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PubMed1998

Transforming growth factor-beta 1 regulates chemokine and complement production by human proximal tubular epithelial cells.

Previously it has been demonstrated that human proximal tubular epithelial cells (PTEC) are able to produce chemokines (such as IL-8 and MCP-1) and complement components (such as C2, C3, C4 and factor H), and that production of these proteins is regulated by pro-inflammatory cytokines such as interleukin-1 alpha (IL-1alpha), tumor necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma). Since TGF-beta is also expressed in the renal interstitium during inflammation, we investigated the effect of TGF-beta on the production of chemokines and complement components by PTEC in culture. Transforming growth factor-beta 1 up-regulated IL-8 production by an average of 4.17 +/- 1.0 fold. macrophage chemoattractant phagocyte (MCP-1) production, on the other hand, was down-regulated by TGF-beta 1 by an average of 2.2 +/- 0.7 fold. The production of C3 and C4 was also down-regulated after incubation with TGF-beta 1 (1.9 +/- 0.3- and 3.0 +/- 1.2-fold, respectively). All effects were dose- and time-dependent and were found to be specific for TGF-beta 1, as assessed by inhibition of the effect with a neutralizing antibody against TGF-beta 1. These data, together with the knowledge that TGF-beta, chemokines and complement components play a role in several types of renal disease, suggest that TGF-beta is involved in the regulation of local expression of chemokines and complement components by tubular cells.

Antibodies, Monoclonal↗
PubMedDate not supplied

[Genetics of complement: recent aspects (author's transl)].

Genetic deficiencies of complement proteins are now more often recognized and analysed more precisely because the structure of the different complement proteins is better known. Partial defects may be detected in some components by the combined utilization of titration techniques, polymorphism studies and linkage analyses. The partial deficiency in C4 seems to be the most frequent protein deficiency in the human. The complement markers on the short arm of the sixth chromosome in man (BF, C2, C4A and C4B) are located in close proximity to the HLA-D/DR region. The combined study of the complement and HLA markers will probably allow the fine structure of the HLA region to be better defined. The association of some diseases with HLA types will probably also be better specified by the definition of associations not only with HLA-B or HLA-D types but also with the BF, C2 and C4 types.

Animals↗
PubMed1984

Inhibition of immune precipitation by complement.

Normal human complement serum (NHS) inhibited precipitin reactions between tetanus toxoid and human or rabbit anti-tetanus toxoid IgG antibody, between bovine serum albumin (BSA) and rabbit anti-BSA IgG antibody, and between hen egg albumin and rabbit anti-egg albumin IgG antibody. Ethylene-diaminetetraacetic acid (EDTA) prevented this inhibition. Mg-ethyleneglycol-bis(aminoethyl)-tetra-acetic acid-(EGTA) also prevented the inhibition except with lower concentrations of antibody and antigen. Therefore, the inhibition of immune precipitation seemed to occur mainly through the classical pathway of complement activation. The alternative pathway was usually dispensable, but it augmented the inhibition. Guinea pig complement serum (NGS) was less effective than NHS in inhibiting immune precipitation. Guinea pig serum deficient in C4 (C4DGS) did not inhibit the immune precipitation. Mouse complement serum was effective for inhibiting precipitation, and C5-deficient serum was as effective as normal serum. Therefore, the inhibition of immune precipitation is considered to occur by activation of complement up to the step of C3. The size of the soluble immune complexes formed in the presence of NHS varied depending on the concentrations of antibody and antigen, even when the ratio of antigen to antibody was constant. On incubation at 37 degrees C immune precipitation was inhibited by 1/2 dilution of NHS for 2 to 3 hr and then gradually increased to the level in the absence of complement. When the immune complexes were formed in the presence of serum containing complement, fragments of C4 and C3 were incorporated into the soluble immune complexes. The C3 fragments incorporated into the soluble complexes were C3b, iC3b, C3c, and C3d, some of which were bound covalently with heavy chains of IgG antibody molecules. Some of the covalent linkages between C3 fragments and IgG seemed to be destroyed by alkali treatment, but not by hydroxylamine treatment. The formation of covalent bonds between IgG and C3 and probably C4 was essential for inhibition of immune precipitation, because inhibitors of their formation, such as putrescine, cadaverine, and salicylhydroxamic acid, effectively prevented the inhibition of precipitation. When antigen and antibody reacted in the presence of mixtures of various combinations of isolated complement components, C1, C4, C2, and C3 showed maximal inhibition of immune precipitation, whereas factors I and H had little effect.

