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PubMed1999

Heparin-coated cardiopulmonary bypass equipment. I. Biocompatibility markers and development of complications in a high-risk population.

OBJECTIVES: 1. To study possible clinical benefits of heparin-coated cardiopulmonary bypass in patients with a broad range of preoperative risk factors. 2. To evaluate the correlation between the terminal complement complex and clinical outcome. 3. To identify clinical predictors of complement activation and correlates of granulocyte activation during cardiac surgery. METHODS: Blood samples from adults undergoing elective cardiac surgery with Duraflo II heparin-coated (n = 81) or uncoated (n = 75) cardiopulmonary bypass sets (Duraflo coating surface; Baxter International, Inc, Deerfield, Ill) were analyzed for activation of complement (C3 activation products, terminal complement complex), granulocytes (myeloperoxidase, lactoferrin), and platelets (beta-thromboglobulin) by enzyme immunoassays. Preoperative risk was assessed by means of the "Higgins' score." Complications (cardiac, renal, pulmonary, gastrointestinal, and central nervous system dysfunction, infections, death) were registered prospectively. Data were analyzed by analysis of variance, logistic regression, and linear regression. RESULTS AND CONCLUSIONS: Sixty-seven percent of the patients had predefined risk factors. Complications developed in 53 patients (34%), equivalently with and without heparin-coated bypass sets (P =. 44-.82), despite a significant reduction in complement and granulocyte activation by heparin coating. No clear-cut relationship between the terminal complement complex and outcome was found, even if it was significant in the models for renal and central nervous system dysfunction and infections (P =.006). The Higgins' score was significantly related to complement activation (P <.05). Approximately 50% of the variation in granulocyte activation was explained by complement (P </=.01) and platelet activation (P <.05), heparin/protamine dose ratio (P =.02), duration of cardiopulmonary bypass (P <.01), and gender (P <.05). Therefore measures reducing complement activation alone will not necessarily reduce granulocyte activation sufficiently for clinical significance.

Aged↗
PubMed1975

Complement components of C3 and C4 in Nigerians.

Serum complement component of C3 was lower in both Nigerian children and adults in corresponding British subjects whereas the concentrations of C4 were similar in all groups. It would appear that in the ontogeny of the complement system the concentration of C4 reaches adult level before that of C3.

Adult↗
PubMed1985

C3 polymorphism in Greece.

The polymorphism of the third component of the human complement (C3) was investigated in a sample of 1,055 unrelated healthy individuals from nine different areas of Greece. The estimated gene frequencies were: C3S = 0.786 and C3F = 0.211. Three individuals were found to have rare variant C3 types. The allele frequencies resemble those reported for other Caucasian populations.

Alleles↗
PubMed1989

Lymphocytes stimulated by allogeneic B cell lines cleave the third component of complement and fix C3 fragments. Their nonspecific lytic capacity is elevated against complement receptor type 2-carrying targets.

Human blood lymphocytes stimulated in mixed cultures by allogeneic B cell lines were shown to cleave C3 molecules. The B cell lines were derived from Burkitt lymphoma patients: 1) established from their EBV-negative lymphoma, 2) the EBV-positive sublines converted in vitro, and 3) lymphoblastoid cell lines (LCL) i.e., B lymphocytes transformed in vitro by EBV. These cell lines differed considerably in their capacity to stimulate allogeneic lymphocytes. The split products of C3 were detected in the supernatants and on the surface of the activated lymphocytes at levels which correlated with the strength of stimulation. Lymphocytes cultured with LCL had the highest levels of thymidine incorporation blast transformation, C3 cleavage, and C3 fragment fixation. Lymphocytes exposed to the EBV-negative Burkitt lymphomas were stimulated weakly and their C3-activating capacity was low. Irrespective of the efficiency of lymphocyte stimulation induced in the cultures, 60 to 70% of the blasts were found to fix C3 fragments. The majority of the lymphocytes which fixed C3 fragments were T blasts that carried the CD3 marker and expressed IL-2R (CD25). CD4 and CD8 cells were represented with equal frequency in the C3-fragment fixing and C3-fragment negative populations. Pre-exposure of the MLC-activated lymphocytes to human serum increased their cytotoxic capacity toward CR type 2-carrying targets. The enhanced lysis was abrogated by F(ab)2 rabbit anti-human C3d or rabbit anti-CR type 2 antibodies. The results suggest that the C3 fragments fixed on the lymphocytes bind to CR on the targets and elevate the avidity of binding between the two interacting cells. This was also indicated by an increase in the frequency of lymphocyte-target conjugates.

