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PubMed1986

Cold urticaria associated with C4 deficiency and elevated IgM.

Various immunologic abnormalities have been implicated in cold urticaria. This is the first report of cold urticaria associated with C4 deficiency and elevated IgM. A 12-year-old male developed urticaria upon exposure to cold. He denied fever, purpura, hemoglobinuria, Raynaud's disease, or arthralgias. Family history was negative for cold urticaria. Immunologic studies revealed elevated IgM (186 mg/dL) as well as decreased CH100 and C4 (8.0 mg/dL). C1, C2, and C3 were normal. Ice cube skin test was positive, but passive transfer tests were negative. Biopsy was not diagnostic for vasculitis, although it revealed a few immunofluorescent deposits of IgM and C4. Complement genetic studies revealed deficiency of two half-null C4 haplotypes expressed as C4A*3QO and B*2QO.

Child↗

PubMed1985

Complement profile in a C1 inhibitor deficient family.

Complement components and anaphylatoxins in a C1 inhibitor (C1INH) deficient family were studied. C4a was increased when C1INH was decreased, and C3a was increased in subjects with systemic lupus erythematosus (SLE)-like symptoms and with angioedema attacks. Danazol was effective in controlling the clinical as well as complement abnormalities including low CH50, C1INH and C4, which increased within 10 days after danazol treatment was started. Two-dimensional immunoelectrophoresis of C1INH showed that there was no functionally or electrophoretically abnormal C1INH present before or after danazol treatment. C3a and C4a were considered to play important roles in the pathogenesis of angioedema and associated SLE-like symptoms.

Anaphylatoxins↗

PubMed1988

Characterization of frequent deletions causing steroid 21-hydroxylase deficiency.

Steroid 21-hydroxylase deficiency is caused by mutations in the CYP21B gene. This gene and a highly homologous pseudogene, CYP21A, alternate with the C4A and C4B genes encoding the fourth component of complement. Classical deficiency alleles are frequently caused by deletions of CYP21B or by gene conversions that transfer deleterious mutations from the CYP21A pseudogene to CYP21B. Gene conversions involving restriction enzyme sites that distinguish CYP21A [e.g., 3.2-kilobase (kb) Taq I fragment] and CYP21B (3.7-kb Taq I fragment) might be confused with actual deletions of CYP21B. To determine the incidence of this type of gene conversion, 15 chromosomes (in 13 families) with absent 3.7-kb Taq I fragments were studied. When hybridized with a 21-hydroxylase probe, all of these chromosomes were associated with absent 2.9-kb Kpn I fragments, 14 of 15 were associated with absent 2.4-kb Bgl II/EcoRI fragments, and 13 of 15 were associated with absent 10-kb Bgl II/EcoRI and 12-kb EcoRI fragments. Thirteen of 15 chromsomes had absent 6.0- or 5.4-kb Taq I fragments when hybridized with a C4 probe. Thus, 2 of 15 chromosomes do not carry deletions and may represent gene conversions; 13 of 15 chromosomes studied have a deletion of approximately equal to 30 kb, leaving behind the C4A gene and a single CYP21A-like gene. Hybridization with specific oligonucleotide probes showed that in all 13 cases this remaining CYP21 gene carried an 8-base-pair deletion, typical of CYP21A, that prevents synthesis of a functional protein. Thus, gene conversions are rarely confused with deletions as a cause of 21-hydroxylase deficiency.

Adrenal Hyperplasia, Congenital↗

PubMed1999

Sex-limited protein: in vitro and in vivo functions.

Mouse complement component C4 exists in two isoforms, C4 and a protein with expression restricted to male animals called sex-limited protein (Slp). Although Slp is about 95% homologous to C4, it is generally believed to be non-functional, at least in conventional haemolytic complement assays. In a previous study, however, we showed that Slp is haemolytically active in a C1-inhibitor (C1INH)-regulated, EDTA-resistant mouse complement activation pathway. To study other possible implications of this finding, we generated constitutively expressing Slp-transgenic mice. The transgene was crossed into otherwise Slp-deficient C57Bl/6J and NZB mice. Members of the third backcross generation of C57Bl/6J mice were tested for functional Slp and classical and alternative complement pathway activities (CH50 and AP50 levels, respectively). Slp-transgenic C57Bl/6J mice showed enhanced CH50, but normal AP50 levels when compared with non-transgenic littermates. To discover a possible protective role for Slp in spontaneous systemic lupus erythematosus (SLE) in NZBxNZW (NZBxW) mice, the third backcross generation of Slp-transgenic NZB mice was mated with NZW mice and the development of SLE in the female offspring was followed. In these introductory experiments, Slp-transgenic NZBxW animals presented with a significantly extended life span. Our results imply that Slp is a mouse complement component with functions which partially resemble some of those of human C4A.

