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PubMed1995

Genomic organization of human complement protein C8 alpha and further examination of its linkage to C8 beta.

Human C8 is one of five complement components (C5b, C6, C7, C8, C9) that interact to form the cytolytic C5b-9 complex on target membranes. It is composed of three nonidentical subunits (C8 alpha, C8 beta, C8 gamma) encoded by separate genes. C8 alpha and C8 beta are linked on chromosome 1p32, whereas C8 gamma is located on 9q22.3-q32. In this study, overlapping genomic clones were isolated and used to decipher the organization of the human C8 alpha gene. The gene contains at least 11 exons spanning approximately 70 kb of DNA. When compared to C6, C8 beta and C9, there is a remarkable similarity in genomic organization, consistent with amino acid sequence comparisons that suggest these proteins are ancestrally related. Regions of each protein that are structurally similar are encoded in exons of correspondingly similar lengths with highly conserved boundaries and phases. Availability of genomic sequence also facilitated a more detailed analysis of C8 alpha and C8 beta linkage. Based on analysis of genomic digests with cDNA probes, the loci were previously reported to be physically linked (< 2.5 kb) and in a 5' alpha-beta 3' orientation. In the present study, results obtained using exon-specific probes indicate the loci are not as closely linked as initially believed. Furthermore, they suggest that cDNA probes used earlier yielded misleading information because they encode exons that are distributed across large segments of genomic DNA.

Amino Acid Sequence↗
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↗
PubMed1989

Phosphorylcholine acts as a Ca2+-dependent receptor molecule for lymphocyte perforin.

Large granular lymphocytes and cytolytic T-lymphocytes (CTL) contain numerous cytoplasmic granules thought to be responsible, at least in part, for the cytolytic activity of these effector cells. Isolated granules are lytic for a variety of target cells and the granule proteins are specifically released upon target-cell interaction. Major proteins in mouse CTL granules are a family of seven serine proteases designated granzymes A to G, and a pore-forming protein called perforin (cytolysin). Purified perforin is cytolytic in the presence of Ca2+ and shows ultrastructural, immunological and amino-acid sequence similarities to complement component C9. Despite these similarities, perforin and C9 are clearly distinct in their mode of target-cell recognition. Whereas C9 insertion is absolutely dependent on a receptor moiety assembled from the complement proteins C5b, C6, C7, and C8 on the target-cell membrane, no requirement for a receptor molecule has been reported for perforin. Here, we demonstrate that phosphorylcholine acts as a specific, Ca2+-dependent receptor molecule for perforin.

Animals↗
PubMed1997

Utilization of host iron sources by Corynebacterium diphtheriae: identification of a gene whose product is homologous to eukaryotic heme oxygenases and is required for acquisition of iron from heme and hemoglobin.

Corynebacterium diphtheriae was examined for the ability to utilize various host compounds as iron sources. C. diphtheriae C7(-) acquired iron from heme, hemoglobin, and transferrin. A siderophore uptake mutant of strain C7 was unable to utilize transferrin but was unaffected in acquisition of iron from heme and hemoglobin, which suggests that C. diphtheriae possesses a novel mechanism for utilizing heme and hemoglobin as iron sources. Mutants of C. diphtheriae and Corynebacterium ulcerans that are defective in acquiring iron from heme and hemoglobin were isolated following chemical mutagenesis and streptonigrin enrichment. A recombinant clone, pCD293, obtained from a C7(-) genomic plasmid library complemented several of the C. ulcerans mutants and three of the C. diphtheriae mutants. The nucleotide sequence of the gene (hmuO) required for complementation was determined and shown to encode a protein with a predicted mass of 24,123 Da. Sequence analysis revealed that HmuO has 33% identity and 70% similarity with the human heme oxygenase enzyme HO-1. Heme oxygenases, which have been well characterized in eukaryotes but have not been identified in prokaryotes, are involved in the oxidation of heme and subsequent release of iron from the heme moiety. It is proposed that the HmuO protein is essential for the utilization of heme as an iron source by C. diphtheriae and that the heme oxygenase activity of HmuO is involved in the release of iron from heme. This is the first report of a bacterial gene whose product has homology to heme oxygenases.

