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Results for “Complement Pathway, Alternative”

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PubMed1980

Characterization of complement resistance in Escherichia coli conferred by the antibiotic resistance plasmid R100.

We have examined the effect of the antibiotic resistance plasmid, R100, on the complement (C) mediated killing of Escherichia coli K-12 strains. The viabilities, in dilute normal rabbit serum (NRS), of 5 such strains were compared with the viabilities of the same strains harboring R100. For 1 strain, J6-2, we also measured the effect of R100 on viability in normal human serum (NHS) and in guinea pig serum (GPS); in NRS, NHS,and GPS devoid of classical C pathway activity; and in NHS devoid of alternative pathway activity. Finally, we compared the depletion of individual complement components in sera exposed to J6-2 and J6-2 harboring R100. Our results demonstrate that 1) R100 renders E. coli K-12 resistant to killing by NRS, NHS, and GPS; 2) the level of resistance, which ranges from 30- to 10,000-fold, is strain dependent and serum dependent; 3) R100 inhibits killing by both the classical and alternative C pathway. Resistance appears to involve a disruption on the C pathway subsequent to the activation of C5.

Animals↗

PubMedDate not supplied

Host defense against Streptococcus pneumoniae: the role of the spleen.

The asplenic patient has an increased susceptibility to bacterial septicemia. Streptococcus pneumoniae is responsible for approximately 50% of the episodes. Although the incidence of septicemia varies among patients of different ages and with different underlying diseases, half of the patients with overwhelming post-splenectomy infection die. Increased susceptibility to overwhelming infection with blood-borne bacteria is due primarily to the absence of a major phagocytic mass with a large blood flow. In the nonimmune host the spleen plays an important role in the phagocytosis and clearance of blood-borne antigens. Asplenic infants younger than two years old or splenectomized patients with an underlying disease that impairs their ability to form specific antibody to S. pneumoniae are at maximal risk for septicemia. In addition, studies of asplenic animals and humans suggest that the spleen has a specific role in the production of antibody. Activation of the alternative complement pathway may be abnormal in patients with anatomical or functional asplenia. Defective clearance of blood-borne bacteria in the nonimmune host, a decrease in antibody formation, and abnormal activation of the alternative complement pathway may be additive defects that place the asplenic host at risk for overwhelming post-splenectomy infection.

Animals↗

PubMed1989

Hereditary, complete deficiency of complement factor H associated with recurrent meningococcal disease.

Complement factor H (beta-1H globulin) is an important regulatory protein which inhibits the spontaneous complement activation via the alternative pathway. We describe a 15-year-old girl without any detectable factor H in plasma. She has had two episodes of meningococcal disease, but is otherwise completely healthy. Secondary to the factor-H deficiency, the levels of factor B, properdin, C3, and C5-C9 were strongly reduced due to spontaneous in vivo activation of the alternative complement pathway. Plasma C3dg was strongly elevated in spite of the factor-H deficiency; apparently erythrocyte CR1 substitutes for factor H in C3 degradation. Neither C3 nor complement lesions were demonstrable on her erythrocytes which did, however, show increased, spontaneous haemolysis in vitro in citrate plasma, but not in serum. The patient is a single child and her parents, who are unrelated and healthy, had half-normal levels of factor H. This reduction of factor H is sufficient to cause increased, spontaneous activation of the alternative pathway.

Antibodies, Bacterial↗

PubMed1977

Immune reactants in cryoproteins. Relationship to complement activation.

Cryoproteins were isolated from the serum of 5 patients with essential cryoglobulinaemia 5 patients with rheumatoid arthritis, and 2 patients with Sjøgren's syndrome. These cryoprecipitates contained IgG, IgM, and IgA as well as complement proteins C1q, C4, C3, and factor B. The cryoprecipitates were analysed further for content of antibody and antigen, and were tested for their ability to activate complement. In the cryoprecipitates of 2 patients with Sjøgren's syndrome, nuclear antigen and antinuclear antibody characteristic of an immunological specificity found in Sjøgren's syndrome were shown. The cryoprecipitates of 6 other patients contained rheumatoid factor and antibody to a lymphocyte nuclear antigen. The solubilized cryoprecipitates were tested by in vitro assays for their ability to activate complement by the classical or alternative pathways. All 12 cryoprecipitates activated the classical pathway. 9 of the 12 cryoprecipitates also activated the alternative complement pathway under conditions which did not involve activation of C1 and C4. These studies show that a high percentage of cryoprecipitates consist at least in part of immune reactants. We discuss the relationship of these findings to pathogenetic mechanisms in disease.