Animals↗
PubMed2004

Human skeletal allograft collection--room for improvement?

AIM: To assess the efficiency of skeletal allograft collection from patients undergoing primary joint arthroplasty at a District General Orthopaedic Unit. METHODS: A two cycle audit was performed. Between cycles procedural changes were implemented to improve the efficiency of allograft collection. The discard rate of donated allograft was also assessed during each cycle. RESULTS: Initially 80 patients were identified. Eight (8/ 80) did not donate allograft due to medical contraindications. Two (2/80) patients underwent intra-operative autologous born grafting. Allograft was not collected from 22 (22/70) suitable patients. As such only 68.6% of suitable bone was collected by the West of Scotland Blood Transfusion Service (WSBTS). Subsequently 100 patients were studied. Twenty-eight (28/100) patients did not donate allograft due to medical contra-indications. Two (2/100) patients underwent intraoperative autologous bone grafting. Eight (8/70) allografts were discarded as a result of logistical problems. As such 88.9% of suitable allograft was collected. Initially 29% of all allograft donated was rejected due to poor patient selection. This subsequently fell to 9.4%. CONCLUSION: By auditing the collection process a significant improvement (c2 = 7.17 df = 1 p = 0.001) in the efficiency of allograft collection was achieved. This was complemented by a significant reduction (c2 = 6.09 df = 1 p = 0.05) in the proportion of unsuitable allograft donated to the WSBTS.

Arthroplasty↗
PubMed1977

Effect of selective complement deficiency on the rate of neutralization of enveloped viruses by human sera.

The capacity of human sera genetically deficient in selective complement (C) components to enhance neutralization of enveloped viruses was examined by kinetic plaque reduction assays. Vaccinia virus, a DNA virus, and vesicular stomatitis virus (VSV), an RNA virus, were studied. Exogenous rabbit: or human antibody to vaccinia virus, and guinea pig or human antibody to VSV were provided in limiting, C-dependent concentrations. IgG antibodies predominated in most of the antisera employed. C5-deficient and C6-deficient human sera consistently supported normal rates of neutralization of either virus; this effect was heat-labile. C4-deficient human serum did hot exceed heat-inactivated serum in any neutralization assay. C1r-deficient serum displayed slight heat-labile neutralizing capacity against vaccinia but none against VSV. C2- and C3-deficient sera consistently exhibited measurable but clearly subnormal rates of neutralization. Two fresh agammaglobulinemic sera failed to inactivate either virus in the absence of added antibody. These results confirm and extend earlier evidence, based on neutralization of herpes simplex and Newcastle disease viruses in the presence of early (IgM) antibody and functionally pure guinea pig C components or C-deficient animal sera, that the late-acting components C5-C9 are not required for C-dependent neutralization. Data on four enveloped viruses now agree that this function is mediated by C1-C3, although C1 plus C4 appear to have some neutralizing capacity. This requirement for C1-C3 is overcome, however, in the presence of higher antibody cohcentrations, suggesting that the contribution of the C system to viral neutralization in vivo may be chiefly in the early phase of infection when antibody is limited.

Antibodies, Viral↗
PubMed1975

Studies on rat complement. I. Immune adherence and immune hemolysis activities of rat serum.

The measurement of immune adherence reactivity of rat complement is possible at 20 degrees C but not at 37 degrees C. At 37 degrees C, EA rat C1423b site was destroyed by C3b inactivator present in rat serum. The optimal temperature for immune hemolysis reactivity of rat serum is either at 20 degrees C or 21 degrees C and dose response curve showed Von Krough equation with 1/n = 0.25 +/- 0.02. Al lower temperature, rat complement showed much more effective formation of C3 site to reacti with human erythrocyte in immune adherence as compared with guinea pig complement. The measurement of immune adherence reactivity of rat complement was not possible due to C3b inactivator at 37 degrees C but possible at 20 degrees C. It is possible due to lowering the reactivity of C3b inactivator and keeping the reactivity to form active C3b site in immune adherence reaction. Rat complement is more effective to make C3 site as compared with guinea pig complement. This explains the reason why EDTA rat serum has known to be most effective source of late acting complement for measurement of C1 and C2.

