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PubMed1998

Human heart generates complement proteins that are upregulated and activated after myocardial infarction.

In human heart, we detected mRNAs and proteins for C1q, C1r, C1s, C2, C3, C4, C5, C6, C7, C8, and C9 with the use of reverse transcriptase-polymerase chain reaction, Western blotting, and immunohistochemical techniques. We found an upregulation of both mRNAs and proteins in areas of recent and old myocardial infarctions. In both situations, the classical complement pathway was activated, with C4d, C3d, and the membrane attack complex (C5b-9) being deposited on damaged cardiac myocytes. These activated complement components were also identified on Western blots of infarcted tissue. Complement mRNAs in infarcted heart tissue were higher than those in liver, and liver complement mRNAs were not upregulated in cases with infarcted hearts. Our results establish that (1) complement proteins are endogenously produced by human heart; (2) the classical complement pathway is fully activated after myocardial infarction; (3) complement activation is directly involved in myocardial damage after ischemic insults; and (4) damage from complement activation may be chronically sustained. These data suggest that inhibition of the complement system should be effective in treating myocardial infarction.

Adult↗
PubMed2004

Biological effects of C1 inhibitor.

C1 inhibitor is a serine proteinase inhibitor (serpin) that regulates activation of both the complement and contact systems. Regulation of complement system activation takes place through inactivation of the classical pathway proteases, C1r and C1s, the lectin pathway protease, MASP2, and perhaps via inhibition of alternative pathway activation by reversible binding to C3b. Regulation of contact system activation takes place through inactivation of plasma kallikrein and coagulation factor XIIa. Deficiency of C1 inhibitor results in hereditary angioedema, which is characterized by recurrent episodes of localized angioedema of the skin, gastrointestinal mucosa or upper respiratory mucosa. A variety of clinical, in vitro and animal experiments indicate that the mediator of increased vascular permeability in hereditary angioedema is bradykinin. Animal models suggest that in addition to its utility in therapy of hereditary angioedema, C1 inhibitor may prove useful in a variety of other diseases including septic shock, reperfusion injury, hyperacute transplant rejection, traumatic and hemorrhagic shock, and the increased vascular permeability associated with thermal injury, interleukin-2 therapy and cardiopulmonary bypass. The therapeutic effect in these disease models very likely results from a combination of complement system activation, contact system activation and perhaps from other activities of C1 inhibitor. These other activities include a direct interaction with endotoxin, which may help to prevent endotoxic shock and an interaction with selectin molecules on endothelial cells, which may serve both to concentrate C1 inhibitor at sites of inflammation and to inhibit the transmigration of leukocytes across the endothelium.

Angioedema↗
PubMed1999

Mechanism of complement-dependent haemolysis via the lectin pathway: role of the complement regulatory proteins.

Mannan-binding lectin (MBL) is an acute phase protein which activates the classical complement pathway at the level of C4 and C2 via two novel serine proteases homologous to C1r and C1s. We recently reported that haemolysis via this lectin pathway requires alternative pathway amplification. The present experiments sought to establish the basis for this requirement, and hence focused on the activity and regulation of the C3 convertases. Complement activation was normalized between the lectin and classical pathways such that identical amounts of bound C4 and of haemolytically active C4,2 sites were present on the indicator cells. Under these conditions, there was markedly less haemolysis, associated with markedly less C3 and C5 deposited, via the lectin pathway than via the classical pathway, particularly when alternative pathway recruitment was blocked by depletion of factor D. Lectin pathway activation was associated with enhanced binding in the presence of MBL of complement control proteins C4bp and factor H to C4b and C3b, respectively, with decreased stability of the C3-converting enzyme C4b,2a attributable to C4bp. Immunodepletion of C4bp and/or factor H increased lectin pathway haemolysis and allowed lysis to occur in absence of the alternative pathway. Thus, the lectin pathway of humans is particularly susceptible to the regulatory effects of C4bp and factor H, due at least in part to MBL enhancement of C4bp binding to C4b and factor H binding to C3b.

Animals↗
PubMedDate not supplied

Complement system in healthy term newborns: reference values in umbilical cord blood.

Activation of the complement system occurs in several diseases. For reliable identification of complement activation in neonates, we establish reference ranges of several components in cord blood of healthy term newborns. For this study, cord blood samples were taken from 125 healthy term newborns. Concentrations of C1r, C2, C5, C7, Properdin, and factors D, H, and I were determined by single radial immunodiffusion. C3a and C5a were measured by specific EIA and complement function was measured by hemolytic assays. The results were expressed as 5th percentile, median, and 95th percentile. The following respective concentrations were found: C1r: 27, 47, 65 mg/l; C2: 12.0, 18.0, 24.0 mg/l; C5: 64, 92, 127 mg/l; C7: 32, 60, 89 mg/l; Properdin: 5.6, 9.7, 14.2 mg/l; factor D: 3.6, 5.2, 7.3 mg/l; factor H: 178, 234, 296 mg/l; and factor I: 15, 24, 32 mg/l. The functional activity of the whole complement system was 24%, 43%, 97% and for the alternative pathway 39%, 58%, 76%. The concentration of the activated split products C3a was 4, 65, 255 microg/l and of C5a, 0.11, 0.26, 1.19 microg/l. These reference values may be important for the detection of deficiencies of native complement proteins or perinatal processes leading to an activation of the complement system.

Adult↗
PubMed1993

Identification of multiple sites of interaction between heparin and the complement system.

Many diverse effects of heparin on the complement system have been reported. In only a few cases have the sites or the mechanisms of these effects been identified. In order to understand these results we sought to comprehensively analyze which complement proteins interact with heparin and which do not. Purified components of the classical, alternative and terminal pathways of complement were radiolabeled and their affinity for heparin determined. Affinity chromatography of normal human serum on heparin-agarose allowed a complete analysis of complement proteins and confirmed the results obtained with radiolabeled purified components. Of the 22 complement proteins examined, 13 bound heparin (C1q, C2, C4, C4bp, C1INH, B, D, H, P, C6, C8, C9, and vitronectin) while 9 did not bind heparin (C1r, C1s, C3, Factor I, C5, C7, C3b, Ba and Bb). These observations help explain the many effects heparin has on the complement system and they identify the proteins which need to be examined in order to explain these effects.

Chromatography, Affinity↗
PubMed1988

C4-binding protein prevents spontaneous cleavage of C3 in sera of patients with hereditary angioedema.

We have studied the effects of polyclonal monospecific Fab' preparations against C1r, C1s, C1INH, C4, C4bp, and fragment Bb of factor B on complement activation in NHS and HAES. Furthermore, we have investigated complement activation in these sera after addition of purified C1s and purified C4bp. Blocking C1INH induced a spontaneous activation of the classical pathway in NHS and to a lesser extent in HAES. Addition of p-C1s resulted in a strong C3 conversion in NHS, but not in HAES. However, after the blocking of C4bp in HAES, addition of p-C1s produced a total C3 consumption. The ration of the protein concentration of C4bp to hemolytically active C4 was eight times higher in HAES than in NHS. This increased ratio may account for the resistance of HAES to the C1s induced C3 cleavage in our in vitro system and the stability of C3 in HAE despite C4 and C2 consumption in vivo.

Angioedema↗
PubMedDate not supplied

Kinetic analysis of immune complex solubilization: complement function in relation to disease activity in SLE.

Solubilization of preformed bovine serum albumin (BSA) rabbit anti-BSA complexes in serum with kinetic analysis, haemolytic complement function, complement proteins C1q, C4, C3 and complexes containing C1 inhibitor (C1 INH-C1r-C1s-C1 INH) were serially investigated in relation to disease activity in 25 patients with systemic lupus erythematosus (SLE). Clinical assessment of disease activity was expressed using a validated global index (SLEDAI). Markedly decreased capacity to solubilize immune complexes in serum was mainly found in sever disease. By serial analysis, evidence of fairly persistently impaired classical pathway function was found in most of the patients. In partial contrast, impaired alternative pathway function was more clearly associated with active severe disease. Immune complex solubilization during short incubation (5-10 minutes) correlated with classical and alternative pathway-mediated haemolysis. Solubilization during long incubation (40 minutes) was correlated with haemolytic alternative pathway function. In some patients gradual impairment of solubilization during short incubation, and reduced classical pathway haemolytic activity were detectable 2-4 months before clinical manifestations prompted therapeutical intervention. SLEDAI was negatively correlated with solubilization during prolonged incubation (40 minutes) and with haemolytic alternative pathway function, further emphasizing involvement of the alternative pathway in severe disease. The findings emphasize the importance of impaired complement function due to complement activation in SLE. Assays for immune complex solubilization or other complement functions appear to be useful for monitoring disease activity in SLE.

