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PubMed1994

[A clinical study of respiratory complication after cardiopulmonary bypass, with special reference to complement activation, WBC and granulocyte elastase].

Complement activation and it's influence on lung injury were studied in 20 patients undergoing cardiopulmonary bypass (CPB). Anaphylatoxins increased remarkably to 3130 +/- 1770 ng/ml in C3a, 2480 +/- 2530 ng/ml in C4a and granulocytes were significantly fewer in left atrium (LA) than right atrium (RA) during CPB. Granulocyte elastase (GEL) was significantly higher in LA than RA at the time of reperfusion. Postoperative respiratory index was well correlated with C3a and GEL. We concluded that lung injury after CBP was caused by anaphylatoxin which aggregated granulocyte in pulmonary vasculature and released GEL during CPB, and anaphylatoxin was produced not only by using CBP but in patient's lung.

Adult↗

PubMed1995

Complement components and fibrinogen: correlations and association with previous myocardial infarction.

Serum complement levels have been found to be predictive of myocardial infarction up to 4 years before the acute event. To assess whether they are a marker of a hypercoagulable state, the serum or plasma levels of C3, C4, C3a, C4a, C1 inactivator, antithrombin III, protein S, protein C, fibrinogen and tissue plasminogen activator were measured in 31 patients with previous myocardial infarction and 33 controls (all males, 40-60 years old). C3, C4 and fibrinogen (which share the common characteristic of being acute phase proteins) were correlated and were associated with previous myocardial infarction, although this association persisted only for C4 in multivariate analysis. None of the coagulative variables directly involved in the complement system differed significantly in the two groups.

Adult↗

PubMed1990

The effect of ethnicity on major histocompatibility complex complement allotypes and extended haplotypes in patients with systemic lupus erythematosus.

Previous studies of patients with systemic lupus erythematosus (SLE) have shown an increased frequency of certain major histocompatibility complex (MHC) markers, including HLA-DR2, DR3, and C4AQ0 (C4A-null), in Caucasian patients. However, most of these studies were of randomly selected, unrelated patients; families were not included, and haplotypes were not determined. In order to define more accurately the possible role of MHC genes in lupus susceptibility, HLA-A, B, C, and DR, as well as BF, C2, C4A, C4B, and GLO, markers were determined in 62 Caucasian patients of known ethnic background, and in the members of their families. The distributions of extended haplotypes (fixed combinations of HLA-B, DR, and complotype alleles), fragments thereof, and individual alleles were determined in SLE patients and controls. The MHC distributions in all patients were compared with haplotypes in a normal Caucasian population. There were no statistically significant differences between the frequencies of any MHC marker, fragment, or extended haplotype in the patients compared with the controls. The patients were categorized into 2 groups of European ancestry (English/Irish; other Europeans), and each group was compared with a group of ethnically matched controls. There was a statistically significantly increased frequency of the alleles C4AQ0 and DR3 and the complotype SC01 in SLE patients of English/Irish descent as compared with ethnically matched controls. The increase in C4AQ0 and DR3 could be accounted for by the fact that they were part of the extended haplotype [HLA-B8;SC01;DR3] and/or its fragment (SC01;DR3). No increase in any MHC marker was observed in the other patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Complement System Proteins↗

PubMed1989

[Anaphylatoxin in the aqueous humor of rabbit with endotoxin induced endophthalmitis].

Anaphylatoxin-activated complement fragment is an important mediator of inflammation. In this study, trends of anaphylatoxin in clinical and experimental endophthalmitis was evaluated. The level of anaphylatoxin (C3a, C4a and C5a) and protein of human aqueous humor aspirated from patients with senile cataracts before surgery was measured. As a model of acute endophthalmitis, endotoxin-Lipopolysaccharide from E. coli (LPS) was used intravitreously in albino rabbits. The level of anaphylatoxin of aqueous humor was measured by radioimmunoassay. The level of C3a was 44.0 +/- 13.4 ng/ml in aqueous humor of cataract patients. An increase of cell count and protein was demonstrated in the aqueous humor of rabbits 24 hrs after endotoxin injection. The level of C3a increased remarkably with time. It was suggested that C3a in aqueous humor of the rabbit eye with endotoxin-induced endophthalmitis plays an important role in chemotaxis and in mediating the inflammatory process.

