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PubMed1981

Influence of age and sex on serum complement components in children.

Concentrations of eight complement components were determined on sera from 419 healthy children (198 boys and 221 girls) aged from 1 to 19 years. A significant correlation between concentration and age for all complement components (C1q, C1s, C4, C3, C5, factor B, properdin, and C1 inhibitor) was observed for girls; in the male population, a significant correlation was present only for C1q, C4, C3, C5, and properdin. The presence of a significant relationship to age suggests that this variable must be considered in establishing normal values of serum complement for children.

Adolescent↗
PubMed2005

Predominant role of IgM-dependent activation of the classical pathway in the clearance of dying cells by murine bone marrow-derived macrophages in vitro.

Soluble molecules including complement components have been shown to facilitate the clearance of dying cells by phagocytes, a process that is important in preventing tissue damage and autoimmunity. However, the extent to which complement is involved in this process and the relative contribution of each of the complement activation pathways is not fully understood. We examined the role of complement in the recognition/uptake of apoptotic thymocytes by murine bone marrow-derived macrophages (BMDM) in vitro using sera from gene-targeted mice. We found this process to be IgM- and complement-dependent, especially when the apoptotic cell-to-BMDM ratio was low, and the level of C3 deposition on apoptotic cells correlated closely with their uptake. The addition of C1q rectified the phagocytic defect seen in the presence of C1q-deficient serum in vitro but had no effect on the phagocytic defect observed with serum deficient in both IgM antibodies and C1q. Similarly, complement activation by IgM antibodies was essential for in vivo C3 deposition on apoptotic cells and their uptake by peritoneal macrophages. Hence, the efficient uptake of dying cells by BMDM requires IgM antibodies and complement.

Animals↗
PubMed2004

Complement synthesis and activation in the brain of SIV-infected monkeys.

Complement is one of the most critical defence tools against cerebral infections, but uncontrolled complement biosynthesis and activation can induce profound brain tissue damage. To clarify the role of complement in the pathogenesis of AIDS-associated neurological disorders, we analysed the synthesis of complement in the brains of SIV-infected rhesus macaques. Using immunohistochemical staining we could show that the cerebral synthesis of complement factors C1q and C3 was strongly upregulated in SIV-infected monkeys compared to the spontaneous synthesis in uninfected control monkeys. Astrocytes, neurons, microglia, infiltrating macrophages and multinuclear giant cells all contribute to the high amounts of C1q and C3 in the brain. Secreted C1q and C3 are also deposited on the membrane of neurons, a prerequisite for formation of the membrane-driven lytic membrane attack complex. The membrane deposition thus might suggest complement-induced lysis of bystander neurons as a potential mechanism for cell damage during viral infection of the brain.

Animals↗
PubMed2005

[The roles of complement 1q and anti-C1q autoantibodies in pathogenesis of lupus nephritis].

OBJECTIVE: To analyze the correlation of serum levels of complement 1q (C1q) and anti-C1q autoantibodies (C1qAb) with renal pathology in lupus nephritis (LN) and to explore the probable mechanism of C1q and C1qAb in the development of systemic lupus erythematosus (SLE), especially LN. METHODS: The serum samples of 80 SLE patients, 40 LN patients and 40 non-LN patients, were collected to detect the level of C1q with single radial immunodiffusion and the level of C1qAb with enzyme-linked immunosorbent assay. Renal biopsy was conducted in 25 of the 32 LN patients so as to observe the deposition of apoptotic cells and apoptotic bodies in the glomeruli with TdT-mediated dUTP nick end labeling. RESULTS: The serum level of C1q was (130 +/- 50) mg/L in the LN patients, significantly lower than that in the non-LN patients [(170 +/- 70) mg/L, P = 0.004]. The serum level of C1qAb (P/N value) was 7 +/- 4 in the LN patients, significantly higher than that in the non-LN patients (4 +/- 3, P < 0.001). The correlation coefficient between C1qAb and C1q in the LN patients was -0.567 (P < 0.01), showing a significant negative correlation. The correlation coefficient between C1qAb and C1q in the non-LN patients was -0.509 (P = 0.001), showing a significant negative correlation. The serum C1q level of the type IV LN patients was significantly lower than that in the type I LN patients, and the serum C1qAb level of the type IV LN patients was significantly higher than that in the type I LN patients (P < 0.05). The serum C1q was significantly lower in the LN patients with renal C1q deposition (++) than in the LN patients with renal C1q deposition (+), however, the serum C1qAb was significantly higher in the LN patients with renal C1q deposition (++) than in the LN patients with renal C1q deposition (+) (both P < 0.05). The serum C1q level was significantly lower in the LN patients with positive IgG deposition than in the LN patients with negative IgG deposition and the serum C1qAb level was significantly higher in the LN patients with positive IgG deposition than in the LN patients with IgG negative deposition (both P < 0.05). The serum C1q level in the LN patients with positive C3 deposition was significantly lower than that in the LN patients with negative C3 deposition (P < 0.05). The serum C1q level in the LN patients with marked apoptotic cells and deposition of apoptotic bodies was significantly lower than that in the LN patients without marked apoptotic cells and deposition of apoptotic bodies, and the serum C1qAb level in the LN patients with obvious apoptotic cells and deposition of apoptotic bodies was significantly higher than that in the LN patients without obvious apoptotic cells and deposition of apoptotic bodies (both P < 0.05). The decrease of serum C1q level and increase of serum C1qAb were significantly positively correlated with the deposition of C1q, IgG, and C3 in the kidney, and with the appearance of apoptotic cells and deposition of apoptotic bodies in the kidney. CONCLUSION: C1q and C1qAb may be involved in the pathogenesis of SLE, especially LN. The probable mechanism may be that they promote renal deposition of circulating immune complexes combined with C1q or promote the renal deposition of apoptotic cells and apoptotic bodies.

