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PubMedDate not supplied

Polymorphism of C3 components and the B factor in patients with chronic renal failure, dialyzed iteratively.

The value of C3, of the cleavage C3 components and of the B factor were determined in 25 normal controls and in 22 patients with chronic renal failure (CRF), iteratively dialyzed. Low values of C3 and progressive hypomorphism of the cleavage components of C3 were observed in the patients at the three moments of determination. The activity of the B factor was also found significantly decreased in the patients. Our results indicated an activation of the complement alternative pathway in the dialyzed patients but the activation through the classic pathway, could not be excluded either. It is concluded that this activation might be due to the initial disease which generated CRF but also to some factors transported by hemodialysis.

Adult↗

PubMed2002

A co-operative interaction between Neisseria gonorrhoeae and complement receptor 3 mediates infection of primary cervical epithelial cells.

Little is known about the pathogenesis of gonococcal infection within the lower female genital tract. We recently described the distribution of complement receptor 3 (CR3) on epithelia of the female genital tract. Our studies further indicate that CR3-mediated endocytosis serves as a primary mechanism by which N. gonorrhoeae elicits membrane ruffling and cellular invasion of primary, human, cervical epithelial cells. We have extended these studies to describe the nature of the gonococcus-CR3 interaction. Western Blot analysis demonstrated production of alternative pathway complement components by ecto- and endocervical cells which allows C3b deposition on gonococci and its rapid conversion to iC3b. Anti-iC3b and -factor I antibodies significantly inhibited adherence and invasion of primary cervical cells, suggesting that iC3b covalently bound to the gonococcus serves as a primary ligand for CR3 adherence. However, gonococcal porin and pili also bound to the I-domain of CR3 in a non-opsonic manner. Binding of porin and pili to CR3 were required for adherence to and invasion of cervical epithelia. Collectively, these data suggest that gonococcal adherence to CR3 occurs in a co-operative manner, which requires gonococcal iC3b-opsonization, porin and pilus. In conjunction, these molecules facilitate targeting to and successful infection of the cervical epithelium.

Bacterial Adhesion↗

PubMed1990

Complement component C3 fixes selectively to the major outer membrane protein (MOMP) of Legionella pneumophila and mediates phagocytosis of liposome-MOMP complexes by human monocytes.

Legionella pneumophila is a facultative intracellular bacterial pathogen that parasitizes human monocytes and alveolar macrophages. Previous studies from this laboratory have shown that monocyte complement receptors CR1 and CR3 and complement component C3 in serum mediate L. pneumophila phagocytosis. In this study, we have explored C3 fixation to L. pneumophila. We developed a whole-cell enzyme-linked immunosorbent assay (ELISA) to measure C3 fixation to the bacterial surface. By this assay, C3 fixes to L. pneumophila that are opsonized in fresh nonimmune serum, and C3 fixation takes place via the alternative pathway of complement activation. Immunoblot analysis of opsonized L. pneumophila indicated that C3 fixes selectively to specific acceptor molecules of L. pneumophila. Consistent with this, when nitrocellulose blots of whole L. pneumophila or bacterial components are incubated in fresh nonimmune serum, C3 fixes exclusively to the major outer membrane protein (MOMP) of L. pneumophila, a porin; C3 does not fix to L. pneumophila LPS on these blots. To further explore the role of MOMP in C3 fixation and phagocytosis, we reconstituted purified MOMP into liposomes. By the ELISA, MOMP-liposomes, but not plain liposomes lacking MOMP, avidly fix C3. Consistent with a dominant role for MOMP in C3 fixation, MOMP-liposomes form a C3 complex of the same apparent molecular weight as whole L. pneumophila in nonimmune serum. Opsonized radioiodinated MOMP-liposomes avidly adhere to monocytes, and adherence is dose dependent upon serum. By electron microscopy, opsonized MOMP-liposomes are efficiently phagocytized by human monocytes, and phagocytosis takes place by a conventional appearing form of phagocytosis. This study demonstrates that C3 fixes selectively to the MOMP of L. pneumophila, and that, in the presence of nonimmune serum, MOMP can mediate phagocytosis of liposomes and, potentially, phagocytosis of intact L. pneumophila by human monocytes.

