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PubMed1997

Degradation of C1-inhibitor by plasmin: implications for the control of inflammatory processes.

BACKGROUND: A correct balance between protease and inhibitor activity is critical in the maintenance of homoeostasis; excessive activation of enzyme pathways is frequently associated with inflammatory disorders. Plasmin is an enzyme ubiquitously activated in inflammatory disorder, and C1-inhibitor (C1-Inh) is a pivotal inhibitor of protease activity, which is particularly important in the regulation of enzyme cascades generated in plasma. The nature of the interaction between plasmin and C1-Inh is poorly understood. MATERIALS AND METHODS: C1-Inh was immunoadsorbed from the plasma of normal individuals (n = 21), from that of patients with systemic lupus erythematosus (n = 18) or adult respiratory distress syndrome (n = 9), and from the plasma and synovial fluid of patients with rheumatoid arthritis (n = 18). As plasmin is a putative enzyme responsible for C1-Inh was examined using SDS-PAGE. In addition, peptides cleaved from C1-Inh by plasmin were isolated and sequenced and the precise cleavage sites determined from the known primary sequence of C1-Inh. Homology models of C1-Inh were then constructed. RESULTS: Increased levels of cleaved and inactivated C1-Inh were found in each of the inflammatory disorders examined. Through SDS-PAGE analysis it was shown that plasmin rapidly degraded C1-Inh in vitro. The pattern of C1-Inh cleavage seen in vivo in patients with inflammatory disorders and that produced in vitro following incubation with plasmin were very similar. Homology models of C1-Inh indicate that the majority of the plasmin cleavage sites are adjacent to the reactive site of the inhibitor. CONCLUSIONS: This study suggests that local C1-Inh degradation by plasmin may be a central and critical event in the loss of protease inhibition during inflammation. These findings have important implications for our understanding of pathogenic mechanisms in inflammation and for the development of more effectively targeted therapeutic regimes. These findings may also explain the efficacy of anti-plasmin agents in the treatment of C1-Inh deficiency states, as they may diminish plasmin-mediated C1-Inh degradation.

Adult↗
PubMed1983

Complete amino acid sequence of the catalytic chain of human complement subcomponent C1-r.

The amino acid sequence of human C1-r b chain hs been determined, from sequence analysis performed on fragments obtained by CNBr cleavage, dilute acid hydrolysis, tryptic cleavage of the succinylated protein, and subcleavages by staphylococcal protease. The polypeptide chain contains 242 amino acids (Mr 27 096), and the sequence shows strong homology with other mammalian serine proteases. The histidine, aspartic acid, and serine residues of the active site (His-57, Asp-102, and Ser-195 in bovine chymotrypsinogen) are located at positions 39, 94, and 191, respectively. The chain which lacks the "histidine-loop" disulfide bridge, contains five half-cystine residues, of which four (positions 157-176 and 187-217) are homologous to residues involved in disulfide bonds generally conserved in serine proteases, whereas the half-cystine residue at position 114 is likely to be involved in the single disulfide bridge connecting the catalytic b chain to the n-terminal a chain. Two carbohydrate moieties are attached to the polypeptide chain, both via asparagine residues at positions 51 and 118.

Amino Acid Sequence↗
PubMed1975

Interaction of C1s and C4. A binding phenomenon.

Addition of enzymatically active 125-I-labeled C1s (the esterase which is part of the activated complex protein of serum designated as the first component of complement or C1) to purified C4 (the naturally occurring fourth component of human serum complement) results in binding of a portion of the C1s to C4 as indicated by sucrose density gradient ultracentrifugation. Demonstration of binding requires hemolytically active C4, but not enzymatically active C1s. The latter was demonstrated by using DFP inactivated C1s as well as fragments of C1s produced by prior protease treatment of the C1s. While treatment of C1s with proteases (human leukocyte lysosomal enzymes, trypsin or plasmin) resulted in progressive inactivation of the enzymatic activity, the decline in esteratic activity occurred at a much slower rate than the decline in functional activity (inactivation of C4 in free solution). The data lead to the probable conclusion that C1s contains an enzymatic (or esteratic) site in addition to a binding site. The latter might be important for positioning a large molecule, such as C4, in order to effect proteolytic cleavage at the proper bond and hence prepare C4 to participate in the complement sequence.

Centrifugation, Density Gradient↗
PubMed2005

Does C-2 kinin exist?

Explore the source record for details and available documents.

Complement C1 Inactivator Proteins↗
PubMed2005

Estrogens and glucocorticoids have opposing effects on the amount and latent activity of complement proteins in the rat uterus.

