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PubMed2004

Reference distributions for complement proteins C3 and C4: a comparison of a large cohort to the world's literature.

The lack of credible reference materials and satisfactory methods for quantifying serum levels has limited the bedside use of complement protein (C3 and C4) measurements. However, great technological strides have been made in the last few years. The remaining barrier to a more relevant and cost-effective use of serum protein data for diagnosis and prognosis is the availability of reliable reference intervals from birth to old age for both males and females. Fifty-one publications reporting reference intervals were identified that meet the criteria used in our prior four studies, and these were analyzed statistically. Previous small studies with constrained age ranges agree, on average, with our larger series of life-long reference ranges. This meta-analysis provides support for our reference ranges and places them in the context of previous publications.

Chemistry, Clinical↗
PubMed1989

C4 and Bf phenotypes in black and Caucasian patients with childhood onset insulin dependent diabetes mellitus.

Certain alleles for the complement proteins, C4 and Bf, have been shown to be markers for insulin-dependent diabetes mellitus (IDDM) in samples of different racial and geographic composition. However, the same markers are not demonstrable in each group studied. Phenotyping for the complement alleles, C4 and Bf was performed on 168 Caucasian and 49 Black patients with IDDM. All of the patients were followed in Memphis, Tennessee and had onset of disease prior to age 18. The Bf*F1 allelic frequency was significantly increased for the Caucasian patients as compared to 93 healthy Caucasian controls (0.063 vs. 0.016) and for the Black IDDM patients as compared to 43 healthy Black controls (0.102 vs. 0.035). C4 phenotype frequencies showed a significant increase of the C4AQ0 (rr = 2.13) and C4A4 (rr = 2.91) phenotypes for the Caucasian IDDM patients as compared to controls, but the frequency of homozygous null C4A was not significantly increased. In addition significant negative associations of IDDM with C4A3 and C4A6 phenotypes and no association with any C4B phenotype were observed in our Caucasian patient population. Our data for Mild-South Blacks with IDDM suggest a similar positive association of IDDM with the BfF1 phenotype (rr = 3.4). However, there was no evidence among Black IDDM patients of the C4AQ0 and C4A4 associations observed in the Caucasian sample. The data support a possible association of IDDM with the C4A2 (rr = 5.86) and C4B2 (rr = 5.26) phenotypes. The hypothesis that racial admixture may account for the higher frequency of IDDM in US Blacks as compared with African Blacks has been forwarded by others.(ABSTRACT TRUNCATED AT 250 WORDS)

Alleles↗
PubMed1988

Metabolites of procainamide and practolol inhibit complement components C3 and C4.

Drug-induced systemic lupus erythematosus arises from toxic side-effects of administration of hydralazine, isoniazid, procainamide and practolol. Hydralazine and isoniazid are nucleophilic drugs and inhibit the covalent binding reaction of complement components, C3 and C4, an effect likely to lead to deposition of immune complexes (a feature of systemic lupus erythematosus). Procainamide and practolol do not themselves inhibit C3 and C4. A range of metabolites and putative metabolites of procainamide and practolol were synthesized, and tested for their ability to inhibit the covalent binding reactions of C3 and C4. The highly nucleophilic hydroxylamine metabolite of procainamide was strongly inhibitory in both tests, as was a putative hydroxylamine metabolite of practolol. These studies indicate a potential role for the hydroxylamine metabolites in mediating the toxic side-effects of procainamide and practolol, and emphasize the need for adequate measurements of hydroxylamine metabolites in human tissue.

Acecainide↗
PubMed2001

In vitro cold activation of complement shown by an overestimation of total complement 4: a study in patients with hepatitis C virus infection.