Animals↗
PubMed1975

Distinction between hereditary and acquired angioneurotic oedema according to the complement system.

It is often impossible to make a clinical distinction between acquired and hereditary acute angioneurotic oedema. Investigation of the complement system is indispensable for this diagnosis to be established. The value of total complement and C4 and C2 are lowered in the sera in the hereditary form (44 cases) and normal in the acquired type (68 cases). The use of tests for the activation of C1 esterase "in vitro" is useful to distinguish these two types of oedema as has been demonstrated by the formal measurement of C1 esterase inhibitor.

Angioedema↗
PubMed2001

Complement C4bC2 complex formation: an investigation by surface plasmon resonance.

Complex formation between the human complement proteins C4b and C2 was investigated by surface plasmon resonance. C4b was immobilised and C2 was used in the fluid phase to measure interaction at different ionic strengths (30-830 mM NaCl) and in the absence and presence of MgCl2. Maximum binding was observed at 30 mM NaCl, and was negligible above 300 mM NaCl. Binding was not greatly influenced by variation in Mg(2+) in the range of 2.5-15 mM. C4bC2 affinity (Kd) was determined by steady-state analysis to be 7.2x10(-8) M in physiological conditions (10 mM Hepes, 2.5 mM MgCl2, 0.75 mM CaCl2 and 140 mM NaCl, pH 7.4). For C4(H2O)C2 complex formation, a Kd of 4.0x10(-8) M was calculated. As far as detected by the applied method, complex formation does not involve conformational changes of one of the binding partners. Consistent with previous reports, C4bC2 binding takes place as a multiple-site binding event in the presence of Mg2+. C4bC2 complex formation in 10 mM Hepes, 2.5 mM EDTA and 140 mM NaCl (pH 7.4) was also observed and the interaction showed characteristics of a single-site binding event. Kd was 1.5x10(-8) M. Complement factor B (FB) was also tested for its binding to immobilised C4b. Weak interaction was observed at FB concentrations in the physiological range (500-1000 nM). Kd was 1.2x10(-6) M, indicating possible cross-reactivity between classical and alternative pathways of the activation of the complement system.

Complement C4↗
PubMed1988

The second component of human complement: use of glycosidases and glucosylation to distinguish the two forms.

The two forms of human plasma C2 that were described in the preceding report (1) were investigated for their functional and biochemical differences. Incubation with the neuraminidase (NAN'dase) of Clostridium perfringens at 37 degrees C resulted in a four- to fivefold increase in the hemolytic activity of both forms. The increase in activity was different than the increase caused by treatment with iodine. The mechanism of increased activity of NAN'dase-treated C2 was the generation of increased molecules of activated C3 (C3b), resulting in more molecules of C5 binding to (C4b, 2a, 3b)n. Removal of N-acetyl-neuraminate from C2 did not alter its binding to a cationic exchanger. Nonenzymatic glucosylation was used to distinguish the two forms of C2. Incubation of highly pure C2 with 14C-D-glucose resulted in the gradual accumulation of radioactivity in acid-precipitable material. The two forms of C2 were glucosylated in vitro for seven days with 14C-D-glucose in phosphate-buffered saline at 25 degrees C. Form 2 bound twice as much 14C-D-glucose as form 1. Glucosylated form 2, but not form 1, lost some of its affinity to bind to a cationic exchanger. Since the interaction between glucose and protein occurs at free amino groups, we conclude that form 2 of C2 has approximately twice as many free amino groups as form 1. This explains the reason for the existence of two forms of C2 in plasma independent of the allelic variant.

Complement C2↗
PubMed1992

Complement profile in primary biliary cirrhosis.

