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PubMed1998

Peroxisome biogenesis disorders: identification of a new complementation group distinct from peroxisome-deficient CHO mutants and not complemented by human PEX 13.

Ten complementation groups of generalized peroxisome biogenesis disorders (PBD), (excluding rhizomelic chondrodysplasia punctata) have been identified using complementation analysis. Four of the genes involved have been identified using two different methods of (1) genetic functional complementation of peroxisome deficient CHO cell mutants and (2) homology searches for human dbEST, based on yeast genes involved in peroxisome biogenesis (PEX genes). We report here the first identification of a new complementation group which is genetically different from peroxisome deficient CHO mutants. There were no complementations by the human PEX 13 gene. The nature of the related gene is being investigated.

Animals↗
PubMed1993

Human chromosome 11 complements ataxia-telangiectasia cells but does not complement the defect in AT-like Chinese hamster cell mutants.

It has been shown that the X-ray-sensitive Chinese hamster V79 mutants (V-E5, V-C4 and V-G8) are similar to ataxia-telangiectasia (A-T) cells. To determine whether the AT-like rodent cell mutants are defective in the gene homologous to A-T (group A, C or D), human chromosome 11 was introduced to the V-E5 and V-G8 mutant cells by microcell-mediated chromosome transfer. Forty independent hybrid clones were obtained in which the presence of chromosome 11 was determined by in situ hybridization. The presence of the region of chromosome 11q22-23 was shown by molecular analysis using polymorphic DNA markers specific for the ATA, ATC and ATD loci. Seventeen of the obtained monochromosomal Chinese hamster hybrids contained a cytogenetically normal human chromosome 11, but only twelve hybrid cell lines were shown to contain an intact 11q22-23 region. Despite the complementation of the X-ray sensitivity by a normal chromosome 11 introduced to A-T cells (complementation group D), these twelve Chinese hamster hybrid clones showed lack of complementation of X-ray and streptonigrin hypersensitivity. The observed lack of complementation does not seem to be attributable to hypermethylation of the human chromosome 11 in the rodent cell background, since 5-azacytidine treatment had no effect on the streptonigrin hypersensitivity of the hybrid cell lines. These results indicate that the gene defective in the AT-like rodent cell mutants is not homologous to the ATA, ATC or ATD genes and that the human gene complementing the defect in the AT-like mutants seems not to be located on human chromosome 11.

Animals↗
PubMed2000

Complement activation by anti-endothelial cell antibodies in MHC-mismatched and MHC-matched heart allograft rejection: anti-MHC-, but not anti non-MHC alloantibodies are effective in complement activation.

Classical complement activation is a major effector mechanism in the development of vascular lesions contributing to allograft rejection. We investigated complement activation by alloantibodies reactive with graft endothelial cell (EC) alloantigens in settings of MHC-mismatched and MHC-matched (non-MHC-mismatched) rat heart transplantation (Tx). Allosera and heart allografts were collected at the day of rejection (day 7-8 and day 28-35 in MHC-mismatched and non-MHC-mismatched Tx respectively) or earlier. Allosera reactivity was studied in vitro using rat-heart-endothelial-cell (RHEC) lines expressing the appropriate donor MHC and non-MHC alloantigen profile. Immunohistochemical analysis of rejected heart allografts showed deposition of alloantibodies in both MHC-mismatched and MHC-matched heart allografts, but expression of C3 was only seen in the vasculature of MHC-mismatched grafts. FACS analysis showed that anti MHC as well as anti non-MHC allosera were reactive with donor EC cell surface antigens. Both sera had similar IgG subclass profiles of anti-endothelial cell antibodies. Complement activation by anti MHC and anti non-MHC alloantibodies on EC was measured by FACS analysis of C3 and C5b-9 (MAC) expression. Distinct expression of C3 was noticed for EC incubated with anti-MHC allosera, but hardly for EC incubated with anti non-MHC allosera. C5b-9 was low but showed no difference between the two allosera. However, complement-mediated cytotoxicity experiments showed that functional (lytic) MAC was induced with anti MHC allosera but hardly with anti non-MHC allosera. Our data show that in settings of MHC-matched heart transplantation alloantibodies against endothelial non-MHC alloantigens are generated, but, in contrast to alloantibodies to MHC alloantigens, these alloantibodies have only poor complement-activating and lytic potentials. Whether anti non-MHC allolantibodies effect other biological processes relevant for heart allograft vasculopathy, including development of graft arteriosclerosis, needs further elucidation.

