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PubMed1988

Opsonins in uterine washings influencing in vitro activity of equine neutrophils.

Uterine washings were found to promote neutrophil mediated killing of Streptococcus zooepidemicus. Depletion of complement and/or specific antibody from the washings significantly reduced bactericidal activity. Phagocytosis of yeast by uterine washings was complement dependent. Inhibition of the classical pathway significantly reduced opsonic activity indicating that, in addition to direct activation via the alternate pathway, antibody may also be involved in yeast phagocytosis.

Animals↗
PubMed1979

Hypocomplementemia associated with naturally occurring lymphosarcoma in pet cats.

Eighty cats were classified by indirect immunofluorescence and histologic diagnosis into four categories: normal, feline leukemia virus (FeLV) infected; normal noninfected; lymphosarcoma-FeLV infected; lymphosarcoma, no FeLV present. All viremic cats with lymphosarcoma were found to be hypocomplementemic and activation of the complement system had occurred via the classical pathway. Sera of cats with lymphosarcoma in the absence of FeLV had varying levels of total hemolytic complement (TCH50) ranging from normal to hypocomplementemic. Approximately 50% of the cats that were viremic but histologically and clinically free of disease had TCH50 levels within normal range, and the remainder exhibited varying degrees of hypocomplementemia.

Animals↗
PubMed1977

Classical and alternative complement pathway activation by pneumococci.

Sixty-two strains of Streptococcus pneumoniae were studied for their abilities to consume selected components of classical and alternative complement pathways in human sera. The classical pathway was blocked by chelating calcium with ethyleneglycol-bios (beta-aminoethyl ether)-N,N-tetraacetic acid and by removing C4. The alternative pathway was blocked by removing factor B. Each strain's activation of the two pathways was compared with its nonimmune reactivity with the Fc region of immunoglobulin G (IgG). Activation of the classical complement pathway appeared to be independent of such Fc reactivity. Highly Fc-reactive strains, however, were shown to activate the alternative pathway more effectively than did less Fc-reactive strains. Since pneumococcal activation of the alternative pathway requires non-immunospecific IgG, these findings suggest that nonimmune binding of IgG on the pneumococcal surface endows it with complement-activating properties.

Complement System Proteins↗
PubMed1987

Evidence for activation of complement in patients with AIDS related complex (ARC) and/or lymphoadenopathy syndrome (LAS).

The complement system was examined in 16 patients with AIDS-related complex (ARC) (n = 5) and/or lymphoadenopathy syndrome (LAS) (n = 11). Of these patients 62.5% showed an impairment of classical and/or alternative pathway activity associated with the presence of cleavage fragments of C3 and/or B and a significant reduction of many complement factors. The data indicate pathological complement activation in these patients through the classical and/or alternative pathway. Complement activation was more severe in patients with ARC than in those with LAS, and greater in drug abusers than homosexuals. The lack of efficient complement in the patients can be considered an 'acquired complement deficiency' with possible importance in the failure to combat the HIV attack.

AIDS-Related Complex↗
PubMed2001

Surfactant protein A regulates complement activation.

Complement proteins aid in the recognition and clearance of pathogens from the body. C1, the first protein of the classical pathway of complement activation, is a calcium-dependent complex of one molecule of C1q and two molecules each of C1r and C1s, the serine proteases that cleave complement proteins. Upon binding of C1q to Ag-bound IgG or IgM, C1r and C1s are sequentially activated and initiate the classical pathway of complement. Because of structural and functional similarities between C1q and members of the collectin family of proteins, including pulmonary surfactant protein A (SP-A), we hypothesized that SP-A may interact with and regulate proteins of the complement system. Previously, SP-A was shown to bind to C1q, but the functional significance of this interaction has not been investigated. Binding studies confirmed that SP-A binds directly to C1q, but only weakly to intact C1. Further investigation revealed that the binding of SP-A to C1q prevents the association of C1q with C1r and C1s, and therefore the formation of the active C1 complex required for classical pathway activation. This finding suggests that SP-A may share a common binding site for C1r and C1s or Clq. SP-A also prevented C1q and C1 from binding to immune complexes. Furthermore, SP-A blocked the ability of C1q to restore classical pathway activity to C1q-depleted serum. SP-A may down-regulate complement activity through its association with C1q. We hypothesize that SP-A may serve a protective role in the lung by preventing C1q-mediated complement activation and inflammation along the delicate alveolar epithelium.