PBC is a chronic progressive liver disease of unknown etiology. Several abnormalities found in PBC support the hypothesis that it may be considered an autoimmune disease. Despite the complex and interesting relationship that exists between autoimmune disorders and the complement system, very few reports on the level of the serum complement component in PBC have been published, and most of these comprised only a few patients or analyzed only a scant number of the complement components. In the present study, sera of 73 PBC patients were analyzed for the levels of 10 complement components. It was found that the levels of most of the serum complement components, including C1q, C2, C3, C5, C7, properdin and factor B were significantly elevated in patients with PBC in comparison to healthy controls. The level of C4 was slightly lower than that of the normal controls (p = 0.019), while the levels of C6 and C8 were within the normal range. The number of PBC patients with serum levels of C4 and C6 < 60% of normal pooled serum was higher than in the respective control groups (6/69 compared with 0/26 and 4/71 compared with 0/27, respectively). However, the difference was not statistically significant. Thus, our study shows alterations in the levels of most complement components in PBC, the reasons for which are discussed.

Autoimmune Diseases↗
PubMed1977

C4 in glomerular lesions of NZB/NZW mice.

Antisera to human C4 can discriminate circulating Ss protein (C4) levels in mice. Since there has been no information on early complement components (C1, C4, C2) in the renal lesions of B/W mice, we applied the indirect immunofluorescence technique to post-mortem sections of kidney from B/W female mice with advanced renal disease. C4 was present in fifteen of the sixteen specimens, usually in a distribution similar to that of IgG or C3. Specificity was demonstrated by differential absorptions with high-Ss serum from C57BL/6 male mice and low-Ss serum from C3H/HeJ female mice. High-Ss-absorbed antiserum did not stain, while low-Ss-absorbed antibody retained much of its activity. This finding parallels the demonstration of early complement components in lesions of clinical lupus nephritis, and is consistent with classic complement pathway activation in B/W disease.

Animals↗
PubMed1983

Surface modulation of classical pathway activation: C2 and C3 convertase formation and regulation on sheep, guinea pig, and human erythrocytes.

We examined the formation of the early classical complement (C) pathway enzymes on sheep (Es), guinea pig (Egp), and human (Eh) erythrocytes (E). Each species' E were sensitized with sufficient IgM or IgG anti-E Ab to establish equal numbers of C1-fixing sites on all E. After sensitization with 100 C1-fixing sites of Ab and excess C1, uptake of C4 was equivalent on all three cell types, judged by anti-C4 binding (for guinea pig C4) or by direct uptake of radiolabeled protein (for human C4). With equal numbers of cell-bound C1 and C4, however, there were marked differences in C2 convertase activity on Es, Egp, and Eh. Sheep EAC14 utilized C2 at least 20 times faster than Egp and Eh bearing the same number of C1 and C4 molecules. C3 cleavage was even further depressed on Egp and Eh, and was not changed by the substitution of oxyC2 for normal human C2. In whole guinea pig serum (GPS), 300 times more C1-fixing sites were required on Egp than on Es to achieve similar amounts of lysis; however, equivalent C3 uptake on Egp and Es was associated with equal extents of lysis, demonstrating that GPS lysis of these cells was regulated by early steps in classical pathway (CP) activation. Incubation of E bearing radiolabeled C4b with Factor I demonstrated that C4b on Egp was highly resistant to cleavage compared to the same protein bound to Es or Eh. Studies with partially purified C3 convertase decay-accelerating factors from Eh stroma demonstrated that these membrane proteins could not account for the observed surface regulation of CP activity because these proteins do not affect the rate of C2 cleavage by EAC14. We conclude that E surface molecules have an important role in modulation of CP activation. This surface-associated CP regulation occurs at the level of cell-bound C4b.

Animals↗
PubMed1980

A newly described control mechanism of complement activation in patients with mixed cryoglobulinemia (cryoglobulins and complement).

Levels in serum of components of complement were studied in a group of 10 patients with mixed cryoglobulinemia. The profiles found in most patients showed decreased levels of the early complement components C1, C4, and C2, with normal levels of C3. Experiments performed to define the mechanism(s) responsible for this unusual complement profile showed that activation of the early complement components in serum was due to the activation of the classical pathway by mixed cryoglobulins. They also showed that the characteristic lack of effect on C3 was due to the action of a previously unrecognized regulatory mechanism upon C3 convertase of the classical pathway mediated by 2 normal serum proteins, namely, the C4 binding protein (C4-bp) and the C3b inactivator (C3bINA).

Complement Activating Enzymes↗
PubMed1975

Hereditary C2 deficiency: Genetic studies and association with the HL-A system.

