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PubMed1987

A chicken sex-limited protein that crossreacts with the fourth component of complement.

Plasma samples from more than 300 inbred chickens were screened by using an immunofixation technique with antibody against the fourth component of complement (C4) from humans. Precipitation patterns of plasma from adult male and sexually immature birds, either male or female, were identical. Plasma from egg-laying hens demonstrated a distinctly different precipitation pattern compared with plasma of other birds, with one additional band appearing 14 to 9 days before production of the first egg. The banding pattern could not be induced in males by progesterone injection and remained unchanged in molted female birds.

Animals↗

PubMed2003

Polymerase chain reaction based C4AQ0 and C4BQ0 genotyping: association with systemic lupus erythematosus in southwest Han Chinese.

OBJECTIVE: To investigate the association of complement C4 null genes (C4Q0, including C4AQ0 and C4BQ0) and C2 gene with systemic lupus erythematosus (SLE) in southwest Han Chinese; 136 patients with SLE and 174 matched controls were genotyped. METHODS: C4 null genes were determined by a polymerase chain reaction (PCR) procedure with sequence specific primers (PCR-SSP). The 2 bp insertion in exon 29, which was previously identified in non-Chinese populations and caused defective C4A genes, was directly typed by sequencing the whole exon 29 using exon specific primers. The exon 6 of complement C2 was also sequenced in both the patients and controls. RESULTS: The frequency of homozygous C4AQ0 allele was 12.5% (17/136) in patients with SLE compared with 1.1% (2/174) in controls (p<0.001, odds ratio (OR)=12.286, 95% confidence interval (95% CI) 2.786 to 54.170). There was no significant difference for homozygous C4BQ0 allele between patients with SLE and controls (p=0.699). Patients with the C4AQ0 gene had an increased risk of acquiring renal disorder, serositis, and anti-dsDNA antibodies compared with those without C4AQ0 (for renal disorder, p=0.018, OR=8.951, 95% CI 1.132 to 70.804; for serositis, p=0.011, OR 4.891, 95% CI 1.574 to 15.198; for anti-dsDNA, p=0.004, OR 7.630, 95%CI 1.636 to 35.584). None of the patients or controls had the 2 bp insertion in exon 29 of the C4 gene. The type I C2 deficiency was not detected in the 310 samples. CONCLUSION: It is suggested that deficiency of C4A (not due to a 2 bp insertion in exon 29), but not C4B or C2, may be a risk factor for acquiring SLE in south west Han Chinese; this results in increased risk of renal disorder, serositis, and anti-dsDNA antibodies in patients with SLE. Racial differences seem to be relevant in susceptibility to SLE

Adolescent↗

PubMed1997

Molecular characterization of complement components (C3, C4, and factor B) in human saliva.

A molecular analysis of complement components (C3, C4, and factor B) in human saliva was performed by SDS-PAGE and immunoblotting. Complement C3 was detected as a molecule composed of a 115-kDa alpha-chain linked to a 70-kDa beta chain by disulfide bonds, and C3 levels ranged from 0.52 to 15.0 micrograms/ml (n = 15). C4 was detected as a triple-chain molecule (98-kDa alpha chain, 73-kDa beta chain, and 33-kDa gamma chain) linked by disulfide bonds, and C4 levels ranged from 0.086 to 4.8 micrograms/ml. Factor B was detected as a 100-kDa single chain, and factor B levels ranged from 0.042 to 0.62/microgram/ml. The sizes and subunit structures of the complement components in human saliva were compatible with those reported in human serum. The results of a hemolytic assay indicated that the complement molecules in human saliva were functionally active. These complement components may participate in the local immune and inflammatory responses in the oral cavity.

Complement C3↗

PubMed1990

A comparison between erythrocyte sedimentation rate (ESR) and selected acute-phase proteins in the elderly.

The erythrocyte sedimentation rate (ESR) and selected acute-phase proteins (APPs) were studied in 101 elderly people (mean age, 72 years) to determine their utility as diagnostic aids in subjects with underlying infections or inflammation. ESR and values for serum immunoglobulin A (IgA), the fourth component of complement (C4), haptoglobin, and alpha-1-antitrypsin (AAT) all correlated with infection or inflammation. C4 was the only test predictive of mortality at six months. Neither ESR nor any of the APPs demonstrated concomitantly high sensitivity, specificity, and positive predictive values. Receiver-operating characteristic curve analysis revealed low true positive to false positive ratios for all of the tests studied. In the elderly, measurement of APPs as a guide to underlying infection or inflammation has limited utility and offers no advantage over the traditional low-cost ESR.

