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PubMed1985

Susceptibility of Campylobacter isolates to the bactericidal activity of human serum.

Although Campylobacter jejuni and related thermophilic organisms are more common human pathogens than are Campylobacter fetus, most bloodstream or systemic isolates are C. fetus. To understand the pathophysiology related to this observation, the authors studied susceptibility to the bactericidal activity of normal human serum of Campylobacter coli, C. jejuni, and C. fetus isolates from feces and blood. In standardized assays, 10 of 15 C. jejuni and related isolates showed 90% kill (mean, 90.6% +/- 5.9); under more stringent conditions, the relatively resistant strains were completely killed. In contrast, all C. fetus strains were highly serum resistant under both standard and stringent conditions. Killing of C. jejuni was ablated by heating serum to 56 C but restored by addition of complement. Both classical and alternative complement pathways may contribute to killing, and adsorption studies demonstrated antibody dependence. Serum resistance may permit systemic infection by C. fetus, whereas complement- and antibody-mediated serum sensitivity of C. jejuni may account for the relative infrequency of systemic invasion.

Antibodies, Bacterial↗
PubMed1993

Opsonic requirements of Helicobacter pylori.

The opsonic requirements of Helicobacter pylori were investigated in a series of experiments with human polymorphonuclear leucocytes (PMNL). Pre-incubation of H. pylori with pooled normal human serum (NHS) in concentrations of 5-20% significantly increased the uptake of radiolabelled bacteria by PMNL. Treatment of the bacteria with NHS 30% caused the release of radiolabel and this effect was abolished by heating serum to 56 degrees C, suggesting that H. pylori is serum-sensitive and that complement is involved. Opsonisation of H. pylori with NHS concentrations of 10-30% significantly increased PMNL chemiluminescence. Removal of specific antibody had no effect. Removal of either the classical or alternative complement pathways produced no significant change in PMNL chemiluminescence, indicating that either pathway is sufficient for opsonisation on its own. The results confirm that complement is the most efficient opsonin for H. pylori.

Analysis of Variance↗
PubMed1986

Pneumococcal intracellular killing is abolished by polysaccharide despite serum complement activity.

Normal human serum absorbed at 0 degrees C with pneumococcal serotype 1, 12, or 25 lost the ability to support polymorphonuclear leukocyte intracellular killing of some pneumococcal serotypes even if immunoglobulin was provided. The absorbed serum contained no organisms but had residual polysaccharide when measured by counterimmunoelectrophoresis against type-specific antisera. The influence of pneumococcal polysaccharide (PPS) on serum support of intracellular polymorphonuclear leukocyte killing was evaluated. Normal human serum was mixed with PPS serotype 1, 12, or 25 at 0 degrees C for up to 120 min and then used as the opsonic source in standard phagocytic killing assays with serotype 1, 12, or 25. Immediately after mixing, each serum combined with PPS serotype 1, 12, or 25 supported killing of all serotypes tested. With increasing time at 0 degrees C with serotype 1 PPS, serum exhibited a marked progressive decline in killing of serotype 25, a similar but less marked impairment in killing of serotype 12, and essentially no impairment for serotype 1. Serum treated with type 25 PPS did not support killing of type 25, but allowed normal killing of types 1 and 12. Incubation with type 12 PPS impaired opsonization of types 12 and 25, but not 1. Addition of PPS-specific antisera did not restore killing. Residual serum hemolytic activity of classic and alternative complement pathways was not reduced below opsonizing levels after 120 min at 0 degrees C. Furthermore, PPS treatment of normal human serum did not alter the attachment or ingestion of 14C-labeled pneumococci by polymorphonuclear leukocytes. Some serotypes of PPS reacted slowly with serum at 0 degrees C, diminishing its ability to support intracellular killing of pneumococci despite serum hemolytic complement activity. Phagocytosis was not inhibited. Specific antibody did not overcome inactivation. Different requirements for the inactivated factor among serotypes may be a characteristic related to organism virulence.

Blood Bactericidal Activity↗
PubMed2025

Multi-ancestry genome-wide meta-analysis of 56,241 individuals identifies known and novel cross-population and ancestry-specific associations as novel risk loci for Alzheimer's disease.

