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PubMed1980

Purified proenzyme C1r. Some characteristics of its activation and subsequent proteolytic cleavage.

1. Upon incubation for 1 h at 37 degrees C, proenzymic C1r was activated by a proteolytic cleavage comparable to that observed in vivo; after reduction and alkylation, two fragments of apparent molecular weights 57 000 and 35 000 were evident on sodium dodecyl sulphate (SDS)-polyacrylamide gel electrophoresis. The activation kinetics were slightly sigmoidal and nearly independent of C1r concentration. They were characterized by a marked thermal dependence (activation energy = 45 kcal/mol). The reaction was inhibited by calcium and p-nitrophenyl-p'-guanidinobenzoate, but poorly sensitive to di-isopropyl phosphorofluoridate. The dependence of the activation rate on pH was unusual; it decreased progressively in the acid range (pH 4.5-6.5) which coincides with the dissociation of the C1r-C1r dimer. Above pH 6.5, the rate increased slightly and showed no clear maximum. These results are consistent with an intramolecular autocatalytic activation mechanism involving the pro-site of each subunit of the C1r-C1r dimer. 2. During a 5 h incubation period at 37 degrees C, C1r underwent two proteolytic cleavages which led to the successive removal of two fragments, alpha (35 000) and beta (7000-11 000) from each subunit, leaving a dimeric molecule of reduced size (Mr = 110 000; s20,w = 6.1 S). The proteolytic process was nearly independent of C1r concentration and characterized by a pH optimum at 8.5-9.0, and a high activation energy (36.8 kcal/mol). Calcium and p-nitrophenyl-p'-guanidinobenzoate, and also di-isopropyl phosphorofluoridate and benzamidine were inhibitors of this reaction. The product, C1r II, retained the original antigenic properties of C1r and a functional active site, but lost the capacity to bind C1s. These results are consistent with an autocatalytic intramolecular proteolysis mediated by the active site of each subunit of the C1r-C1r dimer.

Complement Activating Enzymes↗
PubMed1981

New synthetic inhibitors of C1r, C1 esterase, thrombin, plasmin, kallikrein and trypsin.

p-Guanidinobenzoate derivates were prepared and their inhibitory effects on trypsin, plasmin, pancreatic kallikrein, plasma kallikrein, thrombin, C1r and C1 esterase were examined. Among the various inhibitors tested, 6'-amidino-2-naphthyl-4-guanidinobenzoate dihydrochloride, 4-(beta-amidinoethenyl)phenyl-4-guanidinobenzoate dimethanesulfonate and 4-amidino-2-benzoylphenyl-4-guanidinobenzoate dimethanesulfonate were the most effective inhibitors of trypsin, plasmin, pancreatic kallikrein. plasma kallikrein and thrombin and they strongly inhibited the esterolytic activities of C1r and C1 esterase, and then strongly inhibited complement-mediated hemolysis.

Benzamidines↗
PubMed1987

Effects of inhibitors of C1q biosynthesis on macrophage Fc receptor subclass-mediated antibody-dependent cellular cytotoxicity and phagocytosis.

We examined the effects of the inhibitors of C1q or collagen biosynthesis, 2,2'-dipyridyl (DP), and 3,4-dehydro-DL-proline (DHP) on murine macrophage (M phi) FcR subclass-mediated antibody-dependent cellular cytotoxicity (ADCC) and phagocytosis of sheep erythrocyte targets. Oil-elicited peritoneal M phi from C3HeB/FeJ mice which were cultured for 24 hr with DP (0.08 or 0.10 mM) or DHP (0.8 or 1.0 mM) showed a significant decrease in FcR subclass-mediated ADCC for murine monoclonal IgG2a (FcRI) and IgG2b/IgG1 (FcRII) as well as for heterologous polyclonal IgG. These collagen inhibitors also blocked phagocytosis mediated by both IgG2a- and IgG2b-opsonized erythrocytes. DP was more potent than DHP in blocking FcR effector functions in a reversible fashion and neither inhibitor affected M phi C3b receptor function. Pretreatment of M phi with collagenase resulted in significant reduction in FcR-mediated ADCC and phagocytosis. The inhibition of M phi FcR subclass-mediated ADCC and phagocytosis by collagen C1q synthetic inhibitors or by collagenase treatment further confirms a functional relationship between cell-associated C1q and FcR-dependent functions.

2,2'-Dipyridyl↗
PubMed1983

A new simple method for determination of C1-esterase inhibitor activity in plasma.

A convenient method for the determination of C1-esterase inhibitor activity in plasma samples is described. The method is based on addition of purified C1s to plasma and measuring excess C1s with a new chromogenic tripeptide-p-nitroanilide substrate with a recording spectrophotometer. Addition of C1s to C1-esterase inhibitor-depleted plasma did not result in any appreciable inactivation of the enzyme for three hours. The concentration of C1-esterase inhibitor in 19 healthy individuals was estimated as 1.63 +/- 0.27 (SD) mumol/l. The correlation with C1-esterase inhibitor antigen in these individuals and 19 patients with varying concentrations of C1-esterase inhibitor was excellent. The correlation with an antikallikrein assay was found to be poor.

Complement Activating Enzymes↗
PubMed1987

Recurrent abdominal pain as the sole manifestation of hereditary angioedema in multiple family members.

This paper describes a previously unreported finding of abdominal pain as the only lifelong manifestation of hereditary angioedema in multiple family members. This diagnosis was obscured by the absence of cutaneous, oropharyngeal, and respiratory involvement. Barium studies performed during painful attacks showed transient intestinal wall edema which, along with abnormalities in the C4 level and C1 esterase inhibitor activity, confirmed the diagnosis. It is important that hereditary angioedema be recognized in its various forms so that invasive procedures can be avoided and prophylactic therapy can be administered.