Acute-Phase Proteins↗

PubMed1987

The role of lymphoid cells in antibody-induced suppression of the fourth component of guinea pig complement.

Many laboratories have demonstrated that immunoglobulin production by B cells is controlled by networks of interacting lymphocytes and their products. Our laboratory has demonstrated that complement components produced by macrophages are also regulated by networks of interacting cells and humoral factors. Treatment of mice in vivo or guinea pig cells in vitro with anticomponent antibody specifically inhibits synthesis and secretion of the component by macrophages. We have further characterized the cellular basis for in vitro suppression of the fourth component of guinea pig complement. C4 suppression has been accomplished with dispersed spleen cells as well as intact splenic fragments. This facilitated examination of the cells responsible for long-term C4 suppression. The data suggested that C4 suppression required either cell contact or sufficient concentrations of soluble factors. Long-term suppression of C4 depends upon a lymphoid cell contained in the spleen and in lymph nodes but absent or in insufficient concentration in the peritoneum. The lymphocyte that actively maintains suppression was negative for the guinea pig T-cell marker detected by the monoclonal antibody mc8BE6. Therefore, the critical cell is either another T-cell subset or non-T lymphocyte. These data demonstrate that a network of interacting cells analogous to that proposed to regulate antibody synthesis is also involved in regulating some nonlymphoid cell products.

Animals↗

PubMed2000

Polymorphism of the fourth component of complement in Turks.

An analysis of polymorphism in the fourth component of human complement (C4) was performed on EDTA-plasma from 142 unrelated, randomly selected Turks without collagen-vascular disease or recurrent infections. Plasma samples treated with neuraminidase and carboxypeptidase-B were subjected to high-voltage agarose gel electrophoresis followed by immunofixation. C4B allotypes were further detected in some samples by Western blots with monoclonal antibody 1228 (anti-C4B/Ch1 reactivity). The frequencies of C4A and C4B alleles were determined. Allele C4B*5, which has been found to be relatively common in Asian (Oriental) populations, was not detected in this study. No specific predilection could be noted among the rare variants. C4A*3-C4B*1 was the most common haplotype (n = 40/142, or 28%) but was found less frequently than in Caucasian populations. This finding may be the result of the limited number of samples examined. C4A and/or C4B null allotypes were seen in 49 of 142 (34.6%) subjects. The most frequent C4 null allotype seen was C4B null (37/142, or 26%): 28 subjects had one C4B null allele; 1 had a homozygous deficiency of C4B (C4B*QO, *QO) and 7 had C4A*QO C4B*QO, a double heterozygous haplotype. Frequencies of homozygous haplotype C4A*Q0-C4B*Q0 in the population studied were found to be 0.007. The results of this study demonstrate that the genetic composition of the Turkish population exhibits both similarities and differences with the European population, and ranges between Caucasian and Mongoloid (Asian) populations.

Alleles↗

PubMed1988

Heterogeneity in the gene locus for steroid 21-hydroxylase deficiency.

DNA was analysed from 33 patients with congenital adrenal hyperplasia due to steroid 21-hydroxylase deficiency. In each case Southern blots were prepared from a number of restriction enzyme digests and hybridised with probes for both the 21-hydroxylase and the adjacent fourth component of complement (C4). Evidence for deletion of the active 21-hydroxylase gene (CYP21B) was found in 13 cases and in 10 of these the deletion included the adjacent C4B gene, leading to a hybrid CYP21A/CYP21B gene. Deletion of CYP21B alone was found in one patient, the remaining two cases appearing to have the active gene replaced by the inactive pseudogene. Duplications of the CYP21A-C4B region and deletion of the pseudogene are also described. In a further 12 cases no gross abnormality could be found.

Adrenal Hyperplasia, Congenital↗

PubMed1981

Technical and theoretical considerations in the HLA typing of amniotic fluid cells for prenatal diagnosis and paternity testing.

HLA typing of amniotic fluid cells has been used for the prenatal diagnosis of the HLA linked diseases congenital adrenal hyperplasia (21-OH-deficiency (21-OH-def) type) and complement C4 deficiency and it has also been used for the prenatal determination of paternity. There are, however, technical difficulties in this test associated with the weak expression of some B locus antigens on amniotic fluid cells, and theoretical difficulties related to associations between particular HLA antigens and the 21-OH-def allele. Since certain HLA-B locus antigens are found in significantly increased frequencies among patients with 21-OH-def, there is a relatively high incidence of HLA-B homozygosity among the patients and over 40 per cent of the parents of these patients share one or more HLA-B locus antigens. Results of some prenatal HLA typing tests may thus be difficult to interpret, and supplementary tests should be used whenever possible. HLA typing of amniotic cells is, however, the only available procedure for prenatal diagnosis of C4 deficiency and it is the best available procedure for prenatal determination of paternity. A modification of our original procedure allows HLA typing to be performed with increased numbers of HLA typing sera, and sera with optimum reactivity for amniotic fluid cells have now been selected for the definition of most of the more commonly expressed HLA antigens. Although amniotic fluid cells do not express DR Antigens, amniotic fluid cells can be typed for the HLA-linked marker glyoxalase I (GLO) and this may be the informative for prenatal diagnosis in some cases.

