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PubMed1987

[Components of the classical complement pathway in systemic lupus erythematosus].

Measurements of complement components in sera from patients with systemic lupus erythematosus (SLE) and some of their relatives indicated that decreased levels of CH50, C4 and C2 were mostly related to a genetic deficiency at one or both of the loci coding for C4, at least in those patients in whom decreased C4 levels were associated with normal C1 hemolytic activity. C4 deficiency is either isolated or associated with complement activation. In some patients with C4 deficiency, complement activation could only be demonstrated by measuring plasma level of the C3 cleavage fragment, C3a des Arg. Decreased concentration and/or hemolytic activity of C4 and C2 in SLE cannot be used to assess the activity of the disease.

Complement Activation↗
PubMed1984

Quantitative determination of complement components produced by purified hepatocytes.

In this report we describe, on a quantitative basis, the secretion of complement components by hepatocytes. Primary cultures were established after isolation of the cells from guinea-pig liver and the synthesis of C3, C5, C4 and C2 was measured. The cells were isolated by collagenase perfusion of the liver followed by differential centrifugation. The contamination of the hepatocyte suspension with non-parenchymal cells was less than 1%. At 24 h after plating the cells the kinetics of complement production were measured. C3 and C5 content in the culture medium harvested at different time intervals was determined by a sensitive ELISA. Secretion of C2 and C4 was measured haemolytically using C2 or C4 deficient guinea-pig serum. Under the conditions used hepatocytes secreted C3 at a rate of about 100 ng/10(6) cells/h with a plateau of secretion after 24 h of culture corresponding to about 350,000 molecules/cell/h. C5 secretion was detectable after 3-6 h of culture. The C5 secretion rate was about 15 ng/10(6) cells/24 h. The functional activity of C4 and C2 in the supernatants amounted to about 80 SFU/cell/h if the culture medium was changed every 3 h but dropped significantly if the medium was changed every 12 h. The decrease of the haemolytic activity became stronger if the medium was changed every 24 h. Cycloheximide reversibly inhibited the complement production. Our results show that guinea-pig hepatocytes synthesize considerably more C3 and C5 compared to peritoneal macrophages supporting the hypothesis that hepatocytes provide the major source of plasma complement.

Animals↗
PubMedDate not supplied

Some aspects of the humoral immunity and the phagocytic function in newborn infants.

Newborn infants, particularly those born prematurely, are prone to develop life-threatening pyogenic infections. Different studies have demonstrated impairment of various aspects of the humoral immunity and the phagocytic activity of neutrophils in newborns. We conducted a comprehensive study evaluating the complement function (CH50 and AP50) and the level of the vast majority of the complement components (Clq, Clr, Cls, C2-C9, FB and properdin) in preterm and full-term newborn infants as compared to adults. Furthermore, we investigated the effect of autologous and heterologous serum on the bactericidal activity of neutrophils, by crossing newborn serum with adult cells and vice versa. Results showed that preterm and full-term newborns have an impaired complement activity as compared to adults (CH50 P < 0.05, AP50 < 0.01) and significantly reduced complement components except for C7, which was found to be normal in full-term infants and in most appropriate-for-gestational age preterm newborns at 34-36 weeks. A statistically significant correlation was found between gestational age and the level of most of the complement components. CH50 and AP50 also showed a positive trend which, however, was not statistically significant. No correlation was found between birthweight and complement activity or complement component levels. The neutrophil bactericidal activity of full-term newborns was about one-third that of adults (P < 0.001). Adult serum improved the bactericidal activity of newborn neutrophils by 93%, indicating a considerable neonatal humoral defect. Conversely, neonatal serum blunted the adult bactericidal activity by 86%. Our results support the fact that both humoral and phagocytic functions in newborn infants are impaired, which may possibly account for their increased tendency to develop severe pyogenic infections.

Adult↗
PubMed1991

Acquired C1 inhibitor deficiency associated with systemic lupus erythematosus affecting the central nervous system.

A 22 year old woman with systemic lupus erythematosus affecting the central nervous system had acquired C1 inhibitor deficiency. She was admitted for treatment of psychotic behaviour, but showed no signs of angioedema. The serum complement profile of the patient showed normal C3 concentration and a depletion of C4, C2, C1 inhibitor, and C1q. Her parents had normal complement profiles. An extremely reduced C4 concentration may lead to involvement of the central nervous system in systemic lupus erythematosus.

Adult↗
PubMed1986

Serotherapy of primary rat mammary carcinoma: inhibition by ethylenedinitrilotetraacetic acid but not by [ethylenebis(oxyethylenenitrilo)]tetraacetic acid.

