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PubMed1997

Detection of complement regulatory proteins on soft contact lenses.

PURPOSE: To determine whether the regulators of complement activation, decay-accelerating factor (DAF) and CD59, which have been identified on the cornea and conjunctiva and in soluble forms in tears and lacrimal secretions, are transferred to soft contact lenses worn by normal subjects. METHODS: Following overnight wear of group 4 extended-wear hydrophilic contact lenses by five normal subjects, we examined the lenses immunohistochemically for decay-accelerating factor (DAF) and CD59, two regulators which interfere with the complement cascade at the C3 and C9 steps, respectively. RESULTS: Both proteins were detected on all worn lenses but not on controls. CONCLUSIONS: These findings raise the question of whether these proteins, as do other contact lens-bound proteins, have deleterious effects, or to the contrary, if they maintain their natural activity, might they have protective functions for contact lens wearers.

CD55 Antigens↗

PubMed1992

Immunohistochemical determination of complement activation in joint tissues of patients with rheumatoid arthritis and osteoarthritis using neoantigen-specific monoclonal antibodies.

Murine monoclonal antibodies specific for neoepitopes expressed by C9 incorporated into membrane attack complexes and by membrane-bound C3b and iC3b have been prepared and characterised. These reagents were used to determine the extent and locus of complement activation in synovial-tissues obtained from patients with rheumatoid arthritis and osteoarthritis. In the four rheumatoid arthritis patients there was extensive deposition of C3 activation products and C5b-9 complexes onto the synovial membrane and the pattern of deposition of both neoantigens in serial tissue sections was very similar. There was less extensive staining for C3 and, particularly, C9 neoepitopes on the apical surface of vessel endothelia. In two of four osteoarthritic patients a similar pattern of C3 and C9 neoepitope deposition was found; in the remaining patients no C5b-9 could be located. Synovial vessel walls, but not synovial cells, from both groups of patients stained extensively for the complement regulatory protein CD59. In synovial membranes from patients with osteoarthritis, C9 appeared to be present predominantly in SC5b-9 complexes whereas in rheumatoid arthritis patients no evidence of S-protein incorporation into membrane attack complexes could be demonstrated, suggesting that in rheumatoid arthritis there is damage to the synovial membrane as a result of complement activation and C5b-9 deposition.

Adult↗

PubMed1988

Complement induces a transient increase in membrane permeability in unlysed erythrocytes.

The effects of low concentrations of human serum on antibody-sensitized sheep erythrocytes (EA) were studied. We report that exposure to low concentrations of serum induced a large but transient increase in the membrane permeability of those EA that do not lyse. This change in the permeability of the erythrocyte membrane resulted in net uptake of Na+ and decrease in cell K+, without affecting the total internal cation content. Although exposure to serum also allowed for net uptake of larger molecules like L-glucose, it did not lead to cell swelling. Experiments with sera genetically deficient in one of the terminal complement components showed that C8, but not C9, was required to produce the observed change in membrane permeability. Therefore, we propose that the C5b-8 complex can mediate the transient increase in permeability observed in unlysed erythrocytes during complement activation by whole serum.

Animals↗

PubMed1980

Analysis of solute diffusion across the C5b-9 membrane lesion of complement: evidence that individual C5b-9 complexes do not function as discrete, uniform pores.

We have investigated the diffusion of radiolabeled nonelectrolytes across the membranes of resealed erythrocyte ghosts that had been treated with the terminal complement components C5b-9 and incubated under nonlytic steady state conditions. For all solutes tested, we note that diffusion across the C5b-9 lesion is retarded to rates more than 2 orders of magnitude slower than can be anticipated for a transmembrane diffusional channel of the dimensions suggested by the ultrastructure of the C5b-9 membrane lesion. Furthermore, direct measurement of the relative selectivity of the C5b-9 membrane lesions to permeation by solutes of differing molecular radii suggests that individual membrane lesions are not of uniform functional size. Data are presented that suggest that the functional heterogeneity of the membrane lesion is due to the aggregation of individual membrane bound C5b-9 complexes into larger functional units and not due to variable stoichiometry of C9 within the individual C5b-9 complex.