BACKGROUND: Limited ancestral diversity has impaired our ability to detect risk variants more prevalent in ancestry groups of predominantly non-European ancestral background in genome-wide association studies (GWAS). We construct and analyze a multi-ancestry GWAS dataset in the Alzheimer's Disease Genetics Consortium (ADGC) to test for novel shared and population-specific late-onset Alzheimer's disease (LOAD) susceptibility loci and evaluate underlying genetic architecture in 37,382 non-Hispanic White (NHW), 6728 African American, 8899 Hispanic (HIS), and 3232 East Asian individuals, performing within ancestry fixed-effects meta-analysis followed by a cross-ancestry random-effects meta-analysis. RESULTS: We identify 13 loci with cross-population associations including known loci at/near CR1, BIN1, TREM2, CD2AP, PTK2B, CLU, SHARPIN, MS4A6A, PICALM, ABCA7, APOE, and two novel loci not previously reported at 11p12 (LRRC4C) and 12q24.13 (LHX5-AS1). We additionally identify three population-specific loci with genome-wide significance at/near PTPRK and GRB14 in HIS and KIAA0825 in NHW. Pathway analysis implicates multiple amyloid regulation pathways and the classical complement pathway. Genes at/near our novel loci have known roles in neuronal development (LRRC4C, LHX5-AS1, and PTPRK) and insulin receptor activity regulation (GRB14). CONCLUSIONS: Using cross-population GWAS meta-analyses, we identify novel LOAD susceptibility loci in/near LRRC4C and LHX5-AS1, both with known roles in neuronal development, as well as several novel population-unique loci. Reflecting the power of diverse ancestry in GWAS, we detect the SHARPIN locus with only 13.7% of the sample size of the NHW GWAS study (n = 409,589) in which this locus was first observed. Continued expansion into larger multi-ancestry studies will provide even more power for further elucidating the genomics of late-onset Alzheimer's disease.

Humans↗
PubMed2000

Bactericidal activity of a monoclonal antibody against a recombinant 40-kDa outer membrane protein of Porphyromonas gingivalis.

BACKGROUND: We have cloned the gene for a 40-kDa outer membrane protein (40-kDa OMP) from Porphyromonas gingivalis 381. The recombinant (r)40-kDa OMP has become the subject of considerable interest because of its potential role in the development of a vaccine useful for passive immunization. To develop such a vaccine, it is essential to fully understand the functions of anti-r40-kDa OMP antibody in the host defense against P. gingivalis. To that end, we developed a panel of monoclonal antibodies by immunizing mice with purified r40-kDa OMP. The objective of this study was to determine the bactericidal activity on P. gingivalis by the IgG1 monoclonal antibody Pg-ompA2. METHODS: Bacterial growth measurement, a complement-mediated anti-P. gingivalis assay based on [3H]thymidine uptake, and a 14C-release assay were performed to test the bactericidal activity of Pg-ompA2 to P. gingivalis. RESULTS: In the presence of complement, Pg-ompA2 was lethal to P. gingivalis 381 as well as to the more virulent P. gingivalis strains, including ATCC 53977 and W83. Using component-deficient complement, we determined that Pg-ompA2 killed P. gingivalis by activating both the classical and alternative complement pathways. CONCLUSIONS: Pg-ompA2 has an in vitro complement-mediated bactericidal activity to P. gingivalis. Pg-ompA2 may contribute to the development of a local immunotherapy that can be applied in the gingival crevice of a patient with P. gingivalis-related periodontitis, or be a vaccine candidate.

Animals↗
PubMed1989

Characterization of complement activity in turkeys: evidence for classical and alternative complement pathways.

Complement activity in turkey serum was examined by using inhibitors or activators of mammalian complement. Hemolytic test systems using sheep red blood cells sensitized with specific antibody (SSRBC) and horse red blood cells (HRBC) were developed to measure residual complement activity of turkey sera treated with the various inhibitors or activators. Lysis of SSRBC was blocked by treatment with 6-mM EDTA, 10-mM ethylene glycol-bis-beta aminoethylether N,N,N',N' tetraacetic acid (EGTA), and carrageenan. In contrast, lysis of HRBC was blocked by 6-mM EDTA, but not by 10-mM EGTA or carrageenan. Addition of magnesium to EGTA-chelated serum facilitated the lysis of HRBC but not the lysis of SSRBC. Treatment of serum with zymosan at 1 mg/mL and inulin at 5 mg/mL depleted hemolytic activity against both SSRBC and HRBC, suggesting depletion of components common to both pathways. Differences in the hemolytic activities of sera against SSRBC and HRBC after treatment with the various complement inhibitors and activators demonstrate the presence of two complement pathways in turkeys.

