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PubMed1986

The HLA system in the Korean population.

The frequencies of HLA-A, B, C, DR, and DQ antigens, HLA-D (HTC-defined) haplotypes, and the HLA-linked genetic markers glyoxalase I (GLO), factor B (Bf), C2 and C4 were studied in 162 healthy unrelated Koreans. Antigens A2, A24, A26, B44, B51, Bw62, B35, Cw1, Cw3, DR2, DR4, DRw6, DR7, and DRw8 were observed at frequencies of 15% or greater, and GLO-2, BfS, C4A*3, C2C, C4A*4, C4B*1, and C4B*2 were also frequently observed. The antigens A23, A25, B18, Bw42, Bw47, and B21 were not observed at all. HLA-DR4 was the most common class II antigen and was associated with a series of HLA-D-defined haplotypes including Dw4, Dw10, Dw13, and Dw15. The HLA-DRw6, DR2,Dw8, and DRw8 haplotypes were also found frequently. DR2 haplotypes were either Dw2 or Dw12, while all DRw8 haplotypes tested corresponded to the DB7 or Dw "8.3" specificity that has been described in other Oriental populations. Significant linkage disequilibrium was found between the alleles A2,Cw1; A30,B13; A30,Cw6; A30,DR7; Cw1,Bw22; Cw5,B12; Cw6,B13; Cw6,DR7; B7,DR1; B12,Dw6; B12,DR7; B12,Dw7; B13,DR7, B17,DR3; Bw22,C4B*6; DRw6,BfF; and C4A*4,C4B*2. A comparison of gene frequencies and commonly observed haplotypes between Koreans, Chinese, Japanese, and Caucasians showed that while Koreans share several characteristics in common with other Oriental populations, there are allelic frequencies and haplotypes in Koreans that are distinct.

Complement C2↗
PubMed1991

Deep venous thrombosis in a child with nephrotic syndrome associated with a circulating anticoagulant and acquired protein S deficiency.

Thromboembolic events occur with a frequency of 3-5% in children with nephrotic syndrome (NS). Although numerous abnormalities in all phases of coagulation have been described in NS, the pathogenesis of clotting abnormalities remains poorly understood in this group of patients. We describe a child with long-standing NS in whom a severe deep venous thrombosis and pulmonary embolism secondary to acquired protein S deficiency and a strong lupus-type circulating anticoagulant developed. In addition, this patient had a markedly decreased plasma level of C4b binding protein. Although acquired protein S deficiency has been described in various clinical disorders including NS, our patient is unusual in having C4bBP deficiency, and his is the only reported pediatric case of NS complicated by thromboembolism in which a circulating anticoagulant has been implicated, to our knowledge.

Autoimmune Diseases↗
PubMedDate not supplied

C4 and HLA haplotypes associated with partial inhibition of anti-Rg and anti-Ch.

Rg and Ch typing was performed, by serum inhibition, on 145 families that had been typed for HLA/C4/BF/C2 with a view to assessing partial inhibition (p.i.) of anti-Rg/Ch and its haplotype associations. Rg p.i. was found predominantly with the C4A*3A*2,B*QO homoduplicated C4 haplotype and BFF. The original type of Ch p.i. (Nordhagen et al., 1980) was closely associated with the allotype C4B 2, which also occasionally exhibited complete inhibition (c.i.), but this Ch p.i. was also found with the C4A*1,B*QO haplotype (Rittner et al., 1984a). The second type of Ch p.i. (Giles, 1984) was closely associated with the C4B 1 allotype most frequently in the haplotype C4A*6,B*1 but also with C4A*3,B*1. Both types of Ch p.i. are usually found with BF S. The present data indicate that the determinants of Rg and Ch are not directly related to any particular C4 allotype or extended haplotype. Further examples of C4A 1 with Ch and C4B 5 without Ch determinants have been detected and theoretical considerations are discussed as to how they might have arisen from unequal crossovers in homologous regions that result in hybrid protein molecules.

Alleles↗
PubMed1985

Identification of an additional class of C3-binding membrane proteins of human peripheral blood leukocytes and cell lines.

