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PubMed2000

DNA-Based immunization with Trypanosoma cruzi complement regulatory protein elicits complement lytic antibodies and confers protection against Trypanosoma cruzi infection.

A complement regulatory protein (CRP) of Trypanosoma cruzi was evaluated as a vaccine candidate in a murine model of experimental T. cruzi infection. Recombinant CRP derived from an Escherichia coli expression system and a plasmid encoding the full-length crp structural gene under the control of a eukaryotic promoter were used to immunize BALB/c mice. Immunization with both protein and DNA vaccines resulted in a Th1-type T-cell response, comparable antibody titers, and similar immunoglobulin G isotype profiles. Only mice immunized with the crp DNA plasmid produced antibodies capable of lysing the parasites in the presence of complement and were protected against a lethal challenge with T. cruzi trypomastigotes. These results demonstrate the superiority of DNA immunization over protein immunization with the recombinant CRP. The work also supports the further investigation of CRP as a component of a multigene, anti-T. cruzi DNA vaccine.

Animals↗
PubMed1968

Nature of the complementation products formed by a complementing mutant of neurospora crassa.

The mutant am-14 produces no active nicotinamide adenine dinucleotide phosphate-linked glutamate dehydrogenase (GDH) and no protein showing immunological cross-reaction with the enzyme. Nevertheless, it shows complementation with several other am mutants in heterokaryons. Active GDH can be extracted from heterokaryons formed from am-14 and other mutants which, by themselves, produce more or less inactive varieties of the enzyme. The enzyme from am-14 + am-3 heterokaryons can be partially separated from am-3 mutant GDH on a diethylaminoethyl cellulose column. It is characterized by abnormally high thermolability and by a capacity for activation by glutamate. By the same procedure as brings about hybridization between mutant GDH proteins, it has been possible to recover enzyme with the properties of pure am-3 GDH from a partially purified am-14 + am-3 GDH preparation which was initially substantially free of unhybridized am-3 enzyme. This is interpreted as evidence that the active complementation product is a hybrid oligomer containing am-3 monomers and also am-14 monomers, the latter being unable to aggregate by themselves. Heterokaryons formed from am-14 and wild type produce GDH of abnormally high thermolability, presumably due to the formation of am-14 + am(+) hybrids.

Alleles↗
PubMed1994

Characterization of strains of Neisseria meningitidis recovered from complement-sufficient and complement-deficient patients in the Western Cape Province, South Africa.

Complement deficiency has been associated with increased susceptibility to meningococcal disease. In order to determine whether special meningococcal strains caused disease in complement-deficient (CD) patients, 17 Neisseria meningitidis strains recovered from patients in the Western Cape Province, South Africa, known to be CD were compared with 124 routine isolates obtained from patients living in the same area. Serogrouping of the strains from the CD subjects revealed that the common serogroups, particularly serogroup B, predominated. However, the prevalence of rare serogroups among isolates from CD subjects was significantly higher than that found among isolates from the control group. Sero- and subtyping of the class 1 and class 2 or 3 outer membrane proteins showed no significant difference between isolates from CD subjects and the routine clinical isolates. Multilocus enzyme electrophoresis of the 141 isolates revealed six clusters of electrophoretic types (ETs) and two unrelated ETs. The same degree of genetic diversity existed in ETs of isolates from CD subjects and the control group. However, the ET-5 complex, which is known to be associated with epidemic disease, was found in 22 (18%) of the routine clinical isolates but in none of the isolates from the CD subjects. This difference was marginally significant. What was highly significant was the finding that 8 of the 17 isolates from CD subjects were in one ET cluster, cluster F, which comprised a total of 20 isolates. Thus, our results show a difference in the clonal compositions of the strains that infect CD subjects in comparison with the clonal compositions of those that cause clinical infections in the population at large.

Adolescent↗
PubMed1986

Complementation of a bovine papilloma virus low-copy-number mutant: evidence for a temporal requirement of the complementing gene.

We identified a bovine papilloma virus function encoded by the E6/E7 gene, which is required for both BPV high-copy-number replication and maintenance of transformation of cultured cells. A cDNA copy of this gene was isolated and expressed from a retrovirus vector. We found that complete complementation of a BPV low-copy-number mutant (dl576) by the cDNA encoding the E6/E7 gene was temporally dependent. When both the E6/E7 cDNA and dl576 were introduced together into cells, wild-type replication and stable transformation resulted. In contrast, introduction of the complementing cDNA into cells already carrying dl576 led to only partial amplification of the resident mutant DNA accompanied by a restoration of the transformed phenotype. These results, along with other findings, suggest that the establishment of BPV plasmid replication occurs in two stages: an initial amplification of the incoming DNA followed by stable homeostatic replication which maintains the existing copy number.