Aged↗

PubMed2000

Circumventing complement C3 interference in the analysis of carbohydrate-deficient transferrin in fresh serum.

A method for preventing interference by the glycoprotein complement C3 and its beta-globulin split products in the capillary electrophoretic analysis of carbohydrate-deficient transferrin was developed. Inulin was used to activate the alternate complement pathway and convert native C3 into various degradation products whose electrophoretic mobility no longer coincides with the transferrin glycoforms. Capillary electrophoresis and zone electrophoresis on agarose gel were used to monitor reaction conditions for alternate complement pathway activation. Incubation of 50 microL of fresh serum with 180 microL of a 50 mg/mL inulin slurry for 12 h removed the native C3 peak from the beta region. Inulin treatment did not affect electrophoretic behavior of other beta-globulins, including transferrin. Altering the electrophoretic behavior of complement C3, by treating fresh serum with inulin, permits rapid capillary electrophoresis evaluation of carbohydrate-deficient transferrin glycoforms.

Artifacts↗

PubMed2003

Central role of complement in passive protection by human IgG1 and IgG2 anti-pneumococcal antibodies in mice.

Streptococcus pneumoniae is an important cause of morbitity and mortality worldwide. Capsule-specific IgG1 and IgG2 Abs are induced upon vaccination with polysaccharide-based vaccines that mediate host protection. We compared the protective capacity of human recombinant serogroup 6-specific IgG1 and IgG2 Abs in mice deficient for either leukocyte FcR or complement factors. Human IgG1 was found to interact with mouse leukocyte FcR in vitro, whereas human IgG2 did not. Both subclasses induced complement activation, resulting in C3c deposition on pneumococcal surfaces. Passive immunization of C57BL/6 mice with either subclass before intranasal challenge with serotype 6A induced similar degrees of protection. FcgammaRI- and III-deficient mice, as well as the combined FcgammaRI, II, and III knockout mice, were protected by passive immunization, indicating FcR not to be essential for protection. C1q or C2/factor B knockout mice, however, were not protected by passive immunization. Passively immunized C2/factor B(-/-) mice displayed higher bacteremic load than C1q(-/-) mice, supporting an important protective role of the alternative complement pathway. Spleens from wild-type and C1q(-/-) mice showed hyperemia and thrombotic vessel occlusion, as a result of septicemic shock. Notably, thrombus formation was absent in spleens of C2/factor B(-/-) mice, suggesting that the alternative complement pathway contributes to shock-induced intravascular coagulation. These studies demonstrate complement to play a central role in Ab-mediated protection against pneumococcal infection in vivo, as well as in bacteremia-associated thrombotic complications.

Animals↗

PubMedDate not supplied

[The body's nonspecific resistance factors in a localized experimental infection caused by Bacteroides].

Under local experimental infection induced by bacteroides of Fragilis group the factors of nonspecific organism resistance take an active part in the inflammation process. Phase changes of the state of monocytic-phagocytic and complement systems were observed. Peripheral blood leukocyte phagocytic activity decreased at the primary stage, then followed the complement activation by the alternative pathway mainly. The increase of phagocytic and metabolic activities of those phagocytes taking part in the inflammation, the complement at this stage is activated due to the classical pathway while being at the stage of clinic manifestation. Levels of antibody titres are also increasing.

Animals↗

PubMed1993

Genetic deficiencies of the complement system and association with disease--early components.

Genetic deficiency of one of the early components of the classical pathway of complement (C1q, C1r, C1s, C4 and C2) is often associated with clinical symptoms and immunochemical abnormalities common in idiopathic autoimmune diseases, such as lupus erythematosus, but also with an increased incidence of various, local and generalized infections. These observations are consistent with the current view of the complement system's role in handling immune complexes and combating microbial invasion. However, the absence of absolute correlations in these experiments of nature suggests that genetic defects of the classical pathway act only epistatically to other host factors and the primary etiologies of the associated diseases. In contrast, the strong association of properdin and factor D deficiency with serious infections caused by encapsulated Gram-negative bacteria suggests a more immediate involvement of the alternative pathway in a specific segment of immunity and its pathology. This concept is also supported by the primordial role of the alternative pathway in the evolution of the complement system and the apparent lethality of factor B deficiency. The gene structures of most of these early components have now been elucidated providing the basis for detailed analyses of the defective alleles, the determination of carrier status, and prenatal diagnosis.

