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[Partial lipodystrophy, hypocomplementemia and glomerulonephritis].

Renal involvement is found in 20 to 50% of cases of Partial lipodystrophy (PLD). We report 8 cases of PLD of which 6 had a glomerular nephropathy and 2 had no renal disease but all had persistent hypocomplementemia and 5 had circulating nephritic factor (C3NeF). The analysis of these cases and of all the cases reported in the literature shows the specificity of the glomerular involvement. Membranoproliferative glomerulonephritis (MPGN) with dense intramembranous deposits is a constant finding in PLD with renal involvement. This variety of MPGN is well known for being associated with persistent hypocomplementemia. However, the presence of hypocomplementemia and C3NeF in patients with PLD but without nephritis raises the question of the interrelationship between alternative pathway complement activation and the development of MPGN with or without lipodystrophy. There is no valid explanation in the present state of knowledge for the association of partial lipodystrophy hypocomplementemia, and MPGN. From the answer to this problem should emerge a better understanding of the role of complement in renal disease and in particular in the unusual form of glomerular injury seen in MPGN.

Adolescent↗
PubMed1976

Chemotactic responses of normal human basophils to C5a and to lymphocyte-derived chemotactic factor.

Peripheral blood basophils from normal human subjects responded chemotactically to the complement component C5a and also to the supernatant fluid from cultured human lymphocytes stimulated by mitogens or specific antigen. Basophil chemotactic factor (BCF) was detected in stimulated lymphocyte cultures within 24 hr and increased for the first 3 days. BCF was found after stimulation of lymphocytes by B or T cell mitogens as well as by specific antigen. The amount of BCF in culture fluids was independent of cell proliferation. Monocyte chemotactic factor (MCF) and BCF could not be separated from one another by Sephadex or DEAE chromatography. Both activities were eluted from Sephadex G-100 columns in a m.w. region of about 15,000 daltons and were found after ion exchange chromatography on DEAE in a peak eluted by 0.1 M NaCl. These findings suggest that mitogen or antigen-stimulated lymphocytes secrete a molecule that is chemotactic for both monocytes and basophils. Thus, in the absence of a basophil-specific chemotactic molecule, the preferential accumulation of basophils in certain types of delayed hypersensitivity skin reactions must be due to additional factors such as basophil chemotaxis augmentation factor.

Basophils↗
PubMed1976

Measles infection. Involvement of the complement system.

The complement system was examined in fifty patients with acute, apparently uncomplicated measles; forty-six were children less than 10 years old. Twenty showed evidence of pathological complement activation. In thirteen of these the pattern was consistent with activation of the classical pathway while in the other seven data suggested utilization of an alternative pathway. An additional eleven patients had isolated reduction in Clq without alteration in concentration of other components; these were excluded from the classical pathway group. No patient had detectable immune complexes or C3 splitting activity in serum; however, it is suggested that the abnormal complement patterns observed are likely to indicate the presence of circulating immune complexes in a high percentage of patients with this infection.

Antigen-Antibody Complex↗
PubMed1976

A new activity of complement component C3: cell-bound C3b potentiates lysis of erythrocytes by C5b,6 and terminal components.

EAC4b,3b (sheep erythrocytes carrying rabbit antibody and guinea pig complement component fragments C4b and C3) adsorb human C5b,6 reversibly; the avidity of binding varies inversely with ionic strength. We believe that the receptor of C5b,6 is contributed by the cell-bound C3b because the binding capacity of EAC4b,3b varies with C3b multiplicity and can be blocked with rabbit antibody to guinea pig C3. The fixation of C5b,6 to the erythrocyte-bound C3b serves to concentrate C5b,6 on the cell surface; as a consequence, the hemolytic efficiency of C5b,6 is almost 100 times greater when assayed with EAC4b,3b than with plain erythrocytes. This potentiation represents a hitherto unrecognized function of cell-bound C3b.

Animals↗
PubMed1976

Activation of the alternative complement pathway by water-insoluble glucans of streptococcus mutans: the relation between their chemical structures and activating potencies.

Water insoluble, sticky glucan was synthesized by reacting glucosyltransferase obtained from the sulture filtrate of cariogenic Streptococcus mutans OMZ 176 on sucrose. This glucan (OMZ 176 glucan), that consisted of the backbone chains of consecutive alpha-1, 3 glucosidic linkages (65%) and the side chain of alpha-1, 6 glucosidic bonds (35%), showed an ability to activate the alternative pathway of the complment system in human serum. Water soluble glucans synthesized from the reaction of glycosyltransferases of S. mutans strain AHT, FA-I, and Ingbritt with sucrose, that have a high content of alpha-1,6 and a low content of alpha-1, 3 glucosidic linkages, were less effective to activate the complement system. Sephadex (G-25) and Dextran (T-2,000 and T-40), that consisted exclusively of alpha-1, 6 glucosidic linkages, did not significantly activate the complement system. Controlled Smith degradation products of OMZ 176 glucan, composed of the alpha-1, 3 linked glucose backbone chain alone, lost its activity. From these results it was concluded that both backbone chain of alpha-1, 3 glucose units and branched alpha-1, 6 glucose units were essential for the OMZ 176 glucan to activate the alternative pathway of the human complement system.