Animals↗

PubMed1989

Association of homozygous C4B deficiency with bacterial meningitis.

The fourth component of complement (C4) is encoded by two separate but linked loci (C4A and C4B), each of which produces functionally active C4. Although C4A and C4B share certain antigenic and functional characteristics that identify them as C4, they differ with respect to other structural and functional properties. For example, C4B possesses four times the functional hemolytic activity of C4A. This suggests that homozygous deficiency of C4B might be associated with an increased susceptibility to infection. Forty-six children with bacterial meningitis were examined. Of these, 5 (10.9%) were homozygous deficient for C4B versus 7 (3.1%) of 223 controls (P = 0.038). There was no relation between the prevalence of heterozygous C4B deficiency and meningitis or between the prevalence of either homozygous or heterozygous C4A deficiency and meningitis. These results suggest that homozygous C4B deficiency is a relatively common immunodeficiency disorder that is clinically significant and predisposes children to bacterial meningitis.

Adolescent↗

PubMed1994

Hemolytically inactive C4B complement allotype caused by a proline to leucine mutation in the C5-binding site.

The fourth component of complement (C4) is encoded by two highly homologous genes, C4A and C4B. Only one hemolytically inactive C4A allotype (C4A6) has been reported. No hemolytically inactive C4B allotype has been described. We report the first hemolytically inactive (hi) allotype of C4B, C4B*1 (hi). This unique variant was first recognized by hemolytic overlay assays and confirmed to segregate in the affected pedigree with the major histocompatibility complex haplotype A28,B35,CW4,DR6, C4A3,C4B1(hi), BFF,C2C. By single strand conformational polymorphism, we detected only a migration variant in exon 12 caused by a C to T transition in the second base of codon 459. This mutation results in a leucine substitution for proline (P459L) 1 residue downstream of a residue known to contribute to the C5-binding site. Allele-specific oligonucleotide analysis of samples demonstrated cosegregation of the mutation with the hemolytically inactive allotype in the affected pedigree. Site-directed mutagenesis and expression studies showed that the P459L mutation causes loss of hemolytic function. C4B*1(hi) is the first example of a circulating C4B protein lacking detectable hemolytic activity and the P459L mutation expands our knowledge of the C5-binding site of C4.

Base Sequence↗

PubMed1981

The location of C2, C4, and BF relative to HLA-B and HLA-D.

The loci for HLA-A,B,C,D, and DR are known to be closely linked to the structural loci for the complement components C2, BF, and the duplicated loci for C4, C4A and C4B. Conflicting evidence has been presented for the order of these genes. However, new techniques have made possible identification of markers in the HLA-D and C4 region for nearly all identified haplotypes. In our population we have confirmed five HLA-B-D crossovers and in each case informative allotypes of C2, BF, or C4A and C4B segregated with HLA-D or DR suggesting that the loci for these proteins lie close to HLA-D and DR. These findings may be of importance for resolving problems encountered in the assignment of HLA-D alleles.

Complement C2↗

PubMed1990

[The histologic study of the inner ear in guinea pigs on anaphylatoxin].

Complement is known to relate to many inflammatory reactions. C4a, C3a and C5a, known as anaphylatoxins, are known to cause strong inflammatory reactions. In this study, the role of anaphylatoxins on the pathogenesis in the cochlea was examined. On hundred forty six male Harley guinea pigs, weighing about 350 grs, all susceptible to preyer's reflex, were used in this study. Anaphylatoxins were made from guinea pig serum treated with zymosan, and inoculated into the carotid artery of the guinea pigs. Parts of these animals were sacrificed and examined at ten minutes, one day, two days, three days, seven days, ten days and fifteen days after injection of anaphylatoxins. Pathological changes in inner ears were observed by light microscopy. After 10 minutes, inner ears were found morphologically normal. After one day, inner ears were found to be almost morphologically normal but the stria vascularis was observed with cystic formation. After two days, cystic formations in the stria vascularis were enlarged and Reissner's membranes were collapsed in some other animals. After three days, the stria vascularis in the various cochlear turns except in the basal turn, were extremely atrophied, some cochlear nerves showed degeneration and some cochlea showed endolymphatic hydrops. After seven days, ten days and fifteen days, the morphological changes showed atrophy in the stria vascularis similar to the results observed on the third days. Atrophy in the stria vascularis was improved gradually with time, but the degeneration of the cochlear nerve was not improved. Opinions have been divided on the cause of inner ear disease including Meniere's disease. Many authors have reported that infectious diseases, for example mumps, measles and cytomegalovirus infection, have caused human sensorineural hearing loss. These diseases have been reported to result in atrophy in the stria vascularis, degeneration of the cochlear nerve and some other pathological changes. In this study, it was clearly observed that the atrophy of the stria vascularis, the endolymphatic hydrops and other morphological changes were caused by introduction of anaphylatoxins. These results were similar to the pathological changes observed in inner ear diseases in human beings. Therefore, inflammatory substances, including anaphylatoxins, were closely related to the cause of inner ear diseases. The animal model used in this report is considered to be important for elucidating the pathogenesis of inner ear diseases.

