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PubMed1975

Detection and quantitation in plasma and synovial fluid of a fragment of human C4 with alpha mobility generated during the activation of the complement system.

A newly identified fragment of human C4 was detected, using a particular antiserum, in human serum after activation by heat-aggregated immunoglobulins, but not after activation of the complement alternative pathway. This fragment was shown to have a sedimentation velocity of approximately 2.5S, to be heat stable, and to exhibit alpha mobility in immunoelectrophoresis. This C4alpha mobility fragment was not generated in human C4 deficient serum but was generated in human C2 deficient serum after incubation with heat-aggregated immunoglobulin. After precipitation of native C4 and its higher molecular weight fragments from serum by polyethylene glycol, it was possible to quantitate the lower molecular weight C4 alpha mobility fragment by radial immunodiffusion. In kinetic experiments, it was shown that the C4alpha mobility fragment was generated after some delay when compared to the disappearance of C4 hemolytic activity. Quantitation of the C4alpha mobility fragment may be of further use in human diseases for the evaluation of the catabolism of C4: joint fluids of patients suffering from rheumatoid arthritis contained high levels of the C4alpha mobility fragment, and low concentrations were found in patients with degenerative joint disease.

Animals↗
PubMed1988

Combined homozygous factor H and heterozygous C2 deficiency in an Italian family.

Three of four children in a family have homozygous (less than 1% of normal) deficiency of factor H of the complement system and both parents, who are first cousins, are heterozygous for the same defect. The father and two of the H-deficient siblings also have a partial C2 deficiency. One of the children with combined deficiencies is affected by systemic lupus erythematosus with nephritis. No increased susceptibility to infections has been observed in the family. H deficiency is inherited in an autosomal codominant manner and is independently transmitted from C2 deficiency and HLA haplotypes. In the homozygous state it is associated with very low serum concentrations of B and C3, barely demonstrable as activated molecules. C5 is greatly reduced (less than 5%). Also, properdin and C6-9 are decreased. The findings in this family demonstrate that the occurrence of systemic lupus erythematosus in one of the children affected by a combined deficiency of factor H and C2 raises the question whether this pathology is related to the complete factor H or to the heterozygous C2 deficiency. Complete H deficiency is not necessarily accompanied by overt illness.

Child↗
PubMed1992

Activation of the classical complement pathway by mannose-binding protein in association with a novel C1s-like serine protease.

Serum mannose-binding protein (MBP) is a C-type lectin that binds to terminal mannose and N-acetylglucosamine moieties present on surfaces of certain pathogens and activates the classical complement pathway. In the present study, we describe the mechanism underlying the activation triggered by MBP. The human serum MBP fraction was obtained by sequential affinity chromatography on mannan-Sepharose, anti-IgM-Sepharose and anti-MBP-Sepharose in the presence of calcium ions. This fraction contained a C1s-like serine protease as assessed by C4 consumption. The C1s-like serine protease, designated MBP-associated serine protease (MASP), was separated from MBP by rechromatography on anti-MBP-Sepharose in the presence of ethylenediaminetetraacetic acid. MASP exhibited both C4- and C2-consuming activities. The molecular mass of MASP was estimated to be 83 kD with two polypeptides of heavy (66 kD) and light (L) (31 kD) chains linked by disulfide bonds. The serine residue responsible for protease activity is located on the L chain. Reconstitution experiments using MASP and MBP revealed that combination of the two components restores C4- and C2-activating capacity on mannan. Based on analyses of molecular size, antigenicity, and 11 NH2-terminal amino acid sequences of the L chain, we conclude that MASP is a novel protein different from C1r or C1s. Our findings are not in accord with a proposed mechanism by which MBP utilizes the C1r2-C1s2 complex to initiate the classical complement pathway.

Amino Acid Sequence↗
PubMed1979

In vitro activation of complement by isolated human heart subcellular membranes.