Proteins binding the third component of complement (C3) were isolated by affinity chromatography from surface-labeled solubilized membranes of human peripheral blood cells and cell lines. The isolated molecules were subjected to NaDodSO4/PAGE, and autoradiographs of these gels indicated that C3-binding proteins could be divided into three groups based on Mr: (i) gp200, an approximately 200,000 Mr molecule previously identified as the C3b/C4b receptor or CR1; (ii) gp140, an approximately 140,000 Mr molecule previously identified as the C3d receptor or CR2; and (iii) gp45-70, a heretofore unrecognized group of 45,000-70,000 Mr C3-binding molecules. The cell distribution, Mr, antigenic cross-reactivity, and specificity of gp45-70 were examined. Erythrocytes have no detectable gp45-70, but all leukocyte populations examined possess this group of molecules. On neutrophils and mononuclear phagocytes, CR1 is the predominant C3-binding glycoprotein, but gp45-70 is present on both cell populations and on macrophage and neutrophil cell lines. B plus null cells, chronic lymphocytic leukemia cells, and an Epstein-Barr virus-transformed B-cell line possess CR1, CR2, and gp45-70. On T cells and T-cell lines gp45-70 is the predominant or, in some cases, the only C3-binding protein isolated. gp45-70 is structurally characterized as a broad band or doublet with a mean Mr that is slightly different for each cell population. gp45-70 binds iC3, C3b, and C4b, but not C3d, indicating that the binding region is probably within the C3c portion of C3b. A polyclonal antibody to CR1 and monoclonal antibodies to CR1 and CR2 do not immunoprecipitate gp45-70. While gp45-70 has not been previously characterized on human cells, a C3b-binding glycoprotein of similar Mr is present on rabbit alveolar macrophages. We conclude that gp45-70 is an additional group of membrane proteins present on human leukocytes that possess ligand-binding activity for C3b.

B-Lymphocytes↗
PubMed1992

Effects of C4 null alleles and homoduplications on quantitative expression of C4A and C4B.

The availability of MoAbs now allows the accurate quantification of the individual C4 isotypes, C4A and C4B. Using a sensitive two-site immunoradiometric technique to measure serum levels of C4A and C4B, we studied the relationship between genotype and phenotype and physiological factors affecting C4 expression in 129 fully genotyped healthy subjects. Our results confirm that there is extensive phenotypic overlap between genotypic groups and it was not possible to determine the presence of single null alleles from total serum C4. Of the factors which may influence C4 expression, we found that age contributes a very small influence but that gender has no effect and there was no evidence for the presence of feedback of null alleles on the expression of remaining genes. Potential problems in quantifying C4 arising from the complex relationship between isotypic identity and serotypic recognition were highlighted by the finding of reversed antigenic expression of a C4B*5 molecule which was recognized as C4A by the anti-Rg:1 monoclonal used in these studies. We also confirmed that the extended MHC haplotype associated with Felty's syndrome, HLA-B44, C4A*3, C4BQ*O, HLA-DR4, encodes an expressed, duplicated, C4A gene.

Adult↗
PubMed1989

A new case of 'type II' inherited protein S deficiency.

Protein S inherited deficiency is associated with high risk of recurrent venous thrombotic disease (Broekmans et al, 1985a, b). Protein S exists as two forms in plasma, either free and functionally active or complexed with C4b-binding protein (C4b BP) and inactive (Dahlbäck & Stenflo, 1981). We report here the case of a 26-year-old woman and her brother, 28 years old, both suffering from recurrent venous thrombosis since the age of 20, diagnosed as severe protein S deficiency according to the following data: free protein S: 2.5-3% by ELISA, undetectable by electroimmunodiffusion (EID); total protein S: 13-16% by ELISA, 21-18% by EID, C4b BP: normal levels. Crossed immunoelectrophoresis using anti-protein S antibodies revealed only traces of protein S associated with C4b BP and no free protein S. All these assays were performed in the absence of any anticoagulant therapy. Among the investigated relatives, less severe protein S deficiency was observed in three children of the propositus: total protein S levels ranging from 41% to 50% (EID), 40-53% (ELISA); free protein S levels ranging from 16% to 18% (EID), 10-12% (ELISA); normal C4b BP levels. Crossed immunoelectrophoresis revealed traces of free protein S but a significant amount of protein S associated with C4b BP. From these results, we consider, according to Comp's classification (Comp et al, 1986a), that the propositus and her brother are the second case of protein S deficiency type II to be reported in the literature while her children belong to the type I category.