Animals↗
PubMed1978

A comparison of complement fixation, indirect immunofluorescence for viral late antigens, and anti-complement immunofluorescence tests for the detection of cytomegalovirus specific serum antibodies.

It was shown that, on average, the titres of the sera obtained by both the anti-complement immunofluorescence (ACIF) and indirect immunofluorescence for viral late antigens (IFA-LA) procedures were approximately eight times higher than those obtained by complement fixation. There was no significant difference between the mean ACIF and IFA-LA titres, but the former method was preferred because it was not affected by non-specific staining. When 406 sera were screened for the presence or absence of antibodies, only five sera (1.2%) gave discordant results with the three tests. None of the tests could detect all of the sera that contained specific antibodies while each test detected over 98% of these sera. Thus, the increased sensitivity of the immunofluorescence procedures did not result in an appreciably increased rate of detection of cytomegalovirus seropositive sera.

Antibodies, Viral↗
PubMed1996

Complements of the season: the hazards of testing for complement activation.

As some of the subtleties of the new era of biological testing become appreciated, a few of the more recently introduced tests are starting to cause concern. The evaluation of the ability of a material to activate complement comes into this category. This article explains complement and its activation and attempts to rationalize the need for testing in this complex area.

Complement Activation↗
PubMed1976

Complement receptor lymphocytes in the rabbit. II. The effect of immunization on the complement receptor lymphocyte population in the craining lymph node.

In an attempt to determine the effect of immunization on the size and nature of the complement receptor lymphocyte (CRL) and surface immunoglobulin (SIg)-bearing lymphocyte (B cell) populations, rabbits were injected with 1 mg alum-precipitated keyhole limpet hemocyanin and the cells of the draining popliteal lymph nodes were examined at various intervals for these populations. Comparison to unimmunized control lymph nodes revealed that immunization resulted in an approximate doubling of the percentages of both CRL and B cell populations by the peak of the response, while the cell number increased about 7-to 8-fold. Kinetic analysis of the response indicated that the percentages of CRL and B cells increased essentially in parallel beginning within 40 h after immunization. Simultaneous assay of complement receptor (CR) and SIg disclosed that CRL remained a B cell subpopulation throughout the response. To determine whether cell division could account for the increases in total cell number and per cent CRL and B cells, immunized rabbits were given 3H-thymidine in vivo, and the fraction of labeled (dividing) cells was determined by autoradiography. Results of such experiments were consistent with the possibility that the early increase in cell number and the increase in CRL and B cell percentages were a result of trapping and/or homing of lymphocytes migrating from the peripheral blood. A significant amount of lymphocyte division occurred during later stages of the response.

Animals↗
PubMed1985

The role of complement receptor positive and complement receptor negative B cells in the primary and secondary immune response to thymus independent type 2 and thymus dependent antigens.

Both complement receptor positive (CR+) and complement receptor negative (CR-) B cells have been shown to be involved in the primary immune response to PC-Hy (phosphocholine conjugated hemocyanin), a thymus dependent (TD) antigen which preferentially induces antibody secretion in Lyb-5+ B cells during a primary adoptive transfer assay. CR+ and CR- B cells also responded in a primary adoptive transfer assay to TNP-Ficoll, a thymus independent type 2 (TI-2) antigen which activates only Lyb-5+ B cells. When the secondary immune response to PC-Hy and TNP-Ficoll were analyzed, it was found that most of the immune memory to both antigens was present in the CR- B cell subset. The CR- B cell subset also dominated the secondary immune response to PC-Hy in immune defective (CBA/N X DBA/2N)F1 male mice. These data indicate that CR- B cells dominate the memory response in both the Lyb-5+ and Lyb-5- B cell subsets of normal and xid immune defective mice and suggest that Lyb-5+ and Lyb-5- B cells can be subdivided into CR+ and CR- subsets.

Animals↗
PubMed1975

Complement sensitivity of somatic hybrids of a complement-resistant murine leukemia cell line.