Antigens, Differentiation, B-Lymphocyte↗
PubMed1988

Age-related variations in serum concentrations of the third component of complement in swine.

Single radial immunodiffusion was used to determine the concentration of the third component of complement (C3) in serum from swine in the following age groups; 36 to 60 hours (neonates), 6 to 7 weeks (weanlings), 4 to 5 months (adolescents) and greater than 1 year (adults). Mean serum C3 concentrations, expressed as the percentage of pooled reference sera from 15 adult swine for the 4 groups were 23, 123, 119, and 98%. With the exception of mean values for weanlings and adolescents, all comparisons of group means were significantly different. Regression models were developed to estimate serum C3 concentration in neonates as a function of litter size, birth weight, and total serum IgG concentration. Increases in birth weight and litter size were accompanied by increased serum C3 concentration, possibly reflecting ontogenic variation of the complement system at the end of gestation. Passive transfer of colostral immunoglobulins, as measured by total serum IgG concentration, was inversely related to serum C3 concentration in neonatal swine, suggesting that colostral absorption of C3 has minimal impact on complement activity in neonatal swine.

Aging↗
PubMed1975

In vivo activation of C3 revealed by crossed immunoelectrophoresis as a parameter of immunological activity in disease.

A technique suitable for the demonstration of in vivo activation of the third component of complement (C3) is described, and the results of detailed methodological studies are presented. The technique is a useful tool for monitoring the activity of the humoral immune system in disease states. The serum levels of complement components reflect a balance between synthesis and catabolic rates, while the present method gives a more dynamic picture of the state of the complement system. The results of the application of the technique to different groups of patients are presented.

Anemia, Hemolytic↗
PubMed2005

Ionic binding of C3 to the human pathogen Moraxella catarrhalis is a unique mechanism for combating innate immunity.

Moraxella catarrhalis ubiquitous surface proteins A1 and A2 (UspA1/A2) interfere with the classical pathway of the complement system by binding C4b-binding protein. In this study we demonstrate that M. catarrhalis UspA1 and A2 noncovalently and in a dose-dependent manner bind both the third component of complement (C3) from EDTA-treated serum and methylamine-treated C3. In contrast, related Moraxella subspecies (n = 13) or other human pathogenic bacteria (n = 13) do not bind C3 or methylamine-treated C3. Experiments with recombinant proteins and M. catarrhalis mutants devoid of UspA1/A2 revealed that UspA1/A2 exert their actions by absorbing and neutralizing C3 from serum and restrain complement activation. UspA2 was responsible for most of the effect, and the Moraxella mutant lacking UspA2 was more sensitive to the lytic effect of human serum compared with the wild type. Interestingly, among the large number of bacteria analyzed, only M. catarrhalis has this unique ability to interfere with the innate immune system of complement by binding C3.

Bacterial Outer Membrane Proteins↗
PubMed2000

Novel purification scheme and functions for a C3-binding protein from Streptococcus pneumoniae.