Animals↗
PubMed2005

XP-A cells complemented with Arg228Gln and Val234Leu polymorphic XPA alleles repair BPDE-induced DNA damage better than cells complemented with the wild type allele.

Functional effects of Arg228Gln and Val2343Leu XPA polymorphisms on benzo[a]pyrene-r-7,t-8-dihydrodiol-t-9,10-epoxide-(+/-)-anti (BPDE) survival and repair were investigated in SV40 immortalized XP12RO cells complemented with wild type and polymorphic XPA cDNAs in an inducible cDNA expression system. In contrast to previous studies showing little impact of XPA polymorphisms on UV survival and repair, cells complemented with polymorphic XPAs displayed improved BPDE survival and repair as compared to wild type XPA-complemented cells. Survival after BPDE treatment was measured using AlamarBlue reduction and colony forming ability. Cells expressing low levels of either polymorphic XPA had equivalent or improved survival compared to wild type XPA-complemented cells (XPAwt cells). XPA induction improved BPDE survival in Arg228Gln (R228Q cells) and Val234Leu (V234L cells) complemented cells, but not XPAwt cells. BPDE-induced DNA damage repair was measured both by reactivation after transfection of a luciferase reporter plasmid reacted with BPDE in vitro, and by removal of adducts from genomic DNA of BPDE-treated cells. BPDE-induced DNA damage repair in R228Q and V234L cells expressing XPA at very low levels was similar to repair in XPAwt cells expressing XPA at normal levels. XPA induction improved repair in R228Q and V234L cells but not in XPAwt cells. Our findings suggest that both Arg228Gln and Val234Leu XPAs function better than wild type XPA for BPDE adduct removal. These observations differ from UV repair results suggesting that the differences are lesion specific. The location of the polymorphisms within the putative poly(ADP-ribose) binding domain suggests that poly(ADP-ribose) interaction is important in repair.

7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide↗
PubMed1979

The presence of complement in human cervical mucus and its possible relevance to infertility in women with complement-dependent sperm-immobilizing antibodies.

Full-complement component lytic activity was measured in human midcycle cervical mucus, using a sensitive 51Cr release hemolytic assay. The level measured was 11.5% of the activity of complement in an equal volume of undiluted human serum. The relevance of this level of complement to complement-dependent sperm-immobilizing antibody activity was studied. After 1 hour's incubation with mucus levels of complement, immobilization of about 50% of spermatozoa occurred and after 3 hours' incubation, immobilization of about 70% of spermatozoa occurred.

Antibodies↗
PubMed2003

Expansion of genes encoding complement components in bony fish: biological implications of the complement diversity.

The complement system is a major humoral component of vertebrate defenses for tagging and killing target microorganisms. Recent molecular analyses have uncovered a striking feature of bony fish complement, namely that several complement components are encoded by multiple genes. In this review, the structural diversity of C3, C4, C5, factor B, C2, C1r/s and MASP are discussed with special reference to their functional differentiation, mainly focusing on the common carp (Cyprinus carpio), a tetraploidized teleost. In carp, all the members (C3, C4, C5 and a non-complement protein alpha2-macroglobulin) of the thioester-containing protein family are present in multiple isotypes, differing in the primary structures of various functional sites. Three factor B/C2-like isotypes identified in carp showed distinct expression pattern (sites and inducibility), with one behaving as an acute-phase reactant. Two C1r/C1s/MASP2-like isotypes also contain an amino acid substitution that likely affects their substrate specificity. Overall, the present data suggest that the expanded genes of the carp complement system produce more diversified functional components than are known for mammals. The biological significance of this diversity is discussed.