Amino Acid Sequence↗
PubMed1990

[Meningococcal infection and arthritis].

Arthritic manifestations in patients with meningococcal disease are of varied pathogenesis. Four different pathogenic mechanisms may be involved. Direct bacterial invasion of the synovium and multiplication within the joint (septic arthritis); hypersensitivity reaction or allergic arthritis; intra- or periarticular hemorrhage (hemarthrosis) and iatrogen causes, i.e. reaction to antimicrobial agents, serum therapy etc. Four distinct clinical forms have been described: The septic, culture-positive polyarthritis is seen early in the course of the disease. The sterile "non-infectious" or allergic mono- or oligo arthritis are seen later in the course. Primary meningococcal arthritis. Arthritis may be seen in relation to chronic meningococcemia. Treatment consists primarily of specific antimeningococcal chemotherapy, viz penicillin and non-steroid-anti-inflammatory drugs. The prognosis of meningococcal arthritis is excellent and joint sequelae are rare. Predisposing factors in relation to meningococcal disease are reviewed. The most important are socioeconomic conditions, acute respiratory illness, particularly in relation to age as children less than two years are most susceptible, passive smoking, IgA blocking antibodies, the concentration of complement factors C3, C6, C7, C8, and IgG2-defects.

Arthritis, Infectious↗
PubMed1992

The human complement regulatory protein CD59 binds to the alpha-chain of C8 and to the "b"domain of C9.

The erythrocyte membrane inhibitor of the human terminal complement proteins, surface antigen CD59, has previously been shown to enter into a detergent-resistant complex with either the membrane-bound complex of C5b-8 or C5b-9 (Meri, S., Morgan, B. P., Davies, A., Daniels, R. H., Olavesen, M. G., Waldmann, H. and Lachmann, P. J. (1990) Immunology 71, 1-9; Rollins, S. A., Zhao, J., Ninomiya, H., and Sims, P. J. (1991) J. Immunol, 146, 2345-2351). In order to further define the interactions that underlie the complement-inhibitory function of CD59, we have examined the binding interactions between 125I-CD59 and the isolated components of human complement membrane attack complex, C5b6, C7, C8, and C9. By density gradient analysis, we were unable to detect interaction of 125I-CD59 with any of these isolated complement components in solution. Specific binding of 125I-CD59 to C8 and C9 was detected when these human complement proteins were adsorbed to either plastic or to nitrocellulose, suggesting that a conformational change that accompanies surface adsorption exposes a CD59-binding site that is normally buried in these serum proteins. The binding of 125I-CD59 to plastic-adsorbed C8 and C9 was saturable and competed by excess unlabeled CD59, with half-maximal binding observed at 125I-CD59 concentrations of 80 and 36 nM, respectively. No specific binding of 125I-CD59 was detected for surface-adsorbed human C5b6 or C7 nor was such binding observed for C8 or C9 isolated from rabbit serum. Binding of CD59 to human C8 and C9 was not mediated by the phospholipid moiety of CD59, implying association by protein-protein interaction. In order to further define the binding sites for CD59, ligand blotting with 125I-CD59 was performed after separation of C8 into its noncovalently associated subunits (C8 alpha-gamma and C8 beta) and after alpha-thrombin digestion of C9. These experiments revealed specific and saturable binding of 125I-CD59 to C8 alpha-gamma subunit (half-maximal binding at 75 nM), but not to C8 beta, and specific and saturable binding to the 37-kDa fragment (C9b) of thrombin-cleaved C9 (half-maximal binding at 35 nM), but not to the 25-kDa C9a fragment. Partial reduction of C8 alpha-gamma revealed that only C8 alpha polypeptide exhibited affinity for CD59, and no specific binding to the C8 gamma chain was detected.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1984

C3-independent immune haemolysis: haemolysis of EAC14oxy2 cells by C5-C9 without participation of C3.