Cell Membrane Permeability↗

PubMed2005

The gamma subunit of the eighth complement component (C8) in rainbow trout.

Of the 35 proteins, enzymes, receptors and regulatory components of the complement system, C8gamma is unique in that it is the only lipocalin. C8gamma is a subunit of the C8 molecule, which is one of the five components (C5b, C6, C7, C8 and C9) that interact as a consequence of complement activation to form the membrane attack complex. Until now, C8gamma has been characterized only in mammalian species. In order to elucidate the phylogeny of this molecule, we have cloned the C8gamma subunit in rainbow trout (Oncorhynchus mykiss), a teleost fish representing a critical point in the evolutionary divergence of the complement system. The deduced amino acid sequence of trout C8gamma shows significant identity (37%) to the human C8gamma homolog and much lower to the other known lipocalins. The lipocalin domain is present and all the cysteine residues are conserved. The trout C8gamma gene is probably present as a single copy in the trout genome showing a differential expression pattern among tissues investigated.

Amino Acid Sequence↗

PubMed1999

The four terminal components of the complement system are C-mannosylated on multiple tryptophan residues.

C-Mannosylation is a unique form of protein glycosylation, involving the C-glycosidic attachment of a mannosyl residue to the indole moiety of Trp. In the two examples found so far, human RNase 2 and interleukin-12, only the first Trp in the recognition motif WXXW is specifically C-mannosylated. To establish the generality of protein C-mannosylation, and to learn more about its mechanism, the terminal components of the human complement system (C6, C7, C8,and C9), which contain multiple and complex recognition motifs, were examined. Together with C5b they form the cytolytic agent, the membrane attack complex. These are the first proteins that are C-mannosylated on more than one Trp residue as follows: six in C6, four in C7, C8alpha, and C8beta, and two in C9. Thus, from the 113 Trp residues in the complete membrane attack complex, 50 were found to undergo C-mannosylation. The other important finding is that in C6, C7, C8, and C9 Trp residues without a second Trp (or another aromatic residue) at the +3 position can be C-mannosylated. This shows that they must contain an additional C-mannosylation signal. Whether this is encoded in the primary or tertiary structure is presently unknown. Finally, all modified Trp residues are part of the highly conserved core of the thrombospondin type 1 repeats present in these proteins. Since this module has been found in a large number of other proteins, the results suggest further candidates for C-mannosylation.

Complement Membrane Attack Complex↗

PubMed1991

Immunopathology of subcutaneous rheumatoid nodules.

Nodules obtained from five patients with classical seropositive rheumatoid arthritis were studied by an immunofluorescence technique using polyclonal antibodies to IgG, IgA, IgM, C3c, and fibrin, and monoclonal antibodies to the terminal (C5b-9) complement complex (reaction with a neoantigen in C9 revealed during activation), DR antigens, T cells, macrophages, and interdigitating cells. In all instances the central necrotic areas stained strongly for fibrin and more weakly for IgG, IgA, IgM, C3, and terminal complement complex. The surrounding palisading cells reacted with antibodies to DR and macrophages. In the peripheral granulomatous tissue most of the lymphocytes reacted with the antibodies to T cells, whereas various amounts of the larger mononuclear cells were stained by antibodies to DR antigens, macrophages, and interdigitating cells. In all instances the walls of some of the smaller vessels in the granulomatous tissue stained for fibrin, C3, and terminal complement complex. Plasma cells were not seen except for scattered IgM cells in one nodule. These results support the view that the palisading cells are derived from macrophages, and indicate that there is vasculitis with activation of C3 and the terminal complement pathway in the granulomatous tissue.