Activation of human complement (C) occurred in vitro when mitochondrial membranes isolated from normal human heart tissue were incubated with normal human serum. This activation, as measured by C3 depletion, was not completely inhibited by blocking classical pathway activity in serum treated with EGTA, in C2-deficient serum, or in C1-depleted serum, nor in serum heated at 50 degrees C for 30 min to block the alternative pathway, but it could be prevented by blocking the classical and the alternative pathway simultaneously with EDTA, or by treating heated serum (50 degrees C. 30 min) with EGTA. Factor B was converted in normal serum as well as in EGTA-treated serum, but not in EDTA-treated serum. Mitochondrial membranes had no direct enzymatic or other activity that could inactivate functionally or highly purified C4 or C3, but the membranes could bind and activate C1 either in serum or in functionally pure C1 preparations. C4 also bound to the mitochondrial membranes only in the presence of C1. These data suggest that the activation of C by heart subcellular membranes involved both the classical and the alternative pathways, that the mitochondrial membrane preparations were capable of forming stabel complexes with C1 and C4, but not C3, and that the mitochondrial membrane preparations did not contain enzymes or have inherent properties that could directly cause C3 conversion.

Adsorption↗
PubMed1982

Bactericidal activity of serum for Klebsiella rhinoscleromatis: studies on serum from a patient with rhinoscleroma and sera deficient in antibody or complement.

The in-vitro bactericidal effect of serum for Klebsiella rhinoscleromatis was tested. Experiments with C2-deficient and hypogammaglobulinaemic human sera suggested that killing depended on activation of the classical complement pathway, although the alternative pathway probably amplified the effect. Serum from a patient with active rhinoscleroma, and another cured of the disease, showed normal killing.

Agammaglobulinemia↗
PubMed1975

Complement-mediated bactericidal system: evidence for a new pathway of complement action.

The early components of human complement (C1, C4, and C2) plus certain serum euglobulins will kill pathogenic strains of Shigella sonnei. Serum from patients with hereditary C3 deficiencies and specific antiserums to C3, C5, and C6 were utilized to demonstrate the absence of requirements for late-acting complement components in this unusual bactericidal system.

Antibodies, Bacterial↗
PubMed1996

Complement activation by 3-mercapto-1,2-propanediol immobilized on gold surfaces.

Thiol-modified surfaces are chemically well defined and suited for surface biological model experiments and biomaterials research. 3-Mercapto-1,2-propanediol (mercaptoglycerol, MG), immobilized on gold, spontaneously binds immunoglobulins from human serum and activates the complement system. The surface-bound complement factors were detected by ellipsometry-antibody techniques. The overall complement activation was subsequently corroborated independently with enzyme immunosorbent assay (EIA) and sheep and chicken erythrocyte haemolytic complement techniques. EIA experiments indicated elevated levels of C4d, but no significant increase of factor Bb was evident in the test serum from the MG system. The haemolytic assays show that MG surfaces consume complement factors from both pathways. Ellipsometry revealed that immunoglobulin G (IgG) and complement factor 1q (C1q) are transiently antibody detectable on MG after exposure to whole serum by the use of antibody techniques. Complement factor 3 (C3), C2, C4 and properdin could be detected on the surface, but not factors H and B. The total adsorbed mass and particularly C3 antibody deposition were suppressed by using EGTA-Mg2+ serum. The results suggest that MG surfaces initially activate complement via the classical pathway. Other IgG binding surfaces also appear to behave in a similar manner.

Animals↗
PubMed1982

Antibody-independent classical pathway-mediated opsonophagocytosis of type Ia, group B streptococcus.

The opsonophagocytic requirements of human sera containing endogenous complement for a variety of type Ia, and group B streptococcal strains were defined. Significant reduction (>==90%) in colony-forming units was noted after a 40-min incubation for the highly encapsulated, mouse-passed prototype strain 090 by sera containing moderate to high concentrations of antibody to type Ia polysaccharide (mean, 16.5 mug/ml), whereas bacterial growth occurred in 25 sera with low levels of specific antibody (mean, 2.1 mug/ml). This absolute requirement for a critical amount of specific antibody in promoting opsonophagocytic killing of strain 090 was not found when 18 fresh clinical type Ia isolates were tested. In antibody-deficient and agammaglobulinemic sera, respectively, mean reductions in colony-forming units of 94 and 95% were seen for fresh clinical isolates, whereas strain 090 was not killed by polymorphonuclear leukocytes in the presence of these sera. All strains required a considerable amount of specific antibody for alternative pathway-mediated opsonophagocytosis. That opsonophagocytic killing of clinical type Ia isolates was mediated by the classical pathway in a nonantibody-dependent fashion was shown when MgEGTA chelation of agammaglobulinemic serum or use of serum deficient in C2 resulted in bacterial growth. The addition of C2 to C2-deficient serum restored bactericidal activity of this serum. These experiments indicate that substances other than the exposed surface of the type Ia capsular polysaccharide initiate classical pathway-mediated opsonophagocytosis of clinical isolates of type Ia, group B streptococci by human sera in the absence of immunoglobulin. Perhaps, a deficiency in classical complement pathway function is critical to the susceptibility of neonates to type Ia, group B streptococcal disease.