C3-independent immune haemolysis was studied using EAC14oxy2 cells and purified C5, C6, C7, C8 and C9. We have found that EAC14oxy2 cells were lysed by C5-C9 and that haemolysis occurs, even after pretreatment of the cells and the C5-C9 preparation with anti-C3. This indicates that EAC14oxy2 can be lysed by C5-C9 without any participation of C3. In contrast, EAC1 and EAC14 cells are not lysed by C5-C9, suggesting that our C5-C9 preparation lacks activated complement components, such as C3bBb, C5b6 or C(56)a. Based on our study of the haemolysis of EAC14oxy2, we have determined that: (i) EAC14oxy2 cells are lysed by a preparation of C5, C6, C7, C8 and C9, but no lysis occurs when any one of these complement is absent, (ii) for significant haemolysis of EAC14oxy2, a higher concentration of C5 is necessary as compared to the C5 requirement when haemolysis occurs in the presence of C3, (iii) the degree of haemolysis is linearly related to the concentration of C5 and does not reach a plateau, despite the addition of as much as 3,200 U of C5, and (iv) the degree of haemolysis is linearly related to the concentration of cell bound C42. These observations suggest that, in the absence of C3, the C3 convertase C42 can activate C5 directly, resulting in the formation of the membrane attack complex, C5b-9.

Complement C2↗
PubMed1970

Reactive lysis: the complement-mediated lysis of unsensitized cells. I. The characterization of the indicator factor and its identification as C7.

This paper describes the characteristics of the indicator factor (I) which takes part in reactive hemolysis and its identification as the seventh component of complement. I was shown to be a beta globulin with a sediment coefficient of 5.7S and a molecular weight of about 140,000. Experiments on the depletion of I activity with anti-I antiserum or with activated R euglobulin showed that I was a late acting complement component necessary for the lysis of cells after the EAC142 stage. Complement component analysis of purified I fractions excluded all known components except C7. The physicochemical characteristics of I are compatible with published data on C7. The method of quantitation described represents a convenient method of testing for C7.

Animals↗
PubMed1992

Serum SC5b-9 (terminal complement complex) level, a sensitive indicator of disease activity in patients with Henoch-Schönlein purpura.

The concentration of the terminal complement complex (TCC), SC5b-9, was determined by enzyme immunoassay using 95 serum samples from 30 patients with Henoch-Schönlein purpura (HSP), 27 with other forms of inflammatory skin disease and 20 normal healthy donors. Twenty-five patients with HSP showed significantly increased TCC concentration in the active phase of the disease, during which newly formed urticarial or purpuric macules/papules could be seen. Skin biopsy specimens of skin lesions from patients with elevated TCC levels in nearly all cases contained the membrane attack complex of complement and consisted of C5b, C6, C7, C8, C9 without S protein on the vessel walls. Systemic and local activation of complement may thus possibly occur in HSP. Three patients with various manifestations of the disease were followed over a period of several years during which the active and inactive phases were scanned. TCC elevation in all cases was correlated with exacerbation of the disease. In contrast, C3, C4 and CH50 levels either remained normal or increased and thus were not reliable indicators of disease activity. Measurement of TCC should thus prove quite useful for monitoring the activity of HSP in patients in whom there is complement activation and also serve to facilitate clarification of the functions of complement in the pathogenesis of the disease.

Acute Disease↗
PubMed1989

[Genetic variants of the complement components and HLA-antigens associated in patients with psoriasis vulgaris in Japanese].

Genetic polymorphisms of the serum complement components (C2, C4, C6, and C7) and HLA-antigens were studied in Japanese patients with psoriasis vulgaris. Among these complement components, positive associations with C4A4 and C4B2 were obtained. In addition to the previously reported haplotypes HLA-Cw6-B13 and Cw6-Bw57-DR7, the extended haplotype HLA-Cw11-Bw46-C4A4. 4B2-BFS-C2C-DRw8 may be a high risk haplotype in Japanese patients with psoriasis vulgaris.

Asian People↗
PubMed1980

Fulminant meningococcemia in a child with hereditary deficiency of the seventh component of complement and proteinuria.

