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PubMedDate not supplied

Complement system in healthy term newborns: reference values in umbilical cord blood.

Activation of the complement system occurs in several diseases. For reliable identification of complement activation in neonates, we establish reference ranges of several components in cord blood of healthy term newborns. For this study, cord blood samples were taken from 125 healthy term newborns. Concentrations of C1r, C2, C5, C7, Properdin, and factors D, H, and I were determined by single radial immunodiffusion. C3a and C5a were measured by specific EIA and complement function was measured by hemolytic assays. The results were expressed as 5th percentile, median, and 95th percentile. The following respective concentrations were found: C1r: 27, 47, 65 mg/l; C2: 12.0, 18.0, 24.0 mg/l; C5: 64, 92, 127 mg/l; C7: 32, 60, 89 mg/l; Properdin: 5.6, 9.7, 14.2 mg/l; factor D: 3.6, 5.2, 7.3 mg/l; factor H: 178, 234, 296 mg/l; and factor I: 15, 24, 32 mg/l. The functional activity of the whole complement system was 24%, 43%, 97% and for the alternative pathway 39%, 58%, 76%. The concentration of the activated split products C3a was 4, 65, 255 microg/l and of C5a, 0.11, 0.26, 1.19 microg/l. These reference values may be important for the detection of deficiencies of native complement proteins or perinatal processes leading to an activation of the complement system.

Adult↗
PubMed1979

Binding of immunoglobulin and activation of complement by asbestos fibers.

Asbestos fibers adsorbed IgG from whole human serum in amounts comparable to that taken up by crystals of calcium pyrophosphate or hydroxyapatite, but less than that adsorbed by crystals of monosodium urate monohydrate. Chrysotile asbestos was much more active in binding IgG than was amphibole asbestos. The electrophoretic mobility of adsorbed IgG was a function of the surface charge of the crystal studied. Negatively charged fibers adsorbed cationic IgG, and positively charged fibers adsorbed anionic IgG. Complement activation by asbestos, as judged by electrophoretic conversion of C3, was similar for all fiber types tested. Properdin factor B was also activated in the presence of asbestos. Activation of both properdin factor B and C3 was only partially inhibited by ethylene glycol tetraacetic acid, demonstrating that activation was occurring through both the classical and alternative pathways.

Adsorption↗
PubMed1990

The mechanism of activation of the alternative pathway of complement by cell-bound C4b.

Investigations into the mechanism of alternative pathway-dependent lysis of C4b-coated cells are reported. Test cells (EAC1q4b) were formed by reaction of sheep erythrocytes with antibody, C1 and C4. In C5-deficient serum, more C3b was deposited onto EAC1qC4b than onto control cells (EAC1q). The possibility that the C4bBb enzyme could form was considered, but no C3 convertase activity was generated when magnesium, properdin and factors B and D were added to EAC1qC4b. Binding studies employing radiolabeled components provided evidence that C4b bound the C3 convertase, C3bBbP, through a weak interaction with C3b. These data implied C3 conversion would be localized to the cell surface, thereby amplifying C3b deposition. This could be demonstrated in vitro. C3b, properdin, factor B and factor D were all required and the amplified C3b deposition was not due to deposition onto C4b itself. In serum, C5 convertase activity would be consequently expressed and cell lysis would result. This could be the mechanism by which the sera of C2-deficient patients mediate lysis of antibody coated sheep erythrocytes.

Animals↗
PubMed2005

[Neisseria meningitidis infection. Clinical criteria orienting towards a deficiency in the proteins of the complement].

OBJECTIVE: Complement protein deficiency of the classical pathway or in proteins of the alternate pathway is rare but considerably increase the risk of infection with Neisseria meningitidis. The aim of this study was to determine the clinical criteria of the group at risk. METHODS: Retrospective study of the clinical and biological data of patients exhibiting complement protein deficiency associated with one or several N. meningitidis infections. RESULTS: Forty cases were studied, including 35 classical pathway protein deficiencies, with a predominance of C7 deficiency, 3 properdin deficiencies and 2 acquired C3 deficiencies. More than 60% of the patients exhibited recurrent N. meningitidis infections. Serogroups of rare strains were isolated in 50% of cases. Properdin deficiency was associated with a fulminating form in 2 cases out of 3. The age at onset of the first manifestations varied from 2 months to 32 years. CONCLUSION: A deficiency must be systematically searched for in all patients presenting with a N. meningitidis infection before the age of 6 months or after the age of 5 years. Identification of deficient patients permits the proposal of family screening and appropriate prophylaxis, including preventive vaccination.

