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PubMed1986

HL-A and disease.

Of more than 500 diseases or syndromes studied for HL-A markers, more than 40 are known to be associated with an allele of class I, II, or III. Seven are linked to the HL-A region: six are recessive (idiopathic hemochromatosis, C2, C4A, and C4B deficiencies, congenital and late-onset deficiencies) and one is dominant (spinocerebellar ataxia). In addition, insulin-dependent diabetes mellitus is also linked to HL-A with more than one single locus. HL-A typing is of practical interest for diagnosis of ankylosing spondylitis by B27 antigen determination and for prevention of idiopathic hemochromatosis by genotyping of siblings of the index case. Prenatal diagnosis of 21-OH deficiency by genotyping fetal cells permits genetic counseling. Indeed, the discovery of the relationship between HL-A and disease can be considered a new approach to medical genetics. Extensive use of HL-A technology will probably allow better prediction of risk and may elucidate the mechanisms of certain diseases. For the first time the study of one single immunogenetic system may have a significant effect on public health through the possibility of wide-scale prevention.

Alleles↗
PubMed2001

Analytical considerations for free protein S assays in protein S deficiency.

Protein S is an anticoagulant protein that circulates in plasma in complex with C4b-binding protein (C4BP) or in free form. Deficiency of protein S increases the risk of venous thrombosis. Measurement of free protein S, as compared to total levels, has been shown to be superior for prediction of protein S deficiency. We studied the effects of different handling protocols for an immuno- and a ligand (C4BP)-based assay for free protein S. When the assay was performed at 37 degrees C, the levels of free protein S in plasma from protein S deficient patients were approximately twice those obtained at room temperature. The reason for this phenomenon was that plasmas from protein S deficient patients exhibited a time-, temperature-, and dilution-dependent increase in free protein S, which was more pronounced than corresponding dilution of the normal plasma that was used to create the standard curve. These findings demonstrate the importance of assay procedure and sample handling in assays for free protein S.

Aged↗
PubMed1989

Plasma protein S in disseminated intravascular coagulation, liver disease, collagen disease, diabetes mellitus, and under oral anticoagulant therapy.

Plasma levels of protein S (PS) antigen, both total and free fractions, were measured together with C4b-binding protein (C4bp) and protein C (PC) antigen in 39 patients with disseminated intravascular coagulation (DIC), 34 with liver disease, 17 with collagen disease, 17 with diabetes mellitus, and 51 under stabilized warfarin treatment. In patients with DIC, mean concentrations of total PS and free PS were normal, while PC was reduced and C4bp were elevated. Total PS, free PS, C4bp and PC were all decreased in liver disease, elevated in diabetes mellitus, and normal in collagen disease. In warfarin-treated patients, total PS, free PS and PC were moderately decreased, but the decrease in C4bp was minimal. The concentration of PS correlated positively with PC in liver disease, diabetes mellitus, and during oral anticoagulation, but did not in DIC. These results indicate that PS and PC behave similarly when liver synthetic function is principally affected, but in contrast to PC, PS is hardly consumed during intravascular coagulation.

Administration, Oral↗
PubMed1988

Plasma concentrations of C4b-binding protein and vitamin K-dependent protein S in term and preterm infants: low levels of protein S-C4b-binding protein complexes.

We have determined the plasma concentrations of protein S and C4BP in 25 term and 26 preterm infants by radioimmunoassay. Both the total concentration and the concentration of free protein S were quantified. The concentration of C4BP was very low in preterm infants (mean 6% of the adult level). In term infants, the level had increased to a mean of 18%. Total protein S was decreased both in preterm and term infants, 4.0 mg/l and 6.8 mg/l respectively, as compared to the mean adult concentration, 20.6 mg/l. In preterm infant plasma, free protein S was the predominant (85%) form, probably due to the very low C4BP level. In plasma from term infants, free protein S represented 68% of the total protein S, the corresponding value in adult controls being 37%. The plasma concentration of free protein S in preterm and term infants was 3.3 mg/l and 4.6 mg/l, respectively (mean adult value 7.6 mg/l). These results demonstrate that, while the total protein S concentration in preterm and term infants was very low in comparison to the adult level, the difference in the concentration of the anticoagulant, active, free form of protein S between infants and adults was less pronounced.

Adult↗
PubMed1992

Recurrent venous thrombosis during warfarin treatment related to acquired protein S deficiency.