Adjuvants, Immunologic↗
PubMed1997

Screening for complement deficiency in bacterial meningitis.

Seventy-seven children with bacterial meningitis were screened for complement deficiency. Both the classical and the alternate pathways were normal in 75 patients. Transiently reduced total haemolytic activity of the classical pathway was documented in a boy with meningococcal meningitis. Total haemolytic activity of both the classical and the alternate pathways were reduced in another patient with pneumococcal meningitis: individual complement components determination indicated predominant activation of the alternate pathway.

Adolescent↗
PubMed1995

Complement regulation in the rat glomerulus: Crry and CD59 regulate complement in glomerular mesangial and endothelial cells.

The complement regulators, decay accelerating factor, membrane cofactor protein, and CD59 are present in human glomeruli. Crry is the rodent analogue to the former two proteins. In this study, we examined complement regulation in cultured rat glomerular endothelial cells (GEnC) and mesangial cells (MES). Immunoprecipitation of 125I-labeled membrane proteins and Western blotting studies were performed with anti-Crry and anti-CD59. In both GEnC and MES, Crry was present as 53, 65, and 78 kD proteins. The 20 kD CD59 was apparent in GEnC. CD59 was also present in MES, but in relatively smaller quantities. By Northern analyses, 1.8 kb CD59 mRNA was present in GEnC as well as in RNA from isolated rat glomeruli. mRNA for Crry was present in both GEnC and MES as 2.2 kb species. The functional significance of these proteins was evaluated next. Anti-Thy 1.1 IgG was used to activate the complement classical pathway in MES. To inhibit the function of the complement regulators, anti-CD59 and/or anti-Crry F(ab')2 antibodies were added with anti-Thy 1.1. Inhibition of Crry function led to enhanced cytotoxicity, while there was no effect when CD59 function was inhibited. The complement alternative pathway was studied by adding complement in Mg-EGTA buffer. Inhibition of Crry led to productive alternative pathway activation, which was accentuated by anti-CD59 when Crry was incompletely inhibited. Alternative pathway regulation was also evaluated in GEnC. Inhibition of CD59 function alone had no effect in GEnC, while inhibition of Crry led to significant cytotoxicity from alternative pathway activation. Under conditions in which Crry was inactive, inhibition of CD59 further enhanced cytotoxicity. Therefore, Crry is present in both GEnC and MES and restricts the complement alternative pathway in both cell types. Crry also regulates the classical pathway in MES. CD59 is present and functionally active in GEnC, while it appears to have a minor role in MES.

Animals↗
PubMed1989

Complement activation in human lymphoid germinal centres.

The presence of complement activation products has been studied in morphologically normal human lymphatic tissue from tonsil, spleen and lymph node. Newly established monoclonal antibodies (mAbs) with reactivity against the C4 cleavage fragments C4a, C4b, C4c and C4d were applied on cyrostat sections in the indirect immunoperoxidase staining technique. Irrespective of organ type, C4d activation product could be detected in germinal centres of all secondary lymphoid follicles. To substantiate this finding, the complete sequence of complement activation products was investigated by a series of mono- and polyclonal antibodies to the complement proteins C1, C2, C3, factor B, C5, C9 to C5b-9 neoantigens and to the regulatory complement proteins C4 binding protein (C4bp), factor I, factor H and properdin. Similar to C4d, all secondary follicles exhibited a strong staining reaction for C3d antigens restricted to germinal centres. At the same site, albeit with distinctly weaker intensity, components of the membrane attack complex (MAC) C5b-9 were found. The simultaneous deposition of C1, C4b and C4bp in certain germinal centres indicates that complement activation is induced via the classical pathway. Concomitant deposition of IgM suggests IgM-antigen complexes that have been trapped on follicular dendritic cells (FDC) during normal immune response as the most likely candidates for activators of the classical pathway. Our data demonstrate that human lymphoid germinal centres as important sites of immune regulation closely interrelate with the complete cascade of complement-activation products, including the membrane attack complex (MAC).