Adolescent↗
PubMed1998

Immobilized chicken antibodies improve the detection of serum antigens with surface plasmon resonance (SPR).

Surface plasmon resonance (SPR) and other refractive index and mass sensitive methods are, due to complement activation by mouse monoclonal antibodies and with concomitant high background signal, only rarely used for the detection of antibody-antigen interactions in the blood serum milieu. In the present study chicken IgY and mouse IgG were immobilized to a sensor chip CM5 dextran matrix and compared for their background signal and detection of serum antigen. Ellipsometry with antibodies adsorbed to methylated silicon surfaces was used as a complementary detection method. As expected, fundamental differences in binding properties between the two kinds of antibodies were observed. Mouse antibodies bound large quantities of human serum. Human C1q was detected on mouse IgG and the complement system was activated, as seen from the rapid C3 and properdin depositions. Chicken antibodies bound low quantities of human serum and no human C1q. Moreover, C3 and properdin deposited only after prolonged serum incubations. Addition of EDTA to serum reduced the background signal modestly for both IgG and IgY. Serum samples with different concentrations of human C3 were injected over surfaces with immobilized chicken anti-C3, and the response was measured by SPR. Small concentration differences (< 1.25 micrograms/ml) in a physiologically relevant range (1-40 micrograms/ml after 100 times dilution) could then be detected reproducibly. The SPR signal was totally obscured when a mouse monoclonal anti-C3 antibody was used for the detection.

Animals↗
PubMed1996

Heterozygous and homozygous factor H deficiency states in a Dutch family.

Factor H, a 150-kD protein, is an important down-regulating protein of the alternative pathway of the complement system. Presently, only 15 persons, representing seven families, have been described with homozygous factor H deficiency. Deficiency of this protein, inherited as an autosomal recessive trait and resulting in uncontrolled breakdown of C3, results in depletion of components of the alternative pathway (factor B, properdin) and of the terminal pathway (C5), and is associated with the onset of bacterial infections, glomerulonephritis and systemic lupus erythematosus (SLE). The proband of the family in this study suffered from subacute cutaneous lupus erythematosus and had had meningococcal meningitis due to serogroup X. She had a complete factor H deficiency at the protein level as determined by Western blotting. Among 21 relatives of the proband studied, encompassing three generations, 10 had low factor H levels, including the two children of the proband, indicating a heterozygous factor H deficiency state. In serum samples of the proband and 11 relatives prospectively studied, a strong correlation of factor H levels with C3, C3 haemolytic activity, factor B and properdin levels (P < 0.0001) was found. Alternative pathway protein levels were significantly lower (Mann-Whitney test; Z values 3.6-2.7) in sera from the four heterozygous relatives studied than in sera from the seven non-deficient relatives. In addition, a defect of the 37/42-kD H-related protein was found in the proband and two of 21 relatives, compared with four of 40 controls. A defect of the 24/29-kD H-related protein was present in one of 21 relatives studied and in none of the 40 controls.

Complement Factor H↗
PubMed1978

Autosomal locus regulates inverse relationship between sialic acid content and capacity of mouse erythrocytes to activate human alternative complement pathway.