RADA-1 cells (H-2a), a murine leukemia cell line maintained by serial transfer in histocompatible recipients expressing thymus-leukemia (TL) 1, 2, 3 antigenic determinants, resisted the cytotoxic effects of guinea pig complement (GPC) and TL antiserum. The cells expressed a lower density of TL antigens than did ASL-1 cells, another TL(+) leukemia cell line expressing the same determinants and susceptible to complement (C)-mediated lysis. Stable somatic cell hybrids of RADA-1 cells and LM(TK)- cells (H2k), a TL(minus) thymidine kinase-deficient mutant of mouse L cells, were selected in hypoxanthine-aminopterin-thymidine medium. The hybrid cells expressed the H-2 antigens of both parents and shared a hybrid karyotype. They formed TL 1, 2, 3 antigens as determined by immunofluorescence, mixed hemagglutination methods, the direct isolation of TL antigens from Nonidet P40 extracts of the cells, and the capacity of the cells to reduce by absorption the known titers of TL antiserum. These hybrid cells lost the capacity to resist lysis by TL antiserum and GPC. They were susceptible to the cytotoxic effects of TL 1, 2, 3; TL 2; OR TL 1, 3 antiserum and GPC, even though the density of TL antigens associated with the cells was approximately 25% of their resistant RADA-1 parental cells. These results indicated that the mechanism of resistance to C-mediated lysis was genetically separable from the expression of TL antigens by the cells and that the susceptibility of the cells to the cytotoxic effects of antiserum was related only in part to the density of TL antigens expressed by the cells.

Animals↗
PubMed1991

Effect of complement-protein-C3b density on the binding of complement factor H to surface-bound C3b.

Various amounts of the activation fragment C3b of the complement (C) protein C3 were coupled to Sepharose 4B by catalysis with the C3 convertase of the alternative pathway of C. The binding of radioactively labelled C proteins B and H (= factor H) to the C3b-carrying particles was assayed. It was found that the relative binding of H, but not of B, fell rapidly with decreasing densities of solid-phase C3b, suggesting a sigmoidal relationship between C3b density and binding of H. To study the phenomenon in more detail, preformed C3b was coupled to activated thiopropyl-Sepharose 6B at various densities. By using this model system, it was shown that the binding of H/unit amount of C3b was positively correlated to C3b density up to a C3b concentration of about 0.5 mg/ml of gel, whereas binding of B was independent of C3b density. The results show that accumulation of high densities of C3b on a surface creates high-affinity binding sites for H. Because H has recently been shown to form dimers in solution, the interaction of dimeric H with neighbouring C3b molecules is a likely explanation for the phenomenon. The C3b density effect may be a regulatory mechanism keeping the activation of the alternative pathway of C on activating surface within reasonable limits.

Complement C3-C5 Convertases↗
PubMed1975

Interactions of C-reactive protein with the complement system. II. C-reactive protein-mediated consumption of complement by poly-L-lysine polymers and other polycations.

Cationic homopolymers of poly-L-lysine were found to activate complement (C) via C-reactive protein (CRP) and deplete C3 and C5 as well as early-acting C components. Maximum C consumption was obtained with polymers of 2,000-8,000 daltons; polymers of 1,700, 11,000, and 23,000 daltons were intermediate in reactivity, while L-lysine, lysyl-L-lysine, tetra-L-lysine, and polymers of 70,000-400,000 daltons lacked significant C-consuming activity. Naturally occurring polycations which consumed C in the presence of CRP included myelin basic proteins, cationic proteins of rabbit leukocytes, and both lysine- and arginine-rich histones; poly-L-arginine polymers of 17,000 but not 65,000 daltons also were C-consuming. Polycations without such reactivity included poly-L-orithine (5,000 and 165,000 daltons), egg white and human lysozymes, and Polybrene. The polycations which failed to induce C consumption via CRP, inhibited its consumption by both active polycations and by C-polysaccharide (CPS). The relative inhibitory capacity of phosphorylcholine and polycations in CPS- and polycations-CRP systems was consistent with the concept that phosphate esters and polycations react at the same or an overlapping combining site. The ability of certain polycations to activate C via CRP increases the potential for initiation of host reactions via C. The capacity of other polycations to inhibit C activation via CRP introduces a potential for physiologic or pharmacologic manipulation. These considerations would seem to expand the potential role of CRP in the initiation and modulation of the inflammatory response.

Animals↗
PubMed1986

The terminal complement complex in sera deficient in the eighth component of complement (C8).

The terminal complement complex (TCC) was quantified in sera from patients with a genetic deficiency of C8 alpha-gamma or C8 beta. The individual sera contained only trace amounts of TCC compared with a normal serum pool. The content of TCC increased after mixing the two sera, which was consistent with reconstitution of C8 activity. Only a moderate increase in TCC was obtained after zymosan activation of the individual sera, whereas activation of the mixture resulted in high amounts of TCC. C8 was demonstrated in the TCC of both deficient sera. These results may indicate that functional C8 is present in trace amounts despite the genetic deficiency, and that the terminal pathway may function to some extent although not enough to be detectable in less sensitive assays.

