[Activation of complement during cardiopulmonary bypass--comparative study using 4 different oxygenators].
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Adult↗
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Results for “Complement C4a”
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Autoantibodies and immunogenetics in 30 patients with systemic sclerosis and their families.
Clinical and serological evidence of connective tissue disease was found in a high proportion of 132 family members of 30 patients with systemic sclerosis. In 20 probands with the milder CREST form of the disease, 10 had HLA-DR5 and 12 had null alleles at the C4 loci. None of 11 probands with more severe systemic sclerosis had HLA-DR5; all 11 had null alleles at the C4 loci. All but two of the probands had either HLA-DR5 or a C4 null allele, and this was also the case for the majority of the relatives with autoantibodies. Genetic markers of the major histocompatibility complex, including HLA-DR5 and C4 null alleles, appear to be closely associated with markers of disease in these probands and their families.
Antibodies, Antinuclear↗
Study of HLA class I, class II and complement genes (C2, C4A, C4B and BF) in Japanese psoriatics and analysis of a newly-found high-risk haplotype by pulsed field gel electrophoresis.
Genetic polymorphisms of HLA antigens and HLA-linked serum complement components (C2, C4A, C4B and BF) were investigated in 79 Japanese patients suffering from psoriasis. HLA typing revealed increased frequencies of HLA-A1, A2, B39, Bw46, Cw6, Cw7 and Cw11. Among complement components, positive associations were obtained with C4A4 and C4B2 and a negative association with BFF. The major histocompatibility complex haplotype (supratype), HLA-A2-Cw11-Bw46-C2C-BFS-C4A4-C4B2-DRw8 is purported to be a new high-risk haplotype in Japanese patients with psoriasis. Analysis of patients with this supratype via pulsed field gel electrophoresis showed the existence of specific, extensive DNA deletions near HLA-DR genes, but no disease-specific patterns could be observed by means of this technique. The newly-found high-risk haplotype indicates racial and ethnic differences among psoriatic patients.
Alleles↗
Comparative structural anatomy of the complement anaphylatoxin proteins C3a, C4a and C5a.
The anaphylatoxins are a family of proteins produced during the course of complement activation as the result of cleavage by specific serine proteases. These proteins are involved in a variety of biological functions, including inflammation. Comparative modeling techniques have been used to produce structures for C4a and C5a from the crystal structure of C3a. All three structures have conserved interior residues but very different external side chains and surface shapes and properties. Comparison of the anaphylatoxin structures and of the sequence conservation among different species suggests possible locations for their receptor binding sites and for their specificity residues which permit regulated proteolytic cleavage from precursor.
Amino Acid Sequence↗
Activated complement components C3a and C4a in cerebrospinal fluid and plasma following subarachnoid hemorrhage.
The cerebrospinal fluid (CSF) and plasma levels of the complement components C3a and C4a in 40 patients suffering from subarachnoid hemorrhage (SAH) were quantitated by radioimmunoassay. Serial measurements of the lumbar CSF levels revealed that the C3a and C4a levels were significantly elevated in the initial stage of SAH, but decreased rapidly. Within 48 hours after SAH, the mean C3a and C4a levels in the cisternal, lumbar, and ventricular CSF were significantly higher in patients with delayed ischemic neurological deficits (DIND) than in those without DIND. The serially measured plasma levels of C3a and C4a in patients with DIND were elevated more than in those without DIND, but they did not show a significant change over time. Simultaneous levels of fibrinopeptide A (FPA), an indicator of thrombin activity in CSF, were also measured by radioimmunoassay. There was a significant correlation between CSF-activated complement components and CSF FPA. These results suggest that complement activation occurred in the subarachnoid space soon after SAH, chiefly due to activation of the coagulation system. The higher CSF levels of C3a and C4a in patients with DIND may indicate a relationship between these components and the pathogenesis of cerebral vasospasms.
Adult↗
Correlation between HLA-A2-Bw46-DRw8 haplotype and increased levels of complement components (C4 and C4a) in patients with psoriatic arthritis.
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Arthritis, Psoriatic↗
Definitive RFLPs to distinguish between the human complement C4A/C4B isotypes and the major Rodgers/Chido determinants: application to the study of C4 null alleles.