Animals↗

PubMed1999

Mutations of the type A domain of complement factor B that promote high-affinity C3b-binding.

Factor B is a zymogen that carries the catalytic site of the complement alternative pathway convertases. During C3 convertase assembly, factor B associates with C3b and is cleaved at a single site by factor D. The Ba fragment is released, leaving the active complex, C3bBb. During the course of this process, the protease domain becomes activated. The type A domain of factor B, also part of Bb, is similar in structure to the type A domain of the complement receptor and integrin, CR3. Previously, mutations in the factor B type A domain were described that impair C3b-binding. This report describes "gain of function" mutations obtained by substituting factor B type A domain amino acids with homologous ones derived from the type A domain of CR3. Replacement of the betaA-alpha1 Mg2+ binding loop residue D254 with smaller amino acids, especially glycine, increased hemolytic activity and C3bBb stability. The removal of the oligosaccharide at position 260, near the Mg2+ binding cleft, when combined with the D254G substitution, resulted in increased affinity for C3b and iC3b, a C3b derivative. These findings offer strong evidence for the direct involvement of the type A domain in C3b binding, and are suggestive that steric effects of the D254 sidechain and the N260-linked oligosaccharide may contribute to the regulation of ligand binding.

Amino Acid Sequence↗

PubMed1992

Eosinophil granule cationic proteins regulate complement. I. Activity on the alternative pathway.

Eosinophil granules contain several cationic proteins that mediate tissue damage in allergic disease. The present study examined the capacity and mechanisms by which these cationic proteins regulate activity of the alternative pathway of C. Eosinophil peroxidase and eosinophil cationic protein inhibited formation of cell-bound alternative pathway C3 convertase, causing 50% inhibition of lysis at about 0.19 and 0.75 microgram/10(7) cellular intermediates, respectively. Major basic protein inhibited alternative pathway C3 activity by only 19% at 1.5 micrograms/10(7) cellular intermediates. Eosinophil-derived neurotoxin had no activity on the alternative pathway. The eosinophil granule proteins were examined for the mechanism by which they inhibited alternative pathway activity. Eosinophil peroxidase and major basic protein inhibited fluid phase factor B consumption in a reaction mixture that also contained factors D and C3b, eosinophil-derived neurotoxin had no activity on factor B consumption, and eosinophil cationic protein consumed factor B in the absence of C3b and factor D. Both eosinophil cationic protein and eosinophil peroxidase enhanced the decay of preformed alternative pathway convertase. Lysis of EAC4b,3b cellular intermediates formed to contain a low surface amount of C3b was more inhibited than was lysis of cells formed with a standard amount of C3b on the surface. This suggests that these eosinophil proteins acted predominantly on C3b to regulate alternative pathway activity. We also found that none of the eosinophil granule cationic proteins had any effect on later events after the formation of the C3 convertase. We conclude that although eosinophil-derived neurotoxin (isoelectric pH value (pI) = 8.9) does not regulate alternative pathway activity, the more highly charged eosinophil granule cationic proteins--major basic protein (pI = 10.9), eosinophil cationic protein (pI = 10.8), and eosinophil peroxidase (pI = 10.8)--do share the capacity to regulate C activity and may exert this activity in vivo.

Blood Proteins↗

PubMed1982

Opsonic requirements for phagocytosis of Borrelia hermsii by human polymorphonuclear leukocytes.