Animals↗
PubMed2002

Human umbilical vein endothelial cells express complement receptor 1 (CD35) and complement receptor 4 (CD11c/CD18) in vitro.

We have examined complement receptors on human umbilical vein endothelial cells (HUVEC) and found that they express complement receptor 1 (CR1, CD35) and complement receptor 4 (CR4, CD11c/CD18), but not complement receptor 3 (CR3, CD11b/CD18). Binding of monoclonal antibodies against CR1 (CD35) and CR4 (CD11c/CD18) to HUVEC was demonstrated by flow cytometry. The presence of the corresponding mRNAs was confirmed by reverse transcriptase-polymerase chain reaction (RT-PCR) and sequencing of the amplified cDNA fragments. When HUVEC were treated with inflammatory mediators, chemotactic agents or the secretagogue phorbol-12-myristate-13-acetate (PMA), no change in reactivity to CR1 (CD35) or CR4 (CD11c/CD18) monoclonal antibodies was detected on the surface of the cells compared with untreated cells. The presence of CR1 (CD35) and CR4 (CD1c/CD18) on HUVEC indicates that endothelial cells (EC) have the potential to bind C3b and iC3b, respectively, which both mediate biological effects in the course of complement activation.

Antibodies, Monoclonal↗
PubMed2001

Role and significance of the complement system in mucosal immunity: particular reference to the human breast milk complement.

The complement system plays an important role in a host's defence mechanisms, such as in immune bacteriolysis, neutralization of viruses, immune adherence, immunoconglutination and in enhancement of phagocytosis. The possible role of this important biological system in biological fluids on the mucosal surfaces, including breast milk, has however been largely neglected. Its contribution to the 'common' mucosal immunity is still enigmatic and largely speculative. Assessment of the complement system in human breast milk, which has so far largely been limited to different assays of the individual component proteins, is reviewed. A brief review of the classical and the alternative pathways of complement activation is presented. The potential physiological roles of various complement components and their activation fragments in human milk in particular, and other mucosal surfaces in general, are also presented. It was concluded that the complement system might play a complementary role to other immunological and non-immunological protective mechanisms on the mucosal surfaces.

Complement System Proteins↗
PubMed1980

The role of complement in viral infections. II. the clearance of Sindbis virus from the bloodstream and central nervous system of mice depleted of complement.

The following studies were performed to investigate the mechanism(s) by which the complement system limits Sindbis virus infection in the central nervous system of mice. After the intracerebral inoculation of Sindbis virus, no differences in mortality or viral growth in the central nervous system were observed between normal mice and mice depleted of complement by treatment with cobra venom factor. In addition, animals that had been inoculated subcutaneously with Sindbis virus and depleted of complement after the viremic phase had ended did not show any differences in mortality or viral growth in the central nervous system. In contrast, it was found that after the intracardiac inoculation of virus, complement-depleted mice demonstrated a defect in the clearance of infectious virus from the blood. These studies suggest that the increased growth of virus in the brains of complement-depleted mice after the subcutaneous inoculation of Sindbis virus is due to a defect in clearance of infectious virus from the bloodstream rather than to a primary defect within the central nervous system.

Animals↗
PubMed1995

Complementation of Xanthobacter Py2 mutants defective in epoxyalkane degradation, and expression and nucleotide sequence of the complementing DNA fragment.

Three Xanthobacter Py2 mutants (M3, M8 and M10) lacking epoxyalkane-degrading activity were isolated and characterized. All mutants were able to grow on acetone, the degradation product of 1,2-epoxypropane conversions. Furthermore, they contained the unidentified 'low molecular mass fraction' (LMF) necessary for epoxyalkane-degrading activity. Three cosmids from a gene bank complemented the mutation in M10 and M8 but not in mutant M3. Epoxyalkane-degrading activity in crude extracts of 1,2-epoxypropane-grown complemented mutants was similar to the wild-type activity. Surprisingly, M10 transformed with complementing cosmid pEP9 showed a constitutively expressed epoxyalkane-degrading activity, which was not observed in the wild-type strain. The cosmid pEP9 was conjugated into Xanthobacter autotrophicus GJ10, which is not able to degrade 1,2-epoxypropane. In crude extracts of X. autotrophicus GJ10(pEP9), epoxyalkane-degrading activity was demonstrated, but only after the addition of the LMF from Xanthobacter Py2. Hybridization experiments demonstrated an overlap on complementing cosmids pEP1, pEP3 and pEP9. Subcloning revealed a 4.8 kb EcoRI-HindIII fragment to be necessary for complementing the mutant M10. In the sequence of this fragment four different ORFs were found.