Arthritis, Rheumatoid↗

PubMed1975

Activation of the properdin pathway of complement in patients with gram-negative bacteremia.

To determine the pathway used for activation of complement component C3, serum levels of components C1, C4, C2, C3, C5, C6, and C9 and two properdin factors, properdin and factor B, were measured in 42 patients with gram-negative bacteremia, in 19 of whom shock subsequently developed. Mean levels of the classical components C1, C4, and C2 in bacteremic patients in whom shock subsequently developed did not differ significantly (p greater than 0.05) from those of patients with uncomplicated bacteremia. Levels of properdin, factor B and C3, C5, C6, and C9 were significantly (p less than 0.05) decreased in patients with shock in comparison with those with uncomplicated bacteremia. Taken together, these findings are consistent with activation of C3 and the terminal complement sequence, C5-C9, occurring primarily by the properdin pathway, in patients with gram-negative bacteremia eventuating in shock. Biologically active products released during activation of C3-C9 may contribute to the development of shock.

Bacteria↗

PubMed1989

Immunohistochemical study of the membrane attack complex of complement and S-protein in idiopathic and secondary membranous nephropathy.

Twenty-eight renal biopsies from 12 patients with idiopathic membranous nephropathy (MN), eight patients with lupus MN, and eight patients with hepatitis B virus-(HBV) related MN were investigated by immunofluorescence for the presence of C5b-C9 neoantigens of the terminal sequence of complement and for S-protein, which is a regulatory component of the membrane attack complex (MAC). Glomerular MAC was detected in 50% of patients with idiopathic MN, in 75% of patients with lupus MN, and in only 12.5% of the HBsAg carrier with MN. Glomerular adhesions to Bowman's capsule were associated with a high incidence of glomerular MAC deposition only in patients with idiopathic MN. Lupus patients had a high incidence of MAC deposition and patients with HBV-related MN had a low incidence of MAC deposition, in both cases regardless of the presence of glomerular capsular adhesions. It is unlikely that deposition of S-protein could inhibit the glomerular damage in idiopathic or lupus MN because significant glomerular capsular adhesions and MAC deposition were observed despite the concomitant glomerular deposition of S-protein. It was concluded that activation of terminal components of complement may play a role in glomerular injuries in idiopathic and lupus MN. The rare occurrence of glomerular MAC deposition in HBV-related MN could be related to its distinct immunopathogenetic mechanism and its indolent clinical course.

Complement Membrane Attack Complex↗

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↗

PubMed1985

Immunohistological investigations of PAS-negative globular intracisternal hyalin in human liver biopsy specimens.

Eight liver biopsy specimens from five patients with PAS-negative intracisternal hyalin were investigated by immunofluorescence for: (1) immunoglobulins (Ig) G, A, M, D, E; (2) light chains (kappa and lambda); (3) complement components C1q, C4, C3c, C5, C9; (4) C1-inactivator; (5) C3-activator; (6) alpha 1-antitrypsin; (7) alpha 1-antichymotrypsin; (8) plasminogen; (9) fibrinogen; (10) fibrinogen breakdown products D and E; (11) fibronectin; (12) prealbumin; (13) albumin; (14) betalipoprotein; (15) apolipoprotein; (16) alpha 1- and alpha 2-glycoprotein; (17) cholinesterase; (18) ceruloplasmin; (19) haemopexin; (20) myoglobin; (21) placenta lactogen; (22) transferrin; (23) actin; (24) myosin; (25) cathepsin D; and (26) hepatitis B surface and core antigens (HBsAg and HBcAg). The globules reacted significantly with antisera against C3c (three patients), C4 (three patients), C3-activator (one patient) and fibrinogen (two patients). The cause of the protein accumulation is not clear. Serial studies indicate the possibility of a disturbance of protein secretion and an as yet unidentified immune complex disorder.