Opsonic requirements for phagocytosis by human polymorphonuclear leukocytes (PMNLs) of a laboratory strain of Borrelia hermsii were examined. Intracellular localization of spirochetes was confirmed by electron microscopy and cinephotomicroscopy. Phagocytosis of 3H-labeled spirochetes was increased with higher concentrations of pooled human serum or greater ratios of spirochetes to PMNLs and was unaffected by diminished classical complement pathway activity. Immune rabbit serum markedly increased phagocytosis of spirochetes beyond levels observed with preimmune rabbit serum. Immune rabbit serum also demonstrated direct activity against B. hermsii, which decreased the motility and viability and increased agglutination of the spirochetes independently of complement. Both the direct activity against B. hermsii and the opsonic activity of immune rabbit serum were eliminated by immunoabsorption of immunoglobulins. These observations suggest a role for the alternative complement pathway and for immunoglobulins in the opsonization of spirochetes for phagocytosis by PMNLs. Immunoglobulins may also play a role in the direct clearance of spirochetes.

Animals↗

PubMed2004

Effect of heparin binding on Helicobacter pylori resistance to serum.

The objective of this study was to evaluate the effect of heparin binding to Helicobacter pylori cells on their survival in the presence of fresh rabbit serum with or without active complement components. Three H. pylori strains were compared and the amounts of heparin added reflected the physiological concentrations that can be found in animal tissues. No growth of H. pylori was noted in the presence of serum. Serum with or without active complement produced a reduction in c.f.u. for strains SPM 326, CCUG 17874(T) and SS1. However, addition of heparin resulted in increased survival of bacterial cells in serum with or without active complement. It appears that heparin binding to H. pylori can prevent bacterial cell death due to the alternative complement system. Heparin binding could also protect from heated serum (complement-inactivated), indicating protection from other serum components besides complement. In vivo, the process of heparin binding could possibly result in facilitated colonization due to a higher survival rate.

Animals↗

PubMed1975

Properdin: binding to C3b and stabilization of the C3b-dependent C3 convertase.

A function of P in the alternative complement pathway is to prolong the first order decay of the hemolytic sites on EAC43B in a dose-dependent manner. As the number of initial convertase sites is not changed, even when activated properdin (P) increases the t1/2 10-fold or more, P acts to stabilize rather than to uncover additional sites. P binds to EAC43 to generate EAC43P in a reaction that proceeds slightly more rapidly at 15 degrees C than at 0 degrees C, but reaches the same plateau and does not require divalent cations. The presence of P on EAC43P not only stabilizes the convertase subsequently formed on that cell, but, alternatively, permits transfer to convertase sites on other cells with the stability of the recipient intermediate being dependent on the P available for transfer. The capacity of P to bind to C3b and stabilize C3B contrasts with the inhibitory effect of the C3b inactivator on formation of this amplification convertase.

Animals↗

PubMed1993

[The complement system].

The complement system represents a multitude of activating factors, associated with the cellular membrane and providing for cell lysis. The system is composed of 21 serum proteins and 8 receptors and may be found in cells of various types. The major function of the system consists in its activation which entails a cascade of events terminated by cell lysis. Two complement system activation mechanisms are generally distinguished, one of which is classical and one is alternative. These two mechanisms converge after the activation of the third component (C3) or as a result of interaction between the terminal components (C5, C6, C7, C8 and C9) of the complement cascade. The complement system is linked with the fibrinolytic, blood coagulating and kinin systems.

Complement Activation↗

PubMedDate not supplied

[Reactivity of Candida albicans in the system of the alternative way of complement activation].

The neutrophil-stimulating activity of C. albicans before and after opsonization in the system of the alternative way of complement activation (AWCA) was studied. The study revealed that, in comparison with zymosan, C. albicans exhibited a considerably lower index of AWCA-dependent opsonic effect in reaction with neutrophils. This did not correlate with the capacity of substrates to activate the alternative cascade and with the intensity of phagocytosis. The suggestion on the involvement of C. albicans thermolabile cell-wall components into the negative regulation AWCA-dependent opsonic effect was substantiated.

Candida albicans↗

PubMed1992

Infection caused by Streptococcus pneumoniae in children with sickle cell disease: epidemiology, immunologic mechanisms, prophylaxis, and vaccination.

