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PubMed1987

C6 phenotyping in sera and bloodstains by isoelectric focusing followed by electroimmunoblotting.

The genetic polymorphism of C6 was investigated in 329 unrelated Japanese individuals using isoelectric focusing in polyacrylamide gels followed by an electroimmunoblotting technique. Besides six common phenotypes C6 A, AB, B, AB2, BB2 and B2, six rare variants were observed. The allele frequencies were: C6*A = 0.4422, C6*B = 0.4757, C6*B2 = 0.0714, C6*A3 = 0.0015, C6*M1 = 0.0046 and C6*B3 = 0.0046. The population data confirmed that the C6*B2 allele is the third common allele characterizing Japanese. The present electroimmunoblotting technique was applied to demonstrate C6 types in dried bloodstains. The C6 types were determined from bloodstains stored at 4 degrees C for up to 10 weeks, at room temperature for up to 2 weeks and at 37 degrees C for up to 4 days. The results show that this component system offers a new powerful means for the medico-legal grouping of bloodstains.

Alleles↗
PubMed1987

Generation of an activated form of human C5 (C5b-like C5) by oxygen radicals.

Treatment of purified human C5 with hydrogen peroxide leads to a reduction of functional activity in the classical immune haemolysis assay. The effect of H2O2 is enhanced by traces of iron-EDTA, and becomes even stronger when ascorbic acid is present in addition. The enhancement by iron and protective effects of various radical scavengers indicate that the conversion of C5 is brought about by hydroxyl radicals mainly, generated from H2O2 during its decomposition. By the conversion C5 acquires a new functional property: it becomes capable of binding C6, and the resulting complex C56 lyses non-sensitized red cells in cooperation with the late components C7, C8, and C9 (reactive lysis). In this respect, H2O2-treated C5 resembles the activation fragment of C5, C5b. However, unlike C5b, C5(H2O2) is not fragmented but comprises the whole molecule, according to polyacrylamide gel electrophoresis. In accordance with the lack of cleavage, no chemotactic activity indicating formation of C5a, became apparent after H2O2 treatment of C5. In whole human serum, however, the H2O2 system induces additional processes leading to the generation of C5a activity and indicating C5 cleavage. The pathways to this reaction are as yet not clear. The effect of oxygen radicals on C5 may be the basis of the enhancing effect of stimulated leukocytes on C5 activation in body fluids. Activated leukocytes are known to produce H2O2 and oxygen radicals.

Complement Activation↗
PubMed1993

Vitronectin-mediated inhibition of complement: evidence for different binding sites for C5b-7 and C9.

In the activated complement system, vitronectin (complement S-protein) occupies the metastable membrane binding site of the nascent precursor complex C5b-7, so that the newly formed SC5b-7 is unable to insert into cell membranes. Some evidence also indicates that vitronectin limits on-going membrane-associated pore formation by inhibiting C9 polymerization. It has been assumed that these two stages of terminal complement complex (TCC) inhibition take place through charge interactions between the heparin-binding region of vitronectin and homologous cysteine-rich sequences of the late complement proteins C6, C7, C8 and C9. We examined SC5b-7 formation and inhibition of C9 binding in the TCC using separate haemolytic assays. The mode of action of vitronectin in these assays was compared with two 15mer peptides which span residues 348-379 of the heparin-binding region, and a heparin-affinity polypeptide, protamine sulphate. The results showed that vitronectin acts predominantly through SC5b-7 production with a lesser effect on the inhibition of C9 lytic pore formation. In contrast, protamine sulphate did not prevent C5b-7 membrane attachment, but was a potent inhibitor of C9-mediated lysis. The peptides did not inhibit C5b-7 membrane insertion and only one affected C9 binding. These data suggest that the two stages of TCC inhibition involve separate binding sites on the vitronectin molecule. The site for association with nascent C5b-7 is unknown, whereas inhibition of C9 binding and pore formation takes place through the heparin-binding region.

Amino Acid Sequence↗
PubMed1985

Terminal complement component deficiencies and rheumatic disease: development of a rheumatic syndrome and anticomplementary activity in a patient with complete C6 deficiency.

Hereditary deficiencies of early complement components have usually been associated with the development of rheumatic diseases like systemic lupus erythematosus (SLE), while terminal component deficiency is well known to predispose to recurrent neisserial infection. In contrast, only recently have patients been reported with rheumatic disease and hereditary deficiency of a terminal component. The clinical syndrome in these patients has been characterised as 'SLE-like'. We describe here a third patient with complete C6 deficiency and a systemic rheumatic illness characterised by fever, anaemia, lymphadenopathy, hepatosplenomegaly, episcleritis, and asymmetric arthritis. After blood transfusion her serum became anticomplementary; IgG antibody to human C6 was found to be the cause of anticomplement activity. Persistent absence of C6 in this patient and production of anti-C6 antibody after antigenic challenge indicate hereditary C6 deficiency. This case supports an association between hereditary deficiency of a terminal complement protein and the development of systemic rheumatic disease.