The observation that mouse erythrocytes (E(m)) from 21 inbred strains had variable capabilities to activate the human alternative complement pathway permitted the demonstration that membrane sialic acid content was inversely related to activating capacity and was regulated by codominant alleles of a single autosomal locus. Linear regression analysis also demonstrated a significant inverse correlation between the sialic acid content of E(m) from four inbred strains and the concentration of beta1H required for decay-dissociation of the properdin-stabilized amplification convertase on the E(m). E(m) from F(1) hybrids derived from strains with high and low alternative pathway activating capacities and from their backcrosses exhibited the alternative pathway activating capacities expected if the activity were regulated by alleles of a single autosomal locus. That this same locus predominantly regulated the sialic acid content of E(m) was established by the significant inverse correlation between the sialic acid content and the alternative pathway activating capacity of E(m) from mice of the F(1) and backcross generations. Although the fluid phase interaction of C3, B, and [unk]D continuously generates C3b in a reaction augmented by properdin, it is the covalent attachment of C3b to bystander surfaces deficient in sialic acid that activates the alternative complement pathway at that site because of impaired binding of beta1H to C3b on such surfaces. Thus, discrimination between activating and nonactivating surfaces occurs after C3b deposition, and sialic acid deficiency represents the molecular basis for our earlier finding that activating particles circumvent the regulatory actions of the control proteins of the alternative pathway.

Animals↗
PubMed1962

The complement-dependent bacteriolytic activity of normal human serum. I. The effect of pH and ionic strength and the role of lysozyme.

The bacteriolytic activity of normal human serum on a rough strain of E. coli has been studied by a turbidimetric method. Bacteriolysis was found to be markedly dependent on ionic strength and pH, with optima at micro = 0.06 and pH 8.3-8.5, respectively. The method of cultivating the cells also influenced the rapidity of lysis. Lysis was temperature-dependent and was exhibited by all samples of human serum tested. Microscopically, organisms incubated with serum were observed to swell, loose their rod shape and eventually burst, leaving remnants of the cell membrane in suspension. Sphaeroplasts were obtained by brief exposure of cells to serum followed by dilution into 5 per cent sucrose. The bacteriolytic reaction was shown to require complement. No definite requirement for properdin or specific antibody in this system could be demonstrated by the absorption of serum with zymosan and with homologous cells respectively. The latter procedure was found to reduce bacteriolytic activity by removal of serum lysozyme. Absorption of serum with bentonite also led to loss of bacteriolytic activity which could be restored with lysozyme. The organism was not lysed by lysozyme alone, but lysis occurred with lysozyme + EDTA in tris buffer. The possibility of complement acting independently of antibody or properdin, in certain instances, is discussed in relation to bacterial cell wall structure. Data are presented supporting the hypothesis that the "substrate" of complement in cell membranes is a lipid or lipoprotein.

Antibodies↗
PubMed1999

Human Ehlers-Danlos syndrome type VII C and bovine dermatosparaxis are caused by mutations in the procollagen I N-proteinase gene.

Ehlers-Danlos syndrome (EDS) type VIIC is a recessively inherited connective-tissue disorder, characterized by extreme skin fragility, characteristic facies, joint laxity, droopy skin, umbilical hernia, and blue sclera. Like the animal model dermatosparaxis, EDS type VIIC results from the absence of activity of procollagen I N-proteinase (pNPI), the enzyme that excises the N-propeptide of type I and type II procollagens. The pNPI enzyme is a metalloproteinase containing properdin repeats and a cysteine-rich domain with similarities to the disintegrin domain of reprolysins. We used bovine cDNA to isolate human pNPI. The human enzyme exists in two forms: a long version similar to the bovine enzyme and a short version that contains the Zn++-binding catalytic site but lacks the entire C-terminal domain in which the properdin repeats are located. We have identified the mutations that cause EDS type VIIC in the six known affected human individuals and also in one strain of dermatosparactic calf. Five of the individuals with EDS type VIIC were homozygous for a C-->T transition that results in a premature termination codon, Q225X. Four of these five patients were homozygous at three downstream polymorphic sites. The sixth patient was homozygous for a different transition that results in a premature termination codon, W795X. In the dermatosparactic calf, the mutation is a 17-bp deletion that changes the reading frame of the message. These data provide direct evidence that EDS type VIIC and dermatosparaxis result from mutations in the pNPI gene.

Alternative Splicing↗
PubMed1980

Immunofluorescence findings in human renal amyloidosis.