The incidence of invasive infection due to Streptococcus pneumoniae is 6.9 infections per 100 patient-years among children with sickle cell anemia (SS genotype) who are less than 5 years of age; this rate is 30-100 times that which would be expected in a healthy population of this age. Splenic dysfunction is the major contributor to the increased risk. Postulated abnormalities of immunologic defense mechanisms, including synthesis of polyclonal IgG and IgM, the alternative complement pathway, opsonic activity, and T and B cell interaction, may also enhance risk. Preceding or concomitant viral infection is suspected of predisposing to pneumococcal infection, but no definitive data are available. The most prevalent pneumococcal serotypes causing disease in this setting include types 6, 14, 18, 19, and 23; these same serotypes are most frequently involved in "vaccine failure." Current evidence demonstrates only modest protective efficacy for contemporary pneumococcal vaccines in young patients with sickle cell anemia; thus alternative vaccines are required. Convincing evidence for a protective effect of antibiotic prophylaxis has been obtained in limited time trials. However, presently used prophylactic regimens pose problems related to compliance and provide imperfect protection; moreover, their optimal duration remains unknown.

Anemia, Sickle Cell↗

PubMedDate not supplied

Correlation between inhibited alternative complement activity and the protective effect induced by Nocardia lysozyme digest (NLD) during Klebsiella pneumoniae infection in mice.

Nocardia lysozyme digest (NLD) was administered intraperitoneally (i.p.) at a dose of 500 micrograms/kg to normal and immunosuppressed mice for 3 consecutive days prior to inoculation with Klebsiella pneumoniae. A protective effect was observed when the pathogen was injected subcutaneously and intravenously, as opposed to an aggravating effect obtained in the case of intraperitoneal inoculation The i.p. administration of NLD partially restored the immunosuppression caused by cyclophosphamide but did not change cobra venom-induced deterioration of the infection. The results obtained could be regarded as a consequence of the lowered alternative pathway serum complement activity and the crucial role of the diminished level of complement in the peritoneal cavity.

Adjuvants, Immunologic↗

PubMed1994

Specificity of the thioester-containing reactive site of human C3 and its significance to complement activation.

The specificity of the thioester-containing site in three plasma proteins is regulated by elements of their protein structures other than the thioester bond itself. Human C4A and alpha 2-macroglobulin preferentially form amide linkages while human C3 primarily forms ester linkages with hydroxyl groups. We have examined the thioester in C3 and found evidence of strong preferences for certain carbohydrates, indications of selectivity for specific positions on those carbohydrates and a preference for terminal sugars in polysaccharides. A testable set of rules are derived from these findings which predict preferred attachment sites on polysaccharides. A computer model of the effect of different reactivities on activation of the alternative pathway of complement suggested that organisms might greatly alter their susceptibility to complement with small changes in carbohydrate structure. While a random selection of 20 biological particles showed no correlation between activation and C3b attachment efficiency, subsets of related organisms differing primarily in their surface polysaccharide exhibited stronger correlations. The strongest correlation occurred in a series of the yeasts (Cryptococcus neoformans) possessing capsular polysaccharides with one, two, three or four branching xylose sugars per repeating unit. These organisms exhibited capture efficiencies for metastable C3b from 12% (one-xylose strain) to 41% (four-xylose strain).

Alcohols↗

PubMed1985

Differences in carbohydrate specificities and complement-activating capacity of guinea pig and human antibodies to neuraminidase-treated autologous erythrocytes.