Adult↗
PubMed1985

The modulation of immune complex aggregation by classical pathway-mediated reactions.

Classical pathway (CP)-triggered reactions of complement-modulated immune complex (IC) aggregation (tetanus toxoid/human anti-tetanus toxoid-IgG; ICs of equivalence) were investigated turbidimetrically during the early stages of reaction. Monospecific Fab'- or Fab-fragments (rabbit) directed against certain complement components were used to block the complement function in normal human serum (NHS). Additionally, parts of the reactions were studied using purified complement components. C1q in serum generated by the addition of EDTA as well as purified C1q were found to increase the IC aggregation. In contrast to C1q, macromolecular C1 is able to inhibit IC aggregation, whereas additional participation of C-1 INH reversed this process. The cooperation of the remaining CP proteins (C4, C2, C4bp, and I) reconstituted the inhibition capacity of the complement. Whereas C3 supported significantly inhibition, a significant influence of other effector pathway (EP) components (C5-C9) was not detectable turbidimetrically.

Antigen-Antibody Complex↗
PubMed1987

Levels of some complement components in azoospermic, oligospermic and normospermic Nigerian men.

The levels of complement components (C1q, C4, C3 and C3d) were measured in the sera of nine azoospermic Nigerian men and compared with those of 12 oligospermic and 19 normospermic Nigerian men. The mean values of C1q, C4, C3 and C3d for azoospermic men showed no significant difference from those obtained for the other men. Generally, the individual sera from the azoospermic men did not show abnormally lowered levels of any of the complement components when compared with values obtained for the normospermic group.

Autoimmune Diseases↗
PubMed1986

The detection of complement binding immune complexes by means of 51Cr-labelled indicator cells.

A radioimmunoassay is described for the detection of circulating complement binding immune complexes. The method was found to be highly sensitive but of limited specificity. It is based on the ability of the complexes to bind added complement (C1q-component) so that they are not available for the lysis of 51Cr-labelled chicken red blood cells in a haemolytic system. Sera from 241 patients and 87 healthy persons were studied for the presence of circulating immune complexes. The complement binding capacity is dependent on the disease groups. Patients with immune complex diseases showed a high significant difference to the healthy persons. The experimental conditions and the quality control of the method were described. There was found a very good correlation between complement binding capacity and concentration of heat-aggregated immunoglobulin.

Animals↗
PubMed2002

Evidence for a sustained increase in clonal beta-cell basal intracellular Ca2+ levels after incubation in the presence of newly diagnosed Type-1 diabetic patient sera. Possible role in serum-induced inhibition of insulin secretion.

