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PubMed1989

Complement system protein C4 and susceptibility to hydralazine-induced systemic lupus erythematosus.

21 patients with systemic lupus erythematosus induced by long-term treatment with hydralazine were investigated to see whether susceptibility to this syndrome was associated with deficiency of the classical pathway complement protein, C4. 16 of 21 (76%) patients had one or more C4 null (ie, non-productive) alleles compared with 35 of 82 normal subjects (43%). This difference was significant. The HLA-DR4 antigen, known to be in linkage disequilibrium with the C4B null allele, was also significantly more frequent in the patients (14 of 21 patients compared with 31 of 81 normal subjects). Susceptibility to hydralazine-induced lupus, as in idiopathic systemic lupus erythematosus, may depend partly upon genetically determined C4 levels.

Alleles↗

PubMed1990

C4 from C4-high and C4-low mouse strains have identical sequences in the region corresponding to the isotype-specific segment of human C4.

The human complement component C4 isotypes, C4A and C4B, show a substantial and biologically important difference in chemical reactivity. Murine C4 from different mouse strains has recently been reported to have a comparable difference in reactivity. In human C4, the difference in reactivity has been attributed to the effect(s) of one or more of only four amino acid residues, within a six-residue-long segment of the alpha subunit, which distinguish the two isotypes. In the present study, we sought to assess the role of the corresponding four amino acids in mouse C4 in the strain-specific modulation of C4 reactivity. In order to compare the sequences of the corresponding region in murine C4 among different mouse strains, we used the polymerase chain reaction method to amplify an approximately 229-bp segment of the murine gene that includes the codons for these four amino acid residues. Because the difference in chemical reactivity of murine C4 has been reported to be between C4 from strains which express different levels of C4, we examined sequences from mouse strains C57BL/6, DBA/2, C3H/He, B10.BR and CBA/J; these represent two C4-high strains and three C4-low strains. The amplified segments were cloned into the pUC19 vector and 20 independent clones from each mouse strain were sequenced. Across the entire amplified segment, our results revealed expected isotypic differences between C4 and its nonfunctional isotype in the mouse, Slp, as well as allelic differences among the C4 and Slp genes. However, all of these differences were quite distant from the amino acid residues corresponding to the human isotype-specific residues and those corresponding residues were identical in all five mouse strains. This result indicates that any strain-specific difference in chemical reactivity of murine C4 must be due to a mechanism distinct from that operating in human C4.

Amino Acid Sequence↗

PubMed2005

[C4d]FlowPRA screening--a specific assay for selective detection of complement-activating anti-HLA alloantibodies.

On waiting lists, transplant candidates are routinely screened for potentially harmful complement-fixing alloantibodies using complement-dependent cytotoxicity (CDC) panel-reactive antibody (PRA) testing. We have recently developed a novel cell-independent assay for assessment of complement-activating panel reactivity ([C4d]FlowPRA), which is based on selective flow-cytometric detection of alloantibody-triggered C4 complement split product deposition to human leukocyte antigen (HLA)-coated FlowPRA beads. Serum specimens selected from 120 transplant candidates were evaluated by [C4d]FlowPRA (HLA class I vs II) in comparison with FlowPRA IgG alloantibody screening (HLA class I vs II), a method detecting both complement- and noncomplement-activating alloantibodies, and with CDC-PRA on separated T (T-CDC) or B cells (B-CDC, evaluation on platelet-absorbed sera). For each assay, >/=10% PRA reactivity was considered positive. Comparing complement-dependent PRA assays with standard FlowPRA, the specificity calculated for [C4d]FlowPRA (HLA class I: 92%; class II: 100%) was found to be superior to that of CDC testing (T-CDC-PRA: 79%; B-CDC-PRA: 86%). Because noncomplement-activating alloreactivities were not detected for both techniques, low sensitivities were calculated ([C4d]FlowPRA HLA class I: 61%; class II: 31%; T-CDC-PRA: 70%; B-CDC-PRA: 55%). Compared with CDC-PRA, [C4d]FlowPRA gave a high specificity (HLA class I compared with T-CDC: 89%, HLA class II compared with B-CDC: 95%) but, at least in part because of false-positive CDC results, a modest sensitivity (66% and 38%, respectively). For both HLA classes, we found a highly significant association between absolute [C4d]FlowPRA and CDC-PRA levels (p < 0.0001). Our results suggest that detection of C4 split product deposition to FlowPRA beads may represent an attractive HLA-specific and time-effective alternative to CDC-PRA screening.