Definitive restriction fragment length polymorphisms (RFLPs) representing the exact locations responsible for isotypicity between the human complement components C4A and C4B, and their generally associated major Rodgers (Rg1) and Chido (Ch1) antigenic determinants, have been designed. By means of C4d-specific genomic probe for Southern blot analysis, a C4A gene can be defined by the presence of the 276 bp and 191 bp N1a IV fragments, while a C4B gene can be defined by a single 467 bp N1aIV fragment. In addition, an Rg1-expressing C4 gene can be represented by a 565 bp EcoO 109 fragment, and a Ch1-expressing C4 gene by a 458 bp EcoO 109 fragment, under the same conditions. All these polymorphic restriction fragments can be unambiguously and conveniently detected. In combination with the Taq I polymorphic patterns specific for the C4 loci and for the neighboring 21-hydroxylase genes, the nature and structure of the tandem C4,21-hydroxylase gene complex can be elucidated. In this study, it is inferred that the null allele of the HLA haplotype B44 DR6 C4A3 C4BQO is not a C4B allele, but probably encodes another C4A 3 allotype at the second C4 locus.
Alleles↗
Tumour necrosis factor B gene polymorphism in relation to complotype in couples with spontaneous abortions and in control families.
NcoI restriction fragment length polymorphism (RFLP) of the tumour necrosis factor B (TNFB) gene gives two allelic fragments of 5.5 and 10.5 kb, corresponding to the TNFB*1 and TNFB*2 alleles, respectively. The frequencies of these alleles were analysed in 121 healthy Finns and 56 Finnish couples suffering from recurrent spontaneous abortions (RSA). In the healthy Finns the frequency of TNFB*1 was 37% and that of TNFB*2 63%, of which the frequency of TNFB*1 was significantly increased compared with the Danish population. No deviation was seen between the RSA couples and the Finnish controls. TNF genes are located in major histocompatibility complex class III region close to complement (BF, C4A and C4B) genes. Some complotypes associated most often with the TNFB*1 (S01, S30, S02) and some (S31, F320) with the TNFB*2 allele in the healthy Finns. The combination of the TNFB and the C4 'null' allele differed between the RSA couples and the Finnish controls.
Abortion, Habitual↗
A high frequency of inherited deficiency of complement component C4 in Darwin Aborigines.
A high frequency of serum complement component C4A deficiency may explain the higher prevalence and greater severity of systemic lupus erythematosus reported in Australian Aborigines. Inherited deficiencies of serum complement components C4A, C4B, and C2 were examined in two Australian Aboriginal populations from Darwin and Alice Springs and compared with the prevalence of complement deficiencies in white Australian blood donors. The frequency of C4A deficiency alleles was 29% in Darwin Aborigines compared with 12% in Alice Springs and 17% in Canberra blood donors. Partial C4B deficiency was also higher in Darwin Aborigines than in the other populations. Inherited deficiency of serum complement component C2 was not observed.
Alleles↗
Null alleles of the fourth component of complement and HLA haplotypes in familial systemic lupus erythematosus.
Eight families (121 individuals) with two or more members affected with systemic lupus erythematosus (SLE) were analyzed for histocompatibility antigens (HLA-A, B, C, DR, MT, and MB) and complement antigens (C4A, C4B, and BF). These data were correlated with serological markers (antinuclear antibodies, single- and double-stranded anti-DNA, anti-SM, anti-nRNP, anti-Ro [SS-A], anti-La [SS-B], and biological false-positive tests for syphilis and clinical features. Fifteen members had SLE, and 19 had other immune diseases (subacute cutaneous lupus erythematosus, discoid lupus erythematosus, hypothyroidism, insulin-dependent diabetes mellitus, primary Sjogren's syndrome, immune thrombocytopenic purpura, rheumatoid arthritis, and multiple sclerosis). Twenty-three healthy relatives (seroreactors) had significant titers of circulating antibodies, as did 2 of 17 spouses. There was an increased frequency of null C4 alleles in those individuals with SLE (60%) and healthy relatives (50%) as compared with spouses (24%). Multivariate analysis showed a significant association between SLE and female sex (P =.006), whereas there was no significant association revealed between female sex and other immune diseases. Patients with SLE also had a higher frequency of either C4A or C4B null alleles (P = .01) than those with immune diseases. The C4A homozygous null phenotype was more common in SLE patients than in seroreactors (P = .02). There was a higher frequency of HLA-DR2 and DR3 in individuals with SLE than in those with immune disease (P = .08), seroreactors (P = .02) and normal relatives (P = .002). One totally C4-deficient patient with SLE was identified. These families demonstrate an important association between SLE and the C4 null allele and the HLA-DR2 and DR3. These risk factors, however, cannot account for the development of disease in all individuals.
Adult↗
Complement phenotypes in patients with psoriasis.
Phenotype frequencies for the complement proteins C4A, C4B, Bf (factor B) and C3 were performed for 49 Caucasian patients with psoriasis. The C4*A6 allele was present in 26.6% of the patients as compared to 5.4% of healthy regional Caucasian controls, p less than 0.001, relative risk = 6.28. The C4*A6 allele is known to be in linkage disequilibrium with the HLA B17 allele and to produce a non-functional gene product when it occurs with the B17 allele. HLA B17 is known to be associated with psoriasis in many Caucasian populations. Additional findings in the present study were a significant reduction in the C4B*2 allele frequency, a non-significant increase in the Bf*F allele frequency and no difference for Bf or C3 phenotype frequencies in the patients with psoriasis as compared to the controls.
Complement C3↗
Shared HLA class II-associated genetic susceptibility and resistance, related to the HLA-DQB1 gene, in IgA deficiency and common variable immunodeficiency.
Most cases of selective IgA deficiency (IgA-D) and common variable immunodeficiency (CVID) occur sporadically. However, familial clustering is not uncommon, and the two disorders can occur within the same family. We have previously described positive associations with three DR-DQ haplotypes as well as a strong negative association with DRw15,DQw6,Dw2 in IgA-D. Different amino acids at position 57 of the HLA-DQ beta chain were found to be related to susceptibility and resistance to IgA-D. Now we have found identical, although somewhat weaker, positive and negative DR-DQ associations in a large group of CVID patients (n = 86), as well as the same associations with codon 57 of the DQB1 gene. In addition, we have confirmed our earlier observations in an independent group of IgA-D individuals (n = 69), and in sib-pair analysis we have found linkage of the genetic susceptibility to IgA-D to the HLA class II region. In IgA-D individuals not carrying the three overrepresented DR-DQ haplotypes, the same positive association with a non-aspartic acid residue at position 57 of the HLA-DQ beta chain was seen. The previously reported associations with deletions of the HLA class III genes C4A (fourth component of complement) and CYP21P (steroid 21-hydroxylase pseudogene) were, in our groups of immunodeficient individuals, statistically secondary to the association with the DQB1 allele 0201. The shared HLA class II associations in the two humoral immunodeficiencies support the hypothesis that IgA-D and CVID are related disorders. Disease susceptibility and resistance are most closely associated with a gene(s) within the DR-DQ region, alleles of the DQB1 locus being candidate genes.
Alleles↗
Demonstration of neutrophil chemotactic anaphylatoxins in human dandruff.
In contrast to scales collected from the scalps of nine healthy individuals where a few parakeratotic cells are observable, a large number of parakeratotic cells associated with some infiltrated polymorphonuclear leukocytes (PMNLs) were found in the scales obtained from 11 individuals complaining of dandruff. Therefore, we determined the neutrophil chemotactic properties of the water-soluble extracts of dandruff scales and normal control scalp scales. Aqeous extracts fractionated by Sephadex G-75 showed a potent chemotactic activity only in the fractions of the dandruff patients that eluted with cytochrome C marker (cyt C; molecular weight, 12 kDa). It was comparatively stable to heat but was greatly inhibited by the addition of anti-C5 antiserum. Radioimmunoassay demonstrated that, although small amounts of C5a and C4a anaphylatoxins were demonstratable even in the extracts of normal scalp, they were found in significantly increased amounts in the extracts of dandruff. Moreover, there was a significantly positive correlation between C5a and C4a concentrations in these extracts. These results suggest that classical complement pathway activation with resultant production of C5a anaphylatoxin is involved in the migration of PMNLs into the lesional skin of dandruff.
Adult↗
Three Chido determinants detected on the B5Rg+ allotype of human C4: their expression in Ch-typed donors and families.