Adult↗
PubMed1993

A sensitive peroxidase staining immunoblotting method for measuring total protein S in human plasma.

In plasma, protein S is found in its free form and as a complex with C4b-binding protein. After 125I-protein S was added to normal human plasma and applied to SDS-8% polyacrylamide gel electrophoresis, the autoradiogram of the gel showed only one single band at free protein S position. Applying this evidence, we have developed a peroxidase staining Western Blotting method to quantitate total protein S in human plasma which consists of sodium dodecyl sulfate polyacrylamide gel electrophoresis followed by blotting to nitrocellulose membrane and a sensitive avidin-biotinylated peroxidase staining method (ABC technique). The measurement of protein S by the immunoblotting was reproducible and the coefficient of variation was 7%. As little as 1 ng of protein S could be detected. C4b-binding protein did not affect the measurement of protein S. Compared to other immunoassays, this peroxidase staining immunoblotting method has the advantage of directly estimating the apparent molecular weight of protein of interest, eliminating nonspecific stain and having high sensitivity without using radioisotope.

Avidin↗
PubMed1979

Modulation of the classical pathway C3 convertase by plasma proteins C4 binding protein and C3b inactivator.

We recently described the isolation from human serum of a serum protein (C4 binding protein) that functions as an essential cofactor for C3b inactivator in the proteolysis of fluid-phase C4b and to a much lesser extent, C3b. We show here the role of C4 binding protein in the formation and function of the classical pathway C3 convertase (C42). C4 binding protein interferes with the assembly of the membrane-bound C3 convertase of the classical pathway and accelerates the decay of C42 in a dose-dependent fashion. Its removal from serum by means of specific immune absorption promotes the vigorous consumption of C3 after addition of C1; this effect is abolished by reconstitution with purified C4 binding protein. Although C4 binding protein inhibits the hemolytic function of cell-bound C4b, we did not detect any change in the structure of C4b even after prolonged incubations of EAC14 with C4 binding protein. For this reason, and on the basis of studies of the time required for maximal reactivity (Tmax) of cellular intermediates generated in the presence of C4 binding protein and limited amounts of C2, we conclude that the effects of C4 binding protein are probably mediated by displacing C2a from specific binding sites on C4b. In addition, C4 binding protein enhances the cleavage by C3b inactivator of the alpha' chain of cell-bound C4b. When EAC14 cells were incubated with both control proteins, the Tmax of the cells was prolonged and the lysis was markedly diminished. We conclude that C4 binding protein and C3b inactivator control the C3 convertase of the classical pathway in a fashion similar to that described for beta 1H and C3b inactivator in the alternative pathway.

Animals↗
PubMed1988

Low total protein S antigen but high protein S activity due to decreased C4b-binding protein in neonates.

Protein S, a vitamin K-dependent cofactor for activated protein C, exists in normal adult plasma in a free anticoagulantly active form and in an inactive form complexed to C4b-binding protein. Immunologic and functional levels of protein S and C4b-binding protein in plasma were determined for 20 newborn infants and compared with adult normal pooled plasma. Total protein S antigen levels averaged 23%, similar to other vitamin K-dependent plasma proteins. However, the protein S anticoagulant activity was 74% of that of adult normal plasma. This apparent discrepancy of activity to antigen was shown to be due to low or undetectable levels of C4b-binding protein, which results in the presence of most if not all of protein S in its free and active form. The relatively high level of anticoagulantly active protein S in infants may enhance the potential of the protein C pathway, thereby minimizing risks of venous thrombosis in this group.

Antigens↗
PubMed1985

C4 uremic variant: an acquired C4 allotype.