A previously healthy 14-year-old boy presented with fulminant meningococcemia. He was found to have a total deficiency of C7. His serum totally lacked bactericidal activity against Neisseria meningitidis. Addition of purified C7 restored the serum hemolytic and bactericidal activity. Susceptibility to disseminated Neisseria infections has previously been reported in 3 patients with C7 deficiency, as well as in a few patients with deficiency of C5, C6 and C8. These findings emphasize the importance of intact complement mediated bactericidal activity in host defense against disseminated Neisseria infections. Evaluation of the complement system in individuals with Neisseria infections appears mandatory.

Adolescent↗
PubMed1990

[Terminal complement complex (TTC) levels in plasma and urine from glomerular diseases: enzyme-linked immunosorbent assay (ELISA) using monoclonal antibody against neoantigens of TCC].

In order to get monoclonal antibodies (MoAbs) against neoantigens of terminal complement complex. MoAbs after immunization of mice with polymerized human C9 were screened for reactivities against native and polymerized C9. MoAb 1B4 reacted with tubular C9 polymer, but did not react with either native or sodium dodecyl sulfate-denatured monomeric C9 as revealed by enzyme-linked immunosorbent assay (ELISA) and Western blotting. Moreover, MoAb 1B4 reacted with the terminal complement complex (TCC), that is, membrane attack complex and the fluid-phase SC5b-9 complex. Thus, MoAb 1B4 recognized a neoantigen in the moiety of C9 polymer in the TCC. Thereafter, we measured TCC in plasma and urine with sandwich ELISA using 1B4 and antihuman C7 antibody to evaluate terminal complement activation in patients with glomerular diseases. TCC was detectable in plasma but not in urine from most of normal controls. In plasma, TCC was elevated in 5 of 23 with lupus nephritis and in 6 of 11 with membranoproliferative glomerulonephritis, but all patients with IgA nephritis, focal glomerulosclerosis, membranous glomerulonephritis and minimal change lesions (MC) showed normal levels. In urine, TCC was detectable in most of patients with severe proteinuria (greater than or equal to 100 mg/dl) except MC. The TCC present in urine was partially purified by gel filtration with Sepharose 6B and was found to contain C5, C6, C7, C8, C9, and S protein by ELISA. Although the molecular weight of SC5b-9 complex is similar to IgM, fractional excretion rate of TCC was about 100 times higher than that of IgM. These results suggest that urinary TCC contains SC5b-9 complex like plasma TCC and is mostly derived from renal origin.

Adolescent↗
PubMed1990

Study of genetic polymorphism of seventh complement component in two families with hereditary deficit.

The results of an allelic segregation of C6 and C7 were studied in two Spanish families that have members with C7 deficiency. Absence of C7 in the affected siblings and half of the normal values in their parents were found in both families. The variant responsible for the deficiency (C7Q*0) follows a codominant autosomic inheritance pattern. Establishing allotypes of C6 and C7 by isoelectrofocusing followed by electrophoretic immunoblotting allowed haplotype assignments. In both families the haplotype form responsible for the deficiency seemed to be related to the C6B allotype.

Alleles↗
PubMed1983

Neoantigen of the polymerized ninth component of complement. Characterization of a monoclonal antibody and immunohistochemical localization in renal disease.