To isolate microbial proteins capable of binding the third component of complement (C3), we coupled the free sulfhydryl group of methylamine-inactivated C3 to a thiolSepharose matrix. This simple technique facilitated the purification of the first C3-binding protein isolated from a bacterium (Streptococcus pneumoniae). Both metastable (native) and thioester-disrupted C3 were recognized by this protein; binding of C3 was noncovalent, independent of thioester conformation, and preferential for the C3 alpha-chain. Sequencing of amino-terminal and internal peptides from the C3-binding protein disclosed a proline-rich region spanning approximately 20 amino acids and a signal peptide that had not been previously reported. The gene was isolated from a library of genomic DNA from laboratory strain CP1200 by screening with a 1200 bp PCR product amplified from degenerate oligonucleotides encoding the amino terminal sequence and the internal proline-rich sequence. The open reading frame spanned 1692 bp; all peptide sequences were identified in the translated gene product, which also contained at least three choline-binding repeats at the carboxy-terminus. The gene was conserved, and the translated protein was functionally active in pneumococcal clinical isolates of serotypes 1, 3, 4, 14, and 19F. Serum from a patient recovering from acute pneumococcal infection contained IgG antibodies specific for this protein by immunoblot. Wide conservation among clinical isolates, saturable binding of C3, and the ability to stimulate the human immune response have not previously been reported for this choline-binding protein. A similar biochemical approach should enable the identification of other C3-binding proteins in microorganisms able to elude complement-mediated host defense.

Amino Acid Sequence↗
PubMed1994

Molecular analysis of C3 allotypes in Chinese patients with immunoglobulin A nephropathy.

The third component of complement (C3) exists in two main allotypic forms, C3S and C3F. An increased frequency of the rarer C3F allele has been reported in several autoimmune conditions, including immunoglobulin A nephropathy (IgAN), in white patients. C3F is known to be rare in the Chinese population, but C3 allotypes have not been studied in Chinese patients with IgAN. The molecular basis of the S/F polymorphism has been established recently: a single base change at the DNA level encodes a single amino acid substitution in the protein. A second polymorphism, closely linked to the first, is defined by the monoclonal antibody HAV 4-1, and also is due to a single base change. These polymorphisms therefore can be analyzed at the DNA level. We have used the amplification refractory mutation system, a modification of the polymerase chain reaction, to analyze these two C3 polymorphisms on genomic DNA from 133 Hong Kong Chinese individuals: 54 patients with IgAN and 79 controls. No C3F alleles were present in either group: all individuals were homozygous C3S. Twenty-six patients were also allotyped for the HAV 4-1 polymorphism; all 26 were homozygous HAV 4-1 negative, as would be predicted from the close linkage of this allotype to C3S in other populations. These data indicate that C3F is not a susceptibility allele for IgAN in Hong Kong Chinese individuals, and confirm in a large DNA-based study the rarity of C3F in this population.

Adolescent↗
PubMed1998

Solution structure of Compstatin, a potent complement inhibitor.

The third component of complement, C3, plays a central role in activation of the classical, alternative, and lectin pathways of complement activation. Recently, we have identified a 13-residue cyclic peptide (named Compstatin) that specifically binds to C3 and inhibits complement activation. To investigate the topology and the contribution of each critical residue to the binding of Compstatin to C3, we have now determined the solution structure using 2D NMR techniques; we have also synthesized substitution analogues and used these to study the structure-function relationships involved. Finally, we have generated an ensemble of a family of solution structures of the peptide with a hybrid distance geometry-restrained simulated-annealing methodology, using distance, dihedral angle, and 3J(NH-Halpha)-coupling constant restraints. The Compstatin structure contained a type I beta-turn comprising the segment Gln5-Asp6-Trp7-Gly8. Preference for packing of the hydrophobic side chains of Val3, Val4, and Trp7 was observed. The generated structure was also analyzed for consistency using NMR parameters such as NOE connectivity patterns, 3J(NH-Halpha)-coupling constants, and chemical shifts. Analysis of Ala substitution analogues suggested that Val3, Gln5, Asp6, Trp7, and Gly8 contribute significantly to the inhibitory activity of the peptide. Substitution of Gly8 caused a 100-fold decrease in inhibitory potency. In contrast, substitution of Val4, His9, His10, and Arg11 resulted in minimal change in the activity. These findings indicate that specific side-chain interactions and the beta-turn are critical for preservation of the conformational stability of Compstatin and they might be significant for maintaining the functional activity of Compstatin.