Antibodies, Monoclonal↗
PubMed1994

Non-coordinated biosynthesis of early complement components in a deficiency of complement proteins C1r and C1s.

We report on a 60-year-old woman with systemic lupus erythematosus and a total (95%) C1r and a partial (36%) C1s deficiency. The patient complained about cutaneous lesions on forearms and legs without other systemic involvement. Elevated anti-nuclear, anti-native DNA and anti-SSA antibodies were present. The finding of persistently depressed levels of haemolytic complement activity (CH50) on both serum and plasma, associated with normal levels of C3, C4 and C2 components, and normal alternative pathway haemolytic activity showed a deficiency of an early component of the classical pathway. Indeed C1r component was below the limits of detection whereas C1s component was lowered (36%). The depressed CH50 was only corrected by purified C1r. Biosynthesis of C1r and C1s by patient's monocytes was spontaneously normal but not up-regulated by interferon-gamma for C1r alone, whereas the biosynthesis of C1s, but also of interleukin-6, was increased, indicating a specific disregulation of C1r. The deficiency was associated with a lupus syndrome and a fatal assumed septic shock. This is in agreement with other reported cases.

Cells, Cultured↗
PubMed1985

Complement-mediated solubilization of immune complexes and their interaction with complement C3 receptors.

Some of the molecular events in the complement (C)-mediated solubilization of immune complexes (IC) have been clarified in recent years. The solubilization is primarily mediated by alternative C pathway proteins whereas factors in the classical pathway accelerate the process. Components of the membrane attack complex do not participate in the reaction. Besides affecting the size and solubility of circulating IC the interaction with C factors influences the reactivities of the complexes towards fluid phase reactants and mediates the reversible binding of IC to cellular C3 receptors. Our knowledge of the cellular localization, expression and structure of the C3 receptors, especially the C3b (CR1) receptor, has been considerably extended in the last few years, whereas our understanding of the physiological role of these receptors is still fragmentary. However, it is becoming increasingly evident that impaired solubilization of IC in patients with compromised C function may permit the complexes to deviate from their normal pattern of interaction with C3 receptors probably influencing both the organ distribution and clearance of IC and thereby also their phlogistic potentials.

Antigen-Antibody Complex↗
PubMed1975

Complement activation in seropositive and seronegative rheumatoid arthritis. 125I-C1q binding capacity and complement breakdown products in serum and synovial fluid.

1. The detection and quantitation of immune complex-like material in synovial fluid and in serum from patients with joint diseases was done through the measurement of the capacity to bind radiolabeled C1q. It was found that 65% of synovial fluid samples from seropositive or seronegative RA patients had a high C1q binding capacity as compared to other joint diseases. Immune complex-like material was also detected in 63% of serum samples from seropositive RA patients. 2. The existence of C3 or C3PA breakdown products in synovial fluid from most of the synovial fluids from RA patients probably reflects an activation of the complement system occurring in both forms of the disease. C3PA breakdown products were never found in degenerative or post-traumatic joint diseases and only occasionally in other inflammatory arthritis. Apart from their pathogenic significance, these results may have some interest for the clinical investigation of patients with joint diseases.

Arthritis, Rheumatoid↗
PubMed1990

Phagocytosis of Mycobacterium tuberculosis is mediated by human monocyte complement receptors and complement component C3.