Aged↗

PubMed1983

Identification and structural characterization of two incompletely processed forms of the fourth component of human complement.

Immunoprecipitates of human C4 from EDTA-plasma were incubated with [14C]methylamine and analyzed by sodium dodecyl sulfate (SDS)-polyacrylamide gel electrophoresis and fluorography. In addition to finding label in the alpha-chains of the secreted (C4s) and predominant plasma (C4p) forms of C4, two additional molecules with apparent molecular weights of approximately 168,000 (p168) and approximately 125,000 (p125) covalently incorporated methylamine, indicating the presence of an internal thioester bond. These two molecules were present at a concentration of approximately 5% of total plasma C4 and were not immunoprecipitated by antisera to C3 or alpha 2-macroglobulin. A human hepatoma-derived cell line (HepG2), in addition to synthesizing C4s and small quantities of the polypeptide precursor of C4 (pro-C4), was found to secrete p168 and p125 at concentrations of 14 +/- 4.8 and 21 +/- 9.2% (mean +/- SD), respectively, of total secreted C4. These molecules were not found intracellularly. Both molecules were present on reduced, but not nonreduced, SDS-polyacrylamide gels. Chido (C4B) and Rodgers' (C4A) alloantisera precipitated the C4A and C4B variants of pro-C4, p168, p125, and C4s. Both tryptic and Staphylococcus aureus V8 protease peptide analyses showed homology between p168 and the beta- and alpha-chains and between p125 and the alpha- and gamma-chains. Partial NH2-terminal sequencing revealed that the beta-chain was NH2-terminal in p168 and that the alpha-chain was NH2-terminal in p125. Taken together, these data indicate that p168 and p125 represent uncleaved beta-alpha- and alpha-gamma-fragments of pro-C4, respectively. Thus, in most individuals, plasma C4 consists of five structurally distinct molecules, the single polypeptide precursor (pro-C4), the three-subunit secreted (C4s) and predominant plasma (C4p) forms of C4, and two incompletely processed two-subunit molecules with uncleaved beta-alpha- (p168) or uncleaved alpha-gamma (p125)-subunits. In addition, all five molecules are observed for both C4A (Rodgers) and C4B (Chido) structural genes.

Amino Acid Sequence↗

PubMed1980

Inherited structural polymorphism of the fourth component of human complement.

Human fourth component of complement (C4) was found to be highly polymorphic by agarose gel electrophoresis of neuraminidase-treated plasma. The system allows clear-cut separation of the products of the two C4 genetic loci, C4A (acidic or Rodgers) and C4B (basic or Chido). There are at least six structural variants and a deletion allele at the C4A locus and two structural variants and a deletion allele at the C4B locus. Close linkage with no crossovers was found between the two C4 loci, allowing the definition of C4AB haplotypes, and between C4 haplotypes and the C2 and BF loci of the human histocompatibility complex. Nine C4 haplotypes, each with a frequency of 0.005 or more in Caucasians, were found. These studies provide direct evidence for two distinct but closely linked genetic loci for human C4 in the major histocompatibility complex on the short arm of chromosome 6.

Alleles↗

PubMed1992

Effects of C4 null alleles and homoduplications on quantitative expression of C4A and C4B.

The availability of MoAbs now allows the accurate quantification of the individual C4 isotypes, C4A and C4B. Using a sensitive two-site immunoradiometric technique to measure serum levels of C4A and C4B, we studied the relationship between genotype and phenotype and physiological factors affecting C4 expression in 129 fully genotyped healthy subjects. Our results confirm that there is extensive phenotypic overlap between genotypic groups and it was not possible to determine the presence of single null alleles from total serum C4. Of the factors which may influence C4 expression, we found that age contributes a very small influence but that gender has no effect and there was no evidence for the presence of feedback of null alleles on the expression of remaining genes. Potential problems in quantifying C4 arising from the complex relationship between isotypic identity and serotypic recognition were highlighted by the finding of reversed antigenic expression of a C4B*5 molecule which was recognized as C4A by the anti-Rg:1 monoclonal used in these studies. We also confirmed that the extended MHC haplotype associated with Felty's syndrome, HLA-B44, C4A*3, C4BQ*O, HLA-DR4, encodes an expressed, duplicated, C4A gene.

