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PubMed1989

Inhibition of immune haemolysis by a serum factor found in C3-deficient subjects.

A serum factor, which inhibits haemolysis of the buffer control used in a C3 haemolytic assay, was found in a C3-deficient subject (C3D). Since the buffer control consisted of EAC142, C5 and C6-9 reagent (C6-9R, prepared by treatment of guinea-pig serum with KSCN and hydrazine hydrate), the factor seems to be an inhibitor of C3-independent immune haemolysis. Gel filtration and CM cellulose column chromatography of C3D serum suggested that the inhibitor may be C8. The inhibition was not observed in C8-depleted C3D serum. Furthermore, isolated C8 was found to inhibit haemolysis of EAC142 by C5 and C6-9R in a dose-dependent fashion. Thus, C8 was found to be an inhibitor of C3-independent immune haemolysis in the assay. Further studies revealed that C8 also inhibits haemolysis of EAC142 by C3, C5 and C6-9R (C3 assay system) or that of EAC1423 by C5 and C6-9R (C5 assay system), indicating that C3 or C5 haemolytic activity can be underestimated by the presence of C8 in a sample. C8 did not inhibit haemolysis in the assay system when isolated C6-C9 of human origin were used, but did inhibit haemolysis when isolated C6-C9 of guinea-pig origin was used instead of C6-9R. Thus, it was suggested that the incompatibility of human C8 with guinea-pig C6-C9 might be responsible for this phenomenon. Additional experiments for the mechanism clearly showed that human C8 inhibits the haemolysis of EAC1-7 (EA bearing human C1-C5 and guinea-pig C6 and C7) by guinea-pig C8 and C9 by binding to EAC1-7 prior to guinea-pig C8.

Animals↗
PubMed1995

A clinical method for measuring segmental flexion mobility in the cervico-thoracic spine and a model for classification.

Pain and limitation of spinal mobility are symptoms frequently reported by patients. Many methods have been used to assess the total range of mobility in the different parts of the spine, but there is no method for clinical examination of segmental mobility. The aim of this study was to describe such a technique concerning of segmental flexion mobility in the cervico-thoracic spine, C7-T5, and to present a model for classification of mobility. The results of this study show that the relative flexion mobility examined, according to the Cervico-Thoracic-Ratio technique (CTR), may become a valuable complement to conventional methods of assessing mobility in the cervical spine. The normalized CTR values are less influenced by the individual factors age, body weight, height and number of years at work and the classification model presented makes functional analysis of segmental flexion mobility in the cervico-junction and upper thoracic spine more substantial.

Adult↗
PubMed1984

Molecular composition of the tubular structure of the membrane attack complex of complement.

The composition of the tubular structure of the membrane attack complex of complement (MAC) which migrates as a high molecular weight band (Mr approximately 1.2- 1.3 X 10(6) upon sodium dodecyl sulfate, polyacrylamide gel electrophoresis under reducing conditions was analyzed and compared to the high molecular weight band (Mr approximately 1.1 X 10(6] of tubular poly(C9). The sodium dodecyl sulfate-resistant band of the MAC, designated MAC-poly(C9), is composed of C6, C7, C8 alpha-gamma, and poly(C9), in approximate molar ratios of the protomers of 1:1:1:10-18. This conclusion is based 1) on the results of the incorporation of labeled proteins into MAC-poly(C9); 2) on the immunostaining of MAC-poly(C9) with anti-C6, anti-C7, anti-C8 alpha-gamma, and anti-C9 and its lack of immunostaining with anti-C5 and anti-C8 beta; and 3) on the dissociation of MAC-poly(C9) to 1 mol of C6, C7, C8 alpha-gamma and 10 to 18 mol of C9 upon treatment with 8 M guanidine isothiocyanate. Ultrastructurally the sodium dodecyl sulfate-resistant poly(C9) tubule and MAC-poly(C9) tubule are indistinguishable, suggesting a similar ultrastructure of the C6, C7, C8 alpha-gamma, and C9 subunits in the MAC-poly(C9) tubule. Further analogies among these four proteins are their tendency to form disulfide-linked dimers. It is concluded that the transmembrane channel of the MAC is formed by a tubule in which C6, C7, C8 alpha-gamma are copolymerized with poly(C9), whereas the C5b and C8 beta subunits are not part of the tubule structure and may form the 170-A long appendage of the MAC. This appendage is dissociated upon boiling in sodium dodecyl sulfate whereas the tubule remains stable.