We reported inhibition of growth of primary rat mammary carcinomas after infusions of tumor-bearer plasma absorbed with Protein A-Sepharose or inactivated CNBr Sepharose. Absorbed plasmas were depleted of the third component of complement (C3) (other complement components defined similarly) and C5 but not C1, C4, or C2. These results suggested that activation of the alternative pathway of complement might be involved in the observed antitumor effects. To test this concept sera were treated with ethylenedinitrilotetraacetic acid or [ethylenebis(oxyethylenenitrilo)]tetraacetic acid before absorption with Protein A-Sepharose. Ethylenedinitrilotetraacetic acid, by chelating calcium and magnesium, prevents activation of both the alternative and classical complement pathways. [Ethylenebis(oxyethylenenitrilo)]tetraacetic acid, by chelating calcium but not magnesium, permits activation of the alternative pathway but inhibits activation of the classical complement pathway. Sera in the presence or absence of chelating agent were absorbed with Protein A-Sepharose twice at room temperature. After absorption calcium was added to the sera. Rats were treated by i.v. injection of sera twice a week for 2 weeks. Measurements of tumor size were made weekly for 5-7 weeks and then tumor weight was determined. Groups were compared both for size of index and total tumors. The results can be summarized as follows: tumor-bearer sera before absorption did not inhibit the growth of rat primary mammary carcinomas; tumor-bearer sera after absorption with Protein A-Sepharose showed significant consumption of C3 and did inhibit tumor growth; tumor-bearer sera absorbed in the presence of ethylenedinitrilotetraacetic acid did not show a decrease in C3 functional activity and did not inhibit tumor growth; tumor-bearer sera absorbed in the presence of [ethylenebis(oxyethylenenitrilo)]tetraacetic acid did show a decrease in C3 functional activity and did inhibit tumor growth; sera from normal adult female rats after absorption with Protein A-Sepharose did inhibit tumor growth. The results are consistent with a role for the alternative pathway of complement in the inhibition of growth of rat primary mammary carcinomas observed after treatment with absorbed sera.

Animals↗
PubMed2001

Complement contributes to protective immunity against reinfection by Plasmodium chabaudi chabaudi parasites.

We have studied the impact of deficiency of the complement system on the progression and control of the erythrocyte stages of the malarial parasite Plasmodium chabaudi chabaudi. C1q-deficient mice and factor B- and C2-deficient mice, deficient in the classical complement pathway and in both the alternative and classical complement activation pathways, respectively, exhibited only a slight delay in the resolution of the acute phase of parasitemia. Complement-deficient mice showed a transiently elevated level of gamma interferon (IFN-gamma) in the plasma at the time of the acute parasitemia compared with that of wild-type mice. Although there was a trend for increased precursor frequencies in CD4(+) T cells from C1q-deficient mice producing IFN-gamma in response to malarial antigens in vitro, intracellular cytokine staining of spleen cells ex vivo showed no difference in the numbers of IFN-gamma(+) splenic CD4(+) and CD8(+) cells. In contrast, C1q-deficient animals were significantly more susceptible to a second challenge with the same parasite. C1q-deficient animals showed a reduced level of anti-malarial immunoglobulin G2a (IgG2a) antibody 100 days after primary infection. However, following a significantly higher parasitemia, C1q-deficient mice had increased levels of IgM and IgG2a anti-malarial antibodies. In summary, this study indicates that while complement plays only a minor role in the control of the acute phase of parasitemia of a primary infection, it does contribute to parasite control in reinfection.

Acute Disease↗
PubMed2003

Rheumatic syndromes associated with complement deficiency.

Deficiency of an early component of the classical complement pathway, C1q, C1r/C1s, C4, or C2, regularly produces autoimmunity in man, especially systemic lupus erythematosus. It has long been suggested that disruption of this pathway would lead to the inappropriate handling of immune complexes. An intriguing hypothesis that builds on this idea relates to a defect in clearance of one's own cellular debris, namely apoptotic cells. An attractive feature of this emerging concept is that blebs on apoptotic cells are decorated with antigens to which much of the autoantibody specificity is directed in systemic lupus erythematosus. A second hypothesis, generated primarily from complement deficiencies, relates to an impairment in the humoral immune response or in the regulation of autoreactive B cells. This review begins by summarizing the recognized autoimmune manifestations of complement deficiency and then describes new data derived from targeted gene deletions of complement proteins.