The major histocompatibility complex (MHC)-linked complotype region includes alleles for B, C2, and C4 loci. These loci are closely linked to each other and to HLA-DR on chromosome 6. The duplicated C4 loci, C4A and B, are especially polymorphic. In seven patients with renal insufficiency, we observed a C4 variant with electrophoretic mobility between C4B2 and C4B3. Four of these patients were detected during a study of MHC markers in membranoproliferative glomerulonephritis. Complete complotype and HLA data from families of five of the seven patients demonstrated that the variant was not inherited. The pattern was revealed by immunofixation electrophoresis and also by C4-specific hemolytic overlay. In serial plasma specimens taken from one patient, the C4 variant appeared only after the patient became uremic. However, the variant could not be produced in normal plasma after incubation with C4-depleted uremic plasma. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis under reducing conditions of immunoprecipitated C4 from these patients showed C4A and C4B alpha chains of normal molecular mass; incompletely processed forms of C4 were not observed. We believe that this variant is probably acquired in the presence of uremia and may represent the C4B2.9 allele found by Wank and co-workers in many patients with glomerulonephritis. Family studies are mandatory to distinguish genetic variants from acquired alterations in the C4 phenotype.

Alleles↗
PubMed1984

Study of alleles of the second complement component (C2) on Canadian HLA haplotypes.

Typing for genetic variation in the second complement component C2 was performed on sera from HLA haplotyped Canadian families. Part of the data has been studied and analysed as a population; in addition there is a further random collection of haplotypes bearing the C2*2 allele. In the population data there were 444 separate haplotypes from unrelated parents or other founders: 4.7% of the haplotypes carried the uncommon allele C2*2; one haplotype carried the rare C2*3. Study of C2 2-1 heterozygotes in the population data revealed 59 haplotypes which carried the common C2*1 allele and one which carried a deficiency allele C2*0. The remaining haplotypes carried either C2*1 or else an undetectable C2*0 allele. In the entire data there were 281 meioses informative for C2. The only recombinant between HLA-B and C2 showed the C2 locus to be on the DR side of the B locus. Strong allelic association between C2 *2 and Bw22 and less strong association between C2 *2 and B15 suggested the possibility of two ancestral C2 mutants. Examination of other markers on these and subsequently collected haplotypes do not conflict with this idea since the B15 haplotypes mostly carry C4A *4, C4B *2 whilst the Bw22 haplotypes mostly carry C4A *4, C4B *4. The alternative idea, that there was one original mutant which crossed over from a B15 to a Bw22 haplotype or vice versa is not excluded, however. Since approximate equilibrium has been reached between Bw22 and the HLA-A locus alleles on these C2 *2 bearing haplotypes, we conclude that this mutation is at least 5000 years old. Other haplotypes carrying C2 *2 are assumed to be ancestral recombinants; if this is true, the C2 locus map position between HLA-B and HLA-DR is confirmed. Study of C2 mutation may provide a model for understanding the genetics of some disease susceptibility genes in the HLA region.

Alleles↗
PubMed1986

Steroid 21-hydroxylase deficiency and the major histocompatibility complex.

Steroid 21-hydroxylase (21-OHase) deficiency is an HLA-linked recessive disorder of cortisol biosynthesis that can occur in several forms which differ in severity. Because they are in genetic linkage disequilibrium with different HLA antigens, the inheritance of these forms is consistent with the existence of several alleles at a single locus. When severe 21-OHase deficiency occurs in association with the HLA haplotype A3;Bw47;DR7, there is a simultaneous null allele at one of the C4 loci. This was hypothesized to result from a single deletion or rearrangement affecting the 21-OHase and C4 loci and perhaps the HLA-B gene as well. To test this hypothesis and identify the 21-OHase gene, a cDNA clone was isolated that encoded the cytochrome P450 specific for steroid 21-hydroxylation in the bovine adrenal gland. This clone hybridized to two genes in normal human DNA, but to only one gene in DNA from an individual homozygous for A3;Bw47;DR7. All individuals heterozygous for A3;Bw47;DR7 carry a heterozygous deletion of a cytochrome P450 gene. Cosmid clones have been used to locate the 21-OHase genes both in man and mouse. In both species, there are two 21-OHase genes each located immediately 3' of one of the two C4 genes, and oriented in the same direction as the C4 genes. In man, the gene located 3' of the C4B gene is deleted in 21-OHase deficiency on the Bw47 haplotype, but the gene 3' of the C4A gene is deleted in hormonally normal individuals on the A1;B8;C4AQ0, C4B1;DR3 haplotype. Thus the 21-OHase B gene is normally active in man, but the 21-OHase A gene is not.

