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PubMed1994

Free protein S deficiency in patients with Crohn's disease.

Multifocal intestinal infarctions, due to thrombosis in small vessels, might be a pathogenetic mechanism for Crohn's disease (CD). Deficiency of free protein S may contribute to the development of such thrombotic occlusions. In the present study free protein S was measured in 54 patients with CD. In 31 patients (57.4%) the plasma concentrations of free protein S were below the lower normal range. The mean value of free protein S in CD patients was 72.2%, as compared with 97.5% in healthy subjects (p < 0.01). The concentrations of C4b-binding protein and protein C were similar in the two groups. Free protein S levels were not correlated to disease activity, previous surgery or complications, extraintestinal manifestations, or current medical therapy. The impairment of the protein S/protein C/thrombomodulin system found in patients with CD favours coagulation and might be of importance for both the development of CD and its thromboembolic complications.

Adult↗
PubMed1980

Cleavage of C4b by C3b inactivator: production of a nicked form of C4b, C4b', as an intermediate cleavage product of C4b by C3b inactivator.

We have investigated the mechanism of cleavage of C4b into C4c and C4d by the C3b inactivator (C3bINA) and revealed the formation of a nicked form of C4b as an intermediate cleavage product. The cleavage of C4b by the C3bINA was a two-step reaction. The first cleavage occurred on the alpha-chain (89,000 daltons) yielding two fragments, 73,000 daltons and 16,000 daltons. These fragments were bound to each other or to the beta or gamma chain through disulfide linkages. Therefore, an altered form of C4b, C4b', consisting of four disulfide-linked polypeptide chains with the same m.w. as C4b, was produced as an intermediate cleavage product. Subsequently, the second cleavage occurred on the alpha-chain fragment of 73,000 daltons to produce the two generally recognized fragments, C4c and C4d. In both cleavage reactions, a high m.w. cofactor protein, C4bC3bINACo, which is the same protein described as the C4 binding protein, was required, suggesting that both of the proteolytic processes are catalyzed by the C3bINA.

Complement C3b Inactivator Proteins↗
PubMed1996

C4 and 21-hydroxylase gene deletions in nasopharyngeal carcinoma among the Chinese.

Deletions around the C4 and 21-hydroxylase (21-OH) gene region occur among the Chinese, and C4B together with 21-OHA deletion is the most common. This deletion was found to be strongly associated with human leucocyte antigen (HLA) B58 DRB1*0301, particularly with DRB1*0301. The initial observation of a high frequency of this deletion in nasopharyngeal carcinoma (NPC) was secondary to the B58 DR3 association with NPC. A deletion of 21-OHA alone was observed to be associated with HLA B13 DRB1*1501.

Asian People↗
PubMed1997

Genetic and phenotypic analysis of a large (122-member) protein S-deficient kindred provides an explanation for the familial coexistence of type I and type III plasma phenotypes.

Protein S deficiency is a known risk factor for thrombosis. The coexistence of phenotypic type I (reduction in total and free antigen) and type III (reduction in free antigen only) protein S deficiencies in 14 of 18 families was recently reported. We investigated the cause of this phenotypic variation in the largest of these families (122 family members, including 44 affected individuals) using both molecular genetic and phenotypic analysis. We have identified a sole causative mutation (Gly295Val) in three family members representative of the variable phenotype. Complete cosegregation of the mutation with reduced free protein S antigen levels was found, regardless of the total antigen level. Analysis of phenotypic data showed high correlations between total protein S antigen and age in both normal and protein S-deficient family members, irrespective of gender. Free protein S antigen levels were not influenced by age, a finding explained by an association between beta-chain containing C4b-binding protein (C4bBP-beta+) antigen levels and age. We propose that the identified Gly295Val mutation causes quantitative, or type I, protein S deficiency, and that as age increases the total protein S antigen level normalizes with respect to the reference plasma pool, giving rise to a type III protein S-deficient phenotype.

Adolescent↗
PubMed1992

Monoclonal antibody-based enzyme-linked immunosorbent assays (ELISA) for the measurement of vitamin K-dependent protein S: the effect of antibody immunoreactivity on plasma protein S antigen determinations.