Adrenal Hyperplasia, Congenital↗

PubMed1988

An ancient provirus has imposed androgen regulation on the adjacent mouse sex-limited protein gene.

The mouse sex-limited protein (Slp) gene is dependent on androgen for expression, unlike its homologous neighbor, which encodes the fourth component of complement (C4). We have found that the extensive identity of Slp and C4 is disrupted by an endogenous provirus inserted 2 kb upstream of Slp. The 5' LTR of this element corresponds to the previously characterized hormone-responsive enhancer associated with Slp regulation, leading to the conclusion that the provirus has conferred androgen response on the adjacent Slp gene. The provirus is extremely old, based on LTR sequence divergence, the accumulation of mutations in former retroviral-like coding regions, and its stability within the mouse genome. The association of this transposable element with Slp regulation thus provides a long-sought example of an insertional mutation that has been maintained in evolution.

Androgens↗

PubMed1998

High prevalence of peripheral neuropathy in hepatitis C virus infected patients with symptomatic and asymptomatic cryoglobulinaemia.

BACKGROUND: Fifty per cent of patients with chronic hepatitis C, show detectable cryoglobulinaemia, even though most of them do not show cryoglobulinaemia related symptoms. Peripheral neuropathy is present in most of the patients with symptomatic cryoglobulinaemia, where it may be the first clinical manifestation. The prevalence of peripheral neuropathy in patients with hepatitis C and cryoglobulinaemia is unknown. AIMS: To assess the prevalence of peripheral neuropathy in HCV infected patients with symptomatic or asymptomatic detectable cryoglobulinaemia. PATIENTS AND METHODS: Eighty-nine patients with HCV infection and detectable cryoglobulinaemia underwent electrophysiological studies. RESULTS: Electrophysiological evidence of peripheral neuropathy was found in 37% and was significantly associated with: the presence of cryoglobulinaemia syndrome, older age, higher rheumatoid factor reactivity and immunoglobulin M levels and reduced complement C4 activity. However, electrophysiological evidence of peripheral neuropathy was unrelated to cryocrit levels and type of cryoglobulinaemia and was found in 23/68 patients without any symptoms of cryoglobulinaemia other than pain and paresthesia. CONCLUSIONS: These findings suggest that peripheral neuropathy is frequent in patients with hepatitis C and detectable cryoglobulins. Neuropathy was found to be present in 1/3 of patients without other cryoglobulinaemia-related symptoms, thus a direct or indirect role of HCV, independent of cryoglobulinaemia, in the pathogenesis of nerve damage cannot be ruled out.

Age Factors↗

PubMed1979

The immune complex pathogenesis of glomerulonephritis and pulmonary vasculitis in Behçet's disease.

A kidney and lung biopsy were performed on a patient with active Behçet's disease with renal and pulmonary involvement. Histologic, immunohistochemical and electron microscopic studies of the kidney biopsy specimen revealed a focal segmental necrotizing glomerulonephritis characterized by the presence of numerous subendothelial and occasional intramembranous deposits containing immunoglobulin G (IgG), the third component of complement (C3), the fourth component of complement (C4) and fibrin(ogen). Histologic and immunohistochemical studies of the lung biopsy specimen showed an acute venulitis and septal capillaritis associated with the presence of identical deposits within the walls of affected vessels. Circulating immune complexes were detected in the patient's serum by Raji cell assay. The findings indicate that the glomerulonephritis and pulmonary vasculitis occasionally occurring in Behçet's disease are due to the deposition of circulating antigen-antibody complexes. In addition, they strongly suggest that the majority of the major and minor manifestations of the disease, such as uveitis, cutaneous vasculitis, synovitis and meningoencephalitis, are a result of vascular immune complex deposition.

Behcet Syndrome↗

PubMed2000

Hereditary angioedema with normal C1-inhibitor activity in women.