Alkanes↗
PubMed1996

Quantification of the CD55 and CD59, membrane inhibitors of complement on HIV-1 particles as a function of complement-mediated virolysis.

Previous studies have demonstrated that the murine monoclonal antibody (MoAb) NM-01 activates the human complement classical pathway resulting in lysis of human immunodeficiency virus (HIV). The present study was performed to determine the availability of the V3-loop of gp120 relative to the complement regulatory proteins, CD55 (DAF) and CD59 (HRF20) molecules on HIV. The results demonstrate that CD55 and CD59 exist on HIV virions, along with gp120 molecules. These findings suggest that activation of human complement on free viral particles is induced by MoAb NM-01 and that this occurs regardless of the presence of CD55 and CD59 molecules. The destruction of viral particles was demonstrated by a decrease in infectivity. The involvement of human complement in this process was confirmed with an immunoelectron microscopy technique by the presence of a human C9 to prove membrane attack complex (MAC). The results indicate that NM-01 can induce complement activation because of the ratios of CD55 and CD59 to gp120 molecules on HIV virions. The availability of the gp120 V3 domain on the virion is sufficient for binding of NM-01 and thereby the formation of MAC that results in virolysis.

Antibodies, Monoclonal↗
PubMed1980

A complement-fixation test for enzootic pneumonia of pigs using a complement dilution method.

Complement-fixing antibody to Mycoplasma hyopneumoniae in the serums of pigs experimentally infected with enzootic pneumonia was demonstrated by comparing the haemolytic titre of guinea-pig complement titrated in the presence of heated test serum, M. hyopneumoniae antigen and unheated normal pig serum with the titre obtained when the antigen was omitted. The haemolytic titres against sensitised sheep erythrocytes were determined after a fixation period of 16 to 18 hours at 5 degrees C. When serums, collected at intervals of 3 to 7 days, from 43 pigs exposed to pigs experimentally infected with enzootic pneumonia were tested, 4.6 or more complement units were first fixed 14 to 44 (mean 23.4) days after contact began. Serums collected subsequently fixed from 4.6 to more than 31 complement units. This positive reaction usually persisted until the pigs were killed 4 to 35 weeks after contact began. Thirty-three had gross enzootic pneumonia lesions and 9 had lung lesions detected microscopically. Serum antibody was not detected in 73 weaned pigs aged 7 weeks in a pneumonia-free herd but serums from 9 of 15 unweaned piglets aged 9 to 14 days in the same herd, fixed between 3 and 7 complement units.

Animals↗
PubMed2006

Dissecting the regions of virion-associated Kaposi's sarcoma-associated herpesvirus complement control protein required for complement regulation and cell binding.

Complement, which bridges innate and adaptive immune responses as well as humoral and cell-mediated immunity, is antiviral. Kaposi's sarcoma-associated herpesvirus (KSHV) encodes a lytic cycle protein called KSHV complement control protein (KCP) that inhibits activation of the complement cascade. It does so by regulating C3 convertases, accelerating their decay, and acting as a cofactor for factor I degradation of C4b and C3b, two components of the C3 and C5 convertases. These complement regulatory activities require the short consensus repeat (SCR) motifs, of which KCP has four (SCRs 1 to 4). We found that in addition to KCP being expressed on the surfaces of experimentally infected endothelial cells, it is associated with the envelope of purified KSHV virions, potentially protecting them from complement-mediated immunity. Furthermore, recombinant KCP binds heparin, an analogue of the known KSHV cell attachment receptor heparan sulfate, facilitating infection. Treating virus with an anti-KCP monoclonal antibody (MAb), BSF8, inhibited KSHV infection of cells by 35%. Epitope mapping of MAb BSF8 revealed that it binds within SCR domains 1 and 2, also the region of the protein involved in heparin binding. This MAb strongly inhibited classical C3 convertase decay acceleration by KCP and cofactor activity for C4b cleavage but not C3b cleavage. Our data suggest similar topological requirements for cell binding by KSHV, heparin binding, and regulation of C4b-containing C3 convertases but not for factor I-mediated cleavage of C3b. Importantly, they suggest KCP confers at least two functions on the virion: cell binding with concomitant infection and immune evasion.