B-Lymphocytes↗

PubMed1983

Circulating immune complexes in rheumatoid arthritis with extra-articular manifestations.

Circulating immune complexes (CIC) and complement C4, C3 and CH50 levels in serum were monitored during 6-30 months in 10 patients with rheumatoid arthritis and extra-articular manifestations (EM). A total of 58 observations were made, 17 at times when new EM emerged, 41 at times when the patients were in a steady state. CIC were demonstrated by two methods, viz. a complement consumption test (CCT) and a polyethyleneglycol (PEG) precipitation assay. The precipitates were analysed for their content of IgG, IgM and IgA. The CCT titre decreased significantly at the time of a new EM, whereas PEG precipitates were found most often at this time. Two types of precipitate could be demonstrated. One consisted of IgG only, which was found most often when the patients were in a steady state. The other one was composed of IgG and other immunoglobulins, most often IgA. The latter type was found most often at the time when the patients developed new EM. Subnormal serum complement levels were demonstrated frequently. The level of C4 was significantly lower at the time of a new EM, compared with the level of patients with RA but without EM. The decrease in anticomplementary effect and the signs of complement activation suggest that the qualitative and quantitative changes in CIC observed at the time of new EM were the cause rather than the consequence of the clinical manifestations.

Aged↗

PubMed1993

Complement levels of C4, C3C, factor B, and C1 inactivator in peripheral and retroplacental blood of parturient women with EPH gestosis.

The complement levels were determined in 54 parturient women with EPH gestosis, in 32 normal parturient women and in 24 normal non pregnant women. Complement components: C4, C3c, factor B /Bf/ and C1 inactivator /C1 INA/ were measured by radial immunodiffusion. Peripheral and retroplacental blood were examined. Concentrations of C4, C3c, Bf in peripheral blood of both groups of parturient women were significantly higher than in normal non pregnant women. Peripheral blood of parturient women with EPH gestosis contained significantly higher concentrations of C3c than in normal parturient women. Complement Bf levels of normal parturient women were lower in the retroplacental blood than in the peripheral. The levels of C4 were significantly decreased and C3c increased in the retroplacental blood of parturient women with EPH gestosis when results were compared with retroplacental blood of normal parturient women. Results of present study suggest that complement activation could contribute to the pathogenesis of EPH gestosis.

Complement C1 Inactivator Proteins↗

PubMed1987

Immunoproteins in the endometrium: clinical correlates of the presence of complement fractions C3 and C4.

The presence of complement fractions C3 and C4 in endometrial tissue was studied in a consecutive series of patients undergoing diagnostic laparoscopy, to determine their specific association with endometriosis. The incidence of complement in eutopic endometrium of patients grouped according to four diagnoses was: endometriosis, 66% positive (23 of 35); active pelvic inflammatory disease, 85% positive (11 of 13); combined endometriosis with pelvic inflammatory disease, 25% positive (one of four); laparoscopically normal pelvis, 67% positive (10 of 15). These differences were not statistically significant. Complement was equally likely to be found in proliferative, secretory, menstrual, or inflammatory endometrium. Endometrial complement was found less frequently in patients with severe endometriosis as compared with those with the mild form. Among patients with endometriosis and infertility, complement was much more likely to be found in patients with primary infertility than in those with secondary infertility (p less than 0.007). In short-term follow-up of these patients, the absence of complement in the eutopic endometrium appeared to be a good predictor of subsequent pregnancies.

Complement C3↗

PubMed1988

Effects of anti-C4 antibody on complement production by splenic and peritoneal macrophages.

We have previously shown that administration of anti-C4 antibody to cells in culture can suppress the synthesis and secretion of C4. Lymphoid cells must be present along with the C4 secreting macrophages to achieve suppression of full magnitude and long duration. In this publication we have demonstrated that treatment of peritoneal macrophages with intact anti-C4 antibody results in reduction of intracellular and secreted C4. Intracellular levels of pro-C4 rapidly returned to normal after removal of the suppressing antibody and extracellular levels of C4 secreted into the media returned to normal within 24-48 h. This is in marked contrast to our previously published results with splenic fragments where intracellular pro-C4 remained markedly reduced long after removal of anti-C4. Using pulse-chase experiments we now demonstrate that, after recovery from suppression, intracellular pro-C4 levels remain low in splenic macrophages because nascent C4 is processed through the cell more rapidly. This results in a smaller intracellular pool of C4, even in the face of normal or high levels of C4 synthesis in the postsuppression phase. Finally, we demonstrate that suppression of full magnitude and duration could only be achieved with intact anti-C4 antibody. F(ab')2 fragments were not capable of inducing complete suppression.