We have previously reported that newly diagnosed Type-1 diabetic patient sera potently suppressed insulin secretion from a clonal rat pancreatic beta-cell line (BRIN BD11) but did not alter cell viability. Here, we report that apoptosis in BRIN BD11 cells incubated in various sera types (fetal calf serum (FCS), normal human serum and Type-1 diabetic patient) was virtually undetectable. Although low levels of necrosis were detected, these were not significantly different between cells incubated in sera from different sources. ATP levels were reduced by approximately 30% while nitrite production increased twofold from BRIN BD11 cells incubated for 24 h in the presence of Type-1 diabetic patient sera compared with normal human sera. Additionally, ATP levels were reduced by approximately 40% and DNA fragmentation increased by more than 20-fold in BRIN BD11 cells incubated in FCS in the presence of a pro-inflammatory cytokine cocktail (interleukin-1beta, tumour necrosis factor-alpha and interferon-gamma), compared with cells incubated in the absence of cytokines. Nitric oxide production from BRIN BD11 cells was markedly increased (up to 10-fold) irrespective of sera type when the cytokine cocktail was included in the incubation medium. Type-1 diabetic patient sera significantly (P<0.001) raised basal levels of intracellular free Ca(2+ )concentration ([Ca(2+)](i)) in BRIN BD11 cells after a 24-h incubation. The alteration in [Ca(2+)](i) concentration was complement dependent, as removal of the early complement components C1q and C3 resulted in a significant reduction (P<0.01) of sera-induced [Ca(2+)](i )changes. We propose that the mechanism of Type-1 diabetic patient sera-induced inhibition of insulin secretion from clonal beta-cells may involve complement-stimulated elevation of [Ca(2+)](i) which attenuates the nutrient-induced insulin secretory process possibly by desensitizing the cell to further changes in Ca(2+).

Adenosine Triphosphate↗
PubMedDate not supplied

Complement activation in the adult respiratory distress syndrome following cardiopulmonary bypass.

We investigated complement fractions in patients after extracorporeal circulation for coronary bypass operations or cardiac valve replacement, and in two cases developing an adult respiratory distress syndrome (ARDS) after this type of intervention. The patients presenting an ARDS had significantly increased levels of C3d (p less than 0.001), the small molecular breakdown product of C3, associated with decreased levels of total classic haemolytic activity (p less than 0.05) and of the complement component C1q (p less than 0.001) when compared to a group of 10 patients who had uneventful evolution after bypass. However, all patients undergoing cardiopulmonary bypass had significantly increased levels of C3d (p less than 0.005 or less) associated with significant decrease of various complement components within 24 h after bypass, when compared to a control group of 5 patients investigated after aorto-iliac bypass graft surgery. We conclude that significant complement activation can persist in patients 24 h after bypass and--at higher levels--be a pathogenic and biological marker of ARDS after extracorporeal circulation.

Adult↗
PubMed2004

ACR classification criteria for systemic lupus erythematosus: complement components.

Complement is involved in the pathogenesis of systemic lupus erythematosus (SLE) and has also a seemingly paradoxical protective role in the development of the disease. Low levels of components within the classical pathway of complement especially C1q, C4 and C3 have a high specificity for SLE diagnosis and should be considered as promising for inclusion in classification criteria of SLE.

Biomarkers↗
PubMed1998

Aspects of leukocyte function and the complement system following aerobic exercise in young female gymnasts.

Recent studies have reported reduced immunity in trained athletes. Scant information exists on changes in the immune function among trained children. The purpose of this study was to assess the effect of aerobic exercise on the phagocytic process of neutrophils and the complement system in young athletes. Subjects included prepubertal elite female gymnasts (n = 7) and untrained girls (n = 6) aged 10-12 years. Venous blood was withdrawn before, immediately post and 24 h following a 20-min run at a heart rate of 170-180 beats.min-1. Neutrophil random migration, chemotactic activity, bactericidal function and PMA/FMLP-stimulated superoxide anion release as well as various complement components were assessed. Net chemotaxis was found reduced (P < 0.05) 24 h following exercise (58 +/- 11 vs. 36 +/- 11 cells/field in gymnasts and 47 +/- 7 vs. 42 +/- 8 cells/field in untrained girls pre- and 24 h post-exercise, respectively). The basal values, as well as post-exercise values of bactericidal activity were lower (P < 0.05) in gymnasts as compared with the control group (0.8 +/- 0.3, 0.8 +/- 0.2 and 0.8 +/- 0.1 log decrease of colonies in gymnasts at pre-, immediately post-, and 24 h post-exercise, respectively and 1.1 +/- 0.1, 1.1 +/- 0.1 and 1.0 +/- 0.2 log decrease of colonies in controls, respectively). No significant effect on the bactericidal activity was observed in either group following exercise. The addition of homologous sera did not correct the bactericidal activity. PMA-stimulated superoxide anion release decreased (P < 0.05) among gymnasts immediately following exercise (5.7 +/- 0.4 vs. 4.4 +/- 1.0 mmol O2/10(6) PMN.min) and remained low 24 h later. The same trend was observed in FMLP-stimulated neutrophils but the data were not significant. Significantly decreased levels (P < 0.05) of the early complement components (C1Q, C1R) were also found following exercise (1.34 +/- 0.64 vs. 1.27 +/- 0.28 and 1.09 +/- 0.07 vs. 1.02 +/- 0.06 pre- and post-exercise in gymnasts and untrained, respectively). Furthermore, consistently lower C2 and C3 were observed in gymnasts compared with controls. Neutrophil dysfunction as well as impairment of the complement system seem to occur following exercise.