Animals↗
PubMed1994

In vitro activation of the classical pathway of complement by a streptococcal lipoteichoic acid.

The purpose of this study was to find whether a glycerolphosphate-containing lipoteichoic acid prepared from Streptococcus sobrinus OMZ 176 cells would activate the classical pathway of complement while in solution. Reference activators were lipopolysaccharide from Escherichia coli 0111:B4 and heat-aggregated immunoglobulin G. Serum samples were taken from healthy students. Analysis through crossed immunoelectrophoresis showed that lipoteichoic acid caused an almost complete dissociation of the C1qrs macromolecule. All activators decreased the area of and slowed the electrophoretic mobility of the C4 protein peaks, with lipoteichoic acid causing the most pronounced alterations. Electroimmunoassays showed that lipoteichoic acid separately, yielded detectable amounts of free C1r2s2 subunits; it also generated significantly more trimer complexes between C1r, C1s and C1 inhibitor (C1INH) than did the other two activators. Lipoteichoic acid was, however, a comparatively weak inducer of tetramer C1INH-C1r-C1s-C1INH complexes. Analysis through Western blotting showed that all activators accelerated consumption of C1r, induced complex formations between C1INH and C1s and produced cleavage products of C2. Altogether, the immunochemical analysis gave clear evidence of classical pathway activation by lipoteichoic acid, but its activation profile differed from those seen with lipopolysaccharide and aggregated immunoglobulin G.

Analysis of Variance↗
PubMed1985

Human histocompatibility leukocyte antigen (HLA) haplotype frequencies estimated from the data on HLA class I, II, and III antigens in 111 Japanese narcoleptics.

In order to deduce the predominant haplotypes in Japanese narcoleptics, we have studied a total of 111 Japanese patients with narcolepsy and six multiple-case families for HLA class I and class II antigens, and for class III HLA-linked complement markers. In Japanese narcoleptics, the most frequent haplotypes were B35-DR2, B15-DR2, and B51-DR2. These haplotypes were rare in normal Japanese population. In contrast, the most frequent haplotype of HLA-DR2 in normal Japanese, A24-C blank-Bw52-C4A*2 B*Q0-BF *S-C2*C-DR2-DQw1, had a decreased frequency to one-third of the normal controls. Haplotypes B35-DR2, B15-DR2, and B51-DR2, which were more frequent among Japanese narcoleptics, were different from the haplotype found more frequently among Caucasoid narcoleptics, A3-Cw7-B7-DR2-DQw1. Haplotype analysis on six families showed that B35-DR2 and other rare haplotypes in normal Japanese were associated with narcolepsy. There were four cases without any signs of narcolepsy among 19 subjects with the disease susceptibility haplotypes. This finding suggests an incomplete penetrance of hypersomnia. Haplotype analysis of family members was also useful for the early detection of the high risk children to narcolepsy.

Complement C2↗
PubMed1981

Alternative complement pathway-dependent ingestion of fluolite particles by human granulocytes.

Fluorescent particles (Fluolite) with an average size of 0.1 micrometers were ingested by human granulocytes after incubation in fresh normal human serum (NHS). Ingestion was assessed by visual counting in a fluorescent microscope of cells containing particles. Ingestion required fresh normal serum and did not occur when serum was heated for 30 min at 50 degrees C or in the presence of ethylenediaminetetraacetic acid (EDTA). It did not occur in serum genetically deficient in C3b inactivator or in C3. Phagocytic activity was restored to C3-deficient serum by purified human C3 and to heat inactivated serum by purified factor B. Opsonic activity was present in NHS containing 5 mM Mg++ and 10 mM ethyleneglycoltetraacetic acid (EGTA) and in human serum genetically deficient in human C components C2 and C5. Agammaglobulinemic sera had normal opsonic activity. Opsonization of particles in this system is mediated through the alternative pathway of C activation, and its measurement serves as a simple quantitative functional assay for this system.

Complement Activation↗
PubMed1981

Screening for deficiencies in the classical and alternative pathways of complement by hemolysis in gel.