Abdomen↗
PubMed1977

Role of complement in thrombogenesis. I. Complement-dependent coagulation in a model system.

Chondroitin sulphate was used to isolate from plasma a system that clotted with Russell's viper venom, brain extract and activated contact factors. Clotting appeared to depend on concomitant change in C4, C3 and C1s in the system. Brain extract additionally reacted with C9. Reconstitution of specifically defective plasmas suggested a specific role for each of these complement components in clotting.

Antigen-Antibody Reactions↗
PubMed1988

Detection of the terminal complement complex in patient plasma following acute myocardial infarction.

The mechanisms of inflammation responsible for the myocardial tissue damage seen after an acute myocardial infarction (AMI) have not been clearly identified. Recent lines of evidence, demonstrating depressed sera levels of individual complement components in patients after myocardial infarction, have suggested involvement of the complement (C) system in micro- and macrovascular injury subsequent to AMI. The present study assessed the role of complement as a mediator of myocardial inflammation by quantifying products of complement activation including, the terminal complement complex (TCC) the cytolytic component of the complement system, C1rC1s-C1 inhibitor complex and C3bBbP complex, formed following activation of the classical and alternative pathway, respectively, and anaphylatoxins C3a and C5a in 41 patients following AMI. Plasma TCC and C1rC1s-C1 inhibitor complex concentrations increased up to 32-fold (P less than 0.001) and 8-fold (P less than 0.001), respectively, while the C3bBbP complex, C3a des-Arg and C5a des-Arg each increased over 2-fold (P less than 0.001) 16 h after AMI, and were only minimally detectable during non-inflammatory myocardial conditions. Furthermore, TCC concentrations increased over 150% (P less than 0.001) one day after patients reinfarcted, subsequent to hospitalization for a primary AMI. These results demonstrate activation of complement after AMI and suggest that inflammatory mediators of the complement system may contribute to myocardial tissue damage during the infarction process.

Adult↗
PubMed1990

Trimer and tetramer complexes containing C1 esterase inhibitor, C1r and C1s, in serum and synovial fluid of patients with rheumatic disease.

During activation, the first component of complement C1q (C1r-C1s)2 is dissociated in conjunction with the formation of complexes containing C1 esterase inhibitor (C1-INH). Trimer complexes, with zymogen C1s associated with a firm C1-INH-C1r complex (C1-INH-C1r-C1s) can be distinguished from tetramer complexes C1-INH-C1r-C1s-C1-INH) in which C1-INH is firmly bound to both proteases. In the present study a two-stage electroimmunoassay was developed for the specific measurement of C1-INH-C1r-C1s. In the first step, C1-INH and its complexes were immunoprecipitated with anti-C1-INH during electrophoresis in the presence of Ca2+. In the second step, C1s contained in C1-INH-C1r-C1s was dissociated in the presence of EDTA and was measured by immunoprecipitation with anti-C1s. C1-INH-C1r-C1s were consistently found in normal sera. Normal sera did not contain C1-INH-C1r-C1s-C1-INH as assessed with a previously described ELISA procedure. Sera and synovial fluids from two groups of patients with inflammatory arthritis were investigated. In rheumatoid arthritis patients (n = 15) C1-INH-C1r-C1s complexes were usually found at high concentration both in serum and synovial fluid. C1-INH-C1r-C1s-C1-INH complexes were also present with values that were higher in synovial fluid than in serum, in accord with previous findings of classical pathway activation in the inflamed joints of the patients. Patients with spondylarthritic syndromes (n = 7) had serum and synovial fluid C1-INH-C1r-C1s concentrations that were comparable to those of the rheumatoid arthritis patients. If at all present, C1-INH-C1r-C1s-C1-INH were detected in trace amounts. Thus, C1 activation in patients with spondylarthritic syndromes appeared to be efficiently controlled at the C1r level. Distinguishing between C1-INH-C1r-C1s and C1-INH-C1r-C1s-C1-INH may prove of value in further studies of the activation and control of C1 in disease.

Animals↗
PubMed1989

Methylprednisolone affects inhibitors of the complement and the contact systems; functional and immunochemical studies on alpha 2-macroglobulin and C1 inhibitor.

The effects of methylprednisolone sodium succinate (MP) on main inhibitors of the classical pathway of complement and on the contact system were studied in citrated pool plasma. Endotoxin (2.10(9) ng/l, lipopolysaccharide B, E. coli 026: B6 Difco Laboratories, Detroit, Michigan, USA) and/or MP in doses of 0.1, 1, 5 and 10 mg/ml were incubated with plasma at 37 degrees C. Plasma samples were obtained at timed intervals up to 24 hours for determination of C1 inhibitor (C1inh) and alpha 2-macroglobulin (alpha 2M) values using both functional and immunochemical assays. Plasma containing endotoxin without MP revealed decreases of C1inh and alpha 2M values after 12 hours. Addition of MP in high doses (10 mg/ml) gave an additive effect on the endotoxin-induced decreases of C1inh and alpha 2M values, evident 1 and 12 hours after the beginning of incubation, respectively. When MP alone was added to plasma (5 and 10 mg/ml) also significant decreases in C1inh and alpha 2M values were seen. MP in low doses (0.1 and 1 mg/ml) did not either influence the endotoxin-induced changes in the protease inhibitor functions, or induce significant changes in C1inh and alpha 2M values when incubated in plasma without endotoxin. This study demonstrates that MP in high doses induces marked decreases in plasma C1inh and alpha 2M inhibitory functions and that MP has an additive effect on the endotoxin-induced decreases of these inhibitors.

Blood↗