Positive direct immunofluorescence findings have been occasionally reported for human renal amyloidosis. However, no substantial information describing the frequency of immunomicroscopic pattern has been reported. Twenty-seven renal biopsy specimens with proven amyloidosis were studied by direct immunofluorescence using monospecific antisera against IgG, IgA, IgM, IgD, IgE, kappa and lambda light chains, C3, C4 properdin, alpha-2 macroglobulin, albumin, transferrin, and fibrinogen. Ten biopsy specimens were negative. The remaining specimens showed principally a diffuse immunofluorescent staining of the mesangial areas with various of the above fluorescein-labeled antisera except IgE, albumin, and transferrin antisera, which gave a consistently negative reaction. IgD, properdin, or fibrinogen were weakly identified in only one case. Immunoglobulins and C3 were observed in 14 cases. Kappa and/or lambda light chains were found in nine of ten biopsy specimens so tested. Positive immunofluorescent staining of other elements of the nephron was rarely observed. These results suggest that various immunoreactants, in addition to light chains, can be frequently detected in renal amyloidosis and that passive nonselective absorption of plasma proteins does not explain these immunomicroscopic findings.

Adult↗
PubMed1996

Key role of the alternate complement pathway in hyperacute rejection of rat hearts transplanted into fetal sheep.

Hyperacute rejection (HAR) mediated by xenoreactive natural antibodies (XNA), which are thought to develop in early infancy, is a major impediment to transplantation between widely disparate species. The ability to diagnose certain forms of congenital heart defects early in prenatal life suggests the potential for these defects to be corrected by cardiac transplantation, prior to the development of XNA and host immunocompetence. This study investigated whether discordant cardiac xenotransplantation into fetal and neonatal recipients might obviate HAR due to the relative lack of XNA. Six neonatal lambs at 3 days (n=3) or 7 days (n=3) of life, and two fetal lambs at 125 and 142 days of gestation (term = 145 days) received cardiac grafts from adult Wistar-Furth (275-350 g) rats. All eight cardiac xenografts showed clinical evidence of HAR, with rapid swelling, loss of contractility, and ecchymosis and a mean survival time of 12.5 +/- 6.4 min. Sections of explanted grafts showed classical histologic features of HAR, including interstitial hemorrhages, platelet microthrombi, and edema, without leukocyte infiltration. Immunopathology of grafts harvested from fetal recipients showed a lack of significant intragraft deposition of sheep IgM, IgG, or C1q, but widespread endothelial labeling for C3, factor B, and properdin. In contrast, grafts in neonatal recipients showed IgM, IgG, and C1q deposition, as well as C3, factor B, properdin, and terminal complement (C) components. Fibrin deposition and platelet thrombi were seen in both groups of recipients. Injection of cobra venom factor resulted in prolongation of cardiac xenograft survival in neonatal lambs (n=3) to 12 hr. Analysis by immunohistology showed that normal sera from neonatal and adult, but not fetal, sheep contained IgM and IgG XNA reactive with rat cells. In conclusion, rodent grafts transplanted into fetal sheep undergo HAR, likely through direct activation of the alternate pathway of C, whereas neonatal lambs acquire XNA in the very early postnatal period and reject rat hearts through activation of both the classical and alternate pathways of C. Thus, at least in some species combinations, cardiac transplantation during the early postnatal period, or even in utero, may still be subject to development of HAR.

Acute Disease↗
PubMed1978

Complement and immunoglobulin deposits in the skin of patients with atopic dermatitis.

The immunofluorescent patterns of uninvolved and involved skin biopsies from eight patients with atopic dermatitis were studied, using direct immunofluorescence techniques to identify deposits of the immunoglobulins G, A and M as well as the complement factors C1q, C3, C4, C5, factor B and properdin. Immunoglobulin deposits (mainly IgG) were found in five patients, complement deposits in three patients in the basement membrane zone. In three patients the immunofluorescence was positive for C3, in two patients for C1q, C4 and C5. Regarding the factors of the alternative pathway of the complement system, two patients showed deposits of properdin, one of factor B. The changes were not confined to the eczematous lesions, but were found in uninvolved skin too. The most prominent changes were observed in patients with severe disease.