Complement C3↗

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↗

PubMed1983

Interaction of human beta-endorphin with nonopiate binding sites on the terminal SC5b-9 complex of human complement. Significance of COOH-terminal beta H-endorphin fragments.

We have characterized the binding of 125I-labeled human beta-endorphin (125I-beta H-endorphin) to sites present on the terminal fluid-phase complex of human complement, consisting of complement components C5b, C6, C7, C8, C9, and the S-protein (SC5b-9 complex). Specific binding exhibited saturability, reversibility, structural specificity, temperature dependence, and absence of negative cooperative effects. Binding was maximal at 4 degrees C and pH 7.0; it was diminished by monovalent and divalent cations as well as by increasing concentrations of urea and Triton X-100 and apparently required intact disulfide groups. Binding was not inhibited by a number of opioid peptides sharing common sequences with the NH2 terminus of beta H-endorphin. In contrast, binding was inhibited by beta H-endorphin, N-acetyl-beta H-endorphin, and a series of COOH-terminal beta H-endorphin fragments, where of the COOH-terminal dipeptide Gly-Glu represented the minimal effective structure. Stepwise extension towards the NH2 terminus led to an increased binding affinity of the respective fragment. Computer resolution of competition curves yielded one binding component for several shorter COOH-terminal beta H-endorphin fragments and for beta H-endorphin (1-5) + (16-31), whereas two distinct binding components were obtained when beta H-endorphin (27-31), beta H-endorphin (6-31), N-acetyl-beta H-endorphin or beta H-endorphin were used as inhibitors. This study presents detailed data on the binding of COOH-terminal beta H-endorphin fragments to specific nonopiate binding sites present on the terminal SC5b-9 complex of human complement. We suggest that through this interaction, beta H-endorphin may modulate certain functions within the immune system.

Binding Sites↗

PubMed1984

Complement factor adsorption on solid surfaces--an ellipsometric method for investigation of quantitative aspects.

An optical method, ellipsometry, has been used for quantification of organic material adsorbed from complement sufficient sera on antibody coated solid surfaces. Maximal adsorption of organic material from complement sufficient human sera occurred at about 0.5 micrograms/cm2 of IgG. C3 but not C5, C8 or C9 was detected on the antibody surface incubated with complement sufficient sera. This may indicate that IgG adsorbed on methylized silicon surfaces lack binding sites for complement factors beyond C3. A modification of the method was also used for quantification of migration inhibition of human polymorphonuclear leucocytes (PMNL). Locomotion inhibition fell in a sharp interval from 0.2 to 0.5 micrograms/cm2 of IgG on the surface. We believe that the suggested type of measurements is important for understanding the quantitative relationships between humoral effects such as antibody dependent complement activation and cellular effects such as migration of PMNL.

Adsorption↗

PubMed2005

cDNA cloning and phylogenetic analysis of the sixth complement component in rainbow trout.

The sixth complement protein (C6) is an essential component of the membrane attack complex (MAC); the end product of the lytic pathway of complement activation. The MAC complex constitutes a supramolecular assembly containing the five precursor proteins C5b, C6, C7, C8, and C9. Once assembled on the target surface it forms transmembrane channels that cause membrane damage and cytolysis of complement-opsonized pathogens. Besides mediating direct pathogen elimination, exposure of cells to sublytic doses of MAC can trigger diverse cellular responses such as, cell activation, induction of apoptosis, cell cycle re-entry and proliferation in various biological settings. The terminal complement components (C6-C9) are structurally related proteins, differing in size and complexity. In order to study their evolution, we report here the cloning and molecular characterization of C6 component in rainbow trout. The deduced amino acid sequence of trout C6 exhibits 55 and 44% identity with zebra fish and human orthologs, respectively. The 'domain' architecture of trout C6 resembles that of mammalian counterparts, and the cysteine backbone is also conserved. Finally, trout C6 gene appears to exist as a single copy in the trout genome, and is expressed in a wide range of trout tissues.