Anaphylatoxins↗

PubMed2002

Deficiency of complement-dependent prevention of immune precipitation in systemic sclerosis.

BACKGROUND: Previous studies have indicated that complement may be activated or inherently abnormal in systemic sclerosis (SSc), and it has been suggested that immune complex deposition plays a part in the microvascular damage of this disease. OBJECTIVE: To study several aspects of the complement system in 24 patients with SSc. METHODS: Complement dependent prevention of immune precipitation (PIP) was measured by a sensitive enzyme immunoassay, levels of C1q, C4, and C3 by rocket immunoelectrophoresis, C4 allotypes by high voltage agarose electrophoresis, and C4A, C4B, and C3d by an enzyme linked immunosorbent assay (ELISA). RESULTS: PIP was markedly decreased in the patients with SSc (p<0.001). Abnormal complement activation was detected in nine patients as raised levels of the complement split product C3d. However, a relation between low PIP and complement activation was not seen. PIP was significantly lower in patients who carried the C4A*Q0 allotype (p=0.03), and a strong correlation was found between PIP and C4A concentration (p<0.00001). The PIP defect may, at least in some patients, be associated with the initial phase of the disease. CONCLUSIONS: The results show a previously unrecognised functional defect of complement in SSc; the defect correlates with low levels of classical pathway components and, in particular, C4A.

Adolescent↗

PubMed1994

A new PCR-based typing of the Rodgers and Chido antigenic determinants of the fourth component of human complement.

The Rodgers (Rg) and Chido (Ch) blood groups are antigenic determinants of the fourth component of human complement C4. They are associated with the two isotypes of C4, C4A and C4B, respectively. They serve as markers to distinguish C4A from C4B as well as for the definition of subtypes of common and rare allotypes. As an alternative to the serological typing method using human alloantisera, a PCR typing procedure with sequence-specific primers (PCR-SSP) was designed. The method was tested on selected DNA samples from individuals with well-defined C4 allotypes. No false-positive or false-negative typing results were obtained and all the determinant combinations could be distinguished. The PCR genotyping allowed the detection of all Rg/Ch sequence determinants of each isotype. Thus, reverse antigenicity could also be established in the presence of other C4 allotypes without a segregation study. To exclude the possibility that PCR-typed determinants originate from a non-expressed C4 null gene, a sequence-specific PCR was established detecting a 2-bp insertion in exon 29 described previously as a cause for C4A non-expression. PCR Rg/Ch genotyping provides a fast and efficient method for routine typing in HLA haplotype and disease association studies.

Alleles↗

PubMed1995

Complement analysis in adult patients with a history of bacteremic pneumococcal infections or recurrent pneumonia.

Complement deficiencies are known to be associated with increased susceptibility to bacterial infections. In the present study we investigated 80 patients with either a history of pneumococcal bacteremic infection, or recurrent pneumonia, or both. Hemolytic screening tests for complement deficiency were performed and serum concentrations of C1q, C1s, C2, C3, C4, C4 isotypes, factor B, factor D, and properdin were determined. Complete deficiencies of single complement proteins were not found. 10 patients (12%) had a C4 isotype deficiency, but the frequency of homozygous C4A and C4B deficiency was not significantly increased. Seven patients (9%) had hypocomplementemia with low concentrations of at least 2 complement proteins. One of these patients had profound depletion of classical pathway components and findings suggesting acquired C1 esterase inhibitor deficiency. 16 patients (20%) had minor complement aberrations. A majority of the patients with hypocomplementemia suffered from other conditions associated with pneumococcal infections. However, impaired complement function could be a significant predisposing factor in some patients with invasive pneumococcal infections or recurrent pneumonia.

Acute Disease↗

PubMed1996

Complement-dependent binding of C-reactive protein complexes to human erythrocyte CR1.