Animals↗
PubMed1992

Markers of complement-dependent and complement-independent glomerular visceral epithelial cell injury in vivo. Expression of antiadhesive proteins and cytoskeletal changes.

BACKGROUND: Visceral glomerular epithelial cells (GEC) are an important component of the glomerular filtration barrier to proteins. While ultrastructural GEC changes have frequently been observed in proteinuric states, no suitable light microscopic markers of GEC injury have yet been identified. EXPERIMENTAL DESIGN: We have analyzed in vivo the GEC expression of proteins known to be involved in cell shape changes. SPARC (osteonectin, BM-40) and tenascin (cytotactin, J1, hexabrachion) belong to a group of anti-adhesive glycoproteins, that modulate cell-matrix interactions. We also studied cytoskeletal intermediate filament proteins, including desmin and vimentin. The GEC expression of SPARC, tenascin, desmin, and vimentin was analyzed in various types of GEC injury in the rat, including complement-mediated injury (passive Heymann nephritis, autologous immune complex nephritis, conA anti-conA nephritis), complement-independent injury (nephrotoxic nephritis), toxic injury (aminonucleoside nephrosis) and hypertensive injury (5/6 nephrectomy, angiotensin-II infusion). A complement-mediated model of mesangial cell injury (anti-Thy 1.1 mesangial proliferative nephritis) served as a control. RESULTS: SPARC mRNA and protein were constitutively expressed in normal rat glomeruli. Immunostaining and immunoelectron microscopy primarily localized SPARC to the cytoplasm of GEC. Markedly increased glomerular SPARC synthesis and GEC immunostaining was observed in all instances of complement-mediated GEC injury but in none of the other conditions. In contrast, glomerular immunostaining for tenascin, that also stained in a GEC pattern, either remained unchanged or increased to a minor degree (complement-mediated models). GEC immunostaining for desmin in normal rats was low and variable, and increased significantly in any form of GEC injury but not in anti-Thy 1.1 nephritis. No concomitant increase of GEC immunostaining for vimentin was detectable, which could have been due to the constitutively high expression of vimentin in GEC. CONCLUSIONS: SPARC and desmin, but not tenascin or vimentin, are suitable light microscopic markers of GEC injury. The combined staining for these proteins may be useful in differentiating the mechanisms of GEC injury.

Animals↗
PubMed1999

Mechanism of complement-dependent haemolysis via the lectin pathway: role of the complement regulatory proteins.

Mannan-binding lectin (MBL) is an acute phase protein which activates the classical complement pathway at the level of C4 and C2 via two novel serine proteases homologous to C1r and C1s. We recently reported that haemolysis via this lectin pathway requires alternative pathway amplification. The present experiments sought to establish the basis for this requirement, and hence focused on the activity and regulation of the C3 convertases. Complement activation was normalized between the lectin and classical pathways such that identical amounts of bound C4 and of haemolytically active C4,2 sites were present on the indicator cells. Under these conditions, there was markedly less haemolysis, associated with markedly less C3 and C5 deposited, via the lectin pathway than via the classical pathway, particularly when alternative pathway recruitment was blocked by depletion of factor D. Lectin pathway activation was associated with enhanced binding in the presence of MBL of complement control proteins C4bp and factor H to C4b and C3b, respectively, with decreased stability of the C3-converting enzyme C4b,2a attributable to C4bp. Immunodepletion of C4bp and/or factor H increased lectin pathway haemolysis and allowed lysis to occur in absence of the alternative pathway. Thus, the lectin pathway of humans is particularly susceptible to the regulatory effects of C4bp and factor H, due at least in part to MBL enhancement of C4bp binding to C4b and factor H binding to C3b.