Complement C1↗

PubMed1994

Purification from Vipera lebetina (desert adder) venom of a protein that depletes human complement.

A rapid and efficient procedure for purification from Vipera lebetina venom of a low molecular weight anticomplement protein is described. The procedure used gel filtration on Superose 12, followed by ion-exchange chromatography on a Mono Q column. The purified protein migrated on SDS-PAGE as a single band of about 25,000 Da under nonreducing conditions and as a band of 16,000 Da under reducing conditions. Its isoelectric point was estimated to be 7.6 +/- 0.1. The isolated Vipera lebetina protein was found to decrease the hemolytic activity in human serum measured by assays for classical pathway and alternative pathway activation. The loss of the complement activity could be ascribed, at least in part, to a proteolytic cleavage of the alpha chains of C3 and C4. This protein was also found to be without action on human blood coagulation and on purified fibrinogen and Factor B.

Blood Coagulation↗

PubMed1986

Leishmania species: mechanisms of complement activation by five strains of promastigotes.

The interaction of fresh serum with promastigotes of Leishmania major, L. donovani, L. mexicana mexicana, L. mexicana amazonensis, and L. braziliensis guyanensis results in lysis of all strains tested with either fresh human or guinea pig serum at 37 C for 30 min. Lysis does not occur in the cold and requires divalent cations and complement that is active hemolytically. Serum deficient in the eighth component of complement is not lytic. Lysis of L. major, L. mexicana, and L. braziliensis proceeds fully in human serum containing EGTA/Mg2+ or in guinea pig serum deficient in the fourth complement component. These species consume only small amounts of C4 from human serum and do not require calcium to optimally bind C3. The data indicate that all are activators of the alternative complement pathway and that the classical pathway is not required for the lysis of these organisms. Promastigotes of L. donovani, in contrast, activate the classical pathway. The presence of calcium is required for both optimal C3 binding and parasite lysis, and L. donovani promastigotes consume C4 when incubated in human serum. In high concentrations, human serum agglutinates all tested Leishmania spp. The agglutinating factor does not require divalent cations, is heat stable, and works at 4 C, suggesting that it is an antibody. This "naturally occurring" antibody cross reacts with all Leishmania spp. and agglutinates them. The adsorption of serum with any Leishmania species or with beads that are Protein A coated, removes the agglutinogen. This factor causes a slight enhancement in alternative pathway activation by L. major and mediates the classical activation by L. donovani. In adsorbed serum, L. donovani promastigotes only weakly activate the alternative complement pathway. Increased concentrations of adsorbed serum are therefore necessary for lysis to proceed. The titer can be partially restored by the addition of heat inactivated serum. Using purified components of the classical cascade, we are unable to visualize surface bound C3 on L. donovani promastigotes unless heat inactivated serum is also present. We conclude that all Leishmania spp. promastigotes are susceptible to lysis by normal serum independent of antibody. The presence of small amounts of naturally occurring antibody in human serum enhances the susceptibility of L. donovani promastigotes to lysis by activating the classical complement pathway.

Agglutinins↗

PubMed1982

Opsonization and phagocytosis of mucoid and non-mucoid Pseudomonas aeruginosa strains.

The interaction between Pseudomonas aeruginosa strains (6 non-mucoid and 4 mucoid strains), serum factors and phagocytic cells was investigated. Strains were incubated in different concentrations of normal serum, chelated serum (with only the alternative complement pathway intact), IgG, Cls, C2 and C3 deficient serum and immune serum. After incubation complement consumption, C3 fixation and phagocytosis by polymorphonuclear leukocytes (PMN) were measured. In contrast to normal serum, immune serum raised against a mucoid and a non-mucoid strain exhibited heat-stable opsonic activity. All ten Pseudomonas aeruginosa strains were able to activate complement in 20% normal serum, leading to deposition of the activated form of the third complement component on the bacterial cell wall and to subsequent recognition and phagocytosis. One mucoid and four non-mucoid strains activated the alternative complement pathway and were effectively opsonized in chelated or in Cls, C2 or IgG deficient serum. Although mucoid strains were less able to activate complement via the alternative route, no differences were observed in opsonic requirements and phagocytosis between mucoid and non-mucoid strains.

Complement System Proteins↗

PubMed1980

Alternative and classical complement pathway activity in sera from colostrum-fed and colostrum-deprived neonatal pigs.