C-reactive protein (CRP) is an acute phase serum protein that binds to phosphocholine (PC) on phospholipids and polysaccharides and to protein components of chromatin and small nuclear ribonucleoproteins. Complexes between CRP and ligands activate complement and bind to receptors on phagocytic cells. Although complement is required for CRP-mediated clearance or phagocytosis of ligand-coated erythrocytes, the participation of complement and complement receptors in clearance of soluble CRP complexes has not been examined. We have used PC-conjugated BSA to prepare complexes containing either IgG antibody or CRP. We found similar complement-mediated binding of both types of complexes to human erythrocyte complement receptors (CR1, CD35). We also found that serum deficient in C4A or C4B supported binding of CRP and IgG complexes to erythrocytes. These findings indicate that complexes between CRP and soluble ligands may be cleared by the erythrocyte CR1 pathway described for soluble immune complexes.

Antigen-Antibody Complex↗

PubMed1995

DNase I hypersensitivity mapping and promoter polymorphism analysis of human C4.

Human complement component C4 is encoded by two structurally distinct loci in the major histocompatibility complex (MHC) class III region. The two isotypes, C4A and C4B, differ at only four residues in the C4d fragment, but C4 constitutes the most polymorphic of the complement components. It is not known, however, whether the regions involved in the regulation of C4 expression also display polymorphic variation. By using the technique of DNase I hypersensitivity mapping, we established that the only area of transcriptional activity for C4 in the hepatocyte cell line, HepG2, occurs approximately 500 base pairs upstream of the transcriptional start site. This region was found to be remarkably constant in sequence when analyzed in the context of differing MHC haplotypes including HLA B57, C4A6, C4B1, DR7, which has been correlated with reduced expression of the C4A isotype. Similarly, polymerase chain reaction followed by single-strand conformation polymorphism analysis failed to demonstrate any promoter polymorphisms in 103 individuals comprising 52 systemic lupus erythematosus patients and 51 healthy controls.

Base Sequence↗

PubMed1991

Ex vivo removal of IgE in atopic asthma by extracorporeal plasmoimmunoadsorption (EPIA): development of a clinical adsorbent.

We have developed an immunoadsorbent (IA) for ex vivo removal of IgE after in vitro screening of matrix (Sepharose and tresyl-activated Toyopearl) and ligand (monospecific rabbit polyclonal anti-IgE antiserum and monoclonal antibodies (Abs) or their Fab fragments). Specific adsorptive capacity (SAC) for IgE was maximal in Sepharose-based IA with both types of Abs. Fab-containing IA on Sepharose retained 70-90% of the SAC of native Ab-containing IA. Toyopearl-based IA showed comparable SAC under static conditions but worked unsatisfactorily under continuous flow conditions. To assess the complement-activating capacity (CAC) of IA in vitro anaphylatoxin (C3a, C4a, C5a) generation was applied. CAC was directly related with the amount of immobilized Ab ligand, without depending on Ab specific activity. Fab-containing IA showed more CAC than native Ab-containing IA, and polyclonal IA more than monoclonal IA. Therefore, IA for IgE apheresis were prepared from native monoclonal Abs and CNBr-activated Sepharose CL 4B under aseptic conditions and packed into a glass column. This IA was used in 17 clinical IgE apheresis treatments of five atopic asthma patients. No substantial side effects were observed; in vivo IA effectively removed IgE from plasma (83 to 98%).

Adult↗

PubMed1986

Complotypes, extended haplotypes, male segregation distortion, and disease markers.

From our studies in Caucasian families of HLA, complement, and glyoxalase alleles have developed the concepts of the complotype and the extended haplotype. complotypes are clusters of the four genes for complement proteins encoded within the MHC designated (in arbitrary order) by their BF, C2, C4A, and C4B alleles. They are inherited in families and occur in populations as functionally single genetic units and exhibit linkage disequilibrium with HLA-B and HLA-DR alleles which are complotype, rather than complement gene allele, specific. In Caucasians, there are 10-12 common sets of HLA-B, DR, complotype sets that show significant linkage disequilibrium. These haplotypes constitute 25-30% of all MHC haplotypes in Caucasians. Because there is evidence for relative fixity of alleles on these chromosomes to an unknown extent beyond the HLA-B-DR interval, they have been called extended MHC haplotypes. It appears likely that it is these extended haplotypes that provide most of the known linkage disequilibrium pairs previously reported for MHC alleles as well as many of the known MHC allele-disease associations. The most common extended haplotype [HLA-B8, DR3, SC01], when it carries GLO2, is increased in type I diabetes mellitus and probably a number of other diseases, including gluten-sensitive enteropathy and membranoproliferative glomerulonephritis. In the families with these disorders studied by us, this haplotype exhibits male segregation distortion, a feature displayed by t-mutants found in wild mouse populations. This feature constitutes an important selective advantage for the chromosome and may contribute to the accumulation of susceptibility mutations for a variety of diseases.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1987

Association of HLA-Bw65 with two major complotypes.