Binding, Competitive↗
PubMed1976

Homozygous human C3 deficiency. The role of C3 in antibody production, C-1s-induced vasopermeability, and cobra venom-induced passive hemolysis.

Studies of the family of a patient with marked deficiency of the third component of complement (C3) demonstrated that the patient was homozygous for a blank allele at the C3 locus, C3-. Metabolic studies with purified radiolabeled C3 in the patient revealed a mildly elevated fractional catabolic rate and a markedly reduced synthesis rate, consistent with a lack of C3 synthesis as the patient's primary defect. There was also a mild increase in the rate of conversion of purified C3 added to her serum and incubated at 37 degrees C in vitro. Major blood group-compatible erythrocytes from a patient with paroxysmal nocturnal hemoglobinuria had the same shortened survival in the C3-deficient patient as in a normal control. Although no leukocytosis developed in the patient in spontaneous infection by pyogenic organisms, there was a normal leukocytosis in response to the injection of thyphoid vaccine. The intradermal injection of C-1s, which produces a marked increase in vasopermeability in the skin of normal subjects, produced no definite change in the patient, possibly implicating C3 or a protein in the alternative pathway as the normal mediator of this response. The patient's serum exhibited near-normal immune adherence activity, confirming the lack of requirement of C3 for this function. C5 inactivation and passive hemolysis of unsensitized guinea pig erythrocytes occurred normally in C3-deficient serum on incubation with cobra venom factor, indicating that C3 is not required for these reactions. The patient's humoral antibody response to both protein and carbohydrate antigens was entirely normal, making it unlikely that C3 is required for antigen processing.

Alleles↗
PubMed1993

Therapeutic effect of a new immunosuppressant, FK-506, on vasospasm after subarachnoid hemorrhage.

We hypothesized that the immunological reaction against extravasated blood might play a role in the development of vasospasm after subarachnoid hemorrhage. Under the hypothesis, we had reported significant therapeutic efficacy of cyclosporin A on vasospasm in canine models. We here investigated the efficacy of a new, potent immunosuppressant, FK-506, on vasospasm in animal models. Dogs were randomly classified into sham operated, subarachnoid hemorrhage treated-1 group, (FK-506, 0.3 mg/kg-d, intramuscular injection), and treated-2 group (FK-506, 0.15 mg/kg-d, intramuscular injection). Levels of the third factor of complement (C3) and the activity of serum complement inducing 50% hemolysis of sheep erythrocytes (CH50) in serum were also determined. In the treated groups, the levels of FK-506 in serum were monitored. As for C3 and CH50, there were no statistically significant differences among the groups and there were no changes between Day 1 and Day 7 in any group. Angiographical diameters of a basilar artery on Days 1 and 7 were measured with a computed image analyzer, and the extent of vasospasm was compared among the groups. Statistically significant differences between the sham-operated group and the other three groups were noted. However, under sufficient levels of FK-506 in serum, the extent of vasospasm in either treated group was the same as that in the subarachnoid hemorrhage group. These results indicate a significant discrepancy in the therapeutic mechanism for vasospasm between cyclosporin A and FK-506. They have common aspects in the immunosuppressive mechanism. However, in T-cell suppression, the different mechanism in situ between the two drugs is also postulated.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

Complement component C3-derived neutrophil chemotactic factors purified from exudate of rat carrageenin-induced inflammation.

Two neutrophil chemotactic factors have been purified from the exudate of chronic-phase of rat carrageenin-induced inflammation. Both the factors were derived from the third component of complement (C3); one was an NH2-terminal fragment (C3a) of alpha chain of C3 and another chemoattractant was a COOH-terminal fragment of beta chain, which was referred to as C3 beta c, on the basis of their molecular masses and NH2-terminal amino acid sequences. C3a exhibits potent chemotactic activity for rat neutrophils, and C3 beta c is a novel basic neutrophil chemoattractant with molecular mass of about 11 kDa, suggesting that both chemoattractants play a role in the neutrophil infiltration into inflammatory site of carrageenin-induced inflammation in rats.