Animals↗
PubMed1979

Consumption of C3 via the classical and alternative complement pathways by sera and synovial fluids from patients with rheumatoid arthritis.

Five sera and four synovial fluids from patients with rheumatoid arthritis were found to contain substances which consumed hemolytic C3 in normal human serum (NHS) and in normal guinea pig serum (NGPS). These fluids were then tested for ability to activate the alternative pathway by incubating them with NHS containing MgEGTA and C4 deficient GPS. All sera and two synovial fluids depleted C3 in these reagents, indicating direct activation by the alternative pathway. Density gradient ultracentrifugation demonstrated C3 fixing activity in some specimens in the greater than 19s regions. These substances may also activate complement similarly in vivo and participate in the development of inflammatory processes associated with this disease.

Adult↗
PubMed1989

Antibody complement-dependent bacteriolysis in experimentally induced pasteurellosis in mice.

Affinity-purified bovine immunoglobulin isotypes were bacteriolytic for Pasteurella haemolytica biotype A, serotype 1 (PHA-1). This bacteriolysis was specific and complement-dependent. The IgM and IgG1 were the most active isotypes in the classic complement cascade. These isotypes also induced bacteriolysis through the alternative complement cascade. The comparative bacteriolytic activities of IgG1 and IgM were equal within each cascade; however, the bacteriolytic activities of IgG1 and IgM were lower in the alternative cascade than in the classical cascade. The IgG2 was more bacteriolytic than IgA in the classic and alternative complement pathways. Bovine immunoglobulins passively protected C57BL/6 mice from experimentally induced pasteurellosis. There were no major differences in the protection among hyperimmune sera, purified IgM, or purified IgG. Mice were protected from PHA-1 by approximately 1.9 micrograms of IgG and 1.2 or 0.1 micrograms of IgM. Elimination of murine complement with cobra venom factor 3 reduced PHA-1 clearance in passively immunized C57BL/6 mice. The protective effect of IgM mediated resistance was highly dependent on an intact complement system. The intact complement cascade was associated with enhanced clearance of PHA-1 from the liver. Although PHA-1 was susceptible to antibody complement-mediated bacteriolysis in vitro, the dependence on an intact complement cascade was not absolute in experimentally induced murine septicemic pasteurellosis.

Animals↗
PubMed1997

Involvement of both the classical and alternate pathways of complement in an ex vivo model of xenograft rejection.

BACKGROUND: It is now generally accepted that complement activation is critical for the hyperacute rejection of xenografts. Activation of the classical pathway as the result of the interaction of xenoreactive IgM xenoantibodies with the vascular endothelium has been observed in all species combinations examined to date. A number of studies using a variety of species combinations have also implicated alternate pathway involvement; however, these studies do not enable a conclusion to be drawn as to whether the alternate pathway can be activated in the complete absence of classical pathway activation. METHODS: In this study, human plasma was depleted of both Clq and factor D and then reconstituted with purified Clq or factor D to restore the classical and alternate complement pathways, respectively. The ability of these modified plasmas to prosecute hyperacute rejection was then examined using an ex vivo isolated mouse heart perfusion model based on the Langendorff system. RESULTS AND CONCLUSIONS: In the mouse to human species combination, both the classical and alternate pathways of complement are independently capable of initiating complement activation and mediating xenograft rejection.

Animals↗
PubMed1984

Complement inhibitory and anticoagulant activities of fractionated heparins.