Adolescent↗
PubMed1995

Binding to erythrocyte complement receptor type 1 of BSA/anti-BSA complexes opsonized by C4A3 or C4B1 in the presence of serum.

An in vitro model with human serum and human 0 Rh-negative erythrocytes was used for studies on preformed BSA/anti-BSA complex binding to complement receptor type 1 (CR1). The serum used was first depleted of Clq, factor D and properdin, then of C3, C4 or both and finally reconstituted with the desired proteins (serum reagent). With varying C4 concentrations and 100% C3 present, binding curves obtained for the two C4 isotypes were similar. When the serum reagent was not reconstituted with factor D and properdin there was no difference between the CR1 binding of normal serum and the partially reconstituted serum reagent, nor between the two C4 isotypes in this serum reagent. When C3 at 50% or 100% of normal concentrations was added to the serum reagent together with 100% C4A3 or C4B1, the C4B1-opsonized complexes showed more binding than the C4A3-opsonized complexes. At very low levels of C3 (< 25%) the binding could not be distinguished from the background. The results suggest that the binding of complement opsonized antigen/antibody complexes to erythrocyte CR1 is mediated mainly by C3, originating from activation of the classical pathway, and that the difference in properties between C4A and C4B does not have a major influence.

Animals↗
PubMed2006

Function-blocking antithrombospondin-1 monoclonal antibodies.

BACKGROUND: Thrombospondin-1 (TSP-1) has been implicated in many different processes based in part on inhibitory activities of anti-TSP-1 monoclonal antibodies (mAbs). OBJECTIVE: To map epitopes of 13 anti-TSP-1 mAbs to individual modules or groups of modules spanning TSP-1 and the closely related TSP-2 homolog. RESULTS: The mapping has led to assignment or reassignment of the epitopes of four mAbs, refinement of the epitopes of six mAbs, and confirmation of the epitopes of the remaining three mAbs. ESTs10, P12, and MA-II map to the N-terminal domain; 5G11, TSP127.6, and ESTs12 to the third properdin module; C6.7, HB8432, and P10 to epidermal growth factor (EGF)-like modules 1 and/or 2; and A6.1, mAb133, MA-I, and D4.6 to the calcium-binding wire module. A6.1, which recognizes a region of the wire that is identical in mouse and human TSP-1, reacts with TSP-1 from both species, and also reacts weakly with human TSP-2. Two other mouse antihuman TSP-1 mAbs, A4.1 and D4.6, also react with mouse TSP-1. CONCLUSIONS: Consideration of previous literature and mapping of epitopes of inhibitory mAbs suggest that biological activities are present throughout TSP-1, including the EGF-like modules that have not been implicated in the past. Because the epitopes for 10 of the antibodies likely are within 18 nm of one another in calcium-replete TSP-1, some of the inhibitory effects may result from steric hindrance. Such seems to be the case for mAb133, which binds the calcium-binding wire but is still able to interfere with the activation of latent TGF-beta by the properdin modules.

Amino Acid Sequence↗
PubMed1997

Complement-mediated serum sensitivity among spirochetes that cause Lyme disease.

Borrelia burgdorferi-related isolates were tested for their sensitivity to normal human serum (NHS) and their ability to activate complement. By dark-field microscopy, electron microscopy, and subsurface plating, it was shown that exposure of a Borrelia garinii isolate to 10% or more NHS resulted in immobilization, blebbing, and killing of the spirochetes. These effects were mediated by complement, since they were not seen after heat treatment of NHS, in the presence of EDTA, or in an agammaglobulinemic serum. All seven B. garinii type 5 or 6 and all four VS116/M19 strains were serum sensitive, whereas all eight Borrelia afzelii, five of eight B. garinii type 4, and three of seven B. burgdorferi sensu stricto isolates were serum resistant. The other isolates were partially serum sensitive. Four serum-sensitive B. garinii isolates had been isolated from human cerebrospinal fluid. Most likely, activation of both the alternative pathway and the classical pathway of complement was involved, since bactericidal activity was diminished in properdin-deficient sera as well as in a C1q-depleted serum and in a C4-deficient serum. Bactericidal activity could be restored when a serum lacking C1q or C4 was mixed with a properdin-deficient serum. Isolates with various genetic backgrounds were equally able to activate C3 as measured by enzyme-linked immunosorbent assay. In the presence of Mg-EGTA, C3 was activated by all isolates after exposure to > or = 10% NHS. This study shows that B. burgdorferi-related spirochetes can be either serum sensitive or serum resistant in vitro and that this characteristic is associated with their genetic background.