Complement Membrane Attack Complex↗
PubMed1982

Further characterization of complement resistance conferred on Escherichia coli by the plasmid genes traT of R100 and iss of ColV,I-K94.

We have shown that the traT gene product was responsible for the complement resistance of the R100 plasmid. We compared this resistance with that specified by the iss gene of the ColV,I-K94 plasmid. The levels of resistance specified by the two genes were similar, and there was no additive effect on resistance when both genes were present together. Under conditions in which traT and iss conferred at least a 50- and 10-fold increase in survival, respectively, the consumption of C6, C7, C8, and C9 was the same for bacteria with and without the plasmid genes. This result indicated that it was the action of the terminal complex, not its formation, which was blocked by traT and iss.

Bacteriocin Plasmids↗
PubMed1984

Inhibition of C9 polymerization within the SC5b-9 complex of complement by S-protein.

The effect of S-protein on the polymerization of C9 during assembly of the C5b-9 complex was examined. Utilizing SDS polyacrylamide gradient slab gel electrophoresis, tubular poly C9 was quantitated as SDS resistant protein of 1.1 to 1.3 X 10(6) molecular weight. Poly C9 formation occurred upon incubation of purified C5b-6, C7, C8 and C9 at molar ratios 1:1:1:12. Addition of purified S-protein to the protein mixture or to preassembled C5b-7 or C5b-8 blocked formation of poly C9 in a dose dependent fashion and gave rise to SC5b-9. SC5b-9 assembled from purified proteins or in zymosan-activated serum was visualized in the electron microscope as a wedge-shaped structure of 350 to 400 A length and 30 to 250 A width which lacked tubular poly C9 seen in images of the membrane attack complex (MAC). Using biotinyl-S-protein and colloidal gold particles coated with avidin, S-protein was located at the wide end of the wedge-like SC5b-9 complex. It is concluded that S-protein has a dual function in SC5b-9 assembly. It blocks the membrane site of C5b-7 and it inhibits C9 polymerization by SC5b-8. Accordingly, the main structural difference between SC5b-9 and the MAC is the lack of tubular poly C9.

Binding Sites↗
PubMed1979

Effects of zinc chloride on guinea pig complement component activity in vitro: concentration-dependent inhibition and enhancement.

We have studied the in vitro effects of zinc chloride on the hemolytic activity of each component of the guinea pig classical complement pathway over a wide range (25 to 500 muM) of zinc concentrations. At high concentrations (>200 muM) the activity of all components was strongly inhibited by this metal. Concentrations of 500 muM inhibited C1 and C5 by 80 and 65%, respectively, whereas all other components were inhibited by more than 94%. Zinc chloride at 25 muM produced more varied effects, with C2, C3, and C6 inhibited by 36, 35, and 55%. C7 and C8 were inhibited by approximately 25%, whereas C1, C4, and C9 were not appreciably affected. The activity of the fifth component, on the other hand, was strongly enhanced by the presence of zinc. Concentrations of 25, 50, and 100 muM zinc chloride produced increases of 92, 44, and 18%, respectively, in C5 titers when present during the activation-binding step of this component. Further studies indicated that the activities of cell-bound complement components were unaffected by zinc treatment after activation and/or binding to the sheep erythrocyte surface had occurred. In addition, zinc did not appear to inhibit by causing irreversible denaturation of either total complement proteins or its various components. Rather, it appears that zinc must be present as a reactant during the activation and/or binding step of each component for inhibition or enhancement to occur.

Animals↗
PubMed1996

Role of natural killer cells on engraftment of human lymphoid cells and on metastasis of human T-lymphoblastoid leukemia cells in C57BL/6J-scid mice and in C57BL/6J-scid bg mice.

