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PubMed1990

A prospective study of the risk of an immediate adverse reaction to protamine sulfate during cardiopulmonary bypass surgery.

Protamine sulfate administration may cause life-threatening reactions. We prospectively examined the incidence of immediate adverse reaction after protamine in 243 patients who underwent cardiopulmonary bypass surgery. Twenty-six patients (10.7%) had reactions, and 1.6% had a precipitous drop in blood pressure immediately after protamine administration. Risk factors were previous exposure to protamine, diabetes, history of receiving protamine-containing insulin, and possibly vasectomy. However, neither a positive skin test nor a positive IgE ELISA for antiprotamine antibody predicted that a patient would have a reaction. C4a levels were increased in patients who had reactions as compared with age-, sex-, and cardiac disease-matched patients who did not have reactions, suggesting a role for complement in some reactions. Immediate adverse reactions to protamine are very common, and alternative therapies are urgently needed to eliminate the use of protamine.

Adult↗
PubMed1990

A novel immunoassay for the quantitation of human C4 gene products.

Utilizing mouse monoclonal antibodies which recognize Rodgers 1 and Chido 1 epitopes carried on the C4A and C4B molecules, and heat-aggregated IgG to activate C1, an immunoassay was developed for the quantitation of total C4 as well as C4A and C4B. Interassay variation was 12.4, 11.5 and 10.8%, respectively. The immunoassay was compared to the quantitation of total C4 by radial immunodiffusion by testing 103 random white controls and gave a Pearson's product-moment correlation coefficient of 0.81. Three genetic total-C4-deficient individuals were nonreactive in all three assays. This activated assay is specific, reproducible, and superior to existing methods for the quantitation of C4A and C4B and detection of the heterozygous C4 null state.

Complement C4↗
PubMed1988

Partial C4A deficiency is associated with susceptibility to systemic lupus erythematosus in black Americans.

In a study of 59 black American patients with systemic lupus erythematosus (SLE), we found that partial C4A deficiency occurred twice as frequently as in 59 control subjects (32.3% versus 15.3%; P = 0.02). Complete C4A deficiency, however, occurred in only 1 patient and in no controls. Partial C4A deficiency is a risk factor for SLE in black, as well as in white, SLE populations studied to date. In contrast with white patients, complete C4A deficiency occurs relatively infrequently in black patients with SLE.

Adult↗
PubMed1992

C4 polymorphism in multiplex families with insulin dependent diabetes in the Tunisian population: standard C4 typing methods and RFLP analysis.

The polymorphism of C4A and C4B genes was investigated in Tunisian patients with insulin dependent diabetes (IDDM) and compared to family members (sibs) and to healthy controls. Multiplex families were analysed. A significant increase in C4AQO (26.86% vs 6.90%) and C4BQO (40.29% vs 8.28%) phenotypes was noted in IDDM patients compared with controls. Using RFLP analysis, we confirmed the high frequency of C4 null alleles. We also observed that most of these alleles were genes deleted in IDDM patients (72.23% vs 20% for CA4QO and 74.07% vs 16.70% for C4BQO). A significant decrease in the C4B long (14.92% vs 67.12%) form of the gene was also demonstrated by RFLP analysis compared with controls. Two haplotypes were frequently associated with IDDM patients in whom the C4A and C4B were deleted genes.

Adolescent↗
PubMed1992

Anaphylatoxin generation and distribution during in vitro LDL apheresis.

The extent of anti-apo-B IgG-Sepharose-induced complement activation in serum and plasma (heparin 2 U/ml and ACD-B 1:20) was investigated using an in vitro model of LDL apheresis. The total volume of serum or plasma loaded to the chromatography column was collected in defined aliquots. The washing, desorption and regeneration fluids were processed in the same way. From the obtained values of generated complement split products C3a (desarg), C4a (desarg), C5a (desarg) and complement proteins C3, C4, C5, the conversion rates of the precursor were calculated. In the experiments with serum, 19% of C3, 8% of C4 and 2.3% of C5 were converted by the immunoadsorbent, whereas with plasma 7, 6, and 0.6%, respectively, were found. Furthermore, only 60-74% of total anaphylatoxins were found in the effluent during the loading process. The residual 26-40% was removed from the column with the subsequent washing fluids. Therefore, in the clinical routine, only a reduced part of generated anaphylatoxins will be retransfused to the patient. The fact that C5 is converted to the most limited extent to its biologically active fragment additionally contributes to the understanding of the good clinical tolerability of the LDL apheresis.

Anaphylatoxins↗
PubMed1990

Studies of a C2 DNA polymorphism in RA, Felty's and normal subjects.

A restriction fragment length polymorphism at the C2 locus was studied in rheumatoid arthritis (RA), Felty's and control subjects. No association was found between any C2 variant and either RA itself or within the rheumatoid population with Felty's syndrome. The C2 DNA polymorphism can be used to subdivide Bf*S- as well as Bf*F-bearing haplotypes. The 2.65-kb C2 DNA allele showed allelic association with HLA-B44 and C4B*Q0 and may help to further characterize the haplotype B44-Bf*S-C4A*3-C4B*Q0-DR4, which has previously been described in Felty's syndrome.

Alleles↗
PubMed1990

Differences between C4A and C4B in the handling of immune complexes: the enhancement of CR1 binding is more important than the inhibition of immunoprecipitation.

There are two isotypes of C4--C4A and C4B--, encoded within the major histocompatibility complex with quite different properties. In this study we have compared purified C4A and C4B with regard to their ability to prevent immune complex precipitation and to enhance the binding of both preformed and nascent immune complexes to the receptor CR1 on red cells. C4A was modestly more effective than C4B at inhibiting immunoprecipitation, particularly in antibody excess. In the CR1 binding assay C4A was markedly more effective than C4B in enhancing binding to CR1. This difference was seen with both preformed and nascent immune complexes at equivalence and antibody excess. Thus the major differences between C4A and C4B in regard to immune complex handling is at the level of CR1 binding. Given the strong association of C4A* QO alleles with immune complex-mediated diseases like systemic lupus erythematosus, these findings have important pathogenetic implications.

Antigen-Antibody Complex↗
PubMed1985

C4 phenotypic variation suggests an unusual class III gene organization.

The class III gene markers, C4A, C4B, C2 and BF were determined in 26 HLA genotyped families. In 6 of these families the inheritance of the C4A electrophoretic phenotype, C4A 3, A 2 could not be explained assuming the genetic model that the C4A component is controlled by only one locus (C4A) and suggests that both C4A 3 and C4A 2 are encoded by the same chromosome. This apparently duplicated C4A locus haplotype is common in Northern Europeans occurring at a frequency of at least 6%. In 4 families the C4A 3, A 2 'variant' occurred together with HLA-Bw35 and in 2 together with HLA-Bw55. Furthermore, it was striking that in each family the C4A 3, A 2 'variant' was found exclusively with the complotype FC3/20 which encodes no phenotypically expressed C4B locus product.

Alleles↗
PubMed1987

Gene organization of haplotypes expressing two different C4A allotypes.

The gene organization of C4 haplotypes expressing two different C4A allotypes with a C4B null allele (C4A3A2BQ0 and C4A3A6BQO) was studied using Southern blot analysis with cDNA probes and restriction enzymes which give C4A and C4B locus-specific restriction fragments. These haplotypes were shown to have both a C4A and a C4B locus present, suggesting that the C4B locus expresses a C4A protein. The finding of a 21-OH A and a 21-OH B gene on the C4A3A6BQO haplotype further suggests that this haplotype has the common gene organization C4A, 21-OH A, C4B, 21-OH B. A model explaining C4 null alleles on haplotypes found to have two C4 loci is presented.

Alleles↗
PubMed1999

Deficiency of human complement protein C4 due to identical frameshift mutations in the C4A and C4B genes.

The complement protein C4, encoded by two genes (C4A and C4B) on chromosome 6p, is the most polymorphic among the MHC III gene products. We investigated the molecular basis of C4 deficiency in a Finnish woman with systemic lupus erythematosus. C4-specific mRNA was present at low concentrations in C4-deficient (C4D) patient fibroblasts, but no pro-C4 protein was detected. This defect in C4 expression was specific in that synthesis of two other complement proteins was normal. Analysis of genomic DNA showed that the proposita had both deleted and nonexpressed C4 genes. Each of her nonexpressed genes, a C4A null gene inherited from the mother, a C4A null gene, and a C4B null gene inherited from the father, all contained an identical 2-bp insertion (TC) after nucleotide 5880 in exon 29, providing the first confirmatory proof of the C4B pseudogene. This mutation has been previously found only in C4A null genes. Although the exon 29/30 junction is spliced accurately, this frameshift mutation generates a premature stop at codon 3 in exon 30. These truncated C4A and C4B gene products were confirmed through RT-PCR and sequence analysis. Among the possible genetic mechanisms that produce identical mutations is both genes, the most likely is a mutation in C4A followed by a gene conversion to generate the mutated C4B allele.

Adult↗
PubMed1990

Characterization of two hybrid C4 allotypes (C4A*12 and C4B*3) by electrophoretic, serological and restriction fragment length polymorphism analyses.

Informative pedigree analysis of two rare C4 allotypes is reported. One proband was C4A deficient as a consequence of having one haplotype with a deleted C4A gene, and the second haplotype with two C4B genes--one encoding the common C4B*1 and one encoding a unique hybrid gene product C4B*3. C4B*3 had approximately normal C4B hemolytic activity, a single alpha-chain of MR 94,000 by SDS-PAGE but was positive for Rg:1,2 by hemagglutination inhibition (HAI) and for Rg:1 by Western blotting. The hybrid nature was confirmed by RFLP analysis with a Rg:1-associated fragment by Eco0109 digestion but no C4A-associated fragments by N1aIV digestion were identified. A gene conversion at Locus I which included just the C4 isotype region could explain the structure of C4B*3. The second pedigree had a Rodgers negative C4A*12 allotype. This C4A gene, which segregated with a single 7.0 kb TaqI fragment, encoded a C4A alpha-chain, which was negative for Rg:1 epitope. The affected haplotype lacked the Rg:1-associated fragment by Eco0109 digestion yet had the C4A specific N1aIV digestion fragment. These studies successfully employed RFLP analyses to confirm serologic and electrophoretic observations.

Adolescent↗
PubMed1996

C4 polymorphism and extended HLA haplotypes in Namibian San and Khoi and in South African Xhosa.

We studied C4A and C4B polymorphisms and HLA-B and -DR associations in the San, Khoi and Xhosa. C4A and C4B alleles were determined using conventional protein allotyping methods. The C4A*3, C4B*1 haplotype had a high frequency (30-55%) in all populations. The frequency of C4A*3, C4B*Q0 was 7-19%. The C4A*Q0, C4B*1 haplotype was frequent (15%) in the Khoi but very rare in the San (P < 0.001). C4A*12 A*91, C4B*Q0 was frequent in the Xhosa (15%) but rare in the San and Khoi (P < 0.001). Alleles C4A*5 and C4A*6, and the C4B*2 B*92 duplication were only found in the Xhosa. C4A alleles A*4, A*45, A*58, A*12, A*14, A*19 and the C4A*3 A*91 duplication were only found in the San/Khoi population group. In the San, fourteen extended haplotypes were found in a relatively high frequency (2-7%). In the Xhosa, one extended haplotype (B42, C4A*12 A*91, C4B*Q0, DR18) was found in a very high frequency (13%) and was characteristic for this group; five other extended haplotypes were found with a low frequency (< 3%).

Complement C4a↗
PubMed2004

Genetic basis of tobacco smoking: strong association of a specific major histocompatibility complex haplotype on chromosome 6 with smoking behavior.

The genetic basis for addiction to tobacco smoking--particularly that of the perception of olfactory stimuli that may be important in reinforcing smoking addiction--is largely unknown. A cluster of genes for olfactory receptors is in close proximity to the MHC region on chromosome 6. Polymorphisms of MHC class III genes (RCCX modules, TNFA promoter polymorphisms) were determined in 101 healthy subjects and 232 coronary artery disease (CAD) patients from Hungary with defined tobacco smoking habits. A highly significant association between ever smoking (past + current smokers) and a specific MHC haplotype was observed (odds ratios = 2.14-4.13; P-values = 0.012 to <0.001). This haplotype is characterized by the presence of C4A null alleles and a solitary short C4B gene linked to the TNF2 allele of the promoter for TNFA gene. This haplotype occurred more frequently in the ever smokers than in the never smokers [odds ratio: 4.97 (1.96-12.62); P = 0.001], and such associations were stronger in women (odds ratio = 13.6) than in men (odds ratio = 2.79). An independent study of complement C4 protein polymorphism and smoking habits in Icelandic subjects (n = 351) yielded similar and confirmative results. Considering the documented link between olfactory stimuli and smoking in females, and the presence of a cluster of odorant receptor genes close to the MHC class I region, our findings implicate a potential role of the MHC-linked olfactory receptor genes in the initiation of smoking.