Haemolytic assays were used to compare alternative and classical complement (C) pathway activities in sera obtained from neonatal pigs reared on porcine colostrum, bovine colostrum or an immunoglobulin-free synthetic diet. Dramatic increases in immunoglobulin concentrations were noted in the colostrum-fed animals during the first day of life, but there was not a concurrent, marked increase in either classical or alternative C pathway activity. Whether fed on homologous or heterologous colostrum, neonatal pigs had a similar gradual increase in alternative and classical C pathway activity in the post-natal period. If direct passive absorption of C components occurs in newborn pigs, it has only a minor influence on functional levels of alternative and classical C pathway activity in their sera. In pigs fed homologous and heterologous colostrum there was, respectively, an 83% and 80% increase in classical pathway activity, but only a 13% and 12% increase in alternative pathway activity during the first 3 days of life. Pigs fed the immunoglobulin-free synthetic diet had a 37% increase in classical C and a 24% increase in alternative C pathway activity. Part of the increase in classical C pathway activity in the post-natal period may be caused by a stimulating factor in colostrum. Most if not all of the increase in alternative C pathway activity and some of the increase in classical C pathway activity is most likely caused by normal humoral homeostatic mechanisms in the neonatal pig.

Animals↗

PubMed1989

Inhibition of complement activation in aged individuals due to increased plasma fibronectin concentration.

The influence of fibronectin levels on complement activation by immune complexes and non-immune activators in elderly humans was investigated. The present study demonstrates for the first time a shift in complement activation from the classical to the alternative pathway, if the fibronectin concentration rises above a certain level (near 1 mg/ml). Plasma of elderly individuals often contains large amounts of fibronectin, the reason for which is unknown. While C1 consumption is inhibited under these conditions, C3 depletion remains largely unaffected. This could be due to a compensatory triggering of the alternative reaction sequence caused by fibronectin deposition at and blockade of C1-activating sites. Probable physiologic implications of this changed complement activation pattern are discussed.

Adult↗

PubMed1997

A novel protein that participates in nonself discrimination of malignant cells by homologous complement.

The human complement (C) system protects an individual against substances of nonself origin, including xenografts and microbial pathogens. Human cells express C-regulatory proteins, CD46 and CD55, thereby circumventing attack by C3, a major effector of C. Nevertheless, certain malignant cells, particularly those undergoing apoptotic stress, can activate homologous C, overcoming the regulatory actions of CD46 and/or CD55. The molecular mechanisms whereby malignant cells are tagged by homologous C3 remain largely unknown. We identified a novel gene product that converts human cells into targets for homologous complement. Only malignant cells and cell lines exposed to Fas or X-irradiation stimuli produced this protein, designated M161Ag, which was an unglycosylated 43-kDa protein. Analysis of cloned cDNAs indicated that this molecule was a secretory protein containing five amino acids encoded by TGA codons. Its functions were unique in that once secreted from the tumor cells, it bound back to the surface of these cells and activated homologous complement (C3) via the alternative pathway, allowing for C3 deposition on the membrane. This molecule may offer new insight into innate immunity; surveillance of tumor cells by complement is a common feature in the human immune system.

Amino Acid Sequence↗

PubMed1993

Serum factors and polymorphonuclear leukocytes in human host defence against Neisseria meningitidis. Studies of interactions with special reference to a chemiluminometric technique.

Luminol enhanced chemiluminescence (CL) was used to study the interactions of various serogroups of opsonized or nonopsonized meningococci (MC) with polymorphonuclear leukocytes (PMNL), and the results were compared with those of functional (serum bactericidal activity = SBA, phagocytic killing = PK) and nonfunctional (EIA and IFL) antibody tests. The inherent problems of inter-assay and day-to-day variations of the CL technique were solved by indexing the responses with the use of an international serogroup X reference MC strain (NCTC 10790). When opsonized with serum from healthy adults without a history of meningococcal (MC) disease, the pathogenic MC strains of serogroups A, B, C, Y (Orebro variant) and W-135 gave significantly lower CL indexes than the apathogenic ones of serogroups Y, Z, and 29E and of nongroupable strains (p < 0.001). The same patterns were obtained when the strains were opsonized with serum from Swedish children 1-3 years old and also with serum A Sudanese children. Higher levels of antibodies against MC serogroup A polysaccharide were found in sera from Sudanese children than in those of Swedish ones. Correspondingly, the CL indexes for MC of serogroup A were somewhat higher for the Sudanese children than for the Swedish ones. In spite of this an MC epidemic due to a serogroup A strain could not be avoided in Sudan, but could in Sweden, where the same strain was introduced, indicating that other factors than serum immunity are of importance for avoidance of an MC serogroup A epidemic. In various series of experiments it was shown that the CL technique, like the SBA and PK tests, can discriminate between functional and nonfunctional antibodies in healthy individuals, in patients during and after MC disease and before and after vaccination, whereas EIA and IFL tests cannot. It was also shown that in the presence of serum from healthy individuals without a history of MC disease, both the classical and alternative complement pathways are activated to kill or to induce phagocytosis of apathogenic MC, whereas only the classical pathway is activated for the pathogenic ones. In the presence of serum from an individual vaccinated with MC capsular polysaccharide vaccine (high levels of anti-MC capsular polysaccharide antibodies), the pathogenic MC activate both the classical and alternative complement pathways for induction of phagocytosis. It is concluded that the standardized CL indexing technique for pathogenic and apathogenic MC has several advantages over the laborious and cumbersome SBA and PK assays in demonstrating and measuring the presence of functional anti-MC antibodies. It also has the capacity to discriminate pathogenic from apathogenic MC, and under certain circumstances it might be used as a diagnostic tool.