The severe combined immunodeficiency (scid) mutation was backcrossed onto the C57BL/6J strain background in order to study the role of natural killer (NK) cells in rejection of normal and malignant human lymphohematopoietic cells. C57BL/6J-scid/scid mice showed severe loss of mature T and B cells accompanied by increased percentages of NK1.1+ cells and myeloid cells. Although little or no serum immunoglobulin was detectable prior to 2 months of age, all mice tested had circulating immunoglobulin by 7.5 months of age. C57BL/6J-scid/scid mice had markedly elevated levels of both hemolytic complement activity and NK cell activity compared with C57BL/6J - (+/+) controls. Weekly injections with anti-NK1.1 antibody resulted in elimination of NK cell activity in C57BL/6J-scid/scid mice throughout 8 weeks of treatment. Although human CEM-C7 T lymphoblastoid tumor cells grew slowly in unmanipulated C57BL/6J-scid/scid mice, anti-NK1.1 treatment resulted in increased growth accompanied by metastasis of human lymphoma cells to the brain, liver, and kidney. In contrast to T lymphoblastoid tumor cells, nonmalignant human peripheral blood mononuclear cells engrafted at low levels in anti-NK1.1-treated as well as in unmanipulated C57BL/6-scid/scid mice. Backcrossing of the beige (bgJ) mutation onto the C57BL/6-scid/scid genetic stock caused decreased NK cell activity accompanied by granulocyte defects. C57BL/6-scid/scid bgJ)/bgJ) mice showed metastasis of human CEM-C7 cells to the brain and other organs but supported only low levels of engraftment with human peripheral blood mononuclear cells. These results demonstrate that NK cells, in the absence of an adaptive immune system, function in resistance to metastasis of human lymphomas and suggest that innate immune factors in addition to NK cell function mediate resistance to engraftment of normal human peripheral blood leukocytes.

Animals↗
PubMed1989

A serum protein SP40,40 modulates the formation of membrane attack complex of complement on erythrocytes.

SP40,40 was isolated from the soluble membrane attack complex (SC5b-9) by HPLC using a reverse-phase column. Amino acid compositions of its alpha- and beta-subunits were similar to each other with the exception of glycine content. Amino-terminal sequences of its alpha- and beta-subunits were identical to those of the subunits prepared from human serum, respectively, indicating that there was no degradation of SP40,40 during incorporation into SC5b-9. When guinea pig erythrocytes were incubated with C56f, C7, C8 and C9 in the presence of SP40,40, SP40,40 enhanced the hemolysis. The protein, however, inhibited the hemolysis when erythrocytes were pre-incubated with C56f and SP40,40 prior to the addition of C7, C8 and C9. These findings indicate that SP40,40 modulates the formation of membrane attack complex by interacting with C56f at the first step, and that the co-existence of other factors, besides C56f, is required for the enhancing activity of SP40,40.

Amino Acids↗
PubMed1984

Freeze-thaw activation of the complement attack phase: I. Separation of two steps in the formation of the active C--56 complex.

The activation of the attack phase of C, C5-C9, is generally assumed to be dependent on the enzymes of the C activation pathways which cleave C5 into C5b and C5a. C5b will then form a complex with C6 that binds to membranes and, in the presence of C7-C9, effects cell lysis. In contrast, however, a variety of physicochemical means was found to activate C5 + C6 independently of the convertases and without apparent generation of the C5a peptide. By freezing and thawing of C5 + C6 a hemolytic C--56 activity was generated: (C--56 ).f The activation proceeded in two steps: (1) during a preincubation period of the two components the time and temperature dependent formation of an activatable intermediate was observed and (2) the intermediate C--56 could then be endowed with hemolytic activity by freezing and thawing. The intermediate as well as the activated (C--56)f complex was separated from C5 and C6 by anion exchange chromatography. While the isolated intermediate was labile, the active product after freezing and thawing was stable.

Complement Activation↗
PubMed1979

Neoantigen of the complement membrane attack complex of cytotoxic human peripheral blood lymphocytes.

Neoantigenic determinants (neoAg) specific for the assembling membrane attack complex (MAC) of complement were detected by immunofluorescence microscopy on the surface of cytotoxic lymphocytes during the antibody-dependent cellular cytotoxicity (ADCC) reaction. This study employed antibody-sensitized chicken erythrocytes as target cells, human peripheral blood lymphocytes as effector cells, and RITC-conjugated rabbit F(ab')2-anti-neoAg. NeoAg was present on 60% of ADCC plaque-forming lymphocytes (PFL). Eight out of 182 neoAg-positive PFL were observed in direct contact with their target cells. In these cases MAC-specific neoAg was visualized at the zone of contact between the cells. Anti-neoAg Ig was found to inhibit ADCC plaque assays up to 62%; and 51Cr-release assays up to 79%. Stimulation of lymphocytes by PHA or mixed lymphocyte culture increased the expression of neoAg. In the case of PHA, increased neoAg expression was correlated with an increased incorporation of 14C-leucine into C5, C6, C7, and C8 antigens, which was detected by immunodiffusion and autoradiography.

Animals↗
PubMed1975

Serum-induced inhibition of isotonic fluid absorption by the kidney proximal tubule. III. Further evidence that complement-mediated cell lysis is involved.