Antigen-Antibody Complex↗
PubMed1999

[The complement system--structure, activation, regulation and function].

Activation of the complement system plays a key role in normal inflammatory response to injury but may cause substantial injury when activated inappropriately. The cascade is activated through classical, alternative and lectin pathways. The human complement system is in most cases well controlled by the host, and inappropriate activation and host cell destruction are prevented. The control is mainly mediated by complement regulatory proteins. The use of powerful methodologies in molecular biology, biochemistry and physiology has led to impressive advances in our knowledge of the mechanisms of complement activation and regulation and its role as either a protective or pathogenic factor in human disease. With respect to disease pathogenesis, the complexity of the cascades provides opportunities for several different therapeutic targets within the pathways, and we are about to witness the availability of a variety of complement modulators for specific therapies. This article reviews biological aspects of this important immunological effector mechanism.

Complement Activation↗
PubMed1978

Role of antibody and complement in opsonization of group B streptococci.

A requirement for the classic complement pathway in opsonization of group B streptococci was observed by using both a chemiluminescence and a radiolabeled bacterial uptake technique. The classic pathway increased levels of opsonization for types Ia and II stock and wild strains and for some type III wild strains. In contrast, other type III wild strains and the type III stock strain had accelerated kinetics of uptake in the presence of an intact classic pathway, but the level of opsonization was unchanged from that with antibody alone. We could not demonstrate a significant role for the alternative pathway in opsonizing stock or wild strains of group B streptococci. Futhermore, electrophoretic and complement consumption analysis by hemolytic titration failed to reveal alternative pathway activation by the majority of strains of this group. Therapy aimed at supplying opsonins for these organisms will require the presence of type-specific antibody.

Antibodies, Bacterial↗
PubMed1985

Photodynamic action of uroporphyrin on the complement system in porphyria cutanea tarda.

We investigated the effect of UV light (320-460 nm) on total hemolytic CH50 activity and C3 cleavage in sera obtained from 14 patients with porphyria cutanea tarda. Irradiation with 5, 10, or 50 J/cm2 resulted in a 12%-60% loss of CH50 and a 5%-30% cleavage of native C3 as estimated by planimetric evaluation of the immunoelectrophoretic C3 pattern. The complement changes were most pronounced in sera from patients with active disease and were minimal or absent in patients who were in remission. In all cases, the decrease of CH50 and C3 cleavage was proportional to the plasma-porphyrin concentration and the dose of radiation. After exposure to 320- to 460-nm light, similar changes were seen in normal human serum (NHS) to which exogenous uroporphyrin had been added. Beta-carotene and chloroquine had no inhibitory effect on the photodynamic complement activation. The C3 cleavage in irradiated NHS containing uroporphyrin was not affected by 10 mM EGTA, but was partially inhibited in the presence of 30 mM EDTA, thus indicating that the interaction of photoexcited uroporphyrin with the complement system differs from classical-pathway complement activation.

Aged↗
PubMed1996

Neurofibrillary tangles of Guam parkinson-dementia are associated with reactive microglia and complement proteins.