The mammalian uterus faces unique immunological challenges. It must nurture and protect the semiallogenic fetus from attack by the maternal immune system while guarding against infection by pathogens that compromise fetal and maternal health. Complement has recently been implicated in the etiology of pregnancy loss, but its regulation by steroid hormones and its role in host defense in the uterus are not clearly defined. Here we use biochemical, functional, and physiological assays to elucidate the regulation of complement proteins in the rat uterus. We demonstrate that estrogens (17 beta-estradiol) and glucocorticoids (dexamethasone) have major, but opposing, effects on the amount and latent activity of complement effectors in the uterus. Treatment with 17 beta-estradiol induced vasodilation and an increase in vascular permeability, which resulted in extravasation of plasma and complement into the uterus, rather than de novo complement biosynthesis. In vitro assays revealed that 17 beta-estradiol induced a potent bactericidal activity in uterine luminal fluid and that the antibacterial component was complement. These proinflammatory and immunomodulatory effects were evident within 4 h of treatment and were blocked by coadministration of dexamethasone. We also found that estrogen effects on the vasculature were mediated in part by activation of the contact system and bradykinin B1 receptors. These results indicate that complement plays a central role in innate immunity in the female reproductive tract and suggest that estrogens or glucocorticoids might be used therapeutically to enhance or inhibit complement-dependent processes in the uterus.

Animals↗
PubMed2003

Complement components and their autoantibodies.

The purpose of the immune system is to defend the host from constantly changing microbial pathogens. Autoimmune diseases develop as a consequence of the production of antibodies and/or cells that react with self-antigens, and may recruit other effector mechanisms that result in tissue damage. Thus, in this context, autoimmunity represents an immune response to self-antigens that is sufficient to cause disease. This article is specifically devoted to autoantibodies directed against complement components.

Algorithms↗
PubMed2004

Characterization of recombinant mannan-binding lectin-associated serine protease (MASP)-3 suggests an activation mechanism different from that of MASP-1 and MASP-2.

Mannan-binding lectin (MBL)-associated serine proteases (MASP-1, -2, and -3) are homologous modular proteases that each associate with MBL and L- and H-ficolins, which are oligomeric serum lectins involved in innate immunity. To investigate its physicochemical, interaction, and enzymatic properties, human MASP-3 was expressed in insect cells. Ultracentrifugation analysis indicated that rMASP-3 sedimented as a homodimer (s(20,w) = 6.2 +/- 0.1 S) in the presence of Ca(2+), and as a monomer (s(20,w) = 4.6 +/- 0.1 S) in EDTA. As shown by surface plasmon resonance spectroscopy, it associated with both MBL (K(D) = 2.6 nM) and L-ficolin (K(D) = 7.2 nM). The protease was produced in a single-chain, proenzyme form, but underwent slow activation upon prolonged storage at 4 degrees C, resulting from cleavage at the Arg(430)-Ile(431) activation site. Activation was prevented in the presence of protease inhibitors iodoacetamide and 1,10-phenanthroline but was not abolished upon substitution of Ala for the active site Ser(645) of MASP-3, indicating extrinsic proteolysis. In contrast, the corresponding mutations Ser(627)-->Ala in MASP-1 and Ser(618)-->Ala in MASP-2 stabilized the latter in their proenzyme form. Likewise, the MASP-1 and MASP-2 mutants were each activated by their active counterparts, but MASP-3 S645A was not. Activated MASP-3 did not react with C1 inhibitor; had no activity on complement proteins C2, C4, and C3; and only cleaved the N-carboxybenzyloxyglycine-L-arginine thiobenzyl ester substrate to a significant extent. Based on these observations, it is postulated that MASP-3 activation and control involve mechanisms that are different from those of MASP-1 and -2.

Alanine↗
PubMedDate not supplied

Hereditary angioedema. Long-term follow-up of 88 patients. Experience of the Argentine Allergy and Immunology Institute.

Since the detection of the first patient with hereditary angioedema (HA) in 1978, 88 new patients belonging to 16 families have been referred to our clinic. Eighty patients had Type I disease, 5 Type II, and 3 Type III (secondary). We describe the clinical onset, frequent complications, diagnostic tests of the complement system, and abnormalities of the coagulation pathway linked to complement activation. Particular attention was paid to family members who could present succedaneum symptoms. The results of danazole and other therapies and protective and preventive treatment for surgery also are discussed.

Adolescent↗
PubMed1985

Demonstration of the interaction of native C1 with monomeric immunoglobulins and C1 inhibitor.