Clinical Trials as Topic↗
PubMed1990

[Chronic urticaria and acquired complement deficiency due to a nephritic factor (C3NeF)].

Several studies have suggested that complement activation processes are frequently involved in the pathogenesis of urticaria. We report clinical evolution and studies of complement-mediated functions in a 47-year-old previously described patient presenting with chronic urticaria, in whom we found persistent low complement hemolytic activity (65-75% of normal values), depressed levels of third complement component (C3, between 55% and 65%) and of factor B (between 60% and 75%), together with C1, C4, C2, C5, C5b neoantigen and fluid phase terminal complement (SC5b-9) complex within the normal range, pointing to activation of the alternative pathway. A circulating low affinity C3 nephritic factor (C3NeF), known to enhance cleavage of human serum C3, was detected. The urticarial lesions, which were initially pruritic and persisted for less than 24 hours, became subsequently fixed and burning, and were accompanied by fever and arthralgia. Skin biopsy specimens showed moderate leukocytoclastic vasculitis. Response to varied treatment regimens, including antihistamines and colchicine, was poor. Therapy with oral corticosteroids produced some improvement. The association of chronic urticaria with C3NeF without clinical and biological signs of membranoproliferative glomerulonephritis and partial lipodystrophy has not to our knowledge been reported before. This observation raises the question of a possible role of C3NeF in the pathogenesis of urticaria.

Chronic Disease↗
PubMed1991

Neutrophil adhesion to xenogeneic endothelium via iC3b.

Neutrophils are thought to play an important role in the pathogenesis of hyperacute rejection, a dramatic form of tissue injury caused by the reaction of antigraft antibodies with endothelial cells of an organ allograft or xenograft. We asked whether the interactions of human polymorphonuclear leucocytes (PMN) with xenogeneic endothelium might be promoted by the binding of natural anti-endothelial antibodies and complement by using porcine aortic endothelial cells (PAEC), human serum, and human PMN in an in vitro model of hyperacute rejection. Pretreatment of PAEC with 10% human serum followed by washing markedly increased PMN adhesion from 15.7 +/- 1.8% to 62.5 +/- 3.6% (p less than 0.001). Complement and anti-endothelial antibodies were necessary for the increase, because heat-inactivated serum or serum depleted of IgM did not significantly increase PMN adhesion to treated endothelium. The induction of increased PMN adhesion to PAEC by human serum was observed within 1 min. The essential role of complement was defined using complement-depleted serum. Ten percent C2-deficient serum did not increase PMN adhesion whereas 10% C5-depleted or 10% C8-depleted serum caused the same increase in PMN adhesion as observed with normal human serum. These results suggested that C3 might play a critical role in enhanced neutrophil adhesion. In fact, PAEC treated with 10% human serum for 15 min and incubated with an F(ab')2 antihuman C3 for 10 min completely abolished the enhanced adhesion. PAEC treated with 10% human serum or C5-depleted serum displayed fluorescence of iC3b whereas monolayers treated with heat-inactivated serum or C2-deficient serum were non-reactive. The enhanced PMN adhesion to serum-treated PAEC was mediated through neutrophil receptors binding iC3b because mAb directed against CD11b/CD18 inhibited the serum-enhanced adhesion of PMN. We conclude that PMN adhesion to endothelium can be significantly enhanced by the endothelial deposition of iC3b.

Animals↗
PubMed1971

In vitro studies of complement function in sera of C4-deficient guinea pigs.

In vitro studies were performed utilizing sera from a strain of guinea pigs with a total absence of hemolytically active C4. Previous studies in these animals have demonstrated normal complement-dependent inflammatory reactions, suggesting that they are able to bypass their deficiency of C4. In vitro studies with C4-deficient serum also indicate normal activation of late-acting C components. Thus, endotoxin was capable of fixing normal amounts of the late components of complement (C3-9) in these sera, but did not fix C1 and C2. Antigen-antibody complexes fixed both early and late components of complement, although components beyond C4 were fixed less efficiently than in normal sera. Therefore, both in vivo and in vitro evidence indicates that the C4-deficient guinea pigs possess an alternate pathway for activation of late-acting complement components. Antigenic analysis of C4-deficient serum utilizing both guinea pig anti-C4 antibody and rabbit anti-C4 antibody suggests an absolute deficiency of C4-like molecules. Sera from animals with C4-deficiency were found to have one-half the normal level of C2. Sera from five of eight animals tested had 10-20% normal C1 activity. C3-9 assayed as a complex was normal.