Animals↗

PubMed1992

[Complement (C3 and C4) in patients with rheumatoid arthritis during 6 months of treatment with gold salts].

The aim of research was to establish effect of gold-salts under protected name "Tauredon" Byk Gulden, on the dynamics of fraction of complements C3 and C4 at patients with rheumatoid arthritis. Following the dynamics of both parameters, was performed during 6 months continued application of "Tauredon", on 8 men and 35 women with certain diagnosis. Profile of the age of patients was 50 years old. With continuous observation of patients and their laboratory findings, in regular time intervals, we found out that "Tauredon" has significant influence on increase of level of C3 in serum of patients (P = 0.006) but not in increase of fraction of complement C4 (P = 0.117).

Adult↗

PubMed1996

Extensive conservation of upstream C4 promoter sequences: a comparison between C4A and C4B.

Basal levels of expression of complement C4 vary in individuals but it is unknown whether this is due to gene copy number, protein clearance rates or differences in expression. To investigate whether differences in the promoter region may influence transcription of the C4 genes, we sequenced the promoter region of the C4B1 gene from the HLA-A1, B8, C4AQ0, C4B1, DR3 haplotype and compared this with an equivalent C4A3 region. The promoter regions of the C4 genes were highly conserved, indicating that transcriptional differences are unlikely. An unusual feature of the alignment was the higher level of polymorphism in the RP genes past the breakpoint of deletion/duplication in a region where the highest conservation would be expected.

Base Sequence↗

PubMed1984

Synthesis of complement by guinea pig bronchoalveolar macrophages. Effect of acute and chronic infection with Pseudomonas aeruginosa.

In order to assess the potential role of local production of complement in pulmonary host defenses against bacterial infection, this aspect of bronchoalveolar macrophage function was studied in guinea pigs challenged with Pseudomonas aeruginosa in an acute and chronic infection model. Acute infection resulted in an increase in bronchoalveolar macrophage cell number and an increase in synthesis and secretion rates for the second (C2) and fourth (C4) complement components per macrophage. Manipulation of the airway without introduction of Pseudomonas also increased synthesis of both C2 and C4 when studied 60 h after control solutions were administered. Pseudomonas aeruginosa delivered in agar beads to induce chronic inflammation resulted in specific stimulation of C2 and C4 synthesis at 2 wk and to a lesser extent at 4 wk postchallenge. This increase in local complement synthesis by bronchoalveolar macrophages, in addition to enhancing the local inflammatory response, may serve to facilitate recruitment of intravascular cellular and humoral mediators of host defense against bacterial infection.

Animals↗

PubMed1985

Activation and fragmentation of the third (C3) and the fourth (C4) components of complement: generation and isolation of physiologically relevant fragments C3c and C4c.

The degree of the activation and fragmentation of C4 and C3, including chain structure of the activation products, was evaluated by SDS-PAGE analysis of the C4 or C3 antigens that were withdrawn from the reaction media with appropriate immunoadsorbent beads. Full activation of C4 and C3, and subsequent quantitative conversion of C4b into C4c, and C3b into iC3b took place in fresh NHS after the activation of complement with both aggIgG and CVF. For complete conversion of iC3b to C3c erythrocytes carrying the C3b receptor were added to the already activated serum. Both C4c and C3c were isolated by a 2-step procedure involving (i) an adsorption to and (ii) electrophoretic desorption from the respective immunoadsorbent beads.

Complement Activation↗

PubMed1981

Circulating immune complexes, complement factors C3, C4, C1-inhibitor, alpha-1-antitrypsin and immunoglobulins in asthmatic patients.