The association of native C1 with physiologically relevant proteins was studied by ultracentrifugation. 125I-C1 was centrifuged through numerous sucrose density gradients, each of which contained a different concentration of monomeric (19S) IgM throughout the gradient. The s-rate of C1 (16S) increased with increasing IgM input to a maximum of 32S. In the absence of C1q, the C1r2s2 subunit did not bind to the Ig. In gradients containing physiologic concentrations of IgM (1.3 mg/ml) at 0.14 M ionic strength, the observed s-rate of C1 was 21S. In the presence of 13 mg/ml IgG, C1 sedimented with an s-rate of 19S. Thus, under physiologic conditions, a significant fraction of native C1 is reversibly bound to monomeric Ig. SDS-PAGE analyses show that this interaction does not lead to C1 activation. The interaction of native C1 with C1 inhibitor (C1-In) was studied by ultracentrifugation at physiologic ionic strength. Purified 125I-C1-In alone sedimented with an s-rate of 4S. However in the presence of excess native C1, one-third of the C1-In co-sedimented with C1 at a 16S position. For these studies, 100 microM nitrophenylguanidinobenzoate (NPGB) was present throughout the sucrose density gradient to prevent C1 activation during centrifugation. As the concentration of NPGB was increased, the percent of 125I-C1-In at 16S decreased, indicating that C1-In was binding (reversibly) to the C1 active site region(s), which is at least partially accessible in uncleaved C1. In controls, when NPGB was omitted or activated C1 was used, the s-rate of 125I-C1-In was only 12S due to the release of C1rC1s(C1-In)2 from activated C1. Thus, under physiologic conditions native C1 is reversibly bound to C1-In.

Benzoates↗
PubMed1983

[Physiologic inhibitors of blood coagulation. 2. Alpha 2-macroglobulin, alpha-antitrypsin and the C1 inhibitor of complement].

Three physiological inhibitors of blood coagulation - alpha-2-macroglobulin, alpha-1-antitrypsin, and C-1-inhibitor of complement - are dealt with in a brief survey. The point is that these are proteins of the organism with a defence character which are also able to inhibit an extraordinarily broad spectrum of proteases. Some recent findings about their molecular structure, manner of response, and inhibitory spectrum are represented. Comparisons are made to corresponding proteins in mammals, in alpha-2-macroglobulin and even in lower vertebrates. Moreover, the inherited deficiency of these three inhibitors are represented with respect to human diseases and changes of their blood level in the course of various diseases are referred to.

Animals↗
PubMed1977

Detection of functional complement components in gingival crevicular fluid from humans with periodontal diseases.

Crevicular fluid was collected from patients with periodontitis by a capillary tube procedure. Complement component activities were determined by functional assay systems, with human complement, and partially purified human first complement component (C1) as controls. The complement-fixing properties of the dental plaque of each patient were also examined C1 activity in the crevicular fluid of all patients was approximately 1/8 of whole serum C1 and diminished rapidly with time after collection. There was no significant relationship between C1 concentration and crevicular fluid flow rate. Hemolytic activity of whole complement was also invariable detected when sufficient amounts (8 micronl) of crevicular fluid could be obtained. Dental plaque was found to fix C1. A role for crevicular complement in inflammatory periodontal disease is suggested.

Complement C1↗
PubMed1999

C1q and C4b bind simultaneously to CR1 and additively support erythrocyte adhesion.

Previously, we showed that soluble C1q bound specifically to CR1 on transfected cells. If the CR1-C1q interaction were to participate in immune complex clearance, then this interaction should support E adhesion. Using a tip plate adhesion assay, we found that immobilized C1q mediated adhesion of human E. E binding to C1q was specifically inhibited by polyclonal anti-CR1 Fab fragments. Intact C1 was not efficient as an adherence ligand until it was treated with EDTA or the C1 inhibitor to remove the C1r2C1s2 complex from C1, leaving C1q. Titration of C1q alone, C4b alone, and C1q + C4b indicated that the two complement ligands were additive in their ability to support CR1-mediated adhesion of E. Analysis of binding to immobilized CR1 using a BIAcore instrument documented that C1q, C4b, and C3b binding were independent events. Additionally, C1q-dependent binding of immune complexes and heat-aggregated IgG to E was documented. These experiments confirm that the immune adherence receptor in humans, CR1, is the single receptor for all of the opsonic ligands of complement, provide evidence for a single C1q binding site on LHR-D of CR1, and suggest that C1q may participate in immune clearance.

Antigen-Antibody Complex↗