Adolescent↗

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↗

PubMed2001

Cytolytic complement activity in otitis media with effusion.

Otitis media with effusion (OME) is a chronic inflammation persisting in the middle ear cavity of at least 8 weeks duration. Middle ear effusion (MEE; n = 38), samples from children suffering from OME were investigated for their direct cytolytic activity or an ability to enhance complement lysis of unsensitized bystander cells. Thirteen of the 38 MEEs had direct endogenous haemolytic activity and 27 samples had an ability to enhance serum-initiated lysis. Using an enzyme immunoassay, high levels of terminal complement complexes (TCC) were detected in the MEE samples (mean 34.1 microg/ml, range 5--89 microg/ml). This indicated strong local complement activation that had progressed to the terminal stage. As one potential factor promoting complement activation we identified both monomeric and trimeric properdin in MEE by Western blotting. By stabilizing C3 and C5 convertases properdin accelerates the alternative and terminal pathways of complement. On the other hand, the membrane attack complex (MAC) inhibitor CD59, which was found to be extensively shed into the MEE in a functionally active form, may control excessive cytotoxicity of the MEE. In conclusion, intense complement activation, up to the terminal level, maintains ongoing inflammation in the middle ear cavity and can pose a threat to the local epithelium.

CD59 Antigens↗

PubMed1999

Recombinant glycoproteins that inhibit complement activation and also bind the selectin adhesion molecules.

Soluble human complement receptor type 1 (sCR1, TP10) has been expressed in Chinese hamster ovary (CHO) DUKX-B11 cells and shown to inhibit the classical and alternative complement pathways in vitro and in vivo. A truncated version of sCR1 lacking the long homologous repeat-A domain (LHR-A) containing the C4b binding site has similarly been expressed and designated sCR1[desLHR-A]. sCR1[desLHR-A] was shown to be a selective inhibitor of the alternative complement pathway in vitro and to function in vivo. In this study, sCR1 and sCR1[desLHR-A] were expressed in CHO LEC11 cells with an active alpha(1,3)-fucosyltransferase, which makes possible the biosynthesis of the sialyl-Lewisx (sLex) tetrasaccharide (NeuNAcalpha2-3Galbeta1-4(Fucalpha1-3)GlcNAc) during post-translational glycosylation. The resulting glycoproteins, designated sCR1sLex and sCR1[desLHR-A]sLex, respectively, retained the complement regulatory activities of their DUKX B11 counterparts, which lack alpha(1-3)-fucose. Carbohydrate analysis of purified sCR1sLex and sCR1[desLHR-A]sLex indicated an average incorporation of 10 and 8 mol of sLex/mol of glycoprotein, respectively. sLex is a carbohydrate ligand for the selectin adhesion molecules. sCR1sLex was shown to specifically bind CHO cells expressing cell surface E-selectin. sCR1[desLHR-A]sLex inhibited the binding of the monocytic cell line U937 to human aortic endothelial cells, which had been activated with tumor necrosis factor-alpha to up-regulate the expression of E-selectin. sCR1sLex inhibited the binding of U937 cells to surface-adsorbed P-selectin-IgG. sCR1sLex and sCR1[desLHR-A]sLex have thus demonstrated both complement regulatory activity and the capacity to bind selectins and to inhibit selectin-mediated cell adhesion in vitro.

Animals↗