Adrenal Hyperplasia, Congenital↗
PubMed1998

Molecular heterogeneity of second and fourth components of complement and their genes in systemic sclerosis and association of HLA alleles A1, B8 and DR3 with limited and DR5 with diffuse systemic sclerosis.

Deficiency of the complement component C4 at the functional, protein and gene level and deficiency of complement component C2 at the functional level were investigated and HLA analysis was performed on patients with limited and diffuse systemic sclerosis (SSc). One of the patients with limited SSc (n = 15) had subnormal C4, 1 subnormal C2 and 1 subnormal C4 and C2 activities; the latter patient had HLA alleles A11;B35;Dw1 associated with type II C2 deficiency and therefore most likely had a defect at the C2 locus. One of the patients with diffuse SSC (n = 12) had subnormal C4 and 1 subnormal C4 and C2 activities. C2 deficiencies in patients other than the one with the haplotype associated with C2 deficiency appeared not to be determined by the gene at the C2 locus. The incidence of partial C2 deficiency in a normal Caucasian population is reported to be 16 in 10,000, and that of partial C4 deficiency also appears to be very low. The percentages of C4A*Q0 and C4B*Q0 alleles in normal controls (n = 45) were within the reported range. Seven patients with limited SSc (n = 14) had one or two C4A*Q0 alleles and 2 with diffuse SSc (n = 13) had one C4A*Q0 allele. Thus, the incidence of C4A*Q0 was higher than normal in limited SSc and within the normal range in diffuse SSc. The two-sided Fisher's exact test applied on these data revealed that the association of C4A*Q0 with limited SSc did not reach a significant level (p = 0.10). Two of the 3 patients with limited SSc, who had two C4A*Q0 alleles, carried a heterozygous C4A-21-hydroxylase A (OHA) gene segment deletion as detected by Southern blotting. There was no correlation between the subnormal activity of C4 and the occurrence of one or two C4A*Q0 (and C4A-21-OHA segment deletion). HLA alleles A1, B8 and DR3 (p = 0.002) were associated with limited SSc (n = 23) and DR5(w11) (p = 0.018) with diffuse SSc (n = 17).

Alleles↗
PubMed1991

Oligomeric domain structure of human complement factor H by X-ray and neutron solution scattering.

Factor H is a regulatory component of the complement system. It has a monomer Mr of 150,000. Primary structure analysis shows that the polypeptide is divided into 20 homologous regions, each 60 amino acid residues long. These are independently folding domains and are termed "short consensus repeats" (SCRs) or "complement control protein" (CCP) repeats. High-flux synchrotron X-ray and neutron scattering studies were performed in order to define its solution structure in conditions close to physiological. The Mr of factor H was determined as 250,000-320,000 to show that factor H is dimeric. This structure is maintained at concentrations between 1 and 11 mg/mL in the pH range 5-9. Zn2+ ions are an inhibitor of C3b cleavage by factor I, a reaction in which factor H acts as a cofactor. Additions of Zn2+ to factor H caused it to form oligomers containing 4-10 monomers. The radius of gyration RG of native factor H by X-rays or by neutrons in 0% or 100% 2H2O buffers is not measurable but is greater than 12.5 nm. Two cross-sectional radii of gyration RXS-1 and RXS-2 were determined as 3.0-3.1 and 1.8 nm, respectively. Analyses of the cross-sectional intensities show that factor H is composed of two distinct subunits. The RXS-1 corresponds to the cross-sectional properties of both subunits and exhibits an unusual radiation dependence on the X-ray flux. Since RXS-2 is close to the corresponding RXS of C4b binding protein (91% of which is formed from SCR/CCP domains), it is inferred that the SCR/CCP domains of factor H and C4b binding protein have similar solution structures. The use of hydrodynamic spheres to reproduce literature sedimentation coefficients of 5.5-5.6 S showed that these were compatible with a V-shaped arrangement of two rods (36 spheres each, length 87 +/- 5 nm) joined at an angle of 5 degrees. The use of a similar arrangement of 244 spheres arranged in two rods (length 77 nm) to fit the experimental X-ray and neutron scattering curves showed that the two rods are joined at an angle of 5 degrees. This model corresponds to an actual RG of 21-23 nm. The separation between each SCR/CCP in factor H is close to 4 nm. In the solution structure of factor H, the SCR/CCP domains are in a highly extended conformation.