Amino Acid Sequence↗

PubMed2000

Human complement protein C8 gamma.

Human C8 gamma is a 22 kDa subunit of complement component C8, which is one of five components (C5b, C6, C7, C8, C9) that interact to form the cytolytic membrane attack complex (MAC) of complement. C8 contains three nonidentical subunits (alpha, beta, gamma) that are products of different genes. These subunits are arranged asymmetrically to form a disulfide-linked C8 alpha-gamma dimer that is noncovalently associated with C8 beta. C8 alpha and C8 beta are homologous to C6, C7 and C9 and together these proteins comprise what is referred to as the 'MAC protein family'. By comparison, C8 gamma is distinct in that it belongs to the lipocalin family of small, secreted proteins which have the common ability to bind small hydrophobic ligands. While specific roles have been identified for C8 alpha and C8 beta in the formation and function of the MAC, a function for C8 gamma and the identity of its ligand are unknown. This review summarizes the current status of C8 gamma structure and function and the progress made from efforts to determine its role in the complement system.

Amino Acid Sequence↗

PubMed1982

Biological significance of the C3 nephritic factor in membranoproliferative glomerulonephritis.

Serum levels of the C3 nephritic factor (C3NeF), an IgG autoantibody directed against the C3bBb convertase of the alternative complement pathway, and of eight complement components (C1q, C4, C3, C3d, C5, C9, fB and properdin) were measured in 109 serum samples from 27 patients with idiopathic membranoproliferative glomerulonephritis (MPGN) (type I, 20 cases, and type II, 7 cases) and 14 patients with secondary MPGN. Correlations between the concentrations of C3NeF, serum complement levels and progression of the renal damage were studied during the course of the disease in 14 patients with C3NeF activity. The results showed that (1) C3NeF activity was more frequent in patients with type II MPGN than in patients with type I disease; nevertheless there was a high incidence of this splitting activity in patients with secondary MPGN, (2) high levels of the complement components were present in patients with MPGN, (3) low levels of C3 occurred frequently in type II disease and in secondary MPGN, (4) there was no correlation between C3, fB and C3NeF levels, (5) the presence of C3NeF was associated with a more rapid deterioration of renal function. Longitudinal studies showed that serum levels of C3NeF were not satisfactory for monitoring the clinical course of the illness and, in this respect, are similar to the levels of other autoantibodies in patients with autoimmune disease. As MPGN is a clinical syndrome with various pathogeneses, we suggest that the autoantibody, C3NeF, should be considered only as a marker of some forms of MPGN.

Autoantibodies↗

PubMedDate not supplied

Binding of vitronectin and clusterin by coagulase-negative staphylococci interfering with complement function.

Coagulase-negative staphylococci (CoNS) are commonly associated with infections of prosthetic devices mediated by adsorbed host factors on biomaterial surfaces. Complement activation is known to occur and induce unspecific inflammation around the biomaterials. Human vitronectin (Vn) and clusterin (Clu), two potent inhibitors of complement, can be bound by CoNS. With a hypothesis whether binding of Vn or Clu influences complement activation, two measurements were determined. For Vn, complement activation was measured with a mouse anti-activated human C9 antibody. In the presence of Vn-binding strain, Staphylococcus hemolyticus SM13I, complement activation on a surface pre-coated with Vn occurred as it did in the absence of Vn pre-coating. For S. epidermidis 3380, which does not express binding of Vn, complement activation on a Vn-presented surface was significantly decreased. For Clu, erythrocytes lysis was measured to reflect the end product of complement activation (membrane attack complex). The complement-induced hemolysis increased when human serum was pre-incubated with Clu-binding strains, S. epidermidis J9P. The enhancement of hemolysis by J9P decreased when serum was supplemented by exogenous Clu. The data imply that interaction between CoNS and Vn or Clu interferes with one of their physiological functions, complement inhibition.

Journal Article↗