Two monoclonal antibodies (Mabs) specifically directed to human protein S (PS) - named 5E9E9 and 3B10.25 - were produced and their properties compared to those of 2 previously characterized anti-PS-Mabs (HPS-2 and S10). 3B10.25, similar to S10, was directed to the calcium-free conformation of PS and had virtually identical affinity for free and C4b-binding protein (C4b-BP)-bound PS; 5E9E9 similar to HPS-2, had no calcium-dependency and was selectively directed to free PS. All Mabs were equally reactive to freshly purified and thrombin-cleaved PS. To evaluate the influence of C4b-BP bound PS on PS antigen determinations, ELISA systems employing the four Mabs individually as capture antibody (Ab) and peroxidase-conjugated polyclonal anti-PS IgG as detecting Ab were developed and compared to immunoelectrophoresis (EIA) and to an ELISA employing polyclonal anti-PS IgG as capture and detecting Ab, in the determination of PS in purified systems and in plasma. With all the ELISAs there was parallelism of dilution curves obtained with normal plasma and purified PS; however, supplementation of plasma with purified C4b-BP resulted in loss of parallelism when employing the Mabs directed to free PS as capture Ab. Influence of high C4b-BP on PS antigen determinations was confirmed in a series of plasma samples from patients with C4b-BP levels ranging from 70% to over 200%. Compared to the values obtained with the S10- or 3B10.25 - based ELISAs - which were similar despite a 10-fold difference in sample dilution - plasma PS was underestimated by the ELISAs employing 5E9E9 or HPS-2 while it was overestimated by EIA.(ABSTRACT TRUNCATED AT 250 WORDS)

Antibodies, Monoclonal↗
PubMed1991

CRRP: a guinea pig protein, identified by sequence homology to human CR1, which contains two short consensus repeat motifs and appears not to be transmembrane or secreted.

cDNA from the C4b-binding site of the human C3b/C4b receptor (CR1) was used to find homologous sequences in the guinea pig. This cDNA identified an 18S mRNA species in guinea pig spleen, but not liver. Probing of a guinea pig spleen cDNA library identified clones with identical 1.5-kb inserts, which also hybridized to mRNA in spleen, but not liver. Sequence analysis of the insert revealed a single long open-reading frame coding for a 20,000 Mr protein consisting of two short consensus repeat motifs homologous to human CR1, and unique sequence at the amino- and carboxy-terminals of the short consensus repeats. This sequence did not encode peptides with features of transmembrane domains or signal peptides. Antibody to this complement receptor-related protein-beta galactosidase fusion protein recognized a 20,000 Mr protein in SDS lysates of guinea pig spleen, lymph node, lymphocytes, neutrophils, and peritoneal macrophages. Immunoprecipitation of human serum by this antibody revealed an 180,000 Mr protein reacting both with the anti-guinea pig protein antibody and with anti-human CR1 antibody. Immunoprecipitation of guinea pig serum revealed no protein reacting with the anti-guinea pig protein antibody. Tissue staining of cultured peritoneal macrophages with this antibody showed intracellular staining, as opposed to membrane staining obtained with anti-guinea pig Ig antibody. The lack of membrane expression was confirmed by surface protein radiolabeling experiments and by fluorescent staining of surface proteins. Thus, we have identified a guinea pig protein with homology to human CR1, which may have an unusual property for this class of proteins in that it appears to be intracellular.

Amino Acid Sequence↗
PubMed1990

C3, BF and C4 polymorphisms in Tunisians.

The C3, BF, C4A and C4B polymorphisms were studied in a Tunisian population sample. The allelic frequencies for C3 were S = 0.844 and F = 0.148, and for BF, S = 0.535, F = 0.331, SO7 = 0.075 and F1 = 0.041. The most frequent C4 alleles were A3 and B1 followed in a decreasing order by A2, B2 and the A and B null alleles. The results indicate that the Tunisian population is intermediate between the Caucasian and Arab populations with some trace admixture of African Blacks.

Complement C3↗
PubMed1976

Observations on the antiglobulin tests. II. C4 components on erythrocytes.