Aspergillus niger↗
PubMed1998

Normal thymic selection of TCR transgenic CD4 T cells, but impaired survival in the periphery despite the presence of selecting MHC molecules.

In this paper, we investigate selection in the thymus and survival in the periphery of CD4 T cells, which carry a major histocompatibility class II-restricted transgenic TCR (A18 TCRtg) specific for a natural self Ag, the fifth component of complement (C5). A18 TCRtg thymocytes develop normal numbers of CD4 single-positive (SP) thymocytes, but do not show pronounced overselection as do some other TCR transgenic strains. CD4 SP cells are mature as judged by termination of CD8 synthesis, resistance to cortisone, and functional competence. The kinetics of positive selection, determined by BrdU labeling, are very fast. CD4 SP thymocytes are demonstrable within 2 days of labeling, and within 8 days after labeling a large proportion (20%) of lymph node T cells are recent thymic emigrants. The high number of recent thymic emigrants suggests rapid turnover of CD4 T cells in the periphery, which was confirmed by thymectomy and determination of CD4 T cell life spans. A18 TCRtg T cells have a t(1/2) of approximately 6 wk, despite the presence of selecting MHC molecules. This explains the failure to accumulate high numbers of peripheral T cells and suggests that the MHC-bound ligand(s) responsible for initiating survival signals is limiting for the selection and maintenance of A18 transgenic CD4 T cells.

Animals↗
PubMed1981

Partial characterization of procomplementary activity of porcine serum and its relationship to the fifth component of complement.

The procomplementary factor (PCF) of porcine serum, a component that enhances the hemolytic activity of guinea pig complement, was purified by precipitation with methanol and then by diethylaminoethyl-cellulose chromatography. The PCF substituted for the 5th complement component (C5) in the complement cascade in tests with functionally purified guinea pig complement components. In contrast to human C5, PCF is heat stable at 56 C.

Animals↗
PubMed2005

Requirement of activation of complement C3 and C5 for antiphospholipid antibody-mediated thrombophilia.

OBJECTIVE: Antiphospholipid antibodies (aPL) have been shown to induce thrombosis, activate endothelial cells, and induce fetal loss. The pathogenesis of aPL-induced thrombosis, although not completely understood, may involve platelet and endothelial cell activation as well as procoagulant effects of aPL directly on clotting pathway components. Recent studies have shown that uncontrolled complement activation leads to fetal death in aPL-treated mice. In this study, we tested the hypothesis that aPL are responsible for activation of complement, thus generating split products that induce thrombosis. METHODS: To study thrombus dynamics and adhesion of leukocytes we used in vivo murine models of thrombosis and microcirculation, in which injections of aPL were used. RESULTS: Mice deficient in complement components C3 and C5 were resistant to the enhanced thrombosis and endothelial cell activation that was induced by aPL. Furthermore, inhibition of C5 activation using anti-C5 monoclonal antibodies prevented thrombophilia induced by aPL. CONCLUSION: These data show that complement activation mediates 2 important effectors of aPL, induction of thrombosis and activation of endothelial cells.

Animals↗
PubMed1991

The inhibitory effect of rosmarinic acid on complement involves the C5 convertase.

Rosmarinic acid (RA), a naturally occurring extract from Melissa officinalis, inhibits several complement-dependent inflammatory processes and may have potential as a therapeutic agent for the control of complement activation in disease. Rosmarinic acid has been reported to have effects on both the classical pathway C3-convertase and on the cobra venom factor-induced, alternative pathway convertase. In order to define the mechanism of inhibition, the effect of RA on classical and alternative pathway lysis, C1q binding, the classical pathway convertase, the alternative pathway convertase, membrane attack pathway lysis and the generation of fragments of C3 and C5 during activation, was tested in vitro. The results showed that RA inhibited lysis by the classical pathway more than by the alternative pathway. This effect was dose-dependent with maximum inhibition of classical pathway lysis observed at 2.6 mmoles of RA. There was little effect on C1q binding or on the classical and alternative pathway convertases. However, there was highly significant inhibition of lysis of pre-formed EA43b cells by dilutions of human or rabbit serum in the presence of RA (1 mM); this was accompanied by inhibition of C5a generation. We conclude that the inhibitory effect of RA involves the C5 convertase. Such inhibition could be advantageous to the host in disorders where the terminal attack sequence plays a role in pathogenesis.