Antigen-Antibody Complex↗
PubMed1980

Inhibition of immune complex-mediated activation of complement. Effects of agents modulating activation of, and the activated C1 complex.

Several known chemical compounds were shown to selectively inhibit the interaction between immune aggregates and C1q, the activation of C1r-C1s complex by immune aggregate-bound C1q, and the esterolytic activity of the activated C1s, C1s. These reactions are relevant to the functions of the first complement component, C1, and its activation induced by immune complexes. The effects of these inhibitors on tissue injury mediated by immune complex-induced complement activation, such as immune hemolysis, passive cutaneous anaphylaxis, and experimental glomerulonephritis were examined. The results suggest an approximate correlation between the activity shown on the molecular level and that obtained in vivo. One such compound, suramin, was shown to be an effective inhibitor of PCA and the proteinuria manifestation of EGN while not affecting antibody fixation to tissue or histamine-mediated skin reaction. These results suggest that effective suppression of the initial steps of complement activation may be of value of controlling immune complex-mediated tissue injuries in disease.

Animals↗
PubMed1993

Mapping of MYF5, C1R, MYHL, TPI1, IAPP, A2MR and RNR onto sheep chromosome 3q.

Five new loci, myogenic factor 5 (MYF5), complement 1 receptor (CIR), myosin-like heavy chain (MYHL), islet amyloid polypeptide (IAPP), and alpha-2-macroglobulin receptor (A2MR), were mapped onto sheep chromosome 3q by Southern hybridization to a panel of chromosomally characterized sheep x hamster cell hybrid lines. The location of the triose phosphate isomerase (TPI1) gene and one of the nucleolar organizer regions (RNR) on sheep 3q was confirmed by Southern analysis. This study provides further evidence for the existence of a large conserved chromosomal segment comprising much of sheep chromosome 3q, cattle chromosome 5, and human chromosome 12. The distal evolutionary breakpoint on human chromosome 12, producing the chromosomal segment U23 in cattle marked by aldehyde dehydrogenase (ALDH2), also produces a separate segment in sheep. Neither ALDH2 nor pancreatic lipase (PLA2), which is also distally located on human chromosome 12, were mapped onto sheep chromosome 3q.

Amyloid↗
PubMed1977

Hereditary C5 deficiency in man: genetic linkage studies.

Genetic linkage studies were performed on the only reported kindred with genetic deficiency of the fifth component of complement (C5). Thirty family members in four generations were studied for C5 defiency and 32 genetic marker systems. Of these marker loci, 13 were informative in this pedigree. Most importantly, C5 deficiency was excluded (lod score greater than -2.0) from linkage with the major histocompatibility locus (HLA) from a recombination frequency of greater than 15% (in females). Other marker systems excluded from linkage with C5 deficiency included the ceruloplasmin and Duffy loci at a recombination frequency of less than 15%, and the erythrocyte glyoxalase, MN, and Lewis loci at a recombination frequency of less than 5%. The most positive lod score (1.07, theta=0.05) was for linkage between C5 and haptoglobin, but this score does not reach statistical significance. Thus, among the genes for complement components which can be mapped because of deficiency states or polymorphic gene products, C5 joins C1r, C3 and C6 in not being closely linked to HLA. In contrast, close HLA linkage has been demonstrated for C2, C4, properdin factor B and, in one of two families, C8.

Adolescent↗
PubMed1981

Complement in pneumococcal infections with varying degrees of severity.

Complement component levels (Clq, Cls, C4, C3, factor B and properdin) and C1 subcomponent complexes (C1r-C1s, C1-r-C1-, C1-r-C1-s-C1 inactivator, 1A) were studied in 16 adults with pneumococcal infections varying severity. Patients with fulminant disease and signs of septic shock showed pronounced hypocomplementemia. In patients with pneumococcal pneumonia or meningitis elevated levels of C1-r-C1-s-C1- IA complexes indicated activation of C1, despite normal levels of C1q, C1s, C4 and C3. Moderately decreased properdin values suggested involvement of the alternative pathway. In adults with pneumococcal otitis no changes in the complement profile was found. In contrast, pronounced aberrations of the C1 subcomponents were earlier demonstrated in children with otitis.