Guinea pig erythrocytes desialated by treatment with neuraminidase from Vibrio cholerae were lyzed in autologous serum through a natural-antibody-dependent activation of the classical complement pathway. Lysis was inhibited when a mannose, glucose, galactose or N-acetyl-glucosamine was added to the incubation mixture. Methyl-alpha- or -beta-D-galactopyranosides were poorly effective and N-acetyl-D-galactosamine was not effective at all. Inhibition of lysis by the carbohydrates was due neither to an anti-complementary effect nor to a modification of the osmotic pressure since: (a) they did not alter the total complement haemolytic activity of guinea pig serum, and (b) they did not inhibit lysis of desialated guinea pig erythrocytes in human serum through activation of the alternative complement pathway. The presence of mannose, glucose, galactose or N-acetyl-glucosamine in the incubation mixture resulted in an impaired fixation of natural auto-antibodies on antigenic sites, namely the T-antigen (Thomsen-Friedenreich), which were unmasked following membrane sialic acid removal. When tested under the same conditions, only small percentage of the normal human population showed the phenomenon of lysis of desialated erythrocytes in autologous serum. Lysis was not due to a particular susceptibility of erythrocytes from these individuals to complement-mediated lysis but to the presence in their serum of complement-activating anti-T antibodies. As expected, the activity of human anti-T antibodies was inhibited by galactose and N-acetyl-galactosamine, which are the immunodominant sugars of the human T-antigen. Mannose and glucose had no effect, and methyl- alpha- or - beta-D-galactopyranosides were almost as effective as galactose. The heterogeneity of the human population with regard to the complement-activating capacity of anti-T antibodies could be of significance for the individual response of the host to an infection by a neuraminidase-producing microorganism. That the immunodominant sugars of the T-antigen were different between humans and guinea pigs was further assessed by absorption experiments. We have demonstrated that guinea pig anti-T antibodies were not removed during contact with desialated human red cells which do not have the mannose specificity, whereas human antibodies were almost entirely retained on desialated guinea pig red cells which, beside mannose, express galactose. These results also suggest that guinea pig antibodies are mostly directed towards mannose and glucose.

Agglutination Tests↗

PubMed2004

Complement factor h limits immune complex deposition and prevents inflammation and scarring in glomeruli of mice with chronic serum sickness.

Factor H is the major complement regulator in plasma. Abnormalities in factor H have been implicated in membranoproliferative glomerulonephritis in both humans and experimental animals. It has been shown that factor H on rodent platelets functions analogously to human erythrocyte complement receptor 1 in its role to traffic immune complexes to the mononuclear phagocyte system. C57BL/6 factor H-deficient mice (Cfh(-/-)) and wild-type (wt) controls were immunized daily for 5 wk with heterologous apoferritin to study the chronic serum sickness GN model. Immunizations were started in 6- to 8-wk-old mice, which was before the development of spontaneous membranoproliferative glomerulonephritis in some Cfh(-/-) animals. Glomerular deposition of IgG immune complexes in glomeruli was qualitatively and quantitatively increased in Cfh(-/-) mice compared with wt mice. Consistent with the increase in glomerular immune complexes and possibly because of alternative pathway complement activation, Cfh(-/-) mice had increased glomerular C3 deposition. Wt mice developed no glomerular pathology. In contrast, Cfh(-/-) mice developed diffuse proliferative GN with focal crescents and glomerulosclerosis. In addition, there was significantly increased expression of collagen IV, fibronectin, and laminin mRNA in Cfh(-/-) glomeruli. These data show a role for platelet-associated factor H to process immune complexes and limit their accumulation in glomeruli. Once deposited in glomeruli, excessive complement activation can lead to glomerular inflammation and the rapid development of a scarring phenotype.

Animals↗

PubMed2004

Adjuvant treatment for complement activation increases the effectiveness of photodynamic therapy of solid tumors.