Adult↗

PubMed2005

Increased frequency of C4B*Q0 alleles in patients with Henoch-Schönlein purpura.

Henoch-Schonlein purpura (HSP) is a vasculitis of unknown aetiology, possibly involving immune complexes. The complement system is essential for the clearance of immune complexes. Our aim was to explore the hypothesis that patients with HSP have abnormal complements, contributing to the development of the disease. The study included 56 patients diagnosed with HSP at the Children's Hospital, Iceland between 1984 and 2000, and 98 blood donors as controls. Serum levels of immunoglobulin A, C4A, C4B and mannan-binding lectin were measured and compared between the two groups. C4 null alleles were significantly more common in HSP patients than in controls (P = 0.018) and were carried by 66.1% of the patients compared with 41.2% of the controls. This difference was due to an increased frequency of C4B*Q0 allele in the HSP group (0.25 versus 0.11 in the control group; P = 0.002). The fact that the majority of our patients carried a C4 null allele indicates that children with C4 deficiencies may have an increased risk of developing HSP. This may reflect inadequate complement activity and possibly present an opportunity to identify patients at risk of developing serious morbidity associated with HSP.

Alleles↗

PubMed1989

Subacute cutaneous lupus erythematosus. Genetic markers and clinical and immunological findings in patients.

The role of HLA and complement genes was studied in 13 patients with subacute cutaneous lupus erythematosus. Genetic markers and by combining the major histocompatibility complex class I (HLA-A, -B, and -C), class II (HLA-DR), and class III (properdin factor B [BF] and C4) phenotyping with DNA level analysis of the C4 region. Of our patients, 54% had DR2 antigens and 50% had DR3 antigens, when the frequencies in the controls were 25% and 33%, respectively. The DR3 antigen was associated with annular skin lesions that were associated with a younger age at onset, whereas the DR2 antigen was associated with papulosquamous skin lesions and an older age at onset. The frequency of C4 null alleles was 83% in the patients and 50% in the controls. The null alleles were found in both C4A and C4B loci and were not associated with any special major histocompatibility complex haplotype. The DNA studies showed that the null phenotype mostly resulted from a gene deletion. A highly increased frequency of complement C4 null alleles may be a predisposing factor for cutaneous lupus erythematosus and especially of the subacute cutaneous type.

Adult↗

PubMed1990

Activation of the complement system during immunotherapy with recombinant IL-2. Relation to the development of side effects.

Therapy with high doses of rIL-2 is complicated by the occurrence of hypotensive reactions and the development of a vascular leakage syndrome (VLS). In four patients, who together received seven cycles of high doses of IL-2 (up to 12 x 10(6) U per m2 per day), and who developed these side effects, we observed an unexpected increase in plasma levels of C3a, indicating activation of the complement system. C3a levels markedly increased during IL-2 therapy from 4 nmol/liter (mean level) before therapy to 23 nmol/liter at the end of the cycle. Activation of C3 occurred via the classical pathway inasmuch as C4a levels also increased during therapy. Mean daily C3a levels correlated with signs of the VLS, such as daily weight gain (p less than 0.001) and albumin levels (inverse correlation, p less than 0.001). In five additional patients, who together received seven cycles of lower doses of IL-2 (2 x 10(6) U per m2 per day) and who did not develop a VLS, only moderate increases in C3a levels (up to 13 nmol/liter) were observed. The highest levels at the first day of the regimen (mean: 7 nmol/liter) occurred 8 h after the IL-2 infusion. Thus, administration of IL-2 induces a dose-dependent activation of the complement system in vivo, which appeared to be related to the development of side effects of this therapy, such as the VLS.

Adult↗

PubMed1995

The effect of residue 1106 on the thioester-mediated covalent binding reaction of human complement protein C4 and the monomeric rat alpha-macroglobulin alpha 1 I3.

The histidine at position 1106 of the C4B isotype of human complement is involved in catalyzing the covalent binding of the thioester to glycerol and water. By replacing the histidine with other residues, it was found that tyrosine is also capable of mediating the reaction. We propose that they act as nucleophiles by first attacking the thioester, upon activation, to form acyl intermediates, which subsequently react with the hydroxyl groups of glycerol or water. The monomeric alpha-macroglobulin, alpha 1I3 of the rat, was also studied. Unlike alpha 2-macroglobulin, which is a tetramer, alpha 1I3 has binding properties similar to those of C4A.

Amino Acid Sequence↗

PubMed1990

C4 nomenclature statement (1990).

A common and revised nomenclature of the allotypes of the fourth component (C4) of human complement has been proposed. It is based on the results of the C4 Reference Typing of the VIth Complement Genetics Workshop and Conference, Mainz, FRG, 1989, the previous C4 nomenclature and the guidelines for human gene nomenclature (ISGN). The designation of allotypes derives from their relative electrophoretic mobility, the distinction between C4A and C4B proteins from their relative hemolytic activity. Common alleles retain their single digit numeric designation, intermediate variants their two- or three-digit designations; newly discovered alleles should not interfere with already described variants. At least 13 C4A alleles, 16 C4B alleles as well as non-expressed genes at each C4 locus are presently known. There are also duplicated loci of each C4 gene; they should be designated by repetition of the locus symbol at the haplotype or genotype level. As a phenotype they will be placed in parenthesis without repetition of the locus symbol. Aberrant allotypes or hybrid genes should be explained by a special suffix. No special nomenclature is recommended for restriction fragment length polymorphisms. Their designation should follow the general rules of the ISGN.

Alleles↗

PubMedDate not supplied

Complement C2, C3, C4 and factor B allele distribution in the Gipsy population in Hungary.

Allotype frequencies of four complement proteins (C3, C2, factor B, and C4) were tested in 150 healthy Hungarian and 126 healthy Gipsy individuals living in Hungary. We observed significant differences between the two ethnic groups in the incidence of C3*F, Bf*F, C4A*Q0, C4A*3, C4B*1 and C4B*2 allotypes. Bf*F occurred more frequently among Gipsies, while frequencies for the other three allotypes was lower in this group than in Hungarians. The similarities in the allotype frequencies of C3 and Bf among Gipsy and Gaddis (India) populations supports the Indian origin of the former ethnic group.

Adult↗

PubMed1984

Isolation of cDNA clones specifying the fourth component of mouse complement and its isotype, sex-limited protein.

cDNA clones specific for the fourth component of mouse complement (C4) and its hormonally regulated isotype, sex-linked protein (Slp), were isolated using as a probe a 20-mer synthetic oligonucleotide corresponding to a known sequence of human C4 cDNA. Two types of clones, one specific for C4 (pFC4/10, with a 3.7 kilobase insert) and one specific for Slp (pFSlp/1, with a 4.7 kilobase insert), were isolated from liver cDNA libraries constructed from the Slp-producing FM mouse strain. The cDNA inserts of these clones shared 70% of the restriction sites determined. Only one type of clone was isolated from the Slp-negative DBA/1 strain; this type showed restriction maps indistinguishable from that of pFC4/10. pFC4/10 and pFSlp/1 displayed extensive homology: 94% nucleotide homology and 89% derived amino acid homology in the C4a region and 92% nucleotide homology and 89% derived amino acid homology in the thiol-ester region. An Arg-Gln-Lys-Arg sequence in the beta-alpha junction and a Cys-Ala-Glu-Gln sequence in the thiol-ester site were identified for both proteins. A remarkable divergency between C4 and Slp sequences was recognized in the region immediately following the C4a sequence.

Amino Acid Sequence↗

PubMed1994

Deficiency of the fourth component of complement (C4): a family case.

In this report, an apparently healthy 38-year-old woman with a remarkably low serum C4 value is described together with other family members who had moderately low serum C4. Plasma C4 typing disclosed that the proband inherited two C4B "null" haplotypes. In addition, Southern blot analysis of the C4 gene indicated that the C4A gene was partially deleted on one of these two haplotypes in the proband. We thus concluded that a de novo deletion on the inherited half-null haplotype was the likeliest cause of the low C4 level.

Adult↗

PubMed1996

DNA sequence analysis of the C4 antigen WH: evidence for two mechanisms of expression.