Almost monodisperse heparin fractions (Mw/Mn less than 1.1) were obtained by gel filtration of a commercial heparin. These fractions were assayed for anticoagulant activity (thrombin times and APTT), chromogenic anti-factor Xa activity, inhibitory activity for the human classical complement pathway, carboxyl group content and total sulfate content. Linear relationships were observed between the molecular weight of the heparin fractions and the anti-coagulant activities as determined by thrombin time- and APTT-assay and the classical complement pathway inhibitory activity. On the other hand a hyperbolic-like relationship was observed between the molecular weight of the heparin fractions and the chromogenic anti-factor Xa activity. The heparin fractions did not show significant differences with respect to the carboxyl group and total sulfate content. Low- and high affinity heparin fractions were obtained by affinity chromatography using immobilized AT III. High- and low-affinity fractions greatly differed not only with respect to their APTT activity, but also where their complement-inhibitory activities were concerned. The latter in contrast to literature data available. These differences could not be explained by the observed differences in molecular weight of high and low affinity heparin respectively.

Animals↗
PubMed1992

Inhibition of the classical activation pathway of complement-mediated lysis by monoclonal antibodies to complement components C3c and C3d.

Eight epitope-mapped monoclonal antibodies (MoAbs) to complement component C3d and five to complement component C3c were investigated to determine whether they could inhibit the classical activation pathway of complement-mediated lysis (CML) by using blood group AB red cells sensitized by A or B MoAbs. Three IgM C3d MoAbs and one IgG1 C3c MoAb were able to inhibit CML in a dose-dependent manner. In the presence of excess complement, no inhibition was observed. The greatest inhibition was observed with two high-affinity IgM antibodies that were specific for epitope 1 on the C3d component. Some inhibition was observed with a high-affinity IgM antibody specific for epitope 3 of the C3d component and also with a lower-affinity IgG antibody specific for epitope 1 of the C3c component. The results indicate that some complement MoAbs have the capacity to distinguish between conformationally and/or functionally different forms of red cell-bound C3.

Antibodies, Monoclonal↗
PubMed1992

The role of complement in the host's defense against Haemophilus influenzae.

In vitro studies have shown that Haemophilus influenzae type b (Hib) can activate both the classical and alternative pathways of complement and generate complement-dependent opsonic and bactericidal activities. In vivo studies and observations in complement-deficient patients have established the biologic significance of complement in the host's defense against H. influenzae. The complement system plays a significant role in the host's defense against Hib and against other encapsulated and unencapsulated H. influenzae, mainly by enhancing clearance from the bloodstream through its action as an opsonin in both nonimmune and immune hosts. Patients with genetically determined deficiencies of C3 or of the complement components involved in C3 activation have an increased susceptibility to H. influenzae. More recently, a relatively common deficiency of one isotype of C4 (C4B) has been shown to be associated with invasive Hib disease, suggesting that defects in complement-mediated host defense may be more common in systemic Hib infections than previously appreciated.

Animals↗
PubMed1983

Serum immunoglobulin and complement alterations in interstitial cystitis.

Sera from 41 patients with interstitial cystitis were tested for immunoglobulins (IgA, G, M), complement components (C1q, C3, C4) and for C1-esterase inhibitor. There was a statistically highly significant depletion of the serum levels of complement component C4 (p less than 0.001) and immunoglobulin G was markedly elevated (p less than 0.001). Our results suggest the classical pathway activation of the complement system and support the possibility that a chronic local immunological process is involved in the pathogenesis of the disease.

Complement Activating Enzymes↗
PubMed1985

Development of bactericidal antibody during Branhamella catarrhalis infection.

The recent observation that Branhamella catarrhalis may cause a variety of infections in humans has stimulated interest in human host defenses against this organism. We encountered 21 patients with B. catarrhalis infection: seven with pneumonia, 13 with a purulent exacerbation of chronic bronchitis, and one with purulent sinusitis. Normal human serum (NHS) demonstrated no bactericidal activity against 20 of the 21 isolates. In contrast, 7 of 19 acute and 18 of 20 convalescent sera demonstrated significant bactericidal effects against the corresponding B. catarrhalis isolate. Heating convalescent sera to 56 C for 30 min abolished bactericidal activity. This activity was restored by NHS but not by complement-rich guinea pig serum. Selective blockage of the classic complement pathway eliminated bactericidal activity, whereas selective blockage of the alternative pathway did not. IgG isolated from convalescent serum plus NHS was bactericidal for the corresponding B. catarrhalis isolate. These results suggest that most patients with pulmonary infections due to B. catarrhalis develop a convalescent IgG antibody response that mediates serum bactericidal activity by the classic complement pathway.