The results of our previous studies have suggested that serum-induced inhibition of proximal tubular fluid absorption is due to complement-induced lysis of the tubular cells. The present study provides further evidence in support of this idea as well as other information pertinent to the mechanism of complement activation in vivo. 1. The electrical resistance of the luminal brush border membrane is reduced drastically concomitantly with a drop in cell potential difference when serum is perfused intraluminally. 2. Human C1 inhibitor (30-50 units/ml) does not significantly affect the inhibitory activity of human serum on fluid absorption, suggesting the non-involvement of the classical pathway. 3. Reactive lysis reagents (C56, C7, C8 + C9) partially inhibit fluid absorption when infused into the lumen. 4. In contrast to our previous report (Sato, K. and Ullrich, K.J. (1974) Biochim. Biophys. Acta 354, 182-187), very fresh serum, 10-times diluted can inhibit fluid absorption if perfused for 10 min. 5. Both mouse and guinea pig serum, which are normally inactive, are activated to attack the tubular cells if 1/100 volume rat or rabbit serum is added to them No such activation occurs by mixing guinea pig serum and mouse serum. The available data suggest that the presence of the later complement components but not the heat-labile factor (Factor B) or C3PA or C1 in the added serum is a prerequisite for mouse and guinea pig sera to be activated to inhibit fluid absorption.

Animals↗
PubMed1988

Biochemical characterization of the human complement protein C6. Association with alpha-thrombin-like enzyme and absence of serine protease activity in cytolytically active C6.

Complement protein C6 has been proposed by others to be a serine protease whose activity is obligatory for complement-directed cell lysis. We separated the serine protease (Mr approximately 30,000) activity found associated with apparently homogeneous preparations of C6 from the hemolytically active C6 protein. The protease was characterized as thrombin-like based on substrate specificity, inhibitor profile, and kinetic studies. Although the proteolytic activity of C6 preparations was inhibitable by several inhibitors of serine proteases, the C6 hemolytic activity remained unaffected. Acid-induced (C(5,6)a complex formation between C5 and C6 (protease-free) was demonstrated by ion-exchange fast protein liquid chromatography, reversed-phase high performance liquid chromatography, and reactive cytolytic activity in the presence of C7, C8, and C9; but no cleavage of the alpha-chain of C5 was observed. Diisopropylphosphorofluoridate pretreatment of the components did not affect their ability to generate functionally active (C(5,6)a. Evidently, C6-associated thrombin is not required for formation of functional C(5,6)a. Thus, C6 does not function in the membrane attack pathway of complement as a serine protease. A method for the isolation of homogeneous C6 in the hemolytically fully active form is described. No free sulfhydryl group was detected in C6. The amino acid sequence of 20 amino-terminal residues was determined.

Amino Acid Sequence↗
PubMed1992

Activation of the fifth component of human complement, C5, without cleavage, by methionine oxidizing agents.

Purified human C5 was incubated with chloramine T (Cl-T) or N-chloro-succinimide (N-Cl-S) in barbital buffer, pH 7.2. The treatment led to C5 activation: Cl-T- and N-Cl-S-treated C5 acquired a binding site for C6; upon incubation with C6 and subsequent addition of C7, C8 and C9 a membrane attack complex formed which lysed non-sensitized guinea pig red cells (reactive lysis). While the physiological activation of C5 follows its specific cleavage, the resulting fragment C5b representing the activated C5 and expressing the C6 binding site, the treatment with the mentioned chemicals does not lead to fragmentation of the C5 protein. So, functionally, the product of the chemical treatment is C5b-like, but chemically, it comprises the whole protein; no C5a is released. Cl-T and N-Cl-S are known to more or less selectively oxidize methionine residues in proteins, dependent on the conditions. Other sensitive amino acid residues are tryptophan and cysteine. Conditions were chosen for treatment of C5 with Cl-T which exclude attack on tryptophan, and we have ensured that human C5 does not contain free cysteine residues. Further, oxidation of about 60% of the methionine residues of C5 by Cl-T was demonstrated by amino acid analysis. So, all evidence points to methionine residue(s) as the site of attack of Cl-T and probably also of N-Cl-S. The oxidation product of methionine, its sulphoxide, may cause a change in structural conformation of C5 which involves expression of the C6 binding site. Earlier it was found that oxidation of C5 by hydroxyl radicals leads to its activation without cleavage. Since the properties of this C5b-like product resemble those of the product of treatment with Cl-T and N-Cl-S, it is suggested that the formerly found activation of human C5 by hydroxyl radicals is also mediated by oxidation of methionine residue(s) in the C5 protein.

Chloramines↗
PubMed1987

Inherited deficiencies of complement components in man.

