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PubMed1986

Determination of anaphylatoxin concentrations in suction blisters in patients with psoriasis.

Concentrations of C3a and C4a anaphylatoxins in suction blister fluids were determined by radioimmunoassay in patients with psoriasis and normal controls. Comparison of anaphylatoxin levels between serum samples and blister contents in the same subjects revealed that the levels of both C3a and C4a anaphylatoxins were significantly higher in the former than the latter even in those raised on normal skin, suggesting that the classic complement pathway is activated during suction procedure. Therefore we cannot regard suction blister fluid to be simply representative of undisturbed interstitial tissue fluid as far as the complement system is concerned. There was no difference in anaphylatoxin levels between those from uninvolved skin of psoriatic patients and those from normal controls. However, significantly high anaphylatoxin levels were noted in fluids of suction blisters raised on lesional skin as compared with those produced on uninvolved skin in psoriatic patients.

Adolescent↗
PubMed1989

Individuals with IgA deficiency and common variable immunodeficiency share polymorphisms of major histocompatibility complex class III genes.

IgA deficiency and common variable immunodeficiency are heritable disorders that can occur within the same family. Both immunodeficiencies are characterized by arrests in B-cell differentiation that vary in the extent of the immunoglobulin isotypes involved. A high frequency of major histocompatibility complex supratypes associated with a null allele of the gene encoding the C4A isotype of complement component C4 has been observed in IgA-deficient individuals. In search of a genetic linkage between the two immunodeficiencies, we examined the major histocompatibility complex (MHC) class III genes encoding complement components C2, C4A, and C4B and steroid 21-hydroxylase in addition to the HLA serotypes in individuals with either common variable immunodeficiency or IgA deficiency. Twelve of 19 patients with common variable immunodeficiency (63%, P less than 0.001) and 9 of 16 patients with IgA deficiency (56%, P less than 0.01) had rare C2 alleles and/or C4A and 21-hydroxylase A deletions, whereas these gene features were seen in only 5 of 34 healthy individuals (15%) in the control group. Nine of 11 patients with C4A deletion had an HLA haplotype consistent with the MHC supratype HLA-A1, Cw7, B8, C4AQ0, C4B1, BfS, DR3 previously found to be associated with IgA deficiency. The data support the hypothesis that common variable immunodeficiency and IgA deficiency are related disorders, susceptibility to which is determined by a gene(s) within or near the MHC class III gene region on chromosome 6.

Alleles↗
PubMed1987

Activation of the complement system by recombinant tissue plasminogen activator.

Recent trials have shown that recombinant tissue plasminogen activator (rt-PA) is an effective thrombolytic agent in patients with acute myocardial infarction. Because rt-PA converts plasminogen to plasmin, which is known to activate complement in vitro, we tested the hypothesis that rt-PA can induce in vivo activation of complement. Studies were performed in 12 patients with acute myocardial infarction. Six control patients had patent coronary arteries and did not receive rt-PA; these patients had normal values of the components of the complement system C4a (409 +/- 111 ng/ml) and C5a (8.8 +/- 1.8 ng/ml) with a slight elevation of C3a (204 +/- 6.6 ng/ml) in samples collected before coronary arteriography (253 +/- 25 minutes after onset of pain). After coronary arteriography, there was a slight decrease in the values of C4a (224 +/- 37 ng/ml), C5a (7.3 +/- 1.3 ng/ml) and C3a (164 +/- 35 ng/ml). The remaining six patients had complete coronary occlusion and received rt-PA (80 to 150 mg intravenously). In this treated group, before coronary arteriography the values of C4a (406 +/- 51.6 ng/ml) and C5a (8.1 +/- 1.9 ng/ml) were normal, and those of C3a were slightly elevated (250 +/- 76 ng/ml). All complement values obtained before rt-PA were similar to those in the untreated group. However, after administration of rt-PA (but before any angiographically detectable reperfusion), there was a striking increase in C4a (2,265 +/- 480 ng/ml; p less than 0.01), C3a (600 +/- 89 ng/ml; p less than 0.05) and C5a (30.0 +/- 4.5 ng/ml; p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗
PubMed1991

Immunoblotting human C4 bound to human erythrocytes in vivo and in vitro.

A study of C4 bound to human erythrocytes in vitro and in vivo has been made by immunoblotting with mouse monoclonal anti-C4c and anti-C4d and human polyclonal anti-C4d (Rodgers and Chido) following SDS-PAGE. Multi-banded patterns differentiated between C4A and C4B isotypes. Treatment of EC4b with trypsin eliminated immunoblotting but not agglutination reactions. Serum inactivation (factor I) of EC4b resulted in banding patterns similar to those obtained from patients' EC4d. Treatment of EC4b membranes with NH2OH affected many of the bands, two were lost, one was markedly reduced and others had altered SDS-PAGE mobility. Interpretation of the bands has been made in terms of C4-acceptor complexes and inactivation fragments of C4. A distinct difference in the banding of C4A and C4B isotypes has been detected.

Ammonium Hydroxide↗
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↗
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↗
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↗
PubMed1991

Monoclonal antipeptide antibodies against amino acid residues 1101-1106 of human C4 distinguish C4A from C4B.

Comparison of amino acid sequences of the alpha-chain fragment of human C4, C4d, has shown C4A- and C4B-specific sequences at residues 1101-1106 in which the aspartic acid-histidine substitution at position 1106 may be related to the amide and ester bond forming properties of these molecules. Peptides containing twelve amino acid residues of the C4A- or C4B-specific sequences were synthesized and injected into female Balb/c mice. Serum from 2 mice, one immunized with the C4A-specific peptide and the other with the C4B-specific peptide, gave strong isotype-specific responses in an enzyme-linked immunosorbent assay against affinity-purified C4A3 and C4B2B1. Spleen cells from these mice were fused with the mouse myeloma SP2/0-Ag 14, and two cloned cell lines, AII-1 and BII-1, were established from hybrids. Enzyme-linked immunosorbent assay and western blotting of monoclonal antibodies AII-1 and BII-1 show that the former reacts with the C4A but not with the C4B alpha-chain and the latter with C4B but not with the C4A alpha-chain. Furthermore, immunoblotting of C4 allelic variants showed that AII-1 reacted with all C4A allotypes tested, including A6, A4, A3 and A2, whereas BII-1 reacted with all C4B allotypes tested, including B5, B3, B2, and B1.

Amino Acid Sequence↗
PubMed1986

Demonstration of anaphylatoxins C3a, C4a and C5a in the scales of psoriasis and inflammatory pustular dermatoses.

Complement components C3a, C4a and C5a were assayed in corneal scale extracts from psoriasis and other dermatoses characterized by sterile subcorneal pustules, using radioimmunoassay. Larger amounts were detected in psoriasis and related pustular dermatoses than in extracts of non-inflammatory stratum corneum. It is concluded that complement is activated via the classical pathway and releases the neutrophil chemotactic fragment C5a.

Anaphylatoxins↗