Adult↗
PubMed1986

Hypocomplementemia with low C1s-C1 inhibitor complex in systemic lupus erythematosus.

Ninety-three serum and plasma samples from 45 patients with systemic lupus erythematosus were analyzed for the complex formed by C1s and its inhibitor, as well as for C3, C4, C4a desarginine, and staphylococcal protein A-bound immune complexes. There were statistically significant correlations between C1s-C1 inhibitor complex and CH50, between C1s-C1 inhibitor complex and C4, and between C1s-C1 inhibitor complex and C4a desarginine. Serial studies were performed on 24 patients over a period of 6 months. Seven of 21 patients with hypocomplementemia had persistently normal levels of C1s-C1 inhibitor complex, 7 had transiently abnormal levels of C1s-C1 inhibitor complex, and 7 had sustained abnormal levels of C1s-C1 inhibitor complex. Two of 3 pregnant patients with normal levels of complement had abnormal levels of C1s-C1 inhibitor complex. Staphylococcal protein A-bound immune complexes demonstrated no correlation with any of the complement assays. Complement activation, as measured by C1s-C1 inhibitor complex, is often a transient phenomenon in systemic lupus erythematosus patients with persistent hypocomplementemia.

Antigen-Antibody Complex↗
PubMed2001

Polymorphic markers in MHC class II/III region: a study on Italian patients with myasthenia gravis.

With an Italian case series of 81 Italian patients and 130 controls, we analysed associations between myasthenia gravis (MG) and genetic polymorphisms in the MHC class II/III region. Increases in the frequency of the TNF-B*1, C4A*Q0, C4B*1, DRB1*03 supratype, which is likely part of the 8.1 ancestral haplotype, were maximal in females with early onset (EO) MG vs. controls [p<0.05, relative risk (RR)=9.9]. These patients showed neither a significantly high frequency of thymic hyperplasia, nor high levels of serum anti-acethylcholine receptor antibodies. The DRB1*03 allele was absent in patients with thymoma; however, in comparison with controls, occurrence of this marker was frequent in MG patients (p<0.005; RR=6.2), more frequent in females (p<0.005; RR=7.8) and most frequent in EOMG female patients (p<0.005; RR=15.1). Analysis of the TNF-B*1, C4A*Q0, C4B*1, DRB1*03 supratype and its recombinants showed that the MHC region between C4 and TNF might contain genes that influence susceptibility to MG in females. Polymorphic markers within the supratype, e.g. TNF-B*1 and C4A*Q0, might contribute to pathogenetically significant abnormalities in immune responses in a subset of female MG patients. The combined effect of other intervening genes cannot be excluded.

Adult↗
PubMed2004

The C4A and C4B isotypic forms of human complement fragment C4b have the same intrinsic affinity for complement receptor 1 (CR1/CD35).

Several previous reports concluded that the C4b fragment of human C4A (C4Ab) binds with higher affinity to CR1 than does C4Bb. Because the isotypic residues, (1101)PCPVLD and (1101)LSPVIH in C4A and C4B, respectively, are located within the C4d region, one may have expected a direct binding contribution of C4d to the interaction with CR1. However, using surface plasmon resonance as our analytical tool, with soluble rCR1 immobilized on the biosensor chip, we failed to detect significant binding of C4d of either isotype. By contrast, binding of C4c was readily detectable. C4A and C4B, purified from plasma lacking one of the isotypes, were Cs converted to C4Ab and C4Bb. Spontaneously formed disulfide-linked dimers were separated from monomers and higher oligomers by sequential chromatographic steps. The binding sensorgrams of C4Ab and C4Bb monomers as analytes reached steady state plateaus, and these equilibrium data yielded essentially superimposable saturation curves that were well fit by a one-site binding model. Although a two-site model was required to fit the equilibrium-binding data for the dimeric forms of C4b, once again there was little difference in the K(D) values obtained for each isotype. Independent verification of our surface plasmon resonance studies came from ELISA-based inhibition experiments in which monomers of C4Ab and C4Bb were equipotent in inhibiting the binding of soluble CR1 to plate-bound C4b. Although divergent from previous reports, our results are consistent with recent C4Ad structural data that raised serious doubts about there being a conformational basis for the previously reported isotypic differences in the C4b-CR1 interaction.

Binding, Competitive↗