The association between the HLA-B14 subtypes Bw64 and Bw65 and complement allotypes (C2, Bf and C4) was investigated in both population and family studies. Bf, C4A and C4B allotyping was performed on 37 Bw64 and 35 Bw65 positive unrelated Welsh/English subjects. Sixteen HLA-Bw65 bearing haplotypes were characterized for HLA-ABC, DR and DQ antigens and complement allotypes, including C2. The findings of the population study suggested that the complement haplotype associated with Bw64 is BfS, C4A2, C4B2. The population and family studies revealed two major complement haplotypes associated with HLA-Bw65: (i) C2C, BfF, C4A3, C4A1 - often associated with HLA-A3, Cw8 and DRw13, and (ii) C2C, BfS, C4A2, C4B2 - often associated with HLA-Aw33, Cw8 and DR1 or with A28, Cw8 and DRw13. The HLA-Bw65 bearing haplotypes of three families carried a C4B2B1 duplication of the C4B locus. In these families three C4B gene products were identified in the Bw65 positive members using an anti-C4B monoclonal antibody. It is suggested that most, if not all, HLA-Bw65 bearing haplotypes may possess a C4B locus duplication.

Antibodies, Monoclonal↗

PubMed2002

Development of a novel cytomedical treatment that can protect entrapped cells from host humoral immunity.

Cell therapy is expected to relieve the shortage of donors needed for organ transplantation. When patients are treated with allogeneic or xenogeneic cells, it is necessary to develop a means by which to isolate administered cells from an immune attack by the host. We have developed "cytomedicine," which consists of functional cells entrapped in semipermeable polymer, and previously reported that alginate-poly-L-lysine-alginate microcapsules and agarose microbeads could protect the entrapped cells from injury by cellular immunity. However, their ability to isolate from humoral immunity was insufficient. It is well known that the complement system plays an essential role in rejection of transplanted cells by host humoral immunity. Therefore, the goal of the present study was to develop a novel cytomedical device containing a polymer capable of inactivating complement. In the screening of various polymers, polyvinyl sulfate (PVS) exhibited high anticomplement activity and low cytotoxicity. Murine pancreatic beta-cell line (MIN6 cell) entrapped in agarose microbeads containing PVS maintained viability and physiological insulin secretion, replying in response to glucose concentration, and resisted rabbit antisera in vitro. PVS inhibited hemolysis of sensitized sheep erythrocytes (EAs) and rabbit erythrocytes by the complement system. This result suggests that PVS inhibits both the classical and alternative complement pathways of the complement system. Next, the manner in which PVS exerts its effects on complement components was examined. PVS was found to inhibit generation of C4a and Ba generation in activation of the classical and alternative pathways, respectively. Moreover, when the EAC1 cells, which were carrying C1 on the EAs, treated with PVS were exposed to C1-deficient serum, hemolysis decreased in a PVS dose-dependent manner. These results suggest that PVS inhibits C1 in the classical pathway and C3 convertase formation in the alternative pathway. Therefore, PVS may be a useful polymer for developing an anticomplement device for cytomedical therapy.

Alginates↗

PubMed1989

Drug-induced immune-complex disease.

A range of drugs including hydralazine, isoniazid, procainamide and penicillamine cause toxic side effects which resemble systemic lupus erythematosus (SLE). Deficiencies of C1, C4 and C2 are associated with idiopathic SLE, and these defects may compromise the ability of the patient to deal with immune complexes. Immune complexes with protein as antigen, such as has been reported to be diagnostic of procainamide-induced SLE, interact more with the C4A isotype of C4 than the C4B isotype. It is shown that hydralazine, isoniazid and penicillamine inhibit the covalent binding of C4 to a complement-activating surface and that the drugs themselves become covalently bound to C4. For each of these drugs, C4A is inhibited more than C4B, and it is suggested that this is an important contributory factor in the development of the toxic side effects to these drugs involving immune-complex deposition. For procainamide, it is shown that the hydroxylamine metabolite rather than the drug itself inhibits the covalent binding reaction of C4. Hydralazine, isoniazid and procainamide are metabolised by the polymorphic N-acetyltransferase, and slow acetylators are at increased risk of drug-induced lupus. For procainamide, oxidation to the hydroxylamine form is an alternative metabolic route of increased importance in slow acetylators, and it is suggested that investigation of C4 type in susceptible patients could provide a means of identifying those at greatest risk of immunotoxicity.

Humans↗