Acute Disease↗
PubMed1993

Enhanced neutralization of feline immunodeficiency virus by complement viral lysis.

The ability of complement to inactivate feline immunodeficiency virus (FIV) was examined. Treatment of virus with complement plus sub-neutralizing titers of antiserum resulted in a significant reduction in the virus titer compared with treatment of the virus with complement or antibody alone. One of the mechanisms by which cat complement inactivates FIV was shown to be by viral lysis as determined by a reverse transcriptase release assay. Kinetic studies revealed that viral lysis is initiated soon after the addition of complement to a mixture of virus and antiserum. Treatment of FIV with normal non-complement-inactivated human serum resulted in virus inactivation and release of viral RT in the absence of specific antiserum. It appears that FIV activates complement directly through the classical pathway and that integrity of the membrane attack components is a requirement for FIV lysis by human serum. The vulnerability of two distinct isolates of FIV to complement lysis was compared using complement from different species. Oradell isolate was more sensitive to complement lysis than the Petaluma isolate as assessed by reverse transcriptase release. It appears that factors intrinsic to the virus isolate may influence the amplitude of complement-dependent viral lysis.

Animals↗
PubMed1985

Inhibition of C3 deposition on solid-phase bound immune complexes by lactoferrin.

In the study described here, the effect of human tears and purified lactoferrin was investigated on the deposition of complement components on solid-phase bound immune complexes. After incubating immune complexes with fresh normal human serum, the deposition of complement components (C3, C4 and C5) was measured with an ELISA technique. Rabbit antibodies were used as a constituent of the immune complexes, and so both alternative and classical complement pathway activation could be studied. The addition of human tears or purified lactoferrin to this system resulted in the inhibition of classical pathway deposition of C3 and C5, while C4 deposition was not affected. High concentrations of human tears also inhibited alternative pathway C3 deposition on immune complexes, whereas lactoferrin did not detectably affect this pathway. The inhibition of complement activation by tears was not due to a masking of the immune complexes or the already deposited C3. Experiments with purified lactoferrin furthermore showed that lactoferrin did not bind to the complexes, either before or during complement activation. These findings suggest that the complement inhibitory effect is probably taking place in the fluid phase. Saturation of lactoferrin with iron or copper ions resulted in a markedly diminished effect on the capacity of lactoferrin to inhibit complement activation. C4 deposition on immune complexes was not affected by lactoferrin, which suggested that the inhibition of the classical pathway was due to an effect on the classical C3 convertase. The fact that lactoferrin inhibits the classical, but not the alternative C3 convertase, suggests that the effect is probably not mediated through a competition for certain trace metal ions, but may be caused by protein-protein interactions. The findings reported here indicate that lactoferrin may play an important anti-inflammatory role by modulating activation of the complement system. This observation adds a new property to the already described functions of the iron-binding protein lactoferrin.

Antigen-Antibody Complex↗
PubMed1994

Liposome-complement interactions in rat serum: implications for liposome survival studies.

Serum complement opsonizes particles such as bacteria for clearance by the reticuloendothelial system. Complement has been reported to interact with liposomes and therefore may mediate the reticuloendothelial system clearance of liposomes. This study has used a rat serum model to define some of the characteristics of liposomes which modulate their ability to activate complement. Using functional hemolytic assays and C3/C3b crossed immunoelectrophoresis, we have demonstrated that liposomes activated rat complement in a dose-dependent manner with higher concentrations of liposomes activating higher levels of complement. The detection of complement activation required the inclusion of phospholipids bearing a net charge. Complement activation occurred via the classical pathway; no alternative pathway activation was detected. The presence of cholesterol contributed to complement activation in a dose-dependent manner. Phospholipid fatty acyl chain length did not influence complement activation while the introduction of unsaturated acyl chains markedly decreased levels of complement activation. Liposome size also influenced complement activation with 400 nm unilamellar vesicles more effectively activating complement than 50 nm vesicles for equivalent amounts of exposed lipid. These studies demonstrate that the composition of the liposome greatly affects the in vitro activation of rat serum complement and suggest that the biological half-life of liposomes in the circulation of rats may be altered by changing the liposome composition to reduce complement activation.

Animals↗