Herediatary C2-deficiency has been shown to be transmitted asn an autosomal recessive characteristic. Recent evidence indicates that some genetic factors involved in the control of the complement (C) system in both man and mice are governed by genes localized within the major histocompatibility regionmthis study describes a large pedigree of the paternal family of a C2-deficient patient with systemic lupus erythematosusl It is shown that this condition is transmitted as an autosomal recessive trait, the heterozygous carriers having approximately half normal levels of C2. Furthermore, this trait was shown to be inherited in close linkage with an infrequent HL-A typw, 2,4A2. The maternal, C2-defective chromosome was shown to be transmitted by HL-AW10, W18 haplotypemthis same haplotype was described in a similar study by Fu et al. (6) to be associated with C2 deficiencymfinally, a third haplotype HL-A2,W18 carrying a defective C2 gene was demonstrated in a part of this pedigree.

Complement C2↗
PubMed1979

Familial herpes simplex infection associated with activation of the complement system.

A patient with severe recurrent herpes infection was evaluated for immunologic analysis including a profile of complement components. The peripheral blood lymphocytes from the patient responded by proliferation to herpes simplex antigen but failed to produce leukocyte migration inhibition factor. Herpes simplex antibody titers increased during active infection. Total hemolytic complement (TCH50), the third (C3), fifth (C5), sixth (C6) and seventh (C7) components of complement, and factor B were dramatically reduced; the first (C1), second (C2) and fourth (C4) components of complement were within normal limits. In family members with a history of recurrent herpes simplex, one or more of the later complement components (C5, C6 or C7) was reduced. This study demonstrates the activation of complement in these serums via the alternative pathway.

Adult↗
PubMed1982

Development of a hemolytic assay for mouse complement components in sera and the variation of their levels with age.

The hemolytic activity of C1, C4, C2 and C3-9 of mouse complement in serum could be measured by using each intermediate cells with guinea pig or human complement components. C3 was assayed by immune adherence. Sheep erythrocytes (SRBC) sensitized with rabbit IgM antibody produced no or feeble lysis in the assay for C4 and C2, whereas SRBC sensitized with IgG antibody or unfractionated antiserum did significant lysis. Using these assays, the activity of each component in sera of several H-2 congenic strains was examined. The age-dependent changes of each component levels in BALB/c mice of both sexes were also examined. The differences in levels of C4 and C2 in sera from several strains were not significant in both sexes, while the levels of C3-9 were higher in males than in females. The levels of each component increased with age. The levels of C4 activity and the Ss protein showed good correlation in males but not in females. The correlation between the levels of C3-9 activity and the MuB1 protein was detected in both sexes.

Aging↗
PubMed2005

[Fatal neonatal respiratory distress in Niemann-Pick C2 and prenatal diagnosis with mutations in gene HE1/NPC2].

UNLABELLED: We report the fifth case of neonatal form of type C2 (NP-C2) Niemann-Pick disease with early and fatal respiratory distress. Eleven families presenting such cases are known to date in the world. Since December 2000, isolation of the underlying gene HE1/NPC2 and its mutations has allowed major advances in diagnosis. CASE REPORT: Elisa was born in May 2000. NP-C2 disease was associated with severe respiratory distress leading to death at the age of four months. On the next pregnancy in September 2000, prenatal diagnosis was performed by means of biological tests that required four weeks response time. In December 2000, isolation of the HE1/NPC2 gene located to 14q24.3 and of some of its mutations allowed to characterize the patient as being homozygote for the nonsense mutation E20X. On the the two next pregnancies, prenatal diagnosis was performed at 12 SA, in 48 hours, by the means of mutation analysis. The last fetus was heterozygote for the mutation E20X, allowing the birth at term of a healthy male newborn baby. CONCLUSION: Niemann-Pick type C disease is a rare lysosomal lipid storage disease with severe prognosis. It is characterized by abnormalities of intracellular transport of endocytosed cholesterol. Diagnosis relies on biological tests that require cultured cells. Genetic heterogeneity defines two different genetic complementation groups C1 and C2. Severe and early respiratory distress is more likely to be associated with the rare type C2. Since December 2000, after identification of the disease-causing mutations in the proband, mutation analysis of gene HE1/NPC2 on direct chorionic villus samples allows early and fast (48 hours) prenatal diagnosis.

Carrier Proteins↗