BACKGROUND: Hereditary angioedema (HAE) is a well defined autosomal dominant disease (Mendelian Inheritance in Man #106100) that results from an inherited deficiency of C1 (the activated first component of complement) inhibitor function. We report an unusual variant of HAE with normal biochemical C1-inhibitor function, occurring only in women. METHODS: We screened 574 patients with recurrent angioedema of the skin for presence of HAE. 283 patients were selected, in whom angioedema was associated with abdominal pain attacks or recurrent life-threatening episodes of upper-airway obstruction, or both, rather than with urticaria. We measured C1-inhibitor concentration and functional activity as well as complement C4 concentration and took pedigrees to characterise patients. FINDINGS: 94 HAE cases with C1-inhibitor deficiency, positive family history, or both were identified. Biochemical testing showed that 84 patients from 49 families had a functional C1-inhibitor deficiency. 11 of these patients had no affected family members (probably representing de-novo mutations). Ten women with HAE, from ten families, had normal C1-inhibitor protein concentrations and function, and normal C4 concentration. A more detailed study of these families identified another 26 affected members, who were also all women. Of those women, 14 could be studied and also had normal C1-inhibitor concentration and function. The disease was seen in successive generations, and in offspring of affected mothers, the sex ratio (M/F) was shifted to 1/1.5. INTERPRETATION: HAE with normal C1-inhibitor concentration and function represents a unique genetic disease arising only in women. The formal genetics of this entity are suggestive of an X-linked dominant mode of inheritance. For this disorder we propose the term hereditary angioedema type 3 (HAE III).

Abdominal Pain↗

PubMed1980

Different HLA antigen associations for the functionally active and inactive products of the complement C4F1 allele.

The genetic polymorphism of the fourth component of human complement, C4, was studied in 945 unrelated Caucasian individuals. A third allele of the C4F (Rodgers) locus, termed C4F1 was demonstrated. This allele is characterized using immunofixation electrophoresis, by the presence of an additional fast-moving anodal band of C4 which distinguishes it clearly from the common C4F variant. The allelic frequencies fit the Hardy-Weinberg equilibrium assuming three alleles at the C4F locus: C4F, C4Fo, and C4F1. The functional activity of the C4F variants was investigated using a specific hemolytic overlay technique for C4. It was found that in almost all individuals (75 out of 78), the C4F1 allele codes for a functionally inactive C4 product only when it occurs on an HLA-B17 positive haplotype but that the same allele codes for a functionally active fast variant of C4 when it occurs on an HLS-B37 positive haplotype (18 out of 18). Very strong genetic linkage disequilibrium was observed for the C4F1 allele with HLA-B17 and B37. The active and inactive C4F1 variant also has marked nonrandom gametic association to different alleles of the Bf locus and to HLA-C locus determinants. No further variants of the C4S (Chido) locus have been identified so far. Rodgers (Rg) typing by the plasma inhibition test of anti-Rg antiserum has shown that plasma from individuals homozygous for the C4F1 allele is only able to partially inhibit anti-Rg whereas all C4F positive individuals totally inhibited the reaction.

Alleles↗

PubMed1984

[Plasmapheresis in extra-intestinal manifestations of Crohn's disease].

An assessment was undertaken of the value of plasmapheresis in patients with circulating immune complexes and/or extraintestinal manifestations of Crohn's disease (arthritis, iridocyclitis, erythema nodosum, pyoderma gangrenosum, stomatitis, fever). In 17 patients aged 20 to 50 years (median 34 years) 46 plasmaphereses were performed using a continuous flow-cell separator. Before and after plasmaphereses the concentrations of circulating immune complexes, of complement C4, of the immunoglobulins IgG and IgM and of the proteins alpha-1-antitrypsin, CRP, prealbumin and beta-lipoprotein were determined. 71% of patients given plasmaphereses showed clinical remission of the extraintestinal manifestations and 85% demonstrated a reduction of circulating immune complexes. Clinical follow-up of the patients was documented by the Crohn's Disease Activity Index (CDAI), which was reduced by plasmaphereses to a highly significant degree (p less than 0.005). For patients displaying an acute phase of Crohn's disease with extraintestinal manifestations and/or circulating immune complexes plasmapheresis represents an effective mode of therapy, which, moreover, lacks serious side effects.

Adult↗

PubMed1988

A complex androgen-responsive enhancer resides 2 kilobases upstream of the mouse Slp gene.