Sera from 159 adult asthmatic outpatients (extrinsic, n = 82, intrinsic, n = 65 and acetylosalicylic acid (ASA)-sensitive, n = 12) and from 100 controls were tested for total levels of IgG, IgM, IgA, IgE, complement factors C3, C4, C1-inhibitor, alpha 1-antitrypsin and circulating immune complexes. The following results were observed: (1) a marked increase of IgE in extrinsic asthma; (2) a slight increase of IgM, and (3) an equal increase of complement C4 levels in all three asthma groups; (4) normal mean values of C3 levels with a significantly larger standard deviation of the mean in all three asthma groups; (5) an equally slight decrease of protease inhibitors, such as C1-inhibitor and alpha 1-antitrypsin, and (6) the presence of circulating immune complexes in 22% of extrinsic, in 8% of intrinsic and 13% of ASA-sensitive asthmatics. Circulating immune complexes can be found in all three asthma groups and may correlate with complement deviation.

Adult↗

PubMed1994

Expression of complement C1qB and C4 mRNAs during rat brain development.

This study examined the distribution of complement C1qB and C4 mRNAs during rat brain development by northern blot and in situ hybridization. Both C1q and C4 mRNAs were already present at embryonic day 14 (E14) and showed little change in abundance through six weeks postnatal. At E16, C1qB mRNA was present at high abundance in putative microglia/macrophages in cortical marginal and intermediate zones, and hippocampal analge, but not in the neurogenic ventricular or sub-ventricular zones. C4 mRNA had a broadly similar regional distribution, but was present at lower abundance in a larger number of cells, putatively neurons. The distribution pattern for C1qB and C4 mRNAs did not change appreciably as brain development proceeded. The lower prevalence of C mRNAs in neuroepithelial or subventricular zones suggests an inverse relationship of C mRNA to cell proliferation. The frequency of apoptotic nuclear profiles, which was as much as ten-fold higher at P7 vs. E17, did not correlate anatomically with C1qB or C4 mRNA levels. Thus, the widespread distribution and consistent presence of each C mRNA during development argues against a role for C in programmed cell death during brain development. We suggest that C1q and C4 components have novel roles during brain development that may be unrelated to normal cytotoxic actions of the activated classical C cascade.

Animals↗

PubMed2006

Levels of complement C3 and C4 components in Amerindians living in an area with high prevalence of tuberculosis.

The levels of complement C3 and C4 components were determined in non-indigenous (creoles) and indigenous (Warao) populations, the latter with an extremely high tuberculosis (TB) rate. Serum samples from 209 adults were studied and classified in 4 groups taking into account tuberculin skin tests (TST): (1) the group of Warao patients (58 positive for the TST, WP TST+ and 9 negative for the TST, WP TST-), (2) the group of creole patients (34 positive for the TST, CP TST+ and 9 negative for the TST, CP TST-), (3) the group of healthy Warao controls (38 positive and 14 negative for TST, WC TST+ and WC TST-, respectively), (4) the creole controls (26 positive and 21 negative for the TST, CC TST+ and CC TST-, respectively). With respect to the results concerning the measurement of both complement C3 and C4 components with the exception of the WC TST and the CC groups, the WP TST+ and WP TST- as well as WC TST+ groups showed a significant frequency of individuals with decreased levels of complement C3 component (20.6, 33.3, and 26.3%, respectively) and also C4 component (12.0, 11.1, and 13.3%, respectively) in comparison to both creole patients (CP TST+, 8.82% and CP TST-, 0% and CP TST+, 5.88% and CP TST-, 0%) for C3 and C4, respectively. The study of these parameters carried out in 15 Warao subjects with active infection, before and after anti-TB chemotherapy,statisticallyconfirmedthat the effective chemotherapy did not restore normal levels of the complement C3 and C4 components among Warao patients. Aditional tests for hepatitis B or hepatitis C infection, and the profile of the hepatic proteins were not associated to the deficiency in production of the complement components. In conclusion, the results show that within the Warao population, a high percentage of subjects exhibit decreased levels of both complement C3 and C4 components independent of latent or active infection and the status of TST.

Adolescent↗

PubMed1985

The third (C3) and fourth (C4) components of complement in human liver. Immunocytochemical evidence for hepatocytes as the site of synthesis.

