC), we examined the biosynthesis and regulation of gene expression of the third component of complement in isolated human GEC derived from normal tissue. Metabolic labelling and immunoprecipitation studies demonstrated that C3 protein was synthesized, processed and secreted by GEC under basal conditions. The secreted C3 alpha and beta polypeptide chains had identical electrophoretic mobilities with those of hepatic C3. Examination of cellular RNA using semi-quantitative polymerase chain reaction (PCR) showed that C3 gene expression was present in unstimulated GEC and was increased by stimulation with interferon-gamma (IFN-gamma) in a time- and dose-dependent manner. Tumour necrosis factor-alpha (TNF-alpha), while mediating an increase in monocyte U937 C3 expression, revealed no evidence of regulation of GEC C3 gene expression. These results indicate that human GEC spontaneously express the C3 gene and that increased gene expression is regulated by IFN-gamma. These observations may reflect part of a wider mechanism of protection against or mediation of local, immune-mediated tissue injury.

Cells, Cultured↗
PubMed1982

Structure-function relations in the third component of human complement (C3)-I. Hydrophobic site.

Charge shift electrophoresis and crossed hydrophobic interaction immuno-electrophoresis were used to demonstrate the presence of hydrophobic sites in the human C3 molecule. C3b and C3d were true amphiphilic proteins that could bind to hydrophobic surfaces. To the contrary, native C3, that presented the characteristics of amphiphilic proteins upon charge shift electrophoresis, did not bind to hydrophobic surfaces. These results suggested that the hydrophobic sites were located in the internal part of the C3 molecule and they were exposed in the external part when C3 was activated. The action of chaotropes on C3 was studied in detail and showed that the hydrophobic sites protected the thiolester bond (present in the labile site) from hydrolysis by water and thereby preserved the biological properties of native C3.

Binding Sites↗
PubMed1983

Complement (C3) binding to platelets in autoimmune thrombocytopenia.

In view of conflicting reports on the occurrence of complement binding to platelets in idiopathic autoimmune thrombocytopenic purpura (AITP) we performed measurements of platelet bound C3 in patients with AITP who had elevated levels of platelet bound IgG. Using a quantitative antiglobulin consumption technique 38 out of 42 patients were found to have fixed abnormally large amounts of C3 to their platelets, and a significant positive correlation between the amounts of platelet bound IgG and C3 was shown to exist. In additional experiments antibody eluates were prepared from AITP platelets and were shown to cause the fixation of C3 to normal donor platelets in vitro. Taken together these findings strongly suggest that the C3 binding in AITP is specifically related to the disease process.

Autoantibodies↗
PubMed1985

Complement-mediated solubilization of immune complexes and their interaction with complement C3 receptors.

Some of the molecular events in the complement (C)-mediated solubilization of immune complexes (IC) have been clarified in recent years. The solubilization is primarily mediated by alternative C pathway proteins whereas factors in the classical pathway accelerate the process. Components of the membrane attack complex do not participate in the reaction. Besides affecting the size and solubility of circulating IC the interaction with C factors influences the reactivities of the complexes towards fluid phase reactants and mediates the reversible binding of IC to cellular C3 receptors. Our knowledge of the cellular localization, expression and structure of the C3 receptors, especially the C3b (CR1) receptor, has been considerably extended in the last few years, whereas our understanding of the physiological role of these receptors is still fragmentary. However, it is becoming increasingly evident that impaired solubilization of IC in patients with compromised C function may permit the complexes to deviate from their normal pattern of interaction with C3 receptors probably influencing both the organ distribution and clearance of IC and thereby also their phlogistic potentials.

Antigen-Antibody Complex↗
PubMed1999

Effects of short courses of different doses of prednisone and dexamethasone on serum third component of complement (C3) levels in dogs.

The effect of different doses of prednisone and dexamethasone on serum C3 levels was determined in 35 dogs. Dogs in Group A (n = 15) were administered prednisone (1.1 mg/kg/day) for 14 days; dogs in Group B (n = 10) were given prednisone at 2.2 mg/kg/day for 7 days; dogs in group C (n = 10) were administered dexamethasone (0.25 g/kg/day) for 7 days. Serum C3 concentrations were determined using a sandwich ELISA in samples obtained before and after glucocorticoid administration. Concentrations were expressed as a percentage of a reference standard. No statistically significant differences were found after glucocorticoid administration in all groups. Thus, short-term administration of prednisone and dexamethasone at commonly used doses did not result in significantly lower serum C3 levels.

Animals↗
PubMedDate not supplied

A study of the breakdown of the third component of human complement (C3).

This paper reports the description of fragments of human C3, purified from aged sera. Sera were incubated at different temperatures (4 degrees, 20 degrees and 37 degrees C) for 8 days or more. At 4 degrees C, the major isolated fragment was C3b which showed a heterogeneity of structure. Under reducing conditions, it liberated a 40,000 dalton fragment which reacted against an anti-C3d and which we called "C3d-like". At 20 degrees C, C3b was partially destroyed to yield the C3c- and C3d-fragments. At 37 degrees C, C3d and C3c were obtained. C3c presented a structural heterogeneity. It was made either of two chains of 75,000 daltons or of three chains with 75,000, 38,000 and 31,000 dalton MW. The comparison of these fragments with those obtained by tryptic hydrolysis led us to propose a pathway to the degradation of C3 and to bring some informations about the structure of this molecule.

Complement C3↗
PubMed1991

Interleukin 2 mediates stimulation of complement C3 biosynthesis in human proximal tubular epithelial cells.

Previous reports have suggested the production of complement components C4, C2, and factor B by renal tissue. However, the cells involved in production of complement have not been identified. In this study metabolic labeling experiments demonstrated that human proximal tubular epithelial cells (PTEC) synthesize a 180-kD precursor of C3 that is secreted after proteolytic cleavage into a disulphide linked two-chain molecule as found in plasma. C3 present in culture supernatants of PTEC was functionally active, however, during the culture period there was a partial inactivation of the C3 molecule as assessed by hemolytic titration. Recombinant IL-2 enhances the rate of C3 synthesis in a dose-dependent manner reaching maximal stimulation at doses of 200-400 U/ml IL-2. Northern blot analysis demonstrated a 5.2-kb C3 mRNA species present in PTEC that was increased within 24 h of IL-2 treatment. IL-2-induced enhancement of C3 production by PTEC could be neutralized with specific antibodies to IL-2. This study demonstrates that C3 synthesis in PTEC is upregulated by IL-2, the major cytokine produced by activated T cells.

Animals↗