Analysis of Variance↗
PubMed1981

Antibody-independent binding of the first component of complement (C1) and its subcomponent C1q to the S and R forms of Salmonella minnesota.

Strong bactericidal effects of normal guinea pig and human sera against the Salmonella minnesota S form and an R form (Re) depend on Ca2+, complement component C4, and subcomponent C1q of complement component C1. Therefore, the interaction of C1 and C1q with these forms was investigated. The bacteria directly bound subcomponent C1q, as demonstrated by fixation and transfer tests and by fluorescent methods. Binding of macromolecular C1 was shown by fixation and transfer tests and by C4 consumption. C1 fixation and transfer tests provide evidence that C1 and C1q were bound more tightly to the Re form than to the S form. At physiological ionic strength, all cell-bound molecules were released from the S form, whereas at least 60% remained on the cell surface of the Re form. The Re form showed another binding behavior for C1: preincubation of bacteria with purified C1q totally prevented C1 uptake by the S form, compared to only 10% inhibition of the uptake by the Re form. Therefore, we conclude that macromolecular C1 is bound differently by the S form than by the Re form. The analysis of five other core-deficient mutants of S. minnesota (Ra, Rb, Rc, Rd1, and Rd2) revealed that the difference could be explained by a deficiency of the O-specific polysaccharide. In contrast, all the C1q bound to Ra, Rb, and Rc mutants was detectable by the transfer test. Therefore, we postulate that binding of macromolecular C1 to these mutants must be due to an additional C1 subcomponent besides C1q.

Animals↗
PubMed1983

[Immune complex and complement levels in spontaneous abortions and normal pregnancy].

We gave attention to the following as specific immunological tolerance factors in pregnancy: a) the serum levels of circulated immune complex (IC), b) serum complement levels (C1q, C3, C4, C1-Inhibitor). The results were as follows: In spontaneous abortions measured by C1q binding test (Zubler et al.) IC levels did not differ significantly from those in normal pregnancies in the first trimester, but in both cases, IC levels were slightly higher than the levels in nonpregnant women. C1q and C1-Inhibitor levels in normal pregnancies were significantly lower than in nonpregnant women, and both levels in spontaneous abortions were significantly higher than in normal pregnancies. In cases of artificial and spontaneous abortions, increased IC levels were rapidly lowered to the normal range within 7 days after treatment and lowered C1q and C1-Inhibitor levels also returned to the normal range within 7 days. But these trends were more remarkable in artificial abortions. However, C3 and C4 levels did not change after treatment in either case. A negative correlation between complement levels (C1q, C3, C4) and IC levels in the third trimester was demonstrated in our study.

Abortion, Spontaneous↗
PubMed1997

Anaphylatoxins in fresh-frozen plasma.

BACKGROUND: Fresh-frozen plasma (FFP) is widely used in patients with coagulation disorders and simultaneous complement activation. Complement activation in FFP itself is poorly investigated. STUDY DESIGN AND METHODS: The concentration of anaphylatoxins C3a and C5a, the complement precursors C1q and factor B, and complement function were measured in 40 consecutively administered FFP units in two pediatric neonatal intensive care units. In 12 samples, the measurements were also performed after incubation with inulin. RESULTS: In 15 of 40 FFP units, both anaphylatoxin concentrations were below the upper cutoff levels reported for healthy humans (C3a, 500 microg/L; C5a, 5 microg/L). Anaphylatoxin levels were higher in FFP units produced by apheresis than in those from blood donation. Complement activation of FFP by inulin increased anaphylatoxin concentration, whereas C1q and factor B levels, and complement function remained unchanged. CONCLUSION: Elevated concentrations of anaphylatoxin are frequently found in FFP units produced by apheresis. Studies are necessary to investigate the reasons for complement activation and the possibilities of prevention during apheresis. As the concentrations of complement precursors and complement function did not change with activation in FFP, these studies should include measurement of the anaphylatoxins C3a and C5a.

