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Effect of inherited deficiency of the fifth component of complement on arthritis induced in mice by Mycoplasma pulmonis.

Mycoplasma pulmonis inoculated parenterally into mice deficient in the fifth component of complement (C5) caused a chronic arthritis of significantly greater magnitude than in immunologically normal mice. During the chronic phase of arthritis M pulmonis organisms were isolated from the joints and organs of C5 deficient mice more frequently and in larger numbers than from immunologically normal mice. The implications of the results are discussed in relation to the pathogenesis of M pulmonis induced arthritis and human connective tissue diseases.

Animals↗
PubMed2026

In C5-heterozygous intercrosses, the proportion of C5-homozygous-null female offspring exceeds the expected Mendelian ratio.

The complement system has functions beyond host defense, including roles in development and reproduction. However, the role of complement C5 in fertilization and early embryonic development remains unclear. Here, we investigated the reproductive phenotype of C5-deficient mice on a BALB/c background. C5-/- mice were fertile and showed no obvious reproductive abnormalities under standard laboratory housing conditions. However, offspring from C5+/- × C5+/- mating showed a significant deviation from the expected Mendelian distribution, with an increased proportion of female C5-/- offspring, whereas male offspring showed no comparable distortion. In vitro fertilization reproduced this skewed ratio which was detectable at the blastocyst stage, suggesting that the underlying mechanism operates during fertilization or preimplantation development. Parent-of-origin analysis further suggested a contribution of maternal C5. During preimplantation development, C5, C5a receptor 1 (C5ar1), and C5a receptor 2 (C5ar2) mRNA levels showed distinct dynamic expression profiles. These findings revealed an unexpected sex- and genotype-dependent reproductive phenotype associated with C5 deficiency and suggest that C5-dependent signaling may contribute to genotype-dependent selection during fertilization or preimplantation development. The dynamic expression of C5a receptors further supports a potential role for C5a signaling in early embryonic development and expands the biological role of complement beyond immune defense to include regulation of mammalian reproduction.

complement↗
PubMed1988

Complement C3 and C5 degradation products during hemodialysis treatment: study of an index of membrane bioincompatibility.

In 10 hemodialyses (HD) with cuprophan (CU) and 10 with polyacrylonitrile (PAN), signs of complement activation were investigated by following arterial and venous levels of C3a, C3d and C5a, in order to propose a marker of bioincompatibility. Despite large individual variabilities, significant increases of these molecules were detected at t 20 min, particularly with CU device in the artery and more marked in the vein except for C3d with PAN. During the later stage of HD, while C3a and C5a levels gradually declined, but remained significantly higher than t 0 in all the patients treated with CU, the C3d concentration reached a plateau suggesting a continuous complement activation throughout HD. HD using PAN membranes were associated with a lower C3a, C3d and C5a generation and fewer dialyses generating these products. In some dialyses the higher arterial level of these molecules suggests an extra-dialyzer complement activation especially with PAN membrane. Although C5a venous levels appeared to be the more significant index of complement activation, for clinical purposes we propose the C3d arterial measurement as a reliable, non-expensive and technically simple indicator of membrane intolerance.

Acrylic Resins↗
PubMed1979

Infection in patients with systemic lupus erythematosus. Association with a serum inhibitor of complement-derived chemotactic activity.

We have found subnormal amounts of chemotactic activity in zymosan-treated sera from 13 of 29 patients with systemic lupus erythematosus (SLE). As an explanation for this abnormality, the presence of a uniquely specific, heat-stable inhibitor of complement (C5)-derived chemotactic activity has been documented in sera from 11 of these patients. Sera from 2 other patients contained elevated levels of nonspecific, heat-labile chemotactic factor inactivator (CFI) activity. The serum from 1 patient contained the heat-stable inhibitor as well as elevated levels of CFI. Patients with SLE whose sera contained the heat-stable inhibitor had more active disease clinically, but otherwise they were indistinguishable from patients without the inhibitor. When patients with the heat-stable inhibitor improved clinically, this usually was accompanied by a decrease in serum inhibitory activity. Only one episode of bacterial infection was observed among 16 patients with SLE whose sera yielded normal amounts of chemotactic activity after treatment with zymosan. In contrast, 7 of 11 patients with SLE whose sera contained the heat-stable inhibitor suffered serious bacterial infections. The presence of this heat-stable inhibitor in sera from some patients with SLE may contribute, in part, to their increased susceptibility to infection.

Adolescent↗
PubMed1987

Covalent association of C3b with C4b within C5 convertase of the classical complement pathway.

The C5 convertase of the classical complement pathway is a complex enzyme consisting of three complement fragments, C4b, C2a, and C3b. Previous studies have elucidated functional roles of each subunit (4, 6, 7), but little is known about how the subunits associate with each other. In this investigation, we studied the nature of the classical C5 convertase that was assembled on sheep erythrocytes. We found that one of the nascent C3b molecules that had been generated by the C3 convertase directly bound covalently to C4b. C3b bound to the alpha' chain of C4b through an ester bond, which could be cleaved by treatment with hydroxylamine. The ester bond was rather unstable, with a half-life of 7.9 h at pH 7.4 and 37 degrees C. Formation of the C4b-C3b dimer is quite efficient; e.g., 54% of the cell-bound C3b was associated with C4b when 25,000 molecules of C4b and 12,000 molecules of C3b were present per cell. Kinetic analysis also showed the efficient formation of the C4b-C3b dimer; the rate of dimer formation was similar to or even faster than that of cell-bound monomeric C3b molecules. These results indicate that C4b is a highly reactive acceptor molecule for nascent C3b. High-affinity C5-binding sites with an association constant of 2.1 X 10(8) L/M were demonstrated on C4b-C3b dimer-bearing sheep erythrocytes, EAC43 cells. The number of high-affinity C5-binding sites coincided with the number of C4b-C3b dimers, but not with the total number of cell-bound C3b molecules. Anti-C4 antibodies caused 80% inhibition of the binding of C5 to EAC43 cells. These results suggest that only C4b-associated C3b serves as a high-affinity C5 binding site. EAC14 cells had a small amount of high-affinity C5 binding sites with an association constant of 8.1 X 10(7) L/M, 100 molecules of bound C4b being necessary for 1 binding site. In accordance with the hypothesis that C4b-associated C4b might also serve as a high-affinity C5-binding site, a small amount of C4b-C4b dimer was detected on EAC14 cells by SDS-PAGE analysis. Taken together, these observations indicate that the high-affinity binding of C5 is probably divalent, in that C5 recognizes both protomers in the dimers. The high-affinity binding may allow selective binding of C5 to the convertase in spite of surrounding monomeric C3b molecules.

Animals↗
PubMed1988

Complement activation in patients with renal failure as detected through the quantitation of fragments of the complement proteins C3, C5, and factor B.

Using sensitive and highly specific enzyme-linked immunosorbent assays fragments of the complement proteins C3, C5, and factor B were quantitated in patients with renal failure. During hemodialysis on new cuprophan membranes raised levels not only of C3a, but in addition of activated C3, C5a, and Ba were demonstrated. In patients with chronic renal failure and end-stage renal disease plasma concentrations of Ba and activated C3 were markedly elevated independent of hemodialysis. This finding is taken as an indication of a continuous recruitment of the alternative pathway of complement in these patients. As the detected complement protein fragments are known to exert immune regulatory functions these findings may imply that these peptides are involved in the maintenance of the immune suppressed state in renal failure.

Acute Kidney Injury↗
PubMed1989

Resistance of highly pathogenic Naegleria fowleri amoebae to complement-mediated lysis.

Weakly pathogenic and nonpathogenic Naegleria spp. are readily lysed by human and guinea pig complement. Highly pathogenic Naegleria fowleri are resistant to complement-mediated lysis. Electrophoretic analysis of normal human serum (NHS) incubated with pathogenic or nonpathogenic Naegleria spp. demonstrates that amoebae activate the complement cascade, resulting in the production of C3 and C5 complement cleavage products. To determine whether surface constituents play a role in resistance to complement lysis, trophozoites of Naegleria spp. were subjected to enzymatic treatments prior to incubation in NHS. Treatment of trophozoites with papain or trypsin for 1 h, but not with neuraminidase, increased susceptibility of highly pathogenic Naegleria fowleri to complement lysis. Treatment of trophozoites with actinomycin D or cycloheximide during incubation with NHS or pretreatment with various protease inhibitors for 4 h did not increase the susceptibility of N. fowleri amoebae to lysis. Neither a repair process involving de novo protein synthesis nor a complement-inactivating protease appears to account for the increased resistance of N. fowleri amoebae to complement-mediated lysis.

Animals↗
PubMed1986

Reduction of total hemolytic complement activity with Naja haje cobra venom factor does not prevent endotoxin-induced lung injury in sheep.

We studied the effects of reducing total hemolytic complement activity with Naja haje cobra venom factor on the lung injury caused by intravenously infused endotoxin in 5 unanesthetized sheep with lung lymph fistulas. In normal sheep, infusions of lipopolysaccharide W from Escherichia coli (1.0 micrograms/kg) intravenously over 30 min caused increases in protein-rich lung lymph flow as well as the appearance in plasma and lung lymph of complement (C5)-derived chemotactic activity for polymorphonuclear leukocytes. Reduction of total hemolytic complement activity by treatment with Naja haje cobra venom factor (12 to 17 U/kg intraperitoneally) did not prevent the lung injury caused by endotoxin and also did not prevent the appearance in plasma and lung lymph of chemotactic activity. We conclude that although complement appears to be activated following intravenously infused endotoxin in sheep, a completely intact complement system is not necessary for endotoxin-induced lung injury.

Animals↗
PubMed1990

Localization of the covalent C3b-binding site on C4b within the complement classical pathway C5 convertase, C4b2a3b.

C5 convertase of the classical complement pathway is a trimolecular protein complex consisting of C4b, C2a, and C3b. In the complex there is an ester bond between C3b and C4b. We analyzed the C5 convertase formed on erythrocytes and localized the covalent binding site of C3b to a small region on C4b. The covalently linked C4b.C3b complex was purified from a detergent extract of the erythrocytes and digested with lysyl endopeptidase. An Mr 17,000 fragment containing the ester linkage between C4b and C3b was purified and its amino-terminal sequence was examined. Two amino acids were obtained at each cycle and identified with those in the sequences of C3 and C4. The sequence derived from C3 corresponded to the thioester region. The sequence derived from C4 started at Ala-1186. Alkali treatment of the fragment yielded an Mr 7,000 peptide derived from C4, which thus appeared to span the region of C4 from Ala-1186 to Lys-1259. Therefore, the covalent C3b-binding site on C4b is located within a 74-residue region of the primary structure. This finding supports the notion that after cleavage of C3 by the C4b2a complex, the covalent binding of metastable C3b to C4b is a specific reaction to form a trimolecular complex with a defined quaternary structure.

Amino Acid Sequence↗
PubMed1986

Human alveolar macrophages synthesize the functional alternative pathway of complement and active C5 and C9 in vitro.

Attachment of protein to agarose beads cultured with macrophages in protein-free medium containing 3H-leucine, shows that de novo synthesis of protein with affinity to the beads takes place. We also found that monoclonal antibodies against human C3c, C3g, and a C9-neoantigen as well as polyclonal antibodies against human C5 and C9, bound to agarose beads that had been kept with the macrophage cultures. Demonstration of C3 derivatives on the agarose beads shows that the essential complement factors of the alternative pathway are synthesized and have been activated by the beads. Deposition of C5 and the detection of a neoantigen of C9 on the beads, indicates that the whole terminal complement pathway has been formed and activated. We conclude that human alveolar macrophages form in vitro the functional alternative pathway of complement, C5 and C9, and we have indirect evidence for synthesis of C6, C7, and C8.

Antibodies, Monoclonal↗
PubMed1992

Mesangiocapillary glomerulonephritis associated with meningococcal meningitis, C3 nephritic factor and persistently low complement C3 and C5.

We report two unusual cases in which mesangiocapillary glomerulonephritis occurred in association with meningococcal infection. C3 nephritic factor, an autoantibody to alternate pathway C3 convertase, was present. Low serum complement C3 and C5 levels were also noted. The depressed complement levels, in conjunction with terminal complement complexes at the upper limit of normal, suggest activation of the early and late complement cascade. We suggest that children presenting with meningococcal infection should have a regular urine examination, as well as full complement measurements performed, in view of the association with hypocomplementaemic mesangiocapillary glomerulonephritis. Similarly, prophylactic penicillin should be prescribed for patients with mesangiocapillary glomerulonephritis and persistently low C5 levels to prevent meningococcal complications.

Adolescent↗
PubMed1986

The relationship between bronchoalveolar neutrophil recruitment and bronchoconstriction induced by a soluble extract of cotton bracts.

Byssinosis is characterized by an obstructive bronchitis in some workers exposed to cotton dust. Mechanisms of airway alterations induced by cotton dust are unknown. To study mechanisms of these alterations, we administered an aqueous extract of cotton bract (CBE) to normal human subjects. After CBE inhalation, we demonstrated reproducible reductions in flow rates of variable magnitude. The percentage of polymorphonuclear leukocytes (PMN) recovered by bronchoalveolar lavage (BAL) and total PMN per milliliter BAL fluid were increased after challenge with CBE, and these parameters were correlated (r = 0.556 and r = 0.553, respectively) with the degree of bronchoconstriction induced by CBE. In addition, chemotactic factors for PMN were noted in BAL fluid and in supernatant from BAL cell cultures. The degree of BAL fluid chemotactic activity correlated with the degree of bronchoconstriction induced by CBE. Assessment of molecular sieve column effluent demonstrated BAL fluid to have 3 distinct peaks of chemotactic activity (approximate molecular weight, greater than 25,000, 10,000, and less than 1,000 daltons) and cell culture supernatant to contain 1 peak (approximate MW, 10,000 daltons). Complement activation as one source of BAL chemotactic activity was suggested by almost complete inhibition of BAL chemotactic activity after incubation with antibody to the fifth component of complement (C5) and detection of C5a des Arg in BAL fluid from some subjects challenged with CBE. These findings suggest that exposure of volunteer subjects to CBE results in a bronchoalveolar inflammatory response related to both complement activation and chemotactic factor synthesis by luminal cells.

Adult↗
PubMed1974

Arthritis, deformities, and runting in C5-deficient mice injected with human rheumatoid arthritis synovium.

The pathogenesis of rheumatoid arthritis might be more easily understood and the efficacy of therapeutic measures might be more accurately assessed if a convenient animal replica of this disease were available for laboratory study. Intraperitoneal injection of homogenates of inflamed synovium taken at operation from patients with rheumatoid arthritis produces inflammatory swelling and deformity in the tail and extremities of a proportion of injected mice from a complement (C5)-deficient inbred strain. Swelling of the paws leads to limping of the affected mice. The lesions are transmissible from generation to generation. The results support the theory of a transmissible agent in the inflamed synovium of rheumatoid arthritis patients.

Animals↗
PubMed1988

Protective mechanism of the immune response to a ribosomal vaccine from Pseudomonas aeruginosa. I. In vivo protection studies in compromised animal models.

Studies of the protective activity of a ribosomal vaccine from Pseudomonas aeruginosa in various immunocompromised animal models were performed. The results obtained demonstrated that the vaccine was highly effective in complement (C5)-deficient mice, C3-deficient (cobra venom factor-treated) mice, and leukopenic mice in providing protection against lethal infection with P. aeruginosa. Passive immunization with specific antiserum to the ribosomal vaccine was also effective in leukopenic mice. In mice that were both C5-deficient and leukopenic, the vaccine did not protect mice against lethal infection, but did prolong their survival, whereas in C3-deficient, leukopenic mice significantly enhanced protection was observed. These results were interpreted to suggest the involvement of multiple factors in the protective immune response to the vaccine, including the bactericidal and opsonic activities of specific antibody plus complement and the phagocytic activity of polymorphonuclear leukocytes with opsonized bacteria. Compensation for deficiencies in some of these factors can be obtained by enhancement of other factors through active or passive immunization.

Animals↗
PubMed1975

Trypsin-activated complex of human factor B with cobra venom factor (CVF), cleaving C3 and C5 and generating a lytic factor for unsensitized guinea pig erythrocytes. I. Generation of the activated complex.

A complex formed between cobra venom factor (CVF) and isolated human factor B (B) was found to be converted by trypsin to a stable enzyme, CVF-B which cleaved the third component (C3) and the fifth component (C5) of human complement. The formation of CVF-B by trypsin required divalent cations, whereas the formation of the lytic factor from human serum occurred even in the presence of EDTA. CVF-B purified by gel filtration could initiate the hemolysis of unsensitized guinea pig erythrocytes when incubated with human complement components C5 to C9 in 0.01 M EDTA buffer. C3 was not required for the lysis of guinea pig erythrocytes initiated by CVF-B because of the beta1C precipitation line formed between human serum and anti-beta1C antibody did not inhibit the hemolysis by CVF-B in agarose gel. Treatment of beta1C and beta1F globulins in whole human serum with CVF-B in the presence of 0.01 M EDTA converted them to components with higher mobilities on immunoelectrophoresis.

ABO Blood-Group System↗
PubMed2026

Independent prognostic value of semaphorin-4D, interleukin-1β and complement activation in newly diagnosed multiple myeloma patients.

Multiple myeloma represents a systemic disease of the bone marrow (BM) niche, in which immune and skeletal pathways are tightly interconnected. However, the independent prognostic significance of bone and immune-related markers in newly diagnosed multiple myeloma (NDMM) remains incompletely understood. Semaphorin (Sema) 4D, activin-A, and periostin ELISA, LEGENDplex™ Human Bone Metabolism Panel and proteomic analysis for novel biomarker identification were conducted in 71 consecutive samples from NDMM patients. In 25 patients, genomic analysis was performed on sorted clonal plasma cells. NDMM patients had a median age at diagnosis of 65 years and a median follow-up of 2.5 years. Interleukin (IL)-1β and Sema4D levels predicted progression-free survival (PFS), highlighting their role in disease relapse. Proteomic profiling revealed a systemic signature associated with worse prognosis, enriched in complement activation components. Complement C5 significantly affected PFS and time to progression (TTP). IL-1β and C5 predicted PFS independently of the second revision of the International Staging System (R2-ISS) stage, and a similar trend was noted for Sema4D. Myeloma bone disease (MBD) did not significantly affect overall survival, PFS, or TTP, suggesting that contemporary treatments mitigate its impact. Genomic analyses identified variants associated with inferior PFS, including HLA-DRB5 (c.300_306delinsCGGG) and HLA-DQB1 (c.317_319delinsCGG). Sema4D and the IL-1β-complement cascade emerged as key drivers of disease progression, independent of R2-ISS stage, representing potential prognostic and therapeutic targets in NDMM.

Journal Article↗
PubMed1989

Ba and Bb fragments of factor B activation: fragment production, biological activities, neoepitope expression and quantitation in clinical samples.

Factor B is a centrally important component of the alternative complement pathway. Alternative pathway activation results in factor B cleavage and production of the amino-terminal Ba and the carboxyl-terminal Bb fragments which have molecular weights of approximately 30,000 and 63,000 daltons, respectively. Both Ba and Bb fragments have been reported to express a variety of biological activities in vitro. Thus, binding of Ba and Bb fragments to specific B lymphocyte surface receptors modulates proliferation of prestimulated B cells. In addition, the enzymatically active Bb fragment induces activation and spreading of human and murine macrophages and monocytes as well as regulates C5a des Arg chemotactic activity. The fractional catabolic rate and metabolism of factor B in vivo is similar to that of C3, C4 and C5 complement proteins, which are among the most metabolically active plasma proteins in the circulatory system. Factor B hyperconsumption and increased catabolism, concomitant with factor B fragment production, occurs in a wide variety of diseases, including gram-negative sepsis, autoimmune diseases and burns. Measurement of alternative pathway activation in vivo has been attempted utilized a number of different techniques to quantitate factor B fragments in biological fluids. However, the recent development of enzyme immunoassays (EIA) employing monoclonal antibodies (MoAbs) reactive with factor B fragment neoepitopes provides the best approach currently available for the quantitation of factor B activation fragments. Results obtained using these new MoAb-based EIAs have indicated that factor B fragment concentrations were elevated, as compared with normal donor levels, in EDTA plasma samples obtained from patients with rheumatoid arthritis and systemic lupus erythematosus (SLE). Plasma concentrations of factor B fragments, especially Ba fragment levels, in these patients showed a positive correlation with disease activity scores. One of the highest disease activity correlations was obtained with Ba fragment measurements in SLE plasma samples. In fact, the results strongly suggested that quantitation of Ba fragment levels in SLE plasma samples more accurately reflected disease activity and was a more sensitive predictor of impending flare in these patients than any other test(s) currently available.

Antibodies, Monoclonal↗