Animals↗
PubMed1998

Baculovirus-mediated expression of truncated modular fragments from the catalytic region of human complement serine protease C1s. Evidence for the involvement of both complement control protein modules in the recognition of the C4 protein substrate.

C1s is the modular serine protease responsible for cleavage of C4 and C2, the protein substrates of the first component of complement. Its catalytic region (gamma-B) comprises two complement control protein (CCP) modules, a short activation peptide (ap), and a serine protease domain (SP). A baculovirus-mediated expression system was used to produce recombinant truncated fragments from this region, deleted either from the first CCP module (CCP2-ap-SP) or from both CCP modules (ap-SP). The aglycosylated fragment CCP2-ap-SPag was also expressed by using tunicamycin. The fragments were produced at yields of 0.6-3 mg/liter of culture, isolated, and characterized chemically and then tested functionally by comparison with intact C1s and its proteolytic gamma-B fragment. All recombinant fragments were expressed in a proenzyme form and cleaved by C1r to generate active enzymes expressing esterolytic activity and reactivity toward C1 inhibitor comparable to those of intact C1s. Likewise, the activated fragments gamma-B, CCP2-ap-SP, and ap-SP retained C1s ability to cleave C2 in the fluid phase. In contrast, whereas fragment gamma-B cleaved C4 as efficiently as C1s, the C4-cleaving activity of CCP2-ap-SP was greatly reduced (about 70-fold) and that of ap-SP was abolished. It is concluded that C4 cleavage involves substrate recognition sites located in both CCP modules of C1s, whereas C2 cleavage is affected mainly by the serine protease domain. Evidence is also provided that the carbohydrate moiety linked to the second CCP module of C1s has no significant effect on catalytic activity.

Animals↗
PubMed1981

First component of complement and thrombosis.

The previous demonstration of an association between the collagen-like region of C1q (subcomponent of the first component of complement) and human platelets and of the inhibitory properties of C1q on platelet adhesion and aggregation to or by collagen has led us to consider the first component of complement as a possible modulator of the platelet-collagen interaction. Since collagen represents a major component of the vessel wall, the modification of C1 could play a role in the development of thrombosis. We have therefore studied two patients with abnormalities of complement (low or undetectable C1, C4, C2 and deficiency in C1 inhibitor) who presented with acquired angioneurotic oedema. Both patients had a history of multiple episodes of arterial and/or venous thrombosis. Platelet associated C1q was decreased or undetectable, and this condition was associated with a specific increase of collagen induced aggregation thereby suggesting a possible mechanism for the recurrent thromboembolic episodes.

Adult↗
PubMed1974

Evidence for linkage between HL-A histocompatibility genes and those involved in the synthesis of the second component of complement.

HL-A analysis of a family with C2 deficiency revealed evidence for close linkage between the C2 defect and the histocompatibility HL-A loci. The propositus was homozygous both for C2 deficiency and the HL-A haplotype 10,W18. Among seven children of three double backcross matings, no recombinants were found. The possible significance of such linkage is discussed.

Complement System Proteins↗
PubMed2006

Design of a complement mannose-binding lectin pathway-specific activation system applicable at low serum dilutions.

Recently we showed that alternative pathway (AP) amplification was responsible for more than 80% of specific classical pathway-induced terminal pathway activation under physiological conditions. The present study aimed to design a system for specific lectin pathway (LP) activation applicable at low serum dilutions with a fully functional AP. Comparison between activation of normal human serum (NHS), a mannose-binding lectin (MBL) homozygous D/D-deficient serum, and sera deficient in C1q and C2, all diluted 1 : 2, was essential to document optimal conditions for LP specificity. Mannan on the solid phase of enzyme-linked immunosorbent assay (ELISA) plates was used for activation, showing 0.5 microg mannan/well to give optimal conditions because at this concentration a good signal was preserved for C4 and TCC deposition in NHS, whereas the C3 deposition observed in C2-deficient serum at higher mannan concentrations reached nadir at 0.5 microg/well, indicating a lack of direct AP activation under these conditions. Pooled NHS and C1q-deficient serum gave the same degree of C4 and terminal complement complex (TCC) deposition, whereas deposition of these products was not obtained with MBL-deficient serum. Reconstitution with purified MBL, however, restored the depositions. A blocking anti-MBL monoclonal antibody (mAb) completely abolished the complement deposition, in contrast to a non-inhibiting anti-MBL mAb. Activation of C2-deficient serum induced C4 deposition similar to NHS, but negligible deposition of C3 and TCC, confirming the lack of direct activation of AP. Thus, this assay is unique in being LP-specific at low serum dilution and thus particularly suitable to study LP activation mechanisms and the role of AP amplification under physiological conditions.