Guamanian parkinsonism-dementia, locally described as bodig, is characterized by the widespread appearance of neurofibrillary tangles in cortical and subcortical areas. These tangles have similar regional distribution and immunohistochemical profile to those found in Alzheimer disease (AD). We studied the immunohistochemical staining of these tangles, as well as those of AD, using antibodies to complement proteins and related molecules. In bodig, as in AD, extracellular tangles were intensely decorated with antibodies to C1q, C4d and C3d, but not fraction Bb of factor B, properidin or immunoglobulins. This is evidence that the classical, but not the alternative complement pathway is activated on extracellular tangles and that the activation is independent of antibodies. Immunohistochemical staining for amyloid P, an in vitro activator of complement, was remarkably similar to that for the C1q, C4d and C3d in both bodig and AD. This was not the case for beta-amyloid protein (BAP), another in vitro complement activator. Positive staining was observed in only a minority of extracellular tangles in bodig and was only rarely observed in those of AD. BAP would therefore not appear to be a candidate for activating complement on extracellular neurofibrillary tangles. Reactive microglia and reactive astrocytes were closely associated with complement positive extracellular neurofibrillary tangles, indicating an inflammatory response similar to that seen in AD.

Adult↗
PubMed1994

[Organ xenotransplantation using human complement regulatory factor gene].

For the success of xenotransplantation, hyperacute rejection must be controlled. Hyperacute rejection is induced by the activation of complement system via alternative pathway and/or classical pathway. Complement regulatory factors can inhibit activation of complement system via the both pathways. To overcome hyperacute rejection in organ xenotransplantation, gene engineering in the establishment of xeno-endothelial cells and transgenic animals (mouse and pig) using human complement regulatory factors are studied. In the near future, transgenic pig using human complement regulatory factor genes can be used as a potential donor in organ xenotransplantation.

Animals↗
PubMed1996

Analysis of complement C3 deposition and degradation on Klebsiella pneumoniae.

The majority of Klebsiella pneumoniae serum-resistant strains activate complement and bind C3b, the opsonic fragment of C3, without C5b-9 formation and bacterial killing. The mechanisms leading to C3b deposition without cell death were studied, and the results indicate that serum-resistant strains activate principally the alternative pathway and that serum-sensitive strains activate both the alternative and classical pathways. Bacterial molecules implicated in C3b deposition are the outer membrane porin proteins and smooth and rough lipopolysaccharides. Porins activate both complement pathways, and the rough lipopolysaccharide activates the classical pathway, causing deposition of C3b in serum-sensitive strains. The smooth lipopolysaccharide of serum-resistant strains activates only the alternative pathway, impeding the binding of C1q to porins (S. Albertí, G. Marqués, S. Camprubí, S. Merino, J. M. Tomás, F. Vivanco, and V. J. Benedí, Infect. Immun. 61:852-860, 1993; S. Albertí, F. Rodríguez-Quinónes, T. Schirmer, G. Rummel, J. M. Tomás, J. P. Rosenbusch, and V. J. Benedí, Infect. Immun. 63:903-910, 1995) and rough lipopolysaccharide molecules and thereby preventing activation of the classical pathway. After its deposition, C3b is quickly degraded to iC3b on both types of strains, but the higher-level deposition of C3b on serum-sensitive strains, resulting from activation of both the alternative and classical complement pathways, supports further complement activation and killing of serum-sensitive strains.

Bacterial Proteins↗
PubMed1984

Complement activation by the surface of Plasmodium falciparum infected erythrocytes.

The surface of trophozoite-stage Plasmodium falciparum infected erythrocytes will, in the presence of immune human or owl monkey serum, activate the classical complement pathway. This was demonstrated with a sensitive, enzyme-linked immunosorbent assay which detects the complex, C1s-C1 inhibitor, which is only generated when the classical pathway is activated. A second enzyme-linked immunosorbent assay, as well as Covaspheres coated with affinity-purified anti-C3, showed that immune activation of the classical pathway by infected erythrocytes resulted in the accumulation of significant amounts of C3b on the erythrocyte surface. During the development of the parasite to the trophozoite stage, the erythrocyte membrane is also transformed from a non-activator into a surface capable of activating complement by the alternative pathway. Erythrocytes infected with trophozoite-stage parasites directly activated the alternative complement pathway. This activation led to the specific binding of an average of 15,000 C3b molecules per infected cell. Alternative pathway activation was augmented by anti-parasite antibody. Such conditions mediated the accumulation of an average of 36,000 C3b molecules per infected erythrocyte. The amounts of C3b on the infected erythrocyte surface did not lead to cellular lysis. They are, however, likely to have a major impact on the total in vivo response to this parasite.