Failure of warfarin to prevent new thrombotic processes was observed in three patients with very low free protein S concentrations and high C4b-binding protein (C4bBP) concentrations, and in one patient with hereditary protein S deficiency. We suggest that an increase in C4bBP reduces the free Protein S level, and warfarin treatment causes an additional decrease of free protein S. The four patients presented indicate that such reductions are of clinical importance. Heparin seems preferable as an anticoagulant in this situation, as warfarin given alone is ineffective, or may even be harmful. In a group of pancreatic cancer patients with advanced disease, subnormal mean free protein S was found, whereas mean total protein S concentration, and mean C4bBP concentrations were significantly higher (p less than 0.01) than in healthy controls. These findings indicate that an increase in C4bBP may induce free protein S deficiency contributing to the increased thrombotic tendency in this group of patients. The correlation between free protein S and C4bBP was 0.11, (n.s.), between total protein S and C4bBP 0.73 (p less than 0.0001).

Adult↗
PubMed1997

Stimulation of Sky tyrosine phosphorylation by bovine protein S--domains involved in the receptor-ligand interaction.

Protein S is an anticoagulant vitamin-K-dependent plasma glycoprotein, which acts as a cofactor to activated protein C in the degradation of coagulation factors Va and VIIIa. It has been proposed that protein S has an additional function as a growth factor. Protein S and a structurally similar protein, Gas6, have been found to stimulate members of the Axl/Sky family of receptor tyrosine kinases. Human Gas6 is able to activate Axl and Sky. In contrast, while bovine protein S activates human Sky and its murine homologue, human protein S activates murine Sky but not the human receptor. In the present investigation, we studied the structural background of this species difference. Using protein S chimeras with domains from human and bovine origin, we found that only those chimeras with the steroid-hormone-binding globulin-like (SHBG) region from bovine protein S activate human Sky, indicating that the SHBG region is essential for the interaction. This observation was confirmed by inhibition of Sky phosphorylation by C4b-binding protein, a plasma protein that interacts tightly with the SHBG region of protein S. Another chimeric molecule, composed of the N-terminal 4-carboxyglutamic-acid-containing domain (Gla domain) and the two epidermal-growth-factor-like domains of human factor IX, and the SHBG region of bovine protein S, stimulated the receptor less efficiently. Antibodies directed against the Gla domain of protein S, inhibited the activation of human Sky by bovine protein S. These results indicate that the N-terminal domains of protein S are not essential for activation of the receptor, but contribute to the affinity of the interaction. Our data suggest that protein S might be a ligand of Sky in some species despite the lack of activity of human protein S on human Sky. The bovine/human protein S species difference will be a useful model to establish the structural requirements for the interaction between Sky and its ligands.

Animals↗
PubMed1992

Accelerated decay of the cell bound C4b2a complex by serum of patients with membranoproliferative glomerulonephritis and acute poststreptococcal glomerulonephritis.

Serum from patients with membranoproliferative glomerulonephritis (MPGN) and acute poststreptococcal glomerulonephritis (APSGN) accelerated the decay of the cell bound C4b2a (C42) and C4b hemolytic activity relative to pooled normal human serum (pNHS) after 5 min incubation at 30 degrees C in EDTA-GVB. The accelerated decay of the C42 hemolytic activity was heat stable (56 degrees C 30 min) and was inhibited by monoclonal antibody against human C4 binding protein (MoAb:C4BP) or C4 binding protein (C4BP) depleted serum. C4 nephritic factor (C4NeF) was employed to stabilize the labile classical pathway C3 convertase C42 complex. Serum from patients with MPGN and APSGN reduced the C4NeF stabilizing activity. Sera from 32 of 46 patients with MPGN and all of 7 patients with APSGN reduced the C42 hemolytic activity relative to 50 normal human serum (NHS) after 5 min incubation at 30 degrees C in EDTA-GVB, and there was no relationship with the serum concentration of C4BP. In vivo, accelerated decay of C42 convertase might interfere with the clearing and processing mechanism of circulating immune complexes (IC) by reducing deposition of C3b on the IC lattice.

Acute Disease↗
PubMed1987

Extended major histocompatibility complex haplotypes in patients with gluten-sensitive enteropathy.

We have studied major histocompatibility complex markers in randomly ascertained Caucasian patients with gluten-sensitive enteropathy and their families. The frequencies of extended haplotypes, defined as haplotypes of specific HLA-B, DR, BF, C2, C4A, and C4B allelic combinations, occurring more frequently than expected, were compared on patient chromosomes, on normal chromosomes from the study families, and on chromosomes from normal families. Over half of patient chromosomes consisted almost entirely of two extended haplotypes [HLA-B8, DR3, SC01] and [HLA-B44, DR7, FC31] which, with nonextended HLA-DR7, accounted for the previously observed HLA markers of this disease: HLA-B8, DR3, and DR7. There was no increase in HLA-DR3 on nonextended haplotypes or in other extended haplotypes with HLA-DR3 or DR7. The distribution of homozygotes and heterