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PubMed1987

Clinical evaluation and characterization of a unique C3 breakdown factor detected in a patient with acute glomerulonephritis.

A unique factor causing breakdown of the third component of complement (C3) was detected in a patient with acute glomerulonephritis (AGN). The activity was detected by conversion of C3 in a mixture with normal human serum using crossed immunoelectrophoresis. This factor capable of C3 breakdown was not blocked in the presence of ethylenediaminetetraacetic acid (EDTA), heat-pretreatment (56 degrees C, 30 min) und dialysis against 0.1 M phenylmethylsulfonyl fluoride (PMSF). The factor was isolated and characterized by immunochemical and physicochemical techniques. It had beta-mobility on electrophoresis and was separated at a lighter sedimentation coefficient than 7S by sucrose density gradient ultracentrifugation. The activity was absorbed on a DEAE-cellulose column and was eluted under definite conditions of relative salt concentration. These data appear to suggest that this factor is distinct from C3 nephritic factor (C3NeF), immunoglobulins, immune complexes, and other C3 convertases previously described. Moreover, it is clear that the factor was mainly responsible for the C3 activation observed in the patient with acute glomerulonephritis.

Acute Disease↗

PubMed1994

Estrogenic effects of the antiprogestin onapristone (ZK98.299) in the rodent uterus.

OBJECTIVE: Our purpose was to assess the estrogenic action of onapristone (ZK299). STUDY DESIGN: Three rodent models of estrogen action in the uterus were used. Deoxyribonucleic acid synthesis in the uterine epithelium of neonatal mice was determined by thymidine autoradiography. In adult ovariectomized mice uterine wet weight and progesterone receptor and estrogen receptor concentrations were determined. In immature rats uterine deoxyribonucleic acid synthetic activity was determined by thymidine autoradiography, epithelial hypertrophy and stromal edema were assessed histomorphometrically, and complement C3 protein synthesis was assessed by metabolic labeling in vitro. The effects of ZK299 were challenged with the antiestrogens ICI164,384 and tamoxifen. The ability of ZK299 to displace tritiated estradiol from the estrogen receptor was assessed in cytosolic preparations from mouse uterus. RESULTS: In the neonatal mouse ZK299 stimulated epithelial deoxyribonucleic acid synthesis; two other antiprogestins, RU486 and ZK98.734, had no effect. Three daily injections of ZK299 at 10 micrograms/gm body weight to 6-week-old ovariectomized mice increased uterine progesterone receptor 42%; this effect was blocked by ICI164,384. In another experiment three daily doses of ZK299 (20 micrograms/gm) to 10-week-old ovariectomized mice increased progesterone receptor concentration by 63% and uterine wet weight by 42%. In 21-day-old rats a single injection of ZK299 increased uterine epithelial deoxyribonucleic acid synthesis; this effect was blocked by tamoxifen. Both ZK299 and tamoxifen increased epithelial cell height and thymidine labeling in the stroma. ZK98.734 had no effect on epithelium or stroma. ZK299 also stimulated synthesis of complement C3 by uteri of immature rats. In competitive binding assays ZK299 exhibited weak relative binding affinity (0.05%) for mouse uterine estrogen receptor. CONCLUSIONS: ZK299 can act as a weak estrogen in the rodent uterus, most likely through a direct, low-affinity interaction with the estrogen receptor. Because estrogens may increase the risk for endometrial, breast, and liver cancer, caution is warranted in long-term administration of this drug to women.

Animals↗

PubMed1984

Sperm antibodies, immunoglobulins, and complement in human follicular fluid.

The levels of immunoglobulins (IgG, IgA, IgM), complement (C3, C4, C1EI) and sperm antibodies were determined in plasma and follicular fluid samples from 26 patients undergoing in vitro fertilization (IVF) treatment. The results show that IgG, IgA, C3, C4, and C1EI concentrations in follicular fluid are similar to plasma concentrations (63.1-96.1% of plasma levels). The follicular fluid concentration of IgM was severely reduced, however, being only approximately 10% of plasma concentrations. Sperm antibody titres were compared in three patients using sperm agglutination, immobilization, and immunobead binding. The titres in plasma and follicular fluid were similar, apart from antibodies of IgM class, which were undetectable in follicular fluid.

Antibodies↗

PubMed1980

Immunoglobulins in the semen of men with azoospermia, oligospermia, or self-agglutination of spermatozoa.

One hundred samples of semen showing azoospermia, oligospermia, self-agglutination of spermatozoa, or normal physiologic spermatozoa were examined for evidence of autoimmune disorders. Immunoglobulin A, secretory immunoglobulin A, and complements C3 and C4 were present in a greater proportion of abnormal samples than in normal ones. The immunoglobulin A content of the abnormal samples was markedly increased, and the immunoglobulin G level slightly increased, as compared with normal samples. These findings support the hypothesis that agglutination of spermatozoa in semen is an autoimmune mechanism. They also suggest that, although spermatozoa may activate the mechanism, it is possible that abnormalities of the male genital tract can stimulate the formation of spermatozoal antibodies.

Complement C3↗

PubMedDate not supplied

Lupus anticoagulant and transient severe bleeding tendency in a girl aged nine years.

A 9-year old girl admitted in our clinic for severe hemorrhagic syndrome was found to display a high level of lupus anticoagulant (LA) leading to an important prolongation of phospholipid-dependent coagulation. Positive antinuclear and anti DNA antibodies, as well as very low levels of complement C3 and C4 proteins confirmed the diagnosis of systemic lupus erythematosus. Therapy with cortisone and cyclophosphamide led to normalization of the clotting tests but could not arrest the development of renal and hepatic lesions. The patient is one of the few cases with presence of lupus anticoagulant associated with severe hemorrhagic diathesis, in opposition to the more frequently reported thrombotic tendency connected with antiphospholipid antibodies.

Acute Disease↗

PubMed1977

Immunological abnormalities in coeliac disease and their response to dietary restriction. I. Serum immunoglobulins, antibodies and complement.

Twenty-three patients with coeliac disease were studied whilst on a normal diet and again after a mean period of 15 months on a gluten-free diet. Serum levels of IgG, IgA and IgM, total haemolytic complement, C3, serum autoantibodies and precipitins to dietary proteins were compared to those in age and sex matched control subjects. There was considerable individual variation, but as a group, patients on a normal diet had significantly raised IgA and low IgM and an increased prevalence of antibody to reticulin, smooth muscle and dietary protein. These abnormalities disappeared during the period of dietary restriction suggesting that they are disease epiphenomena rather than primary pathogenetic factors.

Adolescent↗

PubMed2026

Efficacy and Safety of the C3 Inhibitor Pegcetacoplan in Paroxysmal Nocturnal Hemoglobinuria: A Systematic Review and Meta-Analysis.

OBJECTIVE: To evaluate the efficacy and safety of the complement C3 inhibitor pegcetacoplan in patients with paroxysmal nocturnal hemoglobinuria (PNH). METHODS: PubMed, Embase, Web of Science, and Cochrane Library were systematically searched for studies reporting pegcetacoplan use in PNH. Outcomes included transfusion-requirement, hemoglobin normalization, mean hemoglobin levels, lactate dehydrogenase normalization, reticulocyte count normalization, and safety endpoints. Pooled proportions with 95% confidence intervals were calculated using random-effects models, and heterogeneity was assessed using the I2 statistic. RESULTS: Five studies comprising 271 patients were included. Transfusion avoidance was observed in 80.6% of patients, with a pooled transfusion-requirement rate of 19.4%. LDH normalization occurred in 68.5% of patients (I2 = 0%). Hemoglobin normalization was observed in 42.9%, while reticulocyte count normalization reached 66%. Any-grade adverse events occurred in 83.5% of patients, most commonly pyrexia, headache, and dizziness. Serious adverse events occurred in 16.6%, decreasing to 12% after sensitivity analysis. Breakthrough hemolysis was reported in 14.8%, and infections in 17%. CONCLUSION: Pegcetacoplan demonstrates consistent efficacy signals across key hematologic endpoints and an acceptable safety profile, supporting its potential role as an important therapeutic option, particularly in patients with persistent extravascular hemolysis despite C5 inhibition.

Humans↗

PubMed1984

Immunologic studies in allergen-induced late-phase asthmatic reactions.

We have measured plasma histamine, serum neutrophil chemotactic activity (NCA) and complement (C3 and C4) over a 24-hour period in patients experiencing either early- and late-phase (dual) or single early asthmatic reactions to inhaled allergens. There was a significant biphasic elevation in plasma histamine, which paralleled the fall in forced expiratory volume in 1 sec in 10 patients with dual responses, whereas in seven subjects with single early reactions, only a single early increase in histamine concentrations was observed. In general, in the individual subjects, the changes in plasma histamine paralleled both the elevations in serum NCA and the decreases in forced expiratory volume in 1 sec. By gel filtration on Sephacryl S-400, anion exchange chromatography on DEAE Sephacel, and chromatofocusing with Polybuffer Exchanger 94, the major NCA of both the early and the late reactions was associated with proteins having an estimated molecular size of 600,000 daltons, an elution from DEAE Sephacel at 0.15M to 0.30M of NaCl (pH 8.1), and a pI of approximately 6.5. There were no appreciable changes in serum C3 and C4 up to 24 hr after challenge in subjects with late-phase responses. The patterns of asthmatic response were not related to either the total or allergen-specific serum IgE or IgG4 concentrations. These results support the view that mediators of hypersensitivity participate in late-phase as well as early asthmatic reactions.

Adolescent↗

PubMed2001

Some inflammation-related parameters in patients following normo- and hypothermic cardio-pulmonary bypass.

AIMS: One of the complications of Cardio-Pulmonary Bypass is the Systemic Inflammatory Response Syndrome. Cardio-Pulmonary Bypass can be performed under either normothermic or hypothermic conditions. The aim of this study was to compare some inflammation-related parameters of patients following normothermic and hypothermic bypass. Moreover, attempts were undertaken to detect endotoxin, an inflammatory agent that has been implicated in the Systemic Inflammatory Response Syndrome, in the serum of patients. Levels of serum anti-endotoxin antibodies were estimated since they have been reported to negate the effect of endotoxin in the inflammatory syndrome. METHODS AND RESULTS: Seventeen normothermic and 20 hypothermic cases were studied. Blood specimens were collected pre-, off- and post-bypass. Pertinent clinical and surgical data were collected. Hematological parameters (leukocyte, neutrophil and platelet counts) and liver function tests were determined by standard procedures. Endotoxin was determined by the Limulus Lysate Assay and anti-endotoxin antibodies by an enzyme immunoassay. Complement (C3 and C4) levels were determined by radial immunodiffusion. There were increases in leukocyte and neutrophil, and a decline in platelet numbers in both groups of patients. There was a decline in C3 and C4 levels in both groups of patients. Endotoxin was not detected in sera, and anti-endotoxin antibody levels were similar, in both groups of patients. CONCLUSION: There were no significant differences in most of the altered inflammation-related parameters between the two groups of patients. Some of the findings might be partly due to hemo-dilution. The hydrophobic nature of endotoxin among other factors, might have hindered its detection in serum.

Adult↗

PubMed1976

Complex surveillance of Streptococcus pyogenes. III. Immunological characteristics of streptococcal resistance in blood and new aspects of type nonspecific protection.

The influence of nonspecific immunity factors in indifferent human blood on the resistance of M non-typable field streptococci and collection M strains in the absence of anti-M antibodies was studied. The experimental results indicate that primary resistance is conditioned on balanced equipment of the strain with M protein and the nonspecific cofactor receptor [R]. Disbalanced strains were strongly phagocytized, with participation by nonspecific opsonins (complement C3 and nonspecific cofactor), irrespective of their M protein content. M + R--disbalance (selected collection strains) and M--R + disbalance (field strains on artificial media) were observed. The M and R resistance factor equipment of the streptococci probably represents plus and minus variants in the diverse process of the asymptomatic dissemination and pathogenic activity of streptococci in the human population. The given results are manifestly related to the general manner of existence of streptococci, to questions of conditional pathogenicity and to the concept of nonspecific defence against streptococci.

Antibody Specificity↗

PubMed2006

On-chip complement activation adds an extra dimension to antigen microarrays.

Antibody profiling on antigen microarrays helps us in understanding the complexity of responses of the adaptive immune system. The technique, however, neglects another, evolutionarily more ancient apparatus, the complement system, which is capable of both recognizing and eliminating antigen and serves to provide innate defense for the organism while cooperating with antibodies on multiple levels. Complement components interact with both foreign substances and self molecules, including antibodies, and initiate a cascade of proteolytic cleavages that lead to the covalent attachment of complement components to molecules in nanometer proximity. By refining the conditions of antibody profiling on antigen arrays we made use of this molecular tagging to identify antigens that activate the complement system. Antigen arrays were incubated with serum under conditions that favor complement activation, and the deposited complement C3 fragments were detected by fluorescently labeled antibodies. We used genetically C3-deficient mice or inhibition of the complement cascade to prove that the technique requires complement activation for the binding of C3 to features of the array. We demonstrate that antigens on the array can initiate complement activation both by antibody-dependent or -independent ways. Using two-color detection, antibody and complement binding to the relevant spots was measured simultaneously. The effect of adjuvants on the quality of the immune response and binding of autoantibodies to DNA with concomitant complement activation in the serum of mice suffering from systemic autoimmune disease was readily measurable by this new method. We propose that measurement of complement deposition on antigen microarrays supplements information from antibody binding measurements and provides an extra, immune function-related fingerprint of the tested serum.

Animals↗

PubMed1976

Interactions of Pseudomonas aeruginosa with immunoglobulins and complement in sputum.

The interactions of Pseudomonas aeruginosa with humoral factors in the sputum of patients with cystic fibrosis were investigated by using an indirect immunofluorescent technique. Fluorescein-conjugated, monovalent antiserum specific to heavy chains of human immunoglobulin A (IgA), IgG, or IgM and to complement C3 were used. All strains of P. aeruginosa recovered from the sputum specimens of patients with cystic fibrosis were found to be coated with antibodies of IgA, IgG, and IgM classes and with C3. The specificity of the antibody coating was determined. The fluorescence was most intense with IgA and was followed in intensity by IgG, IgM, and C3. No difference was noted between rough and mucoid strains of P. aeruginosa. When the subcultured P. aeruginosa was incubated with the sputum eluates, a similar pattern of fluorescence was demonstrated, indicating that these humoral factors are present in the sputum and that the coating process can take place in the lower respiratory tract of the patients. By single radial immunodiffusion, significant quantities of the humoral factors in the sputum eluates were detected. These findings suggest that P. aeruginosa is opsonized in sputum of patients with cystic fibrosis.

Adolescent↗

PubMed1982

Studies on serum complement and IgE in bronchial asthma.

Serum levels of the third component of complement (C3) were significantly lower in patients with perennial asthma and also in patients with the longer duration of the disease. No change in C3-proactivator (C3PA) and CH50 levels was observed in asthma patients. Significantly raised C4 levels were observed in the patients with late onset asthma. Raised serum IgE levels were found in all the three groups of asthma patients studied (depending on age of onset, duration and periodicity of the disease) above the control group. Within a group no difference was found with the duration or periodicity of the disease. However, low IgE levels were observed in patients with late onset asthma as compared to early onset asthma patients but this difference was not statistically significant.

Adolescent↗

PubMed1976

Penicillamine in rheumatoid arthritis. Connective tissue changes and alterations in serum copper and phase reactants in relation to clinical improvement.

Thirteen patients, aged 27 to 70 years, with definite or classical rheumatoid arthritis were treated with penicillamine for six months. Skin biopsies and blood samples were compared with a clinical evaluation before and after therapy. The analyses of the skin included determinations of total collagen, thermal reaction of collagen, salt soluble collagen, in vitro uptake of 14C-proline and synthesis of 14C-hydroxyproline, as well as determinations of nucleic acids and proteoglycans. Serum concentrations of acute phase reactants, immunoglobulins, complement C3 and C4, rheumatoid factor, and iron, copper, and zinc were also determined. A positive correlation was found between clinical improvement and a fall in the number of granulocytes, a decrease in the concentration of acute phase reactants and serum copper, and an increase in salt soluble collagen of the skin. The total skin collagen decreased during treatment with penicillamine. The changes in skin collagen may reflect a generalized effect of penicillamine on collagen. These alterations may be part of an anti-inflammatory action of penicillamine.

Adult↗

PubMed1985

Plasma therapy of primary rat mammary carcinoma: dependence of consumption of C3 during absorption of plasma with sepharose derivatives on the anticoagulant.

A previous study demonstrated inhibition of growth of primary rat mammary carcinomas after infusion of tumor-bearer plasma absorbed against Sepharose derivatives. In this report we have quantitated changes in individual complement components that occur during absorption of rat plasma with Sepharose derivatives and defined optimal conditions for consumption of the third component of complement (C3) (other complement components defined similarly). The concentration of functionally active C1 to C9 was measured before and after absorption in plasmas from both normal rats and rats with mammary tumors. C3 activity in plasmas from normal and tumor-bearing rats was reduced (consumed) during absorption under appropriate conditions with Sepharose 4B, inactivated CNBr Sepharose, or Protein A-Sepharose. The concentration of functionally active C1 and C4 did not decrease significantly during absorption with Sepharose derivatives. Consumption of C3 in rat plasma was influenced by the anticoagulant and by the time and temperature of incubation with Sepharose derivative. C3 consumption in rat plasma anticoagulated with acid citrate dextrose solution was variable; addition of Mg2+ (5 mM) to plasma anticoagulated with acid citrate dextrose solution augmented C3 consumption. There was no C3 consumption in plasma anticoagulated with ethylenedinitrilotetraacetic acid (a chelator of calcium and magnesium). In contrast, this reduction was observed in plasma anticoagulated with [(ethylenebis(oxyethylenenitrilo)]tetraacetic acid (a chelator of calcium). The results demonstrate optimal conditions for activation of the alternative pathway of complement during absorption of rat plasma with Sepharose derivatives and suggest in vivo experiments to define the role of this pathway in inhibition of growth of mammary tumors.

Absorption↗

PubMed1997

Co-expression and secretion of C3, the third component of complement and a C3-cleaving cysteine proteinase in a highly metastatic human melanoma cell line.

We recently demonstrated that DM-4, a human melanoma cell line highly metastatic in nude mice, expressed a p41 C3-cleaving proteinase. This p41 proteinase is a cysteine proteinase, associated to cell surface and involved in tumorigenicity and metastatic properties of these tumor cells. We demonstrate herein that DM-4 cells also secrete the p41 proteinase. In addition, analysis of cellular components which reacted with the p41 proteinase led us to demonstrate that DM-4 cells synthesized and secreted human C3. Secreted C3 is cleaved by the secreted p41 proteinase and a C3dg-like fragment is generated. This is the first demonstration that a human melanoma cell line co-expresses and co-secretes human C3 and a C3-cleaving cysteine proteinase, antigenically related to procathepsin L.

Animals↗

PubMed1983

Catabolites of the third component of complement in urines of hereditary nephritis patients.

Hereditary nephritis protein (HNP), an unusual urine protein from patients with hereditary nephritis (Alport Syndrome), was purified 120-fold to homogeneity. A slightly larger protein, pro-HNP, was similarly purified and was found to be a precursor of HNP. Both pro-HNP and HNP showed immunological identity to the third component of human complement, C3, and to its catabolite C3c. Pro-HNP had a molecular weight of 143,000 and, in equimolar ratio, polypeptide chains or fragments of molecular weights 75,000, 40,000, and 28,000. The largest and smallest chains contained carbohydrate. HNP had a molecular weight of 141,000 and fragments of molecular weights 60,000, 38,000, 26,000, and 17,000 in equimolar ratio; the two smallest fragments contained carbohydrate. Plasmin digestion of pro-HNP showed that the 75,000-Da chain, identical with the intact beta-chain of C3, broke down to the 60,000- and 17,000-Da fragments of HNP. In both pro-HNP and HNP, the polypeptide chains were linked by disulfide bonds, with the exception of the 17,000-Da fragment of HNP. This fragment was readily dissociated from the rest of the HNP molecule in the presence of sodium dodecyl sulfate. Amino acid analyses showed that both pro-HNP and HNP contained approximately 22 half-cystine residues per molecule. Extinction coefficients, epsilon 1% 1cm, at 280 nm were calculated to be 8.5 and 8.8 for pro-HNP and HNP, respectively.

Amino Acids↗

PubMed1993

Serum immunoglobulin and complement values in scabietic patients.

Immunity entails all the forces concerned with recognition, specific reaction and removal of foreign bodies after they again access into the body of the host. The immune system interacts with genetics and infectious agents as well as with metabolic, endocrine and environmental factors. The serum immunoglobulins (G.M.A. & E.) and complement (C3 and C4) were estimated in sixteen parasitologically proven patients with scabies. The causative agent was Sarcoptes scabiei. The results showed a high significant increase in the mean average of IgG., IgM. and in particular IgE pretreatment than in patients three months after treatment and in patients after treatment than in controls. On the other hand, there was a significant decrease in the mean average in the mean average of IgA after treatment was insignificant compared with controls. The C3 and C4 showed no significant changes in the mean average in the patients before or after treatment compared with controls. The changes in the IgG., IgM. and in particular IgE. may be specific reaction to the parasite or a non specific one to the dead parasite or its faeces or even to a secondary infection developed. On the other hand, the decrease in the IgA. may be due to the mite or its products which interfere with its synthesis. It is concluded that scabies is associated with a humoral immunological response against the mite infestation.

Animals↗