Adolescent↗
PubMed1977

[Anticomplementary activity of a polyanion: pentosan-poly-sulfoester, II.--Mode of action and "in vitro " inhibition of human complement hemolytic activity (author's transl)].

The drug, pentosan-poly-sulfoester (PPS), is a potent in vitro inhibitor of the human complement hemolytic activity. This CH 50 inhibition represents a real anticomplementary activity (ACA), because this drug has no effect on sensitized sheep red blood cells (EA). The inhibition curve of human serum CH 50, by PPS is sigmoidal. The 50% inhibition is obtained for a 1: 650 dilution of PPS, which corresponds to a concentration of 0.08 mg/ml in normal human serum. Hemolytic titrations of C1, C4, C2, C3, and C5 showed a complete inhibition of C4, C2 and C3, and a partial inhibition of C1 (C1q, C1r, C1s, Ca++) and C5, by this drug. The mechanism of such functional inactivation of the different complement components is not yet elucidated.

Complement C2↗
PubMed1993

High molecular weight non-immunoglobulin salivary agglutinins (NIA) bind C1Q globular heads and have the potential to activate the first complement component.

Non-Immunoglobulin Salivary Agglutinins (NIA) which directly bind to microbes [including HIV] were studied for their potential to activate the first complement component (C1). It was determined that NIA had the same specific activity as heat aggregated IgG in binding to C1q and in activating C1. In order to determine the region of C1q which bound to NIA, C1q globular heads and C1q stems (collagen-like regions) were prepared and separated via a Western blot procedure. NIA bound principally to the globular heads of C1q and weakly to the collagen-like stem region. NIA were also studied for their potential to activate native C1 in normal human serum. Heat-aggregated IgG and cardiolipin served as positive controls. It was observed that incubation of isolated NIA with fresh normal human serum resulted in the formation of sodium dodecyl sulfate (SDS)-irreversible complexes of activated C1r-C1 inhibitor and activated C1s-C1 inhibitor and in activated C1s mediated C4 conversion. This indicated that isolated NIA had the potential to directly and effectively mediate classical complement pathway activation. Preincubation of NIA with C1q, blocked NIA mediated C1r and C1s activation and C4 conversion. The concn of NIA required to activate C1r and C1s was similar to that of heat-aggregated human IgG. In kinetic ELISA, NIA or aggregated IgG (positive controls) were first immobilized on microtiter plates, blocked with gelatin then incubated with fresh human serum as a source of complement. Depositions of C4b, C3b and iC3b substantiated that the complement system was effectively activated by immobilized NIA. The optimal relative NaCl concn for C4b deposition was 0.11 M. While pre-incubation of NIA with C1q blocked the subsequent C1 fixing potential of NIA, pre-incubation of NIA with rgp160 [HIV-1] or fibronectin did not interfere with the potential of NIA to fix C1.

Agglutinins↗
PubMed1983

Requirements for the binding of human plasma fibronectin to the C1q subunit of the first component of complement.

We have shown previously that [125I]fibronectin (Fn) binds to solid-phase C1q in a dose-dependent manner. When C1r and C1s were added, the binding of Fn to C1q was abolished; removal of C1r and C1s restored Fn binding to C1q. In this report, we have systematically examined the optimal conditions that favor the Fn-C1q interaction. Our studies show that purified native 125I-Fn binds to C1q in a specific, saturable manner. Maximal 125I-Fn binding to C1q and gelatin occurs at low ionic strength (mu = 0.05) and drops sharply as the ionic strength is increased. At mu = 0.20, the binding to C1q is inhibited by 95%, whereas the binding to gelatin is inhibited by 50%. Optimal binding of Fn to C1q and gelatin occurs between pH 5.5 and 7.5, is decreased by 45% at 4 degrees C, and increases with incubation time; saturation of binding occurs in 60 min at 37 degrees C. Scatchard analysis of binding at mu = 0.05 indicates a single class of high affinity binding sites (Kd = 3.7 X 10(-8) M +/- 0.36 SD). The Kd of the reaction when C1q is bound to either plastic or immune complexes is essentially the same, and, in both cases, increases as the ionic strength of the medium is increased. Finally, significant binding of Fn to C1q can be demonstrated at physiologic ionic strength employing either insoluble immune complexes containing C1q or chemically cross-linked C1q.