This paper describes anti-C4b(ii) antisera shich agglutinate cells from cases of autoimmune haemolytic anaemia, cold-acquired haemolytic anaemia, and certain test cells, using the antiglobulin test. It is suggested that these particular antisera possess activity against C4d absorbed on to erythrocytes. Methods of preparing test cells coated with C3d and C4d are given, together with methods for producing antisera in rabbits active against these components. The significance of these findings is discussed.

Anemia, Hemolytic↗
PubMed2004

Identification of two new C4 alleles by DNA sequencing and evidence for a historical recombination of serologically defined C4A and C4B alleles.

Nucleotide polymorphisms of the C4 genes were investigated by direct sequencing of seven different homozygous typing cells from the 10IHW panels. Two novel sequences were identified within the C4d region of the C4 genes. Our sequencing analyses extend previous findings suggesting that a recombination hot spot is likely to have occurred between codon positions 1157 and 1186 within the C4d region. The classification of electrophoretically defined C4A and C4B alleles can be further subtyped by sequencing. Because the central major histocompatibility complex region that carries various copies of the C4 gene has been associated with a range of disorders; further analysis at the sequence level within the C4 locus may provide informative genetic markers for the investigation of disease-associated polymorphisms.

Alleles↗
PubMed1992

Free protein S deficiency in patients with chronic inflammatory bowel disease.

Free protein S, protein C, and C4b-binding protein (C4b-BP) were measured in randomly selected outpatients: 22 with Crohn's disease (CD) and 16 with ulcerative colitis (UC). Active disease was recorded in 10 patients with CD and 4 with UC. Fourteen patients (63.6%) with CD and 4 (25%) with UC had free protein S values below the normal range, with mean values of 62% and 78% of that found in healthy control subjects (p < 0.01). The C4b-BP level was 127% in patients with CD as compared with 89% in both healthy subjects and UC patients (p < 0.01). The protein C levels were similar in the three groups. The present results add to the factors already known favouring thromboembolic complications in inflammatory bowel disease and which might play a major role both for the pathogenesis and for the increased tendency to venous thromboembolism in these diseases.

Adult↗
PubMed1989

Inherited deficiency of functional and free form protein S.

We studied hemostatic function in a family with a history of venous thromboembolic disease. In the propositus, a 36-year-old male, the results of assays for the coagulation, anticoagulation and fibrinolytic factors were almost normal. However, the functional protein S activity in his plasma was less than 5% of normal. Similar laboratory findings were noted in his paternal uncle and two sisters who had recurrent thrombotic episodes and in his asymptomatic father as well. The mean total protein S antigen level in these five patients was 37% (range 19-66%) by conventional Laurell rocket immunoelectrophoresis. However, by crossed immunoelectrophoresis of their plasmas and Laurell rocket immunoelectrophoresis of the polyethyleneglycol 6000-treated plasmas, the free form of protein S was undetectable in their plasmas. The levels of C4b-binding protein in the plasma of three of the five patients were in normal range, and that those in the remaining two were below the normal level. These findings suggest that the recurrent thrombotic disease in this family is due to inherited deficiency of protein S, particularly of the functionally active free form of protein S.

Adult↗
PubMed1991

Polymorphism of C4 and CYP21 genes in various primate species.

To study the genetic heterogeneity of the C4 and CYP21 genes in selected primate species we used the technique of restriction fragment length polymorphism (RFLP). Genomic DNA was digested using several restriction endonucleases and filters were hybridized with a 500 bp BamHI/KpnI fragment derived from the 5' section of a human C4-cDNA and with a 1700 bp BamHI obtained from a human CYP21 gene. Abundant RFLP heterogeneity was observed for the C4 genes within a rhesus monkey population but not for the chimpanzee colony analyzed. Duplicated C4-CYP21 clusters can be traced back in humans, but also in chimpanzees, orang-utans and rhesus monkeys. Thus, duplication of the basic C4-CYP21 cluster in primates may have happened more than 30 million years ago. Non-duplicated C4-CYP21 regions were found for the gorilla and orang-utan. Apart from this, shortened C4A and C4B genes were observed in chimpanzees, orang-utans and rhesus monkeys, whereas the so-called long variety of the C4A gene appears to be present in humans and orang-utans. This ancestral modification, resulting from an insertion of a 6.5 kb intron in the C4A gene, therefore predates at least speciation of human and orang-utan which is estimated to have taken place more than 12 million years ago.