Animals↗
PubMed1987

Interactions of the platelets in paroxysmal nocturnal hemoglobinuria with complement. Relationship to defects in the regulation of complement and to platelet survival in vivo.

The blood cells of patients with paroxysmal nocturnal hemoglobinuria (PNH) have abnormal interactions with complement. The activity of the alternative pathway C3 convertase on the platelets of 9 out of 19 patients with PNH was elevated. 10 patients had C3 convertase activity within the normal range even though 80-95% of their platelets lacked the complement regulatory protein decay accelerating factor (DAF) that is absent from the affected blood cells in PNH. PNH and normal platelets released factor H when C3 was bound to their surfaces. This may account for the apparent regulation of C3 convertase activity on platelets that lack DAF. The abnormal uptake of the membrane attack complex of complement by PNH III erythrocytes was not seen in PNH platelets. 111Indium-labeled platelet survival times were normal in five of eight patients, which suggests that the lack of the membrane attack complex defect results in normal platelet survival in PNH.

Blood Coagulation Factors↗
PubMed2002

Complement C2 receptor inhibitor trispanning and the beta-chain of C4 share a binding site for complement C2.

Complement C2 receptor inhibitor trispanning (CRIT) of the Schistosoma parasite binds human C2 via the C2a segment. The receptor in vivo functions as C2 decoy receptor by directly competing with C4b for binding to C2. As a result, CRIT is able to limit the extent of classical pathway (CP) C3 convertase formation. We report that the CRIT-extracellular domain 1 (ed1) peptide inhibits CP-mediated complement activation with an ICH(50) of approximately 0.1 microM, the C-terminal 11 aa of CRIT-ed1, named H17, even more effectively. The beta-chain region F222-Y232 of C4 shares 55% identity and 73% similarity with H17. Peptides based on this region also inhibit CP in a dose-dependent manner. As further evidence of C2 binding we showed CRIT-ed1 peptides and homologous C4 beta-chain peptides to inhibit complement in C2 hemolytic assays. We have predicted C4 beta-c F222-Y232 as a C2 binding site which we have termed the CRIT-ed1 domain, and the sequence [F/H]EVKX(4/5)P as a consensus C2-binding sequence. Anti-CRIT-ed1 cross-reacts with the C4 beta-chain and F222EVKITPGKPY232 appears to be the key epitope recognized by this Ab. Furthermore, anti-CRIT-ed1 was found to inhibit CP activation in a total hemolytic assay. We believe that Schistosoma CRIT-ed1, as well as C4 beta-chain peptides based on the CRIT-ed1 domain, function as interface peptides. These peptides, based on C2-binding sequences in CRIT, or C4, competitively inhibit the binding of C2 to C4b and thus limit the activation of C. The C4 peptides, unlike CRIT-ed1, did not inhibit the cleavage of C2 by C1s.

Amino Acid Sequence↗
PubMed1990

Anaphylatoxins and terminal complement complexes in pancreatitis. Evidence of complement activation in plasma and ascites fluid of patients with acute pancreatitis.

Complement activation has been proposed as a mediator of remote complications of acute pancreatitis. Thirty-seven patients with acute pancreatitis were studied with respect to the formation of anaphylatoxins (C3a/C3adesArg, C5a/C5adesArg) and terminal complement complexes (TCC) in plasma and ascites fluid. The patients were classified according to Ranson's criteria. Eighteen patients with moderate or severe pancreatitis had higher maximum plasma C3a/C3adesArg and TCC concentrations than 19 patients with mild pancreatitis. During convalescence, the concentrations had returned to normal. High concentrations of C5a/C5adesArg and TCC were also found in ascites and pancreatic cyst fluid, drawn from patients with moderate or severe pancreatitis. As the terminal complement pathway activation is involved in reactive lysis and anaphylatoxins increase vascular permeability, anemia and impaired respiration in these patients may be influenced by complement activation.

Acute Disease↗