Phototoxic lesions generated in tumor tissue by photodynamic therapy (PDT) are recognized by the host as a threat to the integrity and homeostasis at the affected site. Among the canonical pathways invoked by the host for dealing with this type of challenge is the activation of the complement system, integrating proteins that serve as molecular sensors of danger signals produced by PDT and those initiating signalling cascades coupled into the network of inflammatory and immune responses. Since the activated complement system is a salient participant of the antitumor response produced by PDT, it is worth exploring whether its manipulation can be exploited for the therapeutic benefit. Using mouse tumor models, the present study examined the potential of representative complement-activating agents to act as effective adjuvants to PDT. Tumor-localized treatment with zymosan, an alternative complement pathway activator, reduced the recurrence-rate of PDT-treated tumors, markedly increasing the percentage of permanent cures. In contrast, a similar treatment with heat aggregated gamma globulin (complement activator via the classical pathway) was of no significant benefit as a PDT adjuvant. Systemic complement activation with streptokinase treatment had no detectable effect on complement deposition at the tumor site without PDT, but it augmented the extent of complement activity in PDT-treated tumors. This finding based on immunohistochemistry analysis explains the results of tumor therapy experiments, which showed that systemic treatment with streptokinase or a similar agent, urokinase, enhances the PDT-mediated tumor response. Zymosan and streptokinase administrations produced no beneficial results with PDT of tumors growing in complement-deficient mice. This study, therefore, establishes the potential of complement-activating agents to serve as effective adjuvants to PDT for cancer treatment.

Adjuvants, Immunologic↗

PubMed1997

Reoxygenation of hypoxic human umbilical vein endothelial cells activates the classic complement pathway.

BACKGROUND: Ischemia-reperfusion injury leads to the activation and endothelial deposition of complement. We investigated whether exposure of human umbilical vein endothelial cells (HUVECs) to hypoxia and/or reoxygenation activates complement and decreases HUVEC-surface expression of the C3 regulatory proteins CD46 and CD55. METHODS AND RESULTS: HUVECs were subjected to 0, 12, or 24 hours of hypoxia (O2 = 1%) and then reoxygenated for 3 hours (O2 = 21%) in the presence of 30% human serum. C3 deposition and HUVEC-surface expression of CD46 and CD55 were evaluated by ELISA and flow cytometry. C3 deposition on HUVECs subjected to 12 or 24 hours of hypoxia followed by 3 hours of reoxygenation was significantly greater than normoxic HUVECs. Inhibition of the classic but not the alternative complement pathway during reoxygenation attenuated C3 deposition. Western blot analysis of HUVEC lysates under reducing conditions demonstrated significantly increased iC3b deposition in hypoxic/reoxygenated HUVECs compared with normoxic HUVECs. FACS analysis confirmed iC3b deposition. HUVEC-surface expression of CD46 and CD55 increases after hypoxia and/or reoxygenation. CONCLUSIONS: We conclude that (1) hypoxia and reoxygenation of HUVECs significantly increases iC3b deposition on HUVECs, (2) C3 deposition after hypoxia and reoxygenation is largely mediated by the classic complement pathway, and (3) HUVEC-surface expression of CD46 and CD55 increases after hypoxia and reoxygenation. These data demonstrate that hypoxia and reoxygenation of human endothelial cells activates the classic complement pathway despite an increase in complement C3 regulatory proteins.

Antigens, CD↗

PubMed1991

Elevated plasma levels of the immunosuppressive complement fragment Ba in renal failure.

The complement fragment Ba is a 33 kD activation product of factor B which suppresses human B-lymphocyte functions in vitro. We report that plasma levels of Ba are highly elevated in patients with chronic renal failure (4.84 +/- 3.58 micrograms/ml) and in patients with end-stage renal disease undergoing regular hemodialysis (16.1 +/- 6.1 micrograms/ml) as compared to normals (1.01 +/- 0.30 micrograms/ml). Ba levels were strictly correlated with the creatinine clearance. The urinary excretion of Ba was 165-fold higher in patients with tubular proteinuria than in normals. These results indicate that the kidney is the major catabolic site for Ba. In addition, direct evidence was obtained for an enhanced turnover of the alternative pathway of complement in renal failure that, although it appears to be less important than the renal retention of Ba, contributes to elevated Ba plasma levels in these patients. Ba concentrations in dialysis patients who responded to hepatitis B vaccination were significantly lower than in non-responders. Furthermore, the in vitro IgM synthesis by purified mononuclear cells was negatively correlated with Ba concentrations determined in the plasma of these patients. These results suggest that the accumulation of Ba contributes to the defective immune response in patients with renal failure.

Adult↗