Animals↗
PubMed2000

Free radicals upregulate complement expression in rabbit isolated heart.

Both free radicals and complement activation can injure tissue. Our study determined whether free radicals alter complement production by the myocardium. Isolated hearts from New Zealand White rabbits were perfused on a Langendorff apparatus and exposed to xanthine (X; 100 microM) plus xanthine oxidase (XO; 8 mU/ml) (X/XO). The free radical-generating system significantly (P < 0.05) increased C1q and also increased C1r, C3, C8, and C9 transcription compared with controls. Immunohistological examination revealed augmented membrane attack complex deposition on X/XO-treated tissue. X/XO-treated hearts also exhibited significant (P < 0.05) increases in coronary perfusion pressure and left ventricular end-diastolic pressure and a decrease in left-ventricular developed pressure. N-(2-mercaptopropionyl)-glycine (3 mM), in conjunction with the superoxide dismutase mimetic SC-52608 (100 microM), significantly (P < 0.05) reduced the upregulation of C1q, C1r, C3, C8, and C9 mRNA expression elicited by X/XO. The antioxidants also ameliorated the deterioration in function caused by X/XO. Local complement activation may represent a mechanism by which free radicals mediate tissue injury.

Animals↗
PubMed2004

Proteases of the complement system.

The complement system is a group of about 35 soluble and cell-surface proteins which interact to recognize, opsonize and clear or kill invading micro-organisms or altered host cells (e.g. apoptotic or necrotic cells). Complement is a major part of the innate immune system. Recognition proteins such as C1q, MBL (mannan-binding lectin) and ficolins bind to targets via charge or sugar arrays. Binding causes activation of a series of serine protease proenzymes, such as C1r, C1s and MASP2 (MBL-associated serine protease 2), which in turn activate the atypical serine proteases factor B and C2, which then activate the major opsonin of the system, C3. Activated C3 binds covalently to targets, and is recognized by receptors on phagocytic cells. Two of the complement proteases, factors D and I, circulate not as proenzymes, but in activated form, and they have no natural inhibitors; their substrates are transient protein complexes (e.g. C3bB and C3bH) which form during complement activation. Factor B and C2 also have no natural inhibitor; they are active only when proteolytically cleaved and bound in an unstable, short-lived complex with C3b or C4b. C1r, C1s and the MASPs, in contrast, are regulated more conventionally by the natural serpin, C1-inhibitor. Complement proteases in general have very narrow specificity, and low substrate turnover with both natural and synthetic substrates. Excessive activation of complement is inflammatory, and causes tissue damage (e.g. in rheumatoid arthritis, or in ischaemia/reperfusion injury). Substances that regulate complement activation are likely to be useful in the regulation of inflammation. Complement activation might potentially be controlled at many different steps. Much attention has been focused on controlling the formation or activity of the protease complexes C3bBb and C4b2a (containing activated factor B and C2 respectively), as these generate the inflammatory peptides C3a and C5a.

Complement Activation↗
PubMed1977

Further studies on the identification of the subcomponents of the first component of complement after affinity chromatography of human serum on IgG-sepharose.

Affinity chromatography of serum on IgG covalently linked to Sepharose results in the retention of the proteins of the first component of complement (C1). A fraction called pool II is eluted from this column with 0.025 M EDTA and has previously been shown to contain C1s and a novel protein believed to be part of the C1 complex and called C1t. C1r has now been located in pool II and these three proteins were purified by DEAE cellulose chromatography. C1r and C1s were recovered in the proenzyme form and their identity was established by SDS polyacrylamide gel electrophoresis before and after reduction and alkylation, and on the basis of their esterolytic activities toward different substrates. The properties of C1r from pool II are contrasted with those of the protein recovered from the pool III eluate of the affinity column and previously thought to be C1r.

Chromatography, Affinity↗