Amino Acid Sequence↗
PubMed1990

Intracellular processing of complement pro-C3 and proalbumin is inhibited by rat alpha 1-protease inhibitor variant (Met352----Arg) in transfected cells.

Complement C3, when its cDNA was transfected into COS-1 cells, was synthesized as a precursor, pro-C3, which was intracellularly processed into the alpha and beta subunits, although not completely. A cDNA for rat alpha 1-protease inhibitor (alpha 1-PI) was mutated in vitro to encode its variant with the modified active site (Met352----Arg). In cells co-transfected with the mutant alpha 1-PI cDNA and the C3 cDNA, pro-C3 expressed was secreted without being processed into the subunits. Co-transfection of the mutant alpha 1-PI cDNA and the albumin cDNA also resulted in the inhibition of intracellular conversion of proalbumin into serum-type albumin. No inhibition of the processing of each preform was observed in cells co-transfected with the normal alpha 1-PI cDNA. Taken together, the results indicate that the alpha 1-PI variant (Met352----Arg) expressed inhibits specifically an intracellular enzyme which is involved in the proteolytic processing of both pro-C3 and proalbumin.

Amino Acid Sequence↗
PubMedDate not supplied

Oral administration of pectin-rich plant extract enhances C3 and C4 complement concentration in woman colostrum.

C3 and C4 components of the complement are normally present in human colostrum. These compounds are natural antibacterial agents. Pectin-rich plant extracts have been shown to induce prolactin release and milk synthesis when administered by the oral route in rat. In the present work, extract from a plant rich in pectin, Gossypium herbaceum was given orally to women 2 days after parturition. The extract enhanced concentration of C3 and C4 in colostrum but did not modify the total hemolytic complement activity (TCH50). No change in the concentration of the three compounds was observed in serum of the treated women. Control experiments showed that a treatment by placebo had no effect on colostrum composition. These data suggest that pectin-rich plant extracts favour transfer of C3 and C4 from blood to colostrum by an unknown mechanism. This observation suggests that some plant extracts might be used to reinforce the antibacterial activity of human colostrum.

Adult↗
PubMed1993

Molecular analysis of C3 allotypes in patients with nephritic factor.

The autoantibody nephritic factor (NeF) leads to complement consumption in vivo and is associated with type II mesangiocapillary glomerulonephritis (MCGN II) and partial lipodystrophy (PLD). The third component of complement (C3) exists in two common allotypic forms, C3S and C3F, distinguished at the protein level by electrophoresis. An increased frequency of the rarer C3F allele has been reported in several autoimmune conditions, including one small series of patients with NeF. However, patients with NeF have low levels of circulating C3 so that allotyping at the protein level is difficult. The molecular basis of the S/F polymorphism has recently been established: a single base change at the DNA level encodes a single amino acid substitution at the protein level. A second polymorphism, closely linked to the first, is defined by the MoAb HAV 4-1, and is also due to a single base change. These polymorphisms can therefore be analysed at the DNA level. We have used the amplification refractory mutation system (ARMS), a modification of the polymerase chain reaction (PCR), to analyse these two C3 polymorphisms at the DNA level in 26 patients with NeF. The allele frequencies of C3S and C3F were 0.673 and 0.327 (predicted values 0.79 and 0.2, chi 2 = 4.813, P < 0.05), giving a relative risk of 2.1 for the development of NeF conferred by the presence of a C3F allele. The HAV 4-1 allele frequencies were (-) 0.71 and (+) 0.29, i.e. not significantly different than predicted from the linked C3S/F allele frequencies. This is the largest series of patients with NeF yet published, and our data confirm an association between C3F and NeF. Possible mechanisms for for this link are discussed.

Adolescent↗