Borrelia burgdorferi Group↗
PubMed1987

Isolation and analysis of immune complexes from sera of patients with polymyalgia rheumatica and giant cell arteritis.

Serum samples were obtained from patients with polymyalgia rheumatica (PMR: n = 10) or giant cell arteritis (GCA; n = 7), or both. Samples were taken either before treatment or within one week of starting prednisolone. Immune complexes (IC) were concentrated by polyethylene glycol (PEG) precipitation then purified with either IgG anti-C1q-Sepharose or IgG anti-C3c-Sepharose. Complex components were separated by sodium dodecyl sulphate (SDS) gradient polyacrylamide gel electrophoresis then transferred to nitrocellulose by Western blotting. Identification of proteins was carried out using specific antisera. All the IC contained IgM (mu chain), some contained IgA (alpha chain), and IgG (gamma chain). C1r, C1s, C1q, C3, C4, and C reactive protein (CRP), where tested, were found in most but not all IC. The occurrence of properdin, factor B, alpha 2 macroglobulin (alpha 2M), factor H (beta 1H), C1 esterase inhibitor, and C4 binding protein was also investigated. Immune complexes in PMR and GCA differed from those previously characterized in rheumatoid arthritis (RA)1 purified by anti-C1q-Sepharose which contained immunoglobulins and C1q only. No properdin or factor B were detected in RA IC purified with either anti-C1q-Sepharose or anti-C3c-Sepharose.

Aged↗
PubMed1978

Immunoglobulin and complement in normal skin.

Cryostat sections of normal skin from 57 white adults were examined by direct and indirect immunofluorescence for immunoglobulins, complement factors, and transferrin. The results for basement membrane zone (BMX) were significantly different for the 11 face and 46 non-face biopsies: in the face, IgM was found in five, IgG in two, IgA in one, and C3 in none, whereas, in non-face, IgM was present in six, IgG in none, IgA in one, and C3 in five. The results for dermal vessel walls (DV) were not apparently different for face and non-face; in the 57 biopsies IgM was present in one, IgG in none, IgA in one, and C3 in one. The 11 biopsies from the face and 26 of the non-face biopsies were examined further. No IgD or C4 was identified, but one case (scalp) showed BMZ Clq, properdin, and transferrin, and in two cases (one face, one non-face) DV properdin was found. Cytoid bodies (IgM and IgA) were present in moderate numbers in one case; all other positive reactions were finely granular.

Adult↗
PubMed1991

Complement activation by cigarette smoke.

Lung disease secondary to cigarette smoking is associated with an influx of neutrophils and monocytes into the lower respiratory tract. To determine whether cigarette smoke can generate chemotactic activity, human serum was exposed to cigarette smoke and evaluated for neutrophil and monocyte chemotactic activity. Serum exposed to cigarette smoke attracted significantly greater numbers of neutrophils and monocytes compared with normal human serum exposed to air (P less than 0.01, both comparisons). The increase in chemotactic activity was partially attenuated by EDTA but not by ethylene glycol-bis(beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid (EGTA) and MgCl2 (P greater than 0.05, both comparisons), suggesting activation of the alternate complement pathway. To evaluate the capacity of cigarette smoke to activate the complement system, smoke-exposed serum was evaluated for cleavage of properdin factor B and C3 using immunoelectrophoresis and for C5a using a radioimmunoassay. Cleavage of properdin factor B and C3 was observed in the smoke-exposed serum and C5a was detected in the smoke-exposed serum (112 +/- 31 ng/ml). These data suggest that complement activation may play a role in directing the influx of neutrophils and monocytes into the lungs of cigarette smokers.

Chemotaxis, Leukocyte↗