A study was made of polyspecific human allo-anti-C4, anti-Chido (Ch), which reacts with determinants usually located on C4B protein. Some anti-Ch reagents are capable of reacting with Ch- red cells coated with C4 from Ch:-1,-2,-3 donors. A complex serologic pattern demonstrated three more Ch determinants, Ch4, Ch5, and Ch6, which were detected by haemagglutination-inhibition tests. All Ch:1,2,3 samples were Ch:4,5,6 but samples lacking one or more of the Ch1,Ch2,Ch3 series of determinants also lacked some of the new determinants. MHC typed families demonstrated the inheritance of the new determinants as part of the Ch haplotype, and associations with C4 allotypes and haplotypes have been established. Ch4 always associates with C4B protein. Ch5 and Ch6, normally detected on C4B protein, were detected in several individuals who lacked C4B (BQO allotypes) and were therefore presumed in these instances to be located on the accompanying C4A protein.
Antigens, Surface↗
Two isotypes of human C4, C4A and C4B have different structure and function.
The two types of human C4, C4A and C4B, differ in their amino acid sequence and in their capacity to bind to different acceptor sites. C4B is more efficient than C4A in haemolytic assays; by contrast C4A binds preferentially to immune complexes. In assays comparing haemolysis to processing of immune complexes the two types of C4 differ more than fivefold. Thus, the classical pathway is a duplicated system that allows the formation of a C3 convertase on various substrates: this duplication may be of vital importance to eliminate invading microorganisms. In addition, the clinical observation of an increased incidence of homozygous C4A null alleles in systemic lupus erythematosus may be explained in part by defective processing of immune complexes in the absence of C4A.
Antigen-Antibody Complex↗
[A new case of bronchospasm under extracorporeal circulation].
A case of bronchospasm occurring after the termination of cardiopulmonary bypass is reported. The complement fractions C3a, C4a and C5a were measured before and right after CPB. Complement activation is not specific to CPB but may occur in any thoracotomy. The statistically significant increase in complement C3a without any pulmonary symptomatology has been reported by several authors. Complement activation cannot therefore be considered as the explanation of this bronchospasm.
Bronchial Spasm↗
C4a: the third anaphylatoxin of the human complement system.
The activation peptide C4a was isolated from C1s-cleaved C4, the fourth component of complement. The peptide appeared to be homogeneous by electrophoresis on cellulose acetate and by polyacrylamide gel electrophoresis. C4a has a molecular weight of 8650 and an electrophoretic mobility at pH 8.6 of +2.1 x 10(-5) cm2V-1 sec-1. Carboxypeptidase B released approximately 1 mol of arginine per mol of C4a. The partial COOH-terminal sequence was determined to be Leu-Gln-Arg-COOH. The isolated C4a was spasmogenic for guinea pig ileum at a concentration of 1 microM and it desensitized the muscle (i.e., produced tachyphylaxis) with respect to human C3a anaphylatoxin (at 0.33 microM) but not with respect to human C5a anaphylatoxin. Increased vascular permeability was observed in human skin after intradermal injection of 1 nmol of C4a, as evidenced by immediate erythema and edema formation. The spasmogenic, tachyphylactic, and vascular activities of C4a were abrogated by removal of the COOH-terminal arginine, a property that is characteristic also of the C3a and C5a anaphylatoxins. Contamination of C4a with either C3a or C5a has been ruled out by using radioimmunoassays for these peptides. Although C4a is considerably less active than are C3a and C5a, the present observations suggest that C4a constitutes a heretofore unrecognized anaphylatoxin that is related biologically and chemically to the activation peptides of C3 and C5.
Amino Acid Sequence↗
Relation between complement activation and susceptibility to decompression sickness.
The consequences of complement activation and the symptoms of decompression sickness are similar. Consequently, the relation between the sensitivity of individuals to complement activation by air bubbles and their susceptibility to decompression sickness has been examined. Plasma samples from 34 individuals were incubated with air bubbles, and the concentration of the fluid phase metabolites of complement activation C3a, C4a, and C5a were measured with radioimmunoassays. It was found that both the anaphylatoxins C3a and C5a were produced by the presence of air bubbles but that the anaphylatoxin C4a was not. This finding indicates that air bubbles activate the complement system by the alternate pathway. One group of individuals was found to be particularly sensitive to complement activation by this pathway. They produced 3.3 times more C3a and 5.3 times more C5a in their plasma samples incubated with air bubbles as did the other group. Sixteen individuals were subjected to a series of pressure profiles that were severe enough to produce bubbles in their circulatory system that could be detected by Doppler ultrasonic monitoring. The group of individuals that had been identified as being more sensitive to complement activation by the alternate pathway was also found to be more susceptible to decompression sickness.
Adult↗