Amino acid and protein analyses have allowed the construction of a model for the C4-based Rodgers and Chido blood group antigens. The single low-frequency allele (WH) in this blood group system, however, has not been characterized at the molecular level. Two WH+ donors were studied by C4 agarose gel electrophoreses, immunoblot studies using monoclonal anti-Rg: 1 or anti-Ch: 1, serological phenotyping, polymerase chain reaction-restriction fragment length polymorphism of their C4 genes, and DNA sequencing of the WH allele. The first donor had the C4A1, A3 phenotype; the C4A1 carried Ch: 1, 3, 6 (thus exhibiting reversed antigenicity) and the C4A3 carried the WH antigen. The amino acid sequence of the WH allele was PCPVLD at positions 1101 - 1106, S at position 1157, and VDLL at positions 1188 - 1191. A second donor typed as C4A2, A4, B1 and was also WH+. Immunoblot analysis showed that a C4B1 protein expressed Rg: 1. Sequence analysis of the C4B genes showed the amino acids LSPVIH at positions 1101 - 1106, S at position 1157, and ADLR at positions 1188 - 1191. Thus, the WH antigen is a conformational epitope that can arise through different mechanisms on either a C4A or C4B gene.

Alleles↗

PubMed2003

Membranoproliferative glomerulonephritis associated with hereditary deficiency of the 4th component of complement.

A 10-year-old female patient was found positive for urine protein and occult blood on Japanese school urinary screening. Examination of the blood was normal except low values of the complement system with CH50 13.5 U/ml, C3 45 mg/dl and C4 3 mg/dl. Renal biopsy demonstrated a focal membranoproliferative glomerulonephritis (MPGN). As for the activity of each component of the complement in the early stage of the disease, the C4 activity was markedly declined and the activity of classical pathway component was also decreased, but the activity of alternative pathway component was normal. On the HLA examination, the patient demonstrated a C4 double null haplotype (C4A2, Q0, BQ0 phenotype). A null C4 gene at both the C4A and C4B loci was found in her mother, aunt and grandfather on the mother's side and C4B null allele in her father and her grandmother on the mother's side. The development of the disease is found in 1 case and not in the other, although both have the genetic defect and the mechanism by which the complement is activated remains unknown. Thus, there appear to be many subjects to be studied as to the relationship between the defect of C4 gene and immune competence.

Child↗

PubMed2000

Phase I trial of the recombinant soluble complement receptor 1 in acute lung injury and acute respiratory distress syndrome.

OBJECTIVE: To determine the safety, pharmacokinetics, biological effects, and immunogenicity of recombinant soluble complement receptor 1 (TP10) in patients with acute lung injury (ALI) and acute respiratory distress syndrome (ARDS). DESIGN: Open label, ascending dosage, phase I trial. SETTING: Two academic teaching hospitals. PATIENTS: A total of 24 patients diagnosed with ALI/ARDS. INTERVENTION: A single, 30-min intravenous infusion of 0.1, 0.3, 1, 3, or 10 mg/kg TP10. MEASUREMENTS AND MAIN RESULTS: Serum levels of TP10 increased in proportion to the dose. Mean variable estimates (+/-SD) were half-life of disposition 69.7 +/- 39.7 hrs, plasma clearance 2.39 +/- 1.32 mL/hr/kg, and volume of distribution 190.6 +/- 135.0 mL/kg. Inhibition of complement activity, measured by CH50, was significant for the interaction of dose and time (p = .024). The C3a levels demonstrated a trend for dose which did not reach statistical significance (p = .090) and soluble C5b-9 levels were significant only for dose (p = .023). As expected by the proposed physiologic mechanism, C4a levels were not affected by TP10, dose, or time. The overall mortality rate was 33%. Neither the type nor the frequency rate of specific adverse events were substantially different between dose groups. Seven adverse events in four patients were thought to be possibly related to TP10. CONCLUSIONS: TP10 has a half-life of approximately 70 hrs and at doses > or =1 mg/kg, significantly inhibits complement activity at the levels of C3 and C5 in patients with ALI/ARDS. Complement inhibition was more prolonged over time with TP10 doses of 3 and 10 mg/kg. TP10 appears to be safe at the doses tested. Further studies will be required to completely assess the impact of TP10 on pathophysiology and clinical outcome in patients with ALI/ARDS.

Adult↗