Animals↗
PubMed1985

Determination of plasma protein S--the protein cofactor of activated protein C.

Protein S, an important cofactor of activated protein C, and C4b-binding protein were purified from human plasma. Specific antibodies against the purified proteins were raised in rabbits and used for the development of immunologic assays for these proteins in plasma: an immunoradiometric assay for protein S (which measures both free protein S and protein S complexed with C4b-binding protein) and an electroimmunoassay for C4b-binding protein. Ranges for the concentrations of these proteins were established in healthy volunteers and patients using oral anticoagulant therapy. A slight decrease in protein S antigen was observed in patients with liver disease (0.78 +/- 0.25 U/ml); no significant decrease in protein S was observed in patients with DIC (0.95 +/- 0.25 U/ml). Criteria were developed for the laboratory diagnosis of an isolated protein S deficiency.

Anticoagulants↗
PubMed1995

Inhibition of the intrinsic factor X activating complex by protein S: evidence for a specific binding of protein S to factor VIII.

Protein S is a vitamin K-dependent nonenzymatic anticoagulant protein that acts as a cofactor to activated protein C. Recently it was shown that protein S inhibits the prothrombinase reaction independent of activated protein C. In this study, we show that protein S can also inhibit the intrinsic factor X activation via a specific interaction with factor VIII. In the presence of endothelial cells, the intrinsic activation of factor X was inhibited by protein S with an IC50 value of 0.28 +/- 0.04 mumol/L corresponding to the plasma concentration of protein S. This inhibitory effect was even more pronounced when the intrinsic factor X activation was studied in the presence of activated platelets (IC50 = 0.15 +/- 0.02 mumol/L). When a nonlimiting concentration of phospholipid vesicles was used, the plasma concentration of protein S (300 nmol/L) inhibited the intrinsic factor X activation by 40%. Thrombin-cleaved protein S inhibited the endothelial cell-mediated factor X activation with an IC50 similar to that of native protein S (0.26 +/- 0.02 mumol/L). Protein S in complex with C4b-binding protein inhibited the endothelial cell-mediated factor X activation more potently than protein S alone (IC50 = 0.19 +/- 0.03 mumol/L). Using thrombin activated factor VIII, IC50 values of 0.53 +/- 0.09 mumol/L and 0.46 +/- 0.10 mumol/L were found for native protein S and thrombin-cleaved protein S, respectively. The possible interactions of protein S with factor IXa, phospholipids, and factor VIII were investigated. The enzymatic activity of factor IXa was not affected by protein S, and interaction of protein S with the phospholipid surface could not fully explain the inhibitory effect of protein S on the factor X activation. Using a solid-phase binding assay, we showed a specific, saturable, and reversible binding of protein S to factor VIII with a high affinity. The concentration of protein S where half-maximal binding was reached (B1/2max) was 0.41 +/- 0.06 mumol/L. A similar affinity was found for the interaction of thrombin-cleaved protein S with factor VIII (B1/2max = 0.40 +/- 0.04 mumol/L). The affinity of the complex protein S with C4B-binding protein appeared to be five times higher (B1/2max = 0.07 +/- 0.03 mumol/L). Because the affinities of the interaction of the different forms of protein S with factor VIII correspond to the IC50 values observed for the intrinsic factor X activating complex, the interaction of protein S with factor VIII may explain the inhibitory effect of protein S on the intrinsic factor X activating complex.(ABSTRACT TRUNCATED AT 400 WORDS)

Anticoagulants↗
PubMed1999

Enhancement of protein S anticoagulant function by beta2-glycoprotein I, a major target antigen of antiphospholipid antibodies: beta2-glycoprotein I interferes with binding of protein S to its plasma inhibitor, C4b-binding protein.