Complement Activation↗
PubMed1987

Simultaneous phenotyping of genetic markers for paternity testing.

Time-and cost-saving methods for paternity testing are described. Seventeen genetic systems were divided into six groups: (1) transferrin (Tf), factor B (Bf), and phosphoglucomutase 1 (PGM1); (2) group-specific component (Gc) or alpha 1-antitrypsin (PI) and alpha 2HS-glycoprotein (HSGA); (3) complement components C6 and C7, factor 13B (F13B), and plasminogen (PLG); (4) haptoglobin (Hp), C8 alpha-gamma chain (C81), and factor I (IF); (5) red cell acid phosphatase (ACP), esterase D (ESD), and glutamic-pyruvic transaminase (GPT); and (6) 6-phosphogluconate dehydrogenase (PGD) and glyoxalase I (GLO). Each group of systems was typed simultaneously by electrophoresis or isoelectric focusing (IEF) followed by staining or immunoblotting. These methods are very practical because they afford a considerable saving of time, work and expense, and facilitate semipermanent preservation of electrophoretic patterns.

Blood Grouping and Crossmatching↗
PubMed1977

Prevention by drugs of tachyphylaxis at nicotinic receptors in the cat superior cervical ganglion in situ.

A new compound, AF3 (4-ethyl-6-oxa-1-azatricyclo)4.2.2.02,7)dodecan-5-one), and its 4-phenyl analogue, AF6, embodying the structural elements of acetylcholine in a highly rigid framework, were shown to evoke nicotine-like responses in the nictitating membrane (NM) and blood pressure when applied to the superior cervical ganglion in anaesthetized cats. In this respect, their equiactive molar ratio was (nicotine : 1),20-30. However, at doses that were too low to evoke any response, AF3 appeared to potentiate the responses to nicotine or tetra-methylammonium (TMA) by preventing or abolishing tachyphylaxis to the two latter drugs, the effect being dose-dependent with AF3. DMPP which produces much less tachyphylaxis, or preganglionic nerve stimulation, was little or not potentiated in presence of AF3. It is proposed that potentiation to nicotine or TMA occurs following occupancy by AF3 of a regulatory subsite, thereby preventing further access to it by nicotine or TMA. In this respect, AF3 plays the role of a "neutral" molecule.

Animals↗
PubMed1992

Recurrence of neisserial meningococcemia due to deficiency of terminal complement component.

Recurrent infections with Neisseria meningitidis are attributed to deficiencies of terminal complement components. The serotype most commonly responsible for recurrent N meningitidis infections is serotype Y. We have reported a case of recurrent meningitis due to N meningitidis in a patient who was found to be deficient in the sixth component of complement. Complement deficiencies should be considered in any patient with recurrent infections caused by N meningitidis.

Adult↗
PubMed1997

Contribution of activated macrophages to the process of delayed xenograft rejection.

BACKGROUND: When hyperacute rejection, involving natural xenoreactive antibodies (XAb) and/or complement (C), can be prevented, xenografts (Xgs) undergo delayed xenograft rejection associated with a progressive mononuclear cell infiltration. We have previously shown that XAb formation can be totally suppressed in leflunomide (LF)-treated, T-deficient nude rats receiving hamster hearts. Hence, this model was well-suited to study a role played by other factors, e.g., natural killer (NK) cells and macrophages (Mphi). The relative contribution of Mphi to delayed xenograft rejection was investigated. METHODS: In addition to LF (20 mg/kg/24 hr p.o.), anti-asialoGM-1 serum (1 mg/48 hr i.v.) and N omega-nitro-L-arginine methyl ester (L-NAME; 100 mg/kg/24 hr i.v.) were given. Graft-infiltrating cells, deposition of cytokines (interferon-gamma [IFN-gamma] and tumor necrosis factor-alpha [TNF-alpha]), IgM and C, and expression of endothelial cell (EC) P- and E-selectins were investigated by immunohistochemistry. In some cases, rat rTNF-alpha or anti-TNF-alpha antibodies were injected intravenously. RESULTS: Xgs rejected after 3 days by LF-treated rats showed an absence of IgM, C, and T cells, but the infiltration of NK cells and Mphi, together with the presence of IFN-gamma and TNF-alpha. Addition of NK cell depletion resulted in a significantly prolonged survival of Xgs (6 days; P<0.001) in which NK cells and IFN-gamma had disappeared, but Mphi were still prominent. Additional blockade of Mphi nitric oxide (NO) with L-NAME further prolonged Xg survival (11 days; P<0.001). In these rejected Xgs, Mphi, TNF-alpha, and EC expression of P- and E-selectins was still found, together with platelet thrombi, neutrophil-EC adhesion, and vessel intima lesions. The role of TNF-alpha in initiating this Xg rejection was further demonstrated by the acceleration of Xg rejection after injection of rTNF-alpha and by a synergism between L-NAME and anti-TNF-alpha antibodies in hampering the acceleration of Xg rejection seen after transfer of sensitized Mphi. CONCLUSION: In the absence of XAb, T cells, and NK cells, Mphi can still reject Xgs. Both NO-dependent and NO-independent mechanisms are involved. In the latter case, Mphi-derived, TNF-alpha-associated EC activation may play a role.