Antibodies, Monoclonal↗
PubMed1987

The effect of lactoferrin on complement mediated modulation of immune complex size.

Earlier we showed that human lactoferrin is capable of inhibiting the complement-mediated lysis of antibody-coated erythrocytes due to an inhibition of the formation of the classical C3 convertase. In this report the effect of lactoferrin on complement mediated modulation of immune complex size was studied. Lactoferrin was shown to inhibit the complement-dependent solubilization of immune precipitates with kinetics resembling that seen by others using C2 deficient serum. Lactoferrin, however, did not affect the complement-dependent inhibition of immune precipitation. These findings confirm our earlier observations that lactoferrin has no effect on the activation of the very early complement components (C1 and C4), but inhibits C3 deposition on immune complexes which is a crucial mechanism in immune precipitate solubilization.

Animals↗
PubMed2003

Levels of mannan-binding lectin-associated serine protease-2 in healthy individuals.

The lectin pathway is part of the innate immune system providing a first line of defence against infections. Mannan-binding lectin (MBL) and ficolins, in complex with MBL-associated serine proteases (MASPs), are capable of activating the complement system, thus mediating the destruction of infectious agents. MASP-2 cleaves C4 and C2 and is thus crucial for the activation of downstream complement components. We present an assay for quantifying total MASP-2 in plasma and serum samples. The assay is a sandwich type assay using a combination of two monoclonal anti-MASP-2 antibodies, one directed against the N-terminal part of MASP-2 and the other against its C-terminal part. Based on a population of Danish blood donors, the average MASP-2 concentration was estimated at 534 (S.D.+/-213) ng per ml of plasma. Characterization of the MASP-2 protein in serum showed high stability at 4 degrees C and at ambient temperature but a rapid decline at 37 degrees C. Gel permeation chromatography (GPC) indicated that all MASP-2 in serum is present in complexes with MBL and ficolins.

Animals↗
PubMed1995

IgA and IgG immune complexes increase human macrophage C3 biosynthesis.

We have studied the effect of IgA- and IgG-containing immune complexes on the production of complement proteins C3, factor B and C2 by human monocyte-derived macrophages, using biosynthetic labelling, immunoprecipitation, sodium dodecyl sulphate-polyacrylamide gel (SDS-PAGE) and autoradiography. There was a consistent increase in C3 production and secretion with both IgA and IgG immune complexes. This increase appeared after a 24-hr incubation period of the macrophages in the presence of immune complexes. No change in the biosynthesis of factor B and C2 proteins was observed in these experiments. Concomitant with the enhanced C3 biosynthesis, the immune complexes caused an increase in macrophage tumour necrosis factor (TNF) production; 310 + 24 U/ml/5 x 10(5) cells and 430 + 51 U/ml/5 x 10(5) cells for IgA and IgG immune complexes, respectively, versus 12 + 8 U/ml/5 x 10(5) cells in the control cells. The presence of prednisolone (2 x 10(-5) M) or dexamethasone (1 x 10(-7) M) inhibited the immune complex-induced TNF production, but had no effect on C3-increased synthesis, suggesting that the effect of immune complexes was not mediated by endogenous TNF production. These findings may be relevant to the local inflammatory response in IgA immune complex-mediated diseases, including IgA nephropathy.

Antigen-Antibody Complex↗
PubMed2006

Complement deficiency and disease: an update.

Complement deficiencies are probably vastly under-diagnosed within clinical medicine. Judging from a Swedish study of C2 deficiency, a deficiency with an estimated prevalence of about 1/20,000 in Western countries, less than 10% of the deficiencies of the classical and alternative pathways and the late complement components are identified in Sweden. C1 inhibitor deficiency and deficiencies of MBL and MASP-2 were not included in the assessment. The introduction of new screening methods should facilitate detection of complement deficiencies in clinical practice. In our study of C2 deficiency (n=40), 57% of the patients had a history of invasive infection with encapsulated bacteria, mainly Streptococcus pneumoniae. This emphasizes the importance of the classical and/or the lectin pathway in defence against severe infection. Rheumatological disease, mainly systemic lupus erythematosus was present in 43% of the patients. In addition, a significant association was found between C2 deficiency and atherosclerosis. Complement-dependent disease mechanisms are discussed together with the potential importance of non-complement genes for disease expression in complement deficiencies. Analysis of larger patient groups is required in order to establish guidelines for investigation and treatment of patients with complement deficiency.

Atherosclerosis↗