Complement C3b↗
PubMed1988

Protein S deficiency in sickle cell anemia.

To investigate the status of the protein C-protein S anticoagulant pathway in sickle cell disease, we measured protein C, total and free protein S, and C4b-binding protein levels in 20 subjects with sickle cell disease (Hb SS or SC). Mean total and free protein S levels were both significantly lower in subjects with sickle cell disease than in normal individuals, but greater reductions were observed for free S. The free protein S level was below the mean -2 SD for normal subjects in 12 subjects with sickle cell disease; the total protein S level was below this level in three subjects. Mean C4b-binding protein levels were normal in subjects with sickle cell disease, both during painful crisis and in the steady state, and no correlation was observed between the levels of C4b-binding protein and free protein S, suggesting that the low free protein S level was not caused by increased levels of C4b-binding protein. Crossed immunoelectrophoresis of plasma samples from eight subjects with sickle cell disease showed marked reductions in free protein S, with normal levels of protein S bound to C4b-binding protein. In contrast to the protein S level, mean protein C activity was normal in subjects with sickle cell disease, both during painful crisis and in the steady state. However, the protein C level was below the mean -2 SD for normal subjects on at least one occasion in four subjects with sickle cell disease.(ABSTRACT TRUNCATED AT 250 WORDS)

Anemia, Sickle Cell↗
PubMed1991

DNA analysis in a MHC heterozygous patient with complete C4 deficiency--homozygosity for C4 gene deletion and C4 pseudogene.

Virtually all cases of inherited C4 deficiency appear to be caused by homozygosity for rare MHC haplotypes carrying combined defects of genes coding for the C4A and C4B isotypes. The present analysis concerned a C4-deficient patient with two different MHC haplotypes, [HLA-A2, B40, SC00, DR6] and [HLA-A30, B18, F1C00, DR3]. Digestion of genomic DNA from the patient with Taq I and probing with a 5' cDNA C4 probe and a CYP21-specific probe gave only a 7.0-kb and a 3.7-kb band, respectively. The analysis of restriction fragment length polymorphism in family members showed that both C4-deficient haplotypes contained a C4 pseudogene at the C4 locus I and a CYP21 gene together with a deletion of the C4B gene and the adjacent CYP21P gene. None of the C4 pseudogenes contained C4A- or C4B-specific nucleotide sequences as judged from hybridization studies of polymerase chain reaction products. The findings illustrate the high degree of polymorphism in C4 genes and that both gene deletions and presence of a C4 pseudogene are common as reasons for C4 null alleles. The rare C4 double null alleles appear to have arisen in different MHC haplotypes independently.

Adolescent↗
PubMed1981

Purification from guinea pig erythrocyte stroma of a decay-accelerating factor for the classical c3 convertase, C4b,2a.

A protein with decay-accelerating activity for the classical C3 convertase, C4b2a, has been isolated on the basis of this function from guinea pig erythrocyte stroma. The isolation procedure for decay-accelerating factor of stroma (DAF-S) utilizes butanol extraction and chromatography on DEAE-Sephacel, hydroxylapatite, and phenyl Sepharose. Purified DAF-S has a m.w. of 60,000 and 65,000 on reduced and unreduced SDS gels, respectively, and exhibits m.w. of 30,000 and 175,000 on alkaline gradient gels, suggesting multiples of a 60,000-65,000 subunit. Purified DAF-S elicited a monospecific antiserum whose IgG fraction neutralized the decay-accelerating activity for C4b,2a affixed to 10(7) sheep erythrocytes (EAC1,4,2) in a dose-response fashion. The monospecific antiserum diluted up to 1:5120 agglutinated 1 x 10(6) guinea pig erythrocytes, but not sheep or human erythrocytes, suggesting that DAF-S, an integral membrane protein, has species-specific antigens that are expressed on the surface of the guinea pig erythrocyte.

Animals↗