Animals↗
PubMed2004

Complement C3 and C5 play critical roles in traumatic brain cryoinjury: blocking effects on neutrophil extravasation by C5a receptor antagonist.

The role of complement components in traumatic brain injury is poorly understood. Here we show that secondary damage after acute cryoinjury is significantly reduced in C3-/- or C5-/- mice or in mice treated with C5a receptor antagonist peptides. Injury sizes and neutrophil extravasation were compared. While neutrophil density increased following traumatic brain injury in wild type (C57BL/6) mice, C3-deficient mice demonstrated lower neutrophil extravasation and injury sizes in the brain. RNase protection assay indicated that C3 contributes to the induction of brain inflammatory mediators, MIF, RANTES (CCL5) and MCP-1 (CCL2). Intracranial C3 injection induced neutrophil extravasation in injured brains of C3-/- mice suggesting locally produced C3 is important in brain inflammation. We show that neutrophil extravasation is significantly reduced in both C5-/- mice and C5a receptor antagonist treated cryoinjured mice suggesting that one of the possible mechanisms of C3 effect on neutrophil extravasation is mediated via downstream complement activation products such as C5a. Our data indicates that complement inhibitors may ameliorate traumatic brain injury.

Animals↗
PubMed1991

Complete cDNA sequence of human complement pro-C5. Evidence of truncated transcripts derived from a single copy gene.

Two truncated human C5 clones, pHC5A and pHC5B, were isolated from an adult human liver cDNA library, and contained inserts of 2930 and 2181 bp, respectively. Both clones were polyadenylated and encoded the 5'-end of the C5 pro-molecule, thereby completing the human pro-C5 cDNA sequence. However, near the 3'-ends, at exon/intron boundaries, the nucleotide sequences of pHC5A and pHC5B diverged from each other and from the full-length 6.0-kb C5 cDNA sequence. Clone pHC5A, which overlapped the first human C5 clone described (J-16), encoded most of the C5 signal peptide, the complete beta-chain, the linker peptide, 177 amino acids of the alpha-chain, and contained 144 bp of Alu family consensus sequence encoding 48 amino acids of divergent protein sequence in an open reading frame. Clone pHC5B encoded the entire C5 signal peptide, the beta-chain, the linker peptide, nine amino acids of the alpha-chain, and six amino acids of divergent protein sequence in an open reading frame. Northern blot experiments demonstrated the presence of a 3.0-kb truncated C5 mRNA in adult human liver and a 4.8-kb truncated C5 mRNA in HepG2 cells in addition to the 6.0-kb full-length transcript. Truncated C5 mRNA were not detected in Raji, MOLT-4, human fibroblast or U937 cells, although the full-length 6.0-kb transcript was seen in MOLT-4 cells. Southern blot analyses indicated that the human C5 structural gene is large, complex, and is present in the human genome in a single copy, thereby demonstrating that the truncated C5 clones and mRNA are derived from a single C5 gene by alternative processing events.

Amino Acid Sequence↗
PubMed1991

Role of complements C3 and C5 in the phagocytosis of liposomes by human neutrophils.

During the course of a previous investigation, we noticed that the uptake of liposomes by human polymorphonuclear neutrophils (PMNs) was significantly lower in the presence of heat-inactivated serum compared to that in intact whole serum (Scieszka et al., Pharm. Res. 5:352, 1988). This observation suggested the participation of heat-labile complement components in the phagocytic process. In this report we conclude that complement C3bi is the component responsible for opsonization of the liposome surface. Phagocytosis was not supported by C3-deficient serum, and phagocytosis in whole serum was blocked by the antibody to the receptor for C3bi (CR3) but not by the antibody to the receptor for C3b (CR1). We also found that with C5-deficient serum the level of uptake was minimal but slightly higher than without any serum. When exogenous C5a was added along with C5-deficient serum, uptake levels similar in magnitude to those observed with intact serum were obtained. We conclude that C5a enhances phagocytosis of opsonized liposomes by activating the phagocytic capacity of CR3 on the PMN.

Adolescent↗
PubMed2001

Formation of high-affinity C5 convertases of the alternative pathway of complement.