Animals↗
PubMed1993

Chronic meningococcemia in a child with a deficiency of the sixth component of complement.

Chronic meningococcemia represents an uncommon manifestation of meningococcal disease. Microbial and host factors which may predispose to this form of meningococcal disease are not understood. Although acute meningococcal disease is frequently found in patients with terminal complement deficiencies, the relationship of chronic meningococcemia to complement deficiencies is unclear. We present a case report and a review of the literature describing chronic meningococcemia in association with deficiencies of the complement system. A total of eight cases were identified, all of whom were male. Six of the eight patients were children and two of the eight had a previous history of meningococcal disease. This case report, in conjunction with the previously reported cases, suggests an association between complement deficiencies and chronic meningococcemia.

Bacteremia↗
PubMed1992

Antibodies to meningococcal class 1 outer membrane proteins in South African complement-deficient and complement-sufficient subjects.

Inhibition assays were used to investigate human serum antibodies to the meningococcal class 1 outer membrane proteins. We adapted the whole-cell enzyme-linked immunosorbent assay technique to determine the ability of sera to inhibit the binding of murine subtyping monoclonal antibodies. Serum samples from 33 South African subjects with a deficiency in the sixth component of complement as well as serum samples from various groups of complement-sufficient subjects were investigated. Subjects were subdivided according to whether they were (i) convalescent from Neisseria meningitidis infections, (ii) nonconvalescent, or (iii) controls. Preliminary subtyping investigations had shown that P1.2 was present on 36% of meningococcal clinical isolates from Cape Province, South Africa. Assays with the anti-P1.2 antibodies showed the presence of high antibody levels in many deficient sera and moderately elevated levels in some sera from the complement-sufficient convalescent patients. P1.2, P1.4, P1.15, and P1.16 are epitopes situated on loop 4 of the class 1 outer membrane proteins, whereas P1.7 is on loop 1. Inhibition assays showed that human sera that inhibited binding by P1.2 monoclonal antibodies tended to inhibit the other monoclonal antibodies directed to loop 4 epitopes. This suggests that the epitopes recognized by the human antibodies are not exactly the same as the epitopes recognized by the murine monoclonal antibodies and raises the possibility of the importance of other epitopes.

Antibodies, Bacterial↗
PubMed1988

Studies on the formation of a unique cellular intermediate (EAC14256) from EAC142 and C56.

The binding reaction of C56 to EAC142 was studied. The following was observed: (1) C56 can bind to EAC142, without participation of C3 or C7, to form EAC14256; (2) the efficiency of EAC14256 formation from EAC142 and C56 depends highly on the ionic strength of the buffer; (3) EAC14256, generated from EAC142 and C56, decays spontaneously by elution of C56 into the medium and thus the reaction between C56 and EAC142 is reversible; (4) the receptor on EAC142 for C56 is C2 or C42 on the cell surface, and (5) the binding of C56 to C2 or C42 on cells is independent of the usual (C3-dependent) complement cascade activation. These observations, together with the results of our previous report, indicate that the binding of C56, generated from the activation of C5 by C42 (without C3), to EAC142 may be the initial step of membrane attack complex formation in C3-independent immune hemolysis.

Antibodies↗
PubMed1980

Distribution of complement C'2 and C'6 types in Australian cases of diabetes mellitus.

A series of patients with juvenile onset diabetes (IDDM) and mature onset diabetes (NIDDM) have been typed for genetic variants of two sets of complement factors. For the HLA-linked C'2 system, there was found a significant increase of the C'2 2-1 type in IDDM compared with NIDDM patients or healthy controls. No such increase in any phenotype was observed for the non-HLA-linked C'6 system. These observations emphasize again the genetic distinction between IDDM and NIDDM, and the role of chromosome 6 in controlling susceptibility to the insulin-dependent form of the disease.

Alleles↗