Neighboring genes encoding the mouse sex-limited protein (Slp) and fourth component of complement (C4) show extensive homology. In contrast to C4, however, Slp is regulated by androgen. One region of the Slp gene capable of hormonal response following transfection was located about 2 kilobases upstream of the transcription start site, where the C4 and Slp sequences diverge. This region, delimited here to a 0.75-kilobase fragment, showed cryptic promoter activity as well as androgen responsiveness in either orientation in front of the bacterial chloramphenicol acetyltransferase coding region. When this fragment was placed upstream of a viral long terminal repeat, increased chloramphenicol acetyltransferase expression derived from the viral promoter. Proteins from nuclear extracts specifically bound to four sequences within the region, near sites that are DNase I hypersensitive in vivo and reflect the hormonal and developmental regulation of Slp. Like several other cellular enhancers, this androgen-responsive element seems to be modular in nature and complex in its function.

Acetyltransferases↗

PubMed1991

Identification of complexes between the tyrosine-O-sulphate-binding protein and tyrosine-sulphated proteins in bovine liver membrane lysates.

Rabbit antiserum against electrophoretically purified bovine liver tyrosine-O-sulphate (TyrS)-binding protein was prepared. Affinity-purified antibodies from the antiserum were found to be capable of immunoprecipitating the TyrS-binding protein from the sodium choleate extract of a bovine liver microsomal membrane fraction. Using purified specific antibodies as the probe, Western blot analysis for the presence of TyrS-binding protein/tyrosine-sulphated protein complexes in bovine liver membrane lysates was performed. It was found that the TyrS-binding protein co-precipitated with three tyrosine-sulphated proteins (fibronectin, fibrinogen and complement C4) immunoprecipitated by their respective antibodies. In contrast, for the two non-tyrosine-sulphated proteins (haptoglobin and transferrin) tested, co-precipitation of the TyrS-binding protein was not observed. On employing an affinity gel fractionation technique, it was shown that partially purified TyrS-binding protein exhibited binding affinity towards Sepharose gels covalently bonded to fibronectin or fibrinogen, but not towards Sepharose gels bonded to albumin or transferrin. These results indicate that the TyrS-binding protein formed complexes with tyrosine-sulphated proteins both in vivo and in vitro, and thus provide support for the putative role of the former being the receptor of the latter.

Animals↗

PubMed2004

Inflammation, genetics, and ischemic heart disease: focus on the major histocompatibility complex (MHC) genes.

BACKGROUND: Increasing data suggest that ischemic heart disease (IHD) shares several characteristics with common inflammatory diseases (such as rheumatoid arthritis), in which the pathogenetic role of inflammatory gene polymorphisms is well established. Variants in the genes for the major histocompatibility complex (MHC) molecules on the short arm of chromosome 6 show profound "linkage disequilibrium", leading to the formation of "haplotypes", i.e., frozen blocks of alleles travelling together through generations. DESIGN: We performed a review of published studies linking IHD with gene polymorphisms of the MHC molecules tumor necrosis factor (TNF)-alpha and -beta, the class II DR human leukocyte antigens, heat shock protein 70-1, hemochromatosis related gene, and complement C4. RESULTS: The emerging data are quite conflicting and do not provide definitive evidence for a role of these gene variants in the pathogenesis of IHD; a possible exception is the G252A and polymorphism in the TNF-beta gene (also known as lymphotoxin-alpha) which, in a comprehensive genome-scan linkage analysis of unrelated Japanese, but not in a smaller German population, was linked to myocardial infarction. However, some important biases appear, e.g. different study design and variable linkage disequilibrium among different populations. CONCLUSIONS: Preliminary positive results should encourage future studies to focus on clinical models of IHD with well-codified inflammatory components, using novel methods (such as haplotype analysis) to assess gene polymorphisms and their clinical effect.

Alleles↗

PubMed1988

Immunomodulatory properties of cimetidine in ARC patients.

The immunomodulatory potency of cimetidine, a histamine H2 receptor antagonist, was investigated in 33 AIDS-related complex (ARC) patients performing detailed immunological and clinical evaluations. Cimetidine was administered orally in daily doses of 1200 mg for a period of 5 months with an interruption of therapy after the first 3 months for an interval of 3 weeks. Significant (P less than 0.05) elevations of immunoglobulins (IgG, IgA), complement C4, B-lymphocytes, and OKT4+ (helper/inducer) cells were found after cimetidine intake. The in vitro lymphocyte proliferative response to plant mitogens was significantly increased, and the in vivo cell-mediated hypersensitivity reaction assessed by intradermal application of seven recall antigens improved significantly. These effects were both reversible with the discontinuation of cimetidine and reproducible with repeated administration of the drug. Clinical data such as performance status, body weight, and fever were influenced favorably (P less than 0.05) by cimetidine. The frequency of diarrhea and the lymph node size were also diminished significantly. The data suggest that cimetidine may at least partially restore immunofunctions in AIDS-related complex.

AIDS-Related Complex↗