Cleavage of C5 by C5 convertase is the last enzymatic step in the complement activation cascade leading to the formation of the cytolytic proteolytically activated form of C5 (C5b)-9 complex. In the present study, we examined the effect of the density of C3b (the proteolytically activated form of C3) on the function of the noncatalytic subunit of natural surface-bound forms of the enzyme. A comparison of the kinetic parameters of C5 convertases assembled on three surfaces (zymosan, rabbit erythrocytes, and sheep erythrocytes) were similar and revealed that the average K:(m) decreased approximately 28-fold (5.2-0.18 microM) when the density of C3b was increased from approximately 18,000 to 400,000 C3b/cell. Very-high-affinity C5 convertases were generated when preformed C3 convertases were allowed to self amplify by giving them excess C3. These convertases exhibited K(m) from 0.016 to 0.074 microM, well below the normal plasma concentration of C5 in blood (0.37 microM). The results suggest that in serum convertases formed with monomeric C3b will be relatively inefficient in capturing C5 but will continue to cleave C3 opsonizing the cell surface for phagocytosis, whereas convertases formed with C3b-C3b complexes in areas of high C3b density will primarily cleave C5. The catalytic rate of these convertases approaches maximum velocity, thereby switching the enzyme from cleavage of C3 to cleavage of C5, and production of the cytolytic C5b-9 complex.

Animals↗
PubMed1977

Chemical evidence for common genetic ancestry of complement components C3 and C5.

Sequence studies reveal a marked similarity between the partial primary structures of human C3a and C5a anaphylatoxins. Eight of the first 25 residues are identical when threonine at position 1 in C5a is aligned with glutamine at position 3 in C3a and one gap is inserted in the C3a sequence. A unique cysteinyl-cysteine sequence is conserved in the 2 molecules, which further suggests a genetic relatedness. Computer-generated alignment scores from comparison of the NH2-terminal portions of human C3a and C5a exceeded by 4 standard deviations the score from random permutations of these same sequences. This sequence similarity between the two anaphylatoxins suggests that the respective precursors, C3 and C5, had a common genetic ancestry. The proposed genetic relationship between C3 and C5 may express itself functionally through a similar molecular behavior in complement-dependent cytolysis.

Amino Acid Sequence↗
PubMed1987

IgG binding to cytoskeletal intermediate filaments activates the complement cascade.

The cellular plasma membrane becomes permeable to macromolecules during the cell injury process. This results in exposure of the interior of the cell to plasma proteins and to high-affinity binding of the Fc part of IgG to intermediate filaments (Hansson, G K, Starkebaum, G A, Benditt, E P & Schwartz, S M, Proc natl acad sci USA 81 (1984) 3103). Such IgG binding could be an early step in a process that serves to eliminate the injured cell. We have now identified its effect on the complement system. Intermediate filaments were reconstituted in vitro from purified vimentin, and incubated with plasma proteins. Cross-linker experiments showed binding of the heavy chain of IgG to vimentin, indicating that the vimentin protein carries an Fc-binding site. In contrast, no direct binding of complement factor Clq to vimentin could be detected. Binding of both IgG and Clq could, however, be detected by immunofluorescence when cytoskeletons of cultured endothelial cells were incubated with fresh serum. Therefore, IgG binding to filaments in the presence of serum is accompanied by Clq binding to IgG. This was in turn followed by fixation of C4 and C3 to intermediate filaments in a process that was dependent on both Ca2+, Mg2+ and Clq, indicating that it was part of a complement activation via the classical pathway. Exposure of fresh serum to intermediate filaments also resulted in production of the anaphylatoxic complement cleavage fragment. C3a, with a dose-response relationship between the amount of filaments present and the amount of C3a generated. Chemotactic activity towards granulocytes and monocytes was also generated by exposure of serum to intermediate filaments, and this activity was dependent on the presence of complement factor C5 and on the classical complement activation cascade, implying that it was due to the C5a peptide. Exposure of the interior of the cell to plasma proteins thus results in binding of IgG to intermediate filaments and activation of the complement cascade via the classical pathway. This, in turn generates bioactive mediators which may recruit leukocytes to the injured cell (C5a) and have profound effects on vascular permeability (C3a, C5a). We propose that this is part of a scavenger mechanism for the elimination of damaged cells.

Binding Sites↗
PubMed1985

Effect of C5a on isolated guinea pig atria.

Cleavage of the complement protein C5 by activation of the complement system yields a low molecular weight fragment, C5a. Previous reports of other researchers indicate that among the biological activities of C5a is an ability to alter cardiac function. However, these studies have varying results. The goal of the present study was thus to determine both the chronotropic and inotropic effects of guinea pig C5a and the tachyphylaxis to guinea pig C5a in isolated atria of the guinea pig. Isolated right atria respond to guinea pig C5a with a consistent concentration-related positive inotropic and chronotropic response. An inotropic response to guinea pig C5a was seen in both spontaneously beating right atria and paced left atria. The inotropic and chronotropic responses to guinea pig C5a in the right atria were clearly tachyphylactic. Studies using the H2 receptor antagonist metiamide indicate that the positive chronotropic response to guinea pig C5a is at least in part a histamine-mediated response. Further studies are required to determine whether the conflicting results in various studies are due to the use of C5a from various species.

Adrenergic beta-Antagonists↗