Two assays based on hemolysis in gel were assessed for screening complement (C) component deficiencies. In one assay sensitized sheep erythrocyte (EA) were incorporated in agarose gel containing Ca2+ and Mg2+, in the other guinea pig erythrocytes (GpE) were used in the presence of Mg2+and EGTA. With few exceptions, fresh samples from healthy individuals produced homogeneous areas of complete hemolysis in both assays. Clearly aberrant patterns were observed in approximately 4% of healthy blood donors. Sera from patients having complete deficiencies of Clq, C2 or C4 produced clear lysis of GpE only, whereas in sera lacking C3 or C8 lysis was grossly impaired in both assays. Properdin deficient serum produced very slight lysis of GpE but normal lysis of EA. Reconstitution of these C-deficient sera gave normal lysis. Together, the two assays supplement immunochemical C3 and C4 determinations for screening out C disorders.

Animals↗
PubMed1994

Regulation of synthesis of complement protein C4 in human fibroblasts: cell- and gene-specific effects of cytokines and lipopolysaccharide.

Synthesis and secretion of the class III major histocompatibility complex (MHC) gene product, C4, were detected in human skin fibroblasts by metabolic labelling, immunoprecipitation and SDS-PAGE analysis. Pro-C4 (approximately 185,000 MW) was present in intracellular lysates, and the mature protein was present in extracellular media, with three bands of approximately 93,000, 75,000 and 33,000 MW, corresponding to the alpha, beta and gamma chains, respectively. C4 expression was increased in a dose-dependent manner by interferon-gamma (IFN-gamma), but was unaffected by interleukin-1 beta (IL-1 beta), IL-6 and tumor necrosis factor-alpha (TNF-alpha) alone, each of which augmented the expression of factor B, C3 and other complement proteins synthesized in fibroblasts. Simultaneous incubation of fibroblasts with IFN-gamma and TNF resulted in a synergistic increase in C4 synthesis. RNA blot analyses indicated that regulation of C4 synthesis by IFN-gamma and the combination of IFN-gamma and TNF was mediated primarily at a pretranslational level. Lipopolysaccharide (LPS) had no effect on C4 or HLA-DR synthesis in fibroblasts, either constitutive or IFN-gamma-regulated. These results are in contrast to the effects of LPS in monocytes, where LPS decreased constitutive synthesis and counter-regulated the IFN-gamma-enhanced expression of both C4 and HLA-DR. C2 expression in fibroblasts was also increased primarily by IFN-gamma. However, C2 synthesis was increased by LPS, 1L-1 and TNF, although to a lesser extent than the increase in synthesis of factor B stimulated by these mediators. These results show that up-regulation by IFN-gamma is a common feature of C2 and C4 expression in human cells that constitutively synthesize these proteins. In contrast, regulation of MHC class III and class II genes by LPS, TNF, IL-1, and IL-6 is cell- and gene-specific.

Blotting, Northern↗
PubMed1982

Complement-induced solubilization of C-reactive protein-pneumococcal C-polysaccharide precipitates: evidence for covalent binding of complement proteins to C-reactive protein and to pneumococcal C-polysaccharide.

Insoluble precipitates between C-reactive protein and pneumococcal C-polysaccharide were solubilized by fresh but not heat-inactivated human serum. Solubilization was dependent on the C-reactive protein to C-polysaccharide ratio and the serum concentration and proceeded optimally at 37 degrees C. On 12 to 30% sucrose density gradients solubilized complexes sedimented as a broad peak between the 7S region and the bottom of the tube. In C2-deficient human serum, solubilization was delayed by 30 min and then proceeded at a slow rate. Immunoprecipitation experiments indicated that C3, C4, C5, and to a lesser extent C1q were deposited on solubilized complexes. After dissociating solubilized complexes with EDTA, a considerable percentage of C-polysaccharide coprecipitated with C3, C4, and C5, whereas C-reactive protein coprecipitated with only C3. SDS-PAGE analysis of solubilized precipitates indicated the formation of covalent complexes between fragments of C3 and both C-polysaccharide and C-reactive protein.

C-Reactive Protein↗
PubMed1994

Inhibition of complement activation by natural sulfated polysaccharides (fucans) from brown seaweed.