Isolated inherited deficiency states of almost every complement protein have been recognized. Almost all are autosomal recessive traits. Deficiency of the early-acting components C1, C4 and C2 is associated with increased risk of immune complex disease, particularly systemic lupus erythematosus. Patients with deficiency of C3, factor I or factor H have increased susceptibility to infection by pyogenic bacteria, whereas those with deficiencies of properdin, C5, C6, C7 or C8 are prone to systemic neisserial infection. Inherited deficiency of C1 inhibitor is transmitted as an autosomal dominant trait, is genetically heterogeneous, and is associated with attacks of angioedema and consumption of C4 and C2. There is evidence that a plasmin-modified fragment of C2 is responsible for the angioedema in this disorder. Administration of androgens tends to correct the biochemical abnormalities of hereditary angioedema and to prevent attacks.

Angioedema↗
PubMed1986

An enzyme-linked immunoabsorbent assay for the quantitation of the terminal complement complex from cell membranes or in activated human sera.

A sensitive and simple enzyme-linked immunoabsorbent assay (ELISA) has been developed to measure the terminal complement complex (TCC) in solution. Commercially available antibodies to the native complement (C) components C5 and C9 were used in a double antibody sandwich technique sensitive enough to detect 0.3 microgram/ml of purified TCC. The TCC was not detected in normal human serum (NHS) nor was it generated when sera from patients with a genetic deficiency of functional C5, C7, C8 beta or C9 were activated with cobra venom factor (CVF). If the C8 beta deficient serum was reconstituted with the C8 beta chain and incubated with CVF, TCC were formed and detected by the assay. In in vitro experiments, the TCC was detected in NHS activated by either the classical or alternative pathway even when there was no measurable consumption of C5, C8 or C9. In addition, adaptation of a detergent extraction procedure permitted the quantitation by the assay, of TCC which were generated on sensitized sheep erythrocyte membranes. Experiments to test sample handling conditions showed no generation of TCC in NHS after four freeze/thaw cycles and spontaneous formation only if NHS had been incubated at 37 degrees C for 48 h. The TCC in zymosan-activated NHS were stable at 37 degrees C for 1 week. Patients with C activation associated diseases such as SLE and rheumatoid arthritis had increased levels of TCC that correlated with positive clinical tests for inflammation, even though C levels were normal when measured by routine techniques. These results suggest that this ELISA will provide a valuable tool for studying the role of C in the pathogenesis of C-mediated diseases and in examining the mechanism of tissue injury in in vitro experimental systems.

Animals↗
PubMed1981

Homologous species restriction in lysis of erythrocytes by terminal complement proteins.

The cytolytic efficiency of the terminal complement protein complex, C5b-9, varies with the species of origin of C8 and C9. In the present study, we explored the susceptibility of erythrocytes from various species to lysis by C5b6,7 plus C8 and C9 from different species. EC5b6,7 intermediates were prepared on human, guinea pig, rabbit, mouse, and rat erythrocytes with human C5b6 and guinea pig C7. The degree of lysis of these intermediates by C8 and C9 was found to vary widely depending on the species of the proteins and the target cells. In all cases, lysis was least efficient when C8 and C9 were homologous with respect to the target cell species. This effect was mostly attributable to C9. The inefficient lysis in a homologous system is not due to a failure of C9 binding. Rather, the poor lysis in the homologous system may be attributable to inefficient insertion or channel formation.

Animals↗
PubMed1997

Heterozygous C8beta complement deficiency does not predispose to meningococcal disease.

We have identified 42 Russian patients with homozygous C8beta complement component deficiency, all of whom had experienced at least one episode of systemic meningococcal disease. About 90% of these individuals have a C --> T exchange in exon 9, leading to a premature stop codon. If, like the homozygous-deficient state, heterozygous C8beta deficiency constitutes a risk factor for meningococcal disease, it would be expected to be detected with increased frequency among individuals suffering from this disease. Using allele-specific polymerase chain reaction (PCR), we studied 153 consecutive patients with meningococcal disease admitted to the Moscow Hospital for Infectious Diseases to determine the frequency of C8 null allele. No individuals with heterozygous C --> T exchange were identified among these 153 patients, despite the fact that seven persons were detected who had homozygous C8beta deficiency, caused by the same C --> T exchange in exon 9, and one patient who had C7 component deficiency. Thus, heterozygous deficiency, although more frequent than homozygous deficiency in the general population, does not result in a substantial increase in susceptibility to meningococcal disease.

Complement C8↗