A monoclonal antibody to a neoantigen of the C9 portion of the membrane attack complex (MAC) of human complement has been developed and characterized. The distribution of this neoantigen was assessed by indirect immunofluorescence microscopy in nephritic and nonnephritic renal diseases. The antibody (Poly C9-MA) reacted on enzyme-linked immunosorbent assay (ELISA) with a determinant in complement-activated serum that was undetectable in normal human serum (NHS). Zymosan particles incubated in NHS had positive immunofluorescent staining with Poly C9-MA; however, binding of Poly C9-MA was not observed with zymosan particles incubated in sera deficient in individual complement components C3, C5, C6, C7, C8, or C9. Reconstitution of C9-deficient sera with purified C9 restored the fluorescence with Poly C9-MA. Poly C9-MA reacted positively by ELISA in a dose-dependent manner with purified MC5b-9 solubilized from membranes of antibody-coated sheep erythrocytes treated with NHS but not with intermediate complement complexes. Poly C9-MA also reacted in a dose-dependent manner on ELISA and in a radioimmunoassay with polymerized C9 (37 degrees C, 64 h) (poly C9) but not with monomeric C9. Increasing amounts of either unlabeled poly C9 or purified MC5b-9 inhibited the 125I-poly C9 RIA in an identical manner. These studies demonstrate that Poly C9-MA recognizes a neoantigen of C9 common to both the MAC and to poly C9. By immunofluorescence, Poly C9-MA reacted minimally with normal kidney tissue in juxtaglomerular loci, the mesangial stalk, and vessel walls. Poly C9-MA stained kidney tissue from patients with glomerulonephritis in a pattern similar to that seen with polyclonal anti-human C3. In tissue from patients with nonnephritic renal disease--diabetes, hypertension, and obstructive uropathy--Poly C9-MA was strongly reactive in the mesangial stalk and juxtaglomerular regions, tubular basement membranes, and vascular walls. Poly C9-MA binding was especially prominent in areas of advanced tissue injury. Poly C9-MA frequently stained loci where C3 was either minimally present or absent. These studies provide strong evidence for complement activation not only in nephritic but also in nonnephritic renal diseases.

Adult↗
PubMed1979

Human complement in thrombin-mediated platelet function: uptake of the C5b-9 complex.

Thrombin-mediated platelet aggregation and release is enhanced by the presence of C3, C5, C6, C7, C8, and C9 of human complement. The interaction of thrombin with its receptor on the platelet membrane initiates activation of complement on the platelet surface. Trypsin-mediated platelet function is not enhanced by the addition of complement, probably because trypsin has no receptor on the platelet surface so activation of complement is triggered in the fluid phase and not on the platelet surface. Activation of complement by thrombin led to production of dimers of the C5b-9 complex on the platelet surface. These complexes were eluted from the platelet membrane and were identified physicochemically and morphologically. The mechanism of complement-induced enhancement of platelet function is not clear, however, it probably is mediated via the arachidonic acid transormation pathway because this activity was blocked by known inhibitors of cyclo-oxygenase, namely, aspirin and indomethacin.

Antithrombin III↗
PubMed1993

Systemic meningococcal infections in patients with acquired complement deficiency.

Congenital deficiency of the late components of the complement may predispose the individual to systemic meningococcal infection. Assuming that patients with acquired complement deficiencies may also have an increased risk of contracting meningococcal infections, a retrospective and prospective study to assess this association was conducted. Over 20 years (1970-1989), 30 patients with meningococcemia or meningococcal meningitis, proven by blood or CSF culture, were treated at the Beilinson Medical Center. Only one patient died of the infection. Risk factors were found in three patients (10%). One had a congenital deficiency of C7, and two had acquired complement deficiency due to systemic lupus erythematosus (SLE) and membranoproliferative glomerulonephritis (MPGN). These latter two patients had low serum concentration of C3 and C4 and reduced complement hemolytic activity before onset of the infection. Since the incidence of culture-proven systemic meningococcal infection in the Jewish population in central Israel is 1/100,000, and the prevalence of SLE and MPGN is, at most, 250/100,000, the finding of two patients with meningococcal infection and these rare disorders is over 100 times the expected incidence. We conclude that patients with acquired complement deficiency are at significant risk of meningococcal infection.

Adolescent↗
PubMed1979

Neisseria meningitidis and Neisseria gonorrhoeae bacteremia associated with C6, C7, or C8 deficiency.

We summarize data from 24 previously described or newly diagnosed cases of homozygous deficiency of the sixth, seventh, or eighth components of complement. Thirteen of 24 patients had at least one episode, and usually two or more episodes of Neisseria meningitidis or Neisseria gonorrhoeae bacteremia, or both. Deficiency of C6, C7, or C8 is a meaningful risk factor for repeated neisserial bacteremia; conversely, hemolytic complement studies are indicated in patients who develop recurrent neisserial infections. When a person with C6, C7, or C8 deficiency is identified, family members should also be studied.

Adolescent↗