Thrombosis in the antiphospholipid syndrome has been associated with acquired deficiency of the anticoagulant protein S. We sought evidence that beta2-glycoprotein I, a major target antigen for antiphospholipid antibodies, is involved in regulation of protein S activity. Incubation of purified protein S or plasma with beta2-glycoprotein I reversed functional modulation of protein S by its plasma inhibitor, the C4b-binding protein. In a plasma-free ELISA, beta2-glycoprotein I prevented the binding of protein S and C4b-binding protein when preincubated with immobilized protein S but not when similarly preincubated with C4b-binding protein. beta2-glycoprotein I in fluid phase interfered with precipitation of protein S by sepharose-bound C4b-binding protein. Effects of beta2-glycoprotein I on protein S function were inhibited by one of four monoclonal anti-beta2-glycoprotein 1 antibodies. These data suggest that beta2-glycoprotein I helps maintain adequate plasma levels of circulating free, active protein S. Antiphospholipid (anti-beta2-glycoprotein I) antibodies might cause sporadic thrombosis, at least in part, by impairing this novel regulatory mechanism.

Antibodies, Antiphospholipid↗
PubMed1986

An abnormal plasma distribution of protein S occurs in functional protein S deficiency.

Protein S is a natural anticoagulant present in the plasma that serves as a cofactor for activated protein C. Patients deficient in protein S are subject to recurrent venous thrombotic disease. Protein S deficiency differs from other plasma protein deficiencies in that deficient patients often have normal or only mildly reduced levels of protein S in their plasma as detected by conventional immunologic methods but have markedly reduced functional protein S levels. This apparent discrepancy is due to the presence of two forms of protein S in plasma. The protein S is present free and in a complex with C4b-binding protein. The free form is functionally active, whereas the bound form is not. Examination by crossed immunoelectrophoresis of 31 functionally protein S-deficient individuals from seven families reveals that 29 of the 31 have all or most of their protein S complexed to C4b-binding protein with little or no free protein and have correspondingly low levels of protein S functional activity (type I deficiency). Two related protein S-deficient individuals show a different type of distribution with little or no protein S, either bound or free (type II deficiency). The detection and classification of protein S-deficient individuals requires the application of both a functional assay and an assessment of protein S distribution between bound and free forms.

Carrier Proteins↗
PubMed2001

The association of MHC genes with autism.

Several immune abnormalities have been noted in autistic subjects. These associations have been extended to the Major Histocompatibility Complex (MHC), a section of DNA remarkable for the number of encoded proteins with immunological functions. The strongest MHC association identified thus far is for the null allele of C4B in the class III region. The complex allelic composition of C4 as determined by immunoelectrophoresis is discussed. Low levels of C4 resulting from the null allele may be important in disease pathogenesis especially since C4 has been identified in developing brain neurons. The DNA region just telomeric to C4 has several genes including tumor necrosis factor which encode proteins with immunological functions. These proteins may act in concert with C4 in disease contribution and the genes should be more closely examined.

Autistic Disorder↗
PubMed1986

Functional and immunologic protein S levels are decreased during pregnancy.

Protein S, is a natural anticoagulant protein which serves as a cofactor for activated protein C. During pregnancy and in the postpartum period, functional protein S levels are significantly reduced (38% +/- 17.3%, mean +/- 1 SD) when compared to nonpregnant females (97% +/- 31.6%) (P less than 0.001). In plasma an equilibrium exists between functionally active free protein S and protein S complexed with C4b-binding protein, which is functionally inactive. As a result of this equilibrium either a decreased level of total protein S antigen or an elevation of C4b-binding protein could lead to reduced protein S activity. C4b-binding protein levels measured by enzyme-linked immunoassay are not significantly different in pregnant women versus nonpregnant controls (103.5% +/- 21.2% v 100% +/- 16.9%). However, during pregnancy and in the postpartum period, total protein S levels are reduced (68% +/- 10.7%) compared to nonpregnant controls (100% +/- 17.0%). This difference is significant at P less than 0.001. These data demonstrated that the reduction in protein S activity observed during pregnancy is a result of reduced total protein S antigen.

Carrier Proteins↗