Cells, Cultured↗
PubMed2000

Reduction of neutrophil activation by vitamin E modified dialyzer membranes.

BACKGROUND/AIM: Transient leukopenia during hemodialysis due to neutrophil activation is attributed to bioincompatibility of the dialysis membrane, but the mechanism remains unclear. We studied the mechanism of neutrophilic activation by comparing a vitamin E modified membrane (CLEE) and a regular cellulose membrane (CLSS). METHODS: (1) CLSS and CLEE membranes were used in a crossover clinical study in 7 chronic hemodialysis patients. Neutropenia, CD11b expression, and plasma C3a and myeloperoxidase concentrations were compared between the two dialyzer membranes. (2) Normal blood was circulated through CLEE and CLSS minimodels, and the same parameters were compared. (3) Blood samples with modified complement activities (EDTA: both classical and alternative pathways inactivated; EGTA+Mg: classical pathway inactivated; heating: alternative pathway inactivated; control: no modification) were incubated in the CLSS minimodel, and the neutrophilic activation was compared. RESULTS: In clinical hemodialysis, neutropenia, CD11b expression, and C3a and myeloperoxidase levels were significantly lower when CLEE membranes were used. The same tendency was observed in minimodels. However, the degrees of inhibition in clinical dialysis, especially at the venous line, were significantly higher than in minimodels. As compared with controls, CD11b expression and myeloperoxidase level were significantly lower when both classical and alternative pathways were inactivated or when the classical pathway alone was inactivated, but were not significantly different when the alternative pathway alone was inactivated. CONCLUSIONS: Vitamin E modification of the dialyzer reduces some reactions of neutrophilic activation, such as CD11b expression and myeloperoxidase release, more effectively in the clinical situation than in ex vivo models, suggesting a possible effect of vitamin E in inhibiting bioreactions due to pyrogen in the dialysate. The classical complement pathway is required in membrane-induced neutrophilic activation, at least during the initial stage.

Adult↗
PubMed1998

Complement-dependent clearance of apoptotic cells by human macrophages.

Apoptotic cells are rapidly engulfed by phagocytes, but the receptors and ligands responsible for this phenomenon are incompletely characterized. Previously described receptors on blood- derived macrophages have been characterized in the absence of serum and show a relatively low uptake of apoptotic cells. Addition of serum to the phagocytosis assays increased the uptake of apoptotic cells by more than threefold. The serum factors responsible for enhanced uptake were identified as complement components that required activation of both the classical pathway and alternative pathway amplification loop. Exposure of phosphatidylserine on the apoptotic cell surface was partially responsible for complement activation and resulted in coating the apoptotic cell surface with C3bi. In the presence of serum, the macrophage receptors for C3bi, CR3 (CD11b/CD18) and CR4 (CD11c/CD18), were significantly more efficient in the uptake of apoptotic cells compared with previously described receptors implicated in clearance. Complement activation is likely to be required for efficient uptake of apoptotic cells within the systemic circulation, and early component deficiencies could predispose to systemic autoimmunity by enhanced exposure to and/or aberrant deposition of apoptotic cells.

Annexin A5↗
PubMed1981

Alternative pathway for complement activation triggered by human liver plasma membranes.

Liver plasma membranes (LPM) prepared from normal hepatocytes by centrifugation in sucrose discontinuous gradient, are capable of haemolysing PNH-like cells in the presence of complement or complement plus EGTA or MG2+ ions. In contrast, EDTA or Ca2+ ions inhibit the lysis. The total complement lytic activity is reduced by some 40% when fresh serum is incubated with LPM, whereas the total amount of C4 remains constant. The cross-immunoelectrophoresis studies of fresh serum incubated with LPM demonstrate the appearance of C3 breakdown products, which suggests the activation of the alternative complement pathway. In contrast, the sucrose test, which proceeds mainly through the classical complement pathway, is inhibited by LPM. The possible role of complement in liver disease is discussed.

Cell Membrane↗