Anaphylatoxins↗
PubMed2005

The extracellular matrix and inflammation: fibromodulin activates the classical pathway of complement by directly binding C1q.

Components that propagate inflammation in joint disease may be derived from cartilage since the inflammation resolves after joint replacement. We found that the cartilage component fibromodulin has the ability to activate an inflammatory cascade, i.e. complement. Fibromodulin and immunoglobulins cause comparable deposition of C1q, C4b, and C3b from human serum. Using C1q and factor B-deficient sera in combination with varying contents of metal ions, we established that fibromodulin activates both the classical and the alternative pathways of complement. Further studies revealed that fibromodulin binds directly to the globular heads of C1q, leading to activation of C1. However, deposition of the membrane attack complex and C5a release were lower in the presence of fibromodulin as compared with IgG. This can be explained by the fact that fibromodulin also binds complement inhibitor factor H. Factor H and C1q bind to non-overlapping sites on fibromodulin, but none of the interactions is mediated by the negatively charged keratan sulfate substituents of fibromodulin. C1q but not factor H binds to an N-terminal fragment of fibromodulin previously implicated to be affected in cartilage stimulated with the inflammatory cytokine interleukin 1. Taken together our observations indicate fibromodulin as one factor involved in the sustained inflammation of the joint.

Complement Activation↗
PubMed1985

Molecular cloning and characterization of the complementary DNA and gene coding for the B-chain of subcomponent C1q of the human complement system.

Plasmid clones containing cDNA coding for the B-chain of human Clq were isolated from a liver cDNA library. The longest cDNA insert isolated contained all the coding sequence for amino acid residues B1 to B226 plus a 3' non-translated region of 264 nucleotides that extended into the poly(A) tail, thus accounting for 950 nucleotides of the mRNA. The B-chain mRNA was estimated by Northern-blot analysis to be 1.46 kb (kilobases) long, which indicated that approx. 500 bases were not accounted for in the cDNA clone. A cosmid clone containing the C1q-B chain gene was isolated from a human genomic DNA library. The precise 5' limit of gene was not established, but from the data available it appears that the gene is approx. 2.6 kb long. The coding sequence for residues B1 to B226 in the gene is interrupted by one intron, of 1.1 kb, which is located within the codon coding for glycine at position B36. This glycine residue is located in the middle of the triple-helical regions found in C1q at exactly the position where there is an unusual structural feature, i.e. a bend in each of the helical regions brought about by the interruption of the Gly-Xaa-Yaa repeating triplet sequences in the A- and C-chains and the presence of an 'extra' triplet in the B-chain. Nucleotide sequencing of the 5' end of the gene indicates the presence of a predominantly hydrophobic stretch of 29 amino acids, immediately before residue B1, which could serve as a signal peptide.

Base Sequence↗
PubMed2001

The globular heads of C1q specifically recognize surface blebs of apoptotic vascular endothelial cells.

Complement protein C1q is required to maintain immune tolerance. The molecular mechanism responsible for this link has not been determined. We have previously demonstrated that C1q binds directly and specifically to surface blebs of apoptotic human keratinocytes, suggesting that it may participate in clearance of self Ags generated during programmed cell death. Here, we demonstrate that C1q also binds directly to apoptotic blebs of vascular endothelial cells and PBMC. These apoptotic cells are recognized by the globular heads of C1q, which bind specifically to the surface blebs, and deposition increases as the blebs mature on the cell surface. These observations suggest that C1q may participate in the clearance of apoptotic cells from the circulation and from the walls of the vascular lumen. The interaction of surface blebs with the globular heads of C1q suggests that surface blebs may be capable of directly activating the classical pathway of complement under certain circumstances, generating C4- and C3-derived ligands for receptors such as CR1, CR2, CR3, and CR4. Appropriate recognition of apoptotic cells by C1q and targeted clearance of the molecular contents of surface blebs to complement receptors may be critical for the maintenance of immune tolerance.

Apoptosis↗