We have examined the receptor-ligand interactions and the method of phagocytosis of virulent Mycobacterium tuberculosis by human monocytes. mAb against complement receptors (CR) inhibit adherence and phagocytosis of M. tuberculosis in fresh nonimmune serum. A mAb against the type 1 CR (CR1) inhibits adherence of M. tuberculosis by 40 +/- 5%, and three different mAb against the type 3 CR (CR3) each inhibit adherence by 39 +/- 5% to 47 +/- 4%. A mAb against CR1 used in combination with one of the three mAb against CR3 inhibits adherence by up to 64 +/- 7%. Most strikingly, two mAb used in combination against CR3 inhibit adherence by up to 81 +/- 2%. mAb against other monocyte surface Ag do not significantly influence adherence. In like fashion, mAb against CR but not other monocyte surface Ag inhibit adherence of preopsonized M. tuberculosis in the presence of heat-inactivated serum. By electron microscopy, monocytes ingest all M. tuberculosis that adhere in the presence of nonimmune serum; mAb against CR3 markedly inhibit ingestion. In contrast to CR, the FcR and the beta-glucan-inhibitable receptor for zymosan play little or no role in mediating M. tuberculosis adherence or ingestion. Adherence of M. tuberculosis is serum-dependent, requiring greater than or equal to 2.5% serum for optimal adherence. Heat inactivation of serum markedly reduces adherence of M. tuberculosis (75.5 +/- 7%) and preopsonization of bacteria enhances adherence by 2.9 +/- 0.4-fold. Adherence is also markedly reduced in C3- or factor B-depleted serum; repletion with C3 or factor B increases adherence by 2.1 +/- 0.4-fold and 1.86 +/- 0.05-fold, respectively. Fab anti-C3 IgG markedly inhibits monocyte adherence of preopsonized M. tuberculosis (71 +/- 1%). C component C3 is fixed to M. tuberculosis by the alternative C pathway as determined by a whole bacterial cell ELISA. Human monocytes ingest M. tuberculosis by conventional phagocytosis as viewed by electron microscopy. This study demonstrates that human monocyte CR1 and CR3 mediate phagocytosis of M. tuberculosis and C component C3 in serum is acting as the major bacterium-bound ligand.

Antibodies, Monoclonal↗
PubMed2003

Complement receptors type 1 (CR1, CD35) and 2 (CR2, CD21) cooperate in the binding of hydrolyzed complement factor 3 (C3i) to human B lymphocytes.

The C3b-binding receptor, CR1/CD35, supports CR2/CD21-mediated activation of complement by human B lymphocytes, possibly by associating with CR2 to promote or stabilize the binding of hydrolyzed C3 (C3i), the primary component of the AP convertase, C3i-Bb. To evaluate this hypothesis, we examined the uptake kinetics and binding equilibria for C3i dimer interaction with human blood cells in the absence and presence of CR1- and CR2-blocking mAb. C3i displayed dual uptake kinetics to B lymphocytes, comprising of rapid binding to CR1 and slower binding to CR2. The forward rate constants (k(1)) for CR1 and CR2, operating independently, differed ca. 9-fold (k(1)=193+/-9.4 and 22.2+/-6.0 x 10(3) M(-1)s(-1), respectively). Equilibrium binding of C3i to B lymphocytes was also complex, varying in strength by ca. 13-fold over the C3i concentration range examined. The maximum association constant (K(a, max)=109+/-27.2 x 10(7) l/mole) was ca. 9- and 6-fold greater, respectively, than those for CR1 or CR2 acting alone (K(a)=13.2+/-5.3 and 18.5+/-3.5 x 10(7) l/mole). The high avidity of the CR1-CR2 complex for C3i is consistent with its rates of C3i uptake and release being determined by CR1 and CR2, respectively.

B-Lymphocytes↗
PubMed1981

Hemolysis by the complement of tanned erythrocytes coated with cobra venom factor: a sensitive method to detect the alternative complement pathway activity of serum.

Sheep (Esh), human (Ehu), rabbit (Erab) or guinea pig (Egp) erythrocytes were treated with tannic acid and coated with cobra venom factor (CoVF), which activates the alternative complement pathway (ACP). Tanned erythrocytes (TE) coated with CoVF (TECoVF) were efficiently hemolyzed by guinea pig serum l(GPS) and/or rabbit serum (RabS) in Mg2+-EGTA-GVB (gelatin veronal-buffered saline containing 2 mM MgCl2 and 10 mM ethyleneglycol-bis(beta-aminoethyl ether)N,N'-tetraacetate). The reactivity of TEsh-CoVF, TEhu-CoVF and TErab-CoVF to the ACP of guinea pig and/or rabbit increased with the increased amount of CoVF fixed on TE until it was sensitive enough to be hemolyzed by serum diluted over 80 times in Mg2+-EGTA-GVB. The hemolysis of TECoVF by GPS was confirmed to be the result of ACP activation by the findings that the reaction was inhibited in EDTA-GVB, heating of GPS at 50 degrees C diminished its hemolytic potency, and fractions of factor B and factor D were essential to the sensitization of TECoVF for hemolysis by GPS in EDTA-GVB. On the other hand, none of the TE coated with CoVF were hemolyzed by human serum (HuS) diluted over 1 : 40. Although the low efficiency of HuS in TE-CoVF hemolysis remains to be explained, TE-CoVF will be useful for the detection of ACP activity of guinea pig and rabbit sera.

Animals↗