In the present study, we demonstrate that natural sulfated polysaccharides (fucans) isolated from brown seaweed are potent inhibitors of human complement activation. A fucan fraction of chromatographic molecular weight 22,600, termed BS8, was found to inhibit classical and alternative pathway activation in whole serum in a dose-dependent fashion. Fucan BS8 inhibited formation of the classical pathway C3 convertase by interfering with C1 activation or by inhibiting C4 cleavage and the interaction between C4b and C2. The fucan also inhibited formation/function of the alternative pathway C3 convertase by suppressing the binding of B to C3b and by interfering with the stabilizing function of Properdin. The inhibitory effect of fucans on formation of the C3 convertases was dependent on the molecular weight of the polysaccharide for compounds of chromatographic molecular weight below 16,600. Fucan had no effect on the function of the terminal complex. Since fucans were more efficient than heparin in inhibiting activation of the classical pathway in whole serum and exhibited a lesser specific anticoagulant activity on a molar basis, our results suggest that these natural sulfated polysaccharides have a potential for use as anti-complementary and anti-inflammatory agents.

Complement Activation↗
PubMed1982

Effect of plicatic acid on human serum complement includes interference with C1 inhibitor function.

In an earlier study, we presented evidence that plicatic acid (PA) activated C in normal human serum (NHS) by an immunoglobulin-independent mechanism that did not involve factor B of the alternative pathway and that required Ca++ for initiation. The present paper further verifies that PA acts through the classical pathway. In PA-treated NHS, titers of C1, C4, C3, and C5 decreased after incubation at 37 degrees C, but in C2-deficient serum, only the titers of C1 and C4 were decreased after identical PA treatment. Activation of purified precursor C1 did not occur when it was incubated with PA at concentrations that would have produced C1 consumption in serum. Thus, PA added to serum initiates activation of the classical pathway, but is incapable of activating C1 directly. PA added to a mixture of native C4 and activated C1s did not alter the kinetics or the extent of C4 inactivation by the C1s. However, when mixtures of C4, C1s, and C1-In were incubated with PA, the ability of the inhibitor to inactivate the C1s was markedly reduced. These data indicate that the mechanism by which PA activates C in serum may involve interference with the normal regulatory mechanism that controls C1 activity.

Angioedema↗
PubMed1981

Hemolytic complement and its components in Syrian hamsters: a study of five strains uninfected and infected with Brugia pahangi.

Complement profiles were tested in outbred (LVG) Syrian hamsters (Mesocricetus auratus) and compared to the MHA, LHC, PD4, and CB inbred strains. The total C and C component concentrations in the sera varied among the strains and were in the following ranges in untreated animals (in CH50 units per ml): total C, 140-260 (undetectable in PD4 and CB); Cl, 14,000-25,000; C2, 200-800 (except PD 4 and CB); C3, 40,000 and 80,000; C4, 2,000-2,800 (except PD4 and CB); C4, 40,000-80,000; C6, 3,600-6,000 (undetectable in PD4 and CB); C7, 50,000-350,000; C8, 10,000-30,000; C9, 30,000-60,000. The PD4 and CB strains had undetectable total C and C6, and their exact C2 and C4 levels could not be determined, but were lower than in the other strains. The MHA strain had the highest total C levels, but had significantly lower (1/3 or less) C7 levels than the other strains of hamsters. Infection of hamsters with the filarid nematode Brugia pahangi for four to five months produced moderate decreases in the total C and C3 levels, but varied changes in other C components. Six infected and three uninfected animals died during the experiment from spontaneous enteritis and weight loss.

Animals↗
PubMed1987

In vitro effects of organic solvents on immunity indicators in serum.

Serum treatment in vitro with organic solvents (chloroform, ether, toluene) failed to produce an effect on immunoglobulin levels and activity. After chloroform and ether treatment, no complement activity could be determined, with chloroform-treated serum beginning to express anticomplement activity against autologous, allogenic and xenogenic sera. The classical pathway of complement activation (C1, C4, C2, C3) was primarily inhibited, whereas the alternative pathway remained unaffected. Chloroform-treated sera exhibited significantly declined levels of C1-INH, C3 and C4 as well as of circulating immune complexes. Toluene did not influence any of the parameters tested, while ether blocked complement activity without affecting either the concentration or activity of the other components under investigation. The obtained findings are discussed from the aspect of organic solvent applications in preparing immune products and determining immunity indicators in the serum or other biological fluids.

Antibodies↗