We localized the third (C3) and fourth (C4) components of complement by light and electron microscopic immunocytochemistry in liver biopsy specimens from patients without overt liver disease or with chronic hepatitis. In both groups it was found that almost all hepatocytes contained the two complement proteins in protein-generating organelles, i.e., the perinuclear spaces, cisternae of the rough endoplasmic reticulum, Golgi apparatus, and cytoplasmic transport vesicles. In addition, the sinusoidal membrane and vesicles that appeared to be fused with the membrane were positive for C3 and C4. The complement proteins were absent from the protein-synthesizing apparatus of other kinds of cells, but they were present in phagosomes of Kupffer cells. We conclude that hepatocytes but not other cells in the human liver synthesize C3 and C4. In addition, a plausible pathway for transport of the complement proteins from hepatocytes into the blood circulation was identified.

Complement C3↗

PubMed1989

An update on Rodgers and Chido, the antigenic determinants of human C4.

Rodgers (Rg) and Chido (Ch) blood groups are antigenic determinants of the fourth component of human complement (C4). Nine determinants have been defined by means of hemagglutination-inhibition (HAI) with polyspecific human antiserums. The association of C4A isotypes with Rg and of C4B isotypes with Ch is strong hut not complete. Derived amino acid sequences from the C4d region of selected C4 allotypes of known antigenic expression have provided support for the previously reported complex serologic interrelationships. A structural model for antigenic determinants at four polymorphic sites, incorporating sequential and conformational epitopes, was subsequently proposed. Allotype and Rg/Ch data obtained from donors and patients, many with accompanying families, have augmented the model and revealed no exceptions. The antigenic determinants, therefore, make an important contribution to the complex polymorphism of C4.

Journal Article↗

PubMed1990

Renal disease in a patient with hereditary complete deficiency of the fourth component of complement.

Hereditary complete deficiency of the fourth component of complement (C4) is an extremely rare disorder with 17 cases reported so far. Twelve of these patients suffered from a systemic-lupus-erythematosus-like illness. The patient we here describe presented with severe Henoch-Schönlein purpura (HSP) at the age of 17. Immunofluorescence of a kidney biopsy showed granular deposits of IgG, IgA, IgM, C3 and fibrinogen in the mesangium and segmentally along the basement membrane. Six years later, the patient developed hypertension and nephrotic syndrome. Renal function deteriorated rapidly. He was on hemodialysis for 12 months and then received a cadaveric kidney graft. After 2 years of uncomplicated course, microhematuria and proteinuria developed. Immunofluorescence of a transplant biopsy was virtually identical to the pattern in the patient's own kidneys. We thus conclude that the patient had recurrence of his primary disease in the graft. Three and a half years after transplantation hemodialysis had to be restarted. This unique case supports the current view that deficiency of classical pathway components predisposes to the development of immune complex diseases and that the complement system is activated via the alternate pathway in HSP. Furthermore, we assume that complete C4 deficiency was the major cause for the recurrence and unfavorable outcome of HSP in the graft.

Adult↗

PubMed2005

Upregulation of the immune system in primary hypercholesterolaemia: effect of atorvastatin therapy.

OBJECTIVES: High levels of plasma high sensitivity C-reactive protein (CRP), sensitive to therapy with statins, have been described in hypercholesterolaemia. In vitro evidence shows that CRP activates the complement system, which, in turn, leads to an increased expression of ICAM-1. Our objectives were to verify whether primary hypercholesterolaemia (PHC) is associated with an upregulation of the inflammatory/immune response, and whether this is sensitive to atorvastatin. METHODS AND RESULTS: We examined the levels of sICAM-1, C3, C4 complement fractions in 48 patients with PHC, with (CAD group) or without (No-CAD group) coronary artery disease (CAD) in comparison with a group of 48 healthy controls. The two patient groups were studied before and after atorvastatin therapy. Both hypercholesterolaemic groups showed higher mean values of sICAM-1, C3 and C4 (P < 0.0001) when compared with the controls. The two groups of patients responded differently to atorvastatin therapy. After 3 months, the C3 levels normalized in both groups of patients (P < 0.02 compared with basal values); C4 was greatly reduced only in the CAD group (P < 0.01). After 12 months of therapy, in CAD group C3 mean levels were still significantly lower than baseline values (P < 0.01); a further decrease in the C4 values (P < 0.05 with respect to levels after 3 months of therapy) and also a substantial reduction in sICAM-1 values (P < 0.001 with respect to basal values) were observed. CONCLUSIONS: High plasma values of C3 and C4 in PHC cluster with high values of sICAM-1, distinguish subjects with CAD and could be used to monitor the anti-inflammatory effect of statin therapy in these patients.

Adult↗