Total complement 4 (C4) levels, when analysed on the Beckman Array nephelometer, were found to increase number of serum specimens [predominantly from patients with hepatitis C virus (HCV) infection] after overnight storage at 4 degrees C. In order to investigate whether the phenomenon of in vitro cold-dependent activation of complement (CDAC) was the explanation for this increase, paired specimens were collected from 63 patients with HCV infection in tubes with no anticoagulant (serum) and in tubes containing EDTA (which inhibits complement activation). C4 levels increased after overnight storage at 4 degrees C in 33 serum specimens (52%). In contrast, no increase in C4 levels was observed in any of the 63 EDTA specimens. Immunofixation of intact and activated C4 products confirmed that complement activation had taken place in the serum specimens in which C4 levels had increased after storage. There was a higher frequency of hepatitis C viraemia (P<0.0001), HCV antibody positivity (P<0.05) and the presence of rheumatoid factor (P<0.05) in the group of patients in whose serum samples CDAC had occurred (n = 33) than in the other group (n = 30). As a result of our findings on C4 analysis in stored serum specimens, we would recommend potassium EDTA plasma as the specimen of choice for complement analysis on the Beckman Array.

Blood Chemical Analysis↗
PubMed1983

Some proteins not belonging to the clotting or to the kallikrein-kinin system altered by kallikrein.

Plasma kallikrein activation occurs frequently during blood drawing and subsequent plasma handling. The purified enzyme was incubated with ceruloplasmin, inter-alpha-trypsin inhibitor and complement factor C4. Proteolysis caused by this enzyme was compared with the degradative effects of plasmin and thrombin. Among these proteins C4 proved to be most easily degraded; its cleavage products can interact with C4-binding protein.

Blood Coagulation↗
PubMedDate not supplied

Immunology of chronic generalized periodontitis. 2. Estimation of total hemolytic complement (CH 50) and its fractions C3 and C4.

The total hemolytic complement activity (CH50) and its fractions C3 and C4 were determined in forty patients with chronic generalized periodontitis (CGP). The values were compared with an equal number of age and sex matched periodontally healthy controls. Total hemolytic complement activity was expressed as number of CH50 units per ml of blood, while C3 and C4 levels were assessed by radial immunodiffusion and expressed as mg%. The observations showed a significant increase in CH50, C3 and C4 levels in the sera of patients with CGP. The study reveals the role of complement system in the pathogenesis of chronic generalized periodontitis.

Adult↗
PubMed1978

Influence of proquazone (Biarison) on the levels of complement components (C3 and C4) in synovial fluid and on IgM in serum in patients with active rheumatoid arthritis. A preliminary report.

Four patients with erosive rheumatoid arthritis and one with psoriasis arthropathy were treated with 600-900 mg/day proquazone for 4-7 weeks. All patients had acute knee effusions. The complement components C3 and C4, as well as IgG, IgA, IgM and total protein, were measured in both the synovial fluid and serum before and after treatment. In the 4 patients with rheumatoid arthritis, a marked increase in C3 and/or C4 levels in the synovial fluid was found, correlating in 3 cases with a good clinical response. However, no corresponding changes in complement levels were recorded in the serum. The patient with psoriasis arthropathy did not show any reaction. These preliminary results suggest that proquazone may influence the immunological processes in rheumatoid arthritis.

Adult↗
PubMed1998

A critical role for complement in maintenance of self-tolerance.

The role of complement in the maintenance of self-tolerance has been examined in two models: an immunoglobulin transgenic model of peripheral tolerance and a lupus-like murine model of CD95 (Fas) deficiency. We find that self-reactive B lymphocytes deficient in complement receptors CD21/CD35 or transferred into mice deficient in the complement protein C4 are not anergized by soluble self-antigen. In the second model, deficiency in CD21/CD35 or C4 combined with CD95 deficiency results in high titers of anti-nuclear antibodies leading to severe lupus-like disease. These findings suggest a novel role for the complement system in B cell tolerance and provide insight into the genetic association of complement deficiency with susceptibility to systemic lupus erythematosus.

Animals↗
PubMed1978

Complement changes during exercise-induced asthma.

Two groups of asthmatic children, one with and one without a history of post-exercise wheezing, and one non-asthmatic adult, were exercised on a treadmill, and their complement levels were measured before and after exercise. The first group of patients had the most obvious fall in FEV 1 and all showed a slight rise in haemolytic complement following exercise. Two of the patients of the second group also had a rise in haemolytic complement. The C4 titre did not change in any of the asthmatic children who did not wheeze after exercise, but there were changes, albeit inconsistent, in the titres of C4 in four of the six patients who exhibited post-exercise wheezing. C3 breakdown products were not detected in any of the sera, following exercise. The role of complement in exercise-induced bronchospasm is not clear, but there does appear to be a greater lability of the complement system in patients who are susceptible to this form of provocation.

Asthma↗
PubMed2001

Mannose-binding lectin accelerates complement activation and increases serum killing of Neisseria meningitidis serogroup C.

The capacity for different lipo-oligosaccharide (LOS) sialylation patterns of Neisseria meningitidis serogroup C to influence the binding and function of the innate humoral component, mannose-binding lectin (MBL), was investigated. By use of flow cytometry and immunogold electron microscopy, a clinical isolate with reduced endogenous LOS sialylation was found to bind more MBL than did strains with higher endogenous sialylation. MBL binding was reduced but not ablated if the same strain was allowed to exogenously sialylate its LOS structures after incubation with cytidine-5'-monophospho-neuraminic acid. MBL binding led to an increased rate of complement activation, with enhanced deposition of the complement components C4 and C5b-9, and this correlated with an increase in bactericidal activity. LOS sialylation appears to be an important determinant of MBL binding to N. meningitidis and can modulate complement-dependent killing of the bacterium. These findings could explain the observed susceptibility to meningococcal disease of individuals genetically deficient in MBL.

Acute-Phase Proteins↗
PubMed1984

C4 allotyping distinguishes HLA-B14.1 and B14.2 subgroups.

Complement allotyping (C4, C2, and BF) was performed in 60 unrelated individuals and 15 families characterized for the subtypes (14.1 and 14.2) within HLA-B14. Eighty-seven percent of B14.2 individuals typed positive for the rare C4A2 variant. In contrast, less than 7% of B14.1 individuals were positive for this C4 allotype which is in keeping with a control background frequency. Family studies revealed that three distinct complotypes (complement haplotypes) are characteristic for the two HLA-B14 subgroups. The SC22 and FC31 complotypes characterize the B14.2 subtype, whereas SC31 appears to define B14.1.

Complement C4↗
PubMed1986

Serum complement values (C3 and C4) to differentiate between systemic lupus activity and pre-eclampsia.

It is often difficult to differentiate between an exacerbation of systemic lupus erythematosus (SLE) and intercurrent pre-eclampsia in a patient with SLE since the manifestations of both entities include proteinuria and hypertension. This study was undertaken to determine wether serum C3 and C4 values can help distinguish SLE activity from pre-eclampsia. In 21 nonpregnant women of child-bearing age, the mean C3 level was 124 +/- 5 mg/dl and the mean C4 was 31 +/- 1 mg/dl. In 24 normal women in the third trimester of pregnancy, the C3 and C4 levels were elevated (165 +/- 4 mg/dl, p less than 0.001 versus nonpregnant control women; 37 +/- 2 mg/dl, p less than 0.01 versus nonpregnant control women, respectively). In 17 women in the third trimester of pregnancy with documented pre-eclampsia, the mean C3 level was 162 +/- 4 mg/dl, no different from that in normal pregnant women (p less than 0.001 versus nonpregnant control women; p = NS versus normal pregnant women), and the mean C4 was 29 +/- 3 mg/dl, lower than that found in normal pregnant women (p less than 0.02 versus normal pregnant women). Antinuclear antibody was absent at titers of less than 1:20 in all of these pre-eclamptic patients. In contrast, pregnant women with SLE has significantly lower C3 (103 +/- 13 mg/dl) and C4 (15.3 +/- 3.6 mg/dl) values during the third trimester of pregnancy than either normal pregnant women (p less than 0.001 for C3 and C4) or women with pre-eclampsia (p less than 0.001 for C3 and p less than 0.004 for C4) during the third trimester of pregnancy. Of the eight women with SLE in whom serial complement values were determined, three had falling C3 or C4 levels, and in each, there was a flare of SLE activity either during or immediately after pregnancy. None of the five patients with a rising C3 concentration had a flare of disease activity; however, pre-eclampsia developed in one of these patients, characterized by hypertension and proteinuria. Thus, measurement of serum C3 and C4 can help differentiate between SLE activity and pre-eclampsia, since both C3 and C4 are significantly lower in women with SLE than women with pre-eclampsia, and serum C3 and C4 concentrations rise during uncomplicated or pre-eclamptic pregnancy in women with SLE.

Adult↗
PubMed2001

2,3,7,8-tetrachlorodibenzo-p-dioxin and natural immunity: lack of an effect on the complement system in a guinea pig model.

We examined the complement system as a potential target for toxicity of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in normal Hartley guinea pigs. Guinea pigs were injected intravenously with 0.5 microg/kg TCDD and bled at weekly intervals up to 1 month following injection. Serum samples were collected at each time point and assayed for total hemolytic complement activity (CH50), alternative pathway complement activity (AH50) and complement component C4 functional activity. Injection of TCDD led to a wasting syndrome, as observed by a lower body weight gain in TCDD-treated animals when compared to control animals. However, at this dose, TCDD failed to induce any significant change in complement activity as determined by all three methods used in this study. The results indicate that, at 0.5 microg/kg body weight, a dose slightly lower than the LD50 value in guinea pigs, TCDD fails to affect the complement system.

Animals↗
PubMed1985

Biosynthesis of complement components by cultured rat hepatocytes.

Hepatocytes which had been isolated from the livers of Charles River rats were cultured in vitro. The cells were shown to synthesize albumin and the complement components C4, C2, C3 and B. Pulse-label studies with [35S]methionine showed that C4 and C3 were synthesized as single polypeptide chains. Pro-C4 did not appear to be converted into the plasma form of C4 intracellularly, whereas cell lysates contained the alpha- and beta-chains of plasma C3 as well as pro-C3. It is concluded that culture of rat hepatocytes in vitro provides a useful technique for studies of the synthesis of complement components.

Albumins↗
PubMed1975

Complement-mediated bactericidal system: evidence for a new pathway of complement action.

The early components of human complement (C1, C4, and C2) plus certain serum euglobulins will kill pathogenic strains of Shigella sonnei. Serum from patients with hereditary C3 deficiencies and specific antiserums to C3, C5, and C6 were utilized to demonstrate the absence of requirements for late-acting complement components in this unusual bactericidal system.

Antibodies, Bacterial↗
PubMed1983

Immunological evaluation of renal transplant patients: changes in levels of beta-2-microglobulin, immunoglobulins and complement components during graft rejection.

Levels of IgG and IgM and complement components C4 and C3 were measured using rate nephelometry and serum levels of beta-2-microglobulin (beta 2m) by rocket immunoelectrophoresis (RIEP) and these assays have been applied serially following cadaveric renal transplantation on 28 patients 14 of whom were treated with cyclosporin A. There were 31 rejection episodes of which 7 were irreversible. Elevated pre-transplant serum beta 2m levels fell rapidly in the first 24-48 hr post-transplant in all patients with primary functioning grafts and the mean base-line control value was 4.5 +/- 1.27 micrograms/ml in patients with stable graft function in the period 5-10 days post-transplant. At the onset of all 31 rejection episodes however the level of beta 2m increased compared to control values and significantly exceeded the 95% confidence limits of +/- 2.0 micrograms/ml. Control values for serum IgG and IgM were significantly lower than paired pre-transplant levels and, whereas IgM increased during rejection episodes with significant differences between paired rejection and control values, no significant changes in IgG levels were detected. In contrast mean control values for C4 and C3 were not significantly different to mean pre-transplant values; however, mean levels of C4 and C3 decreased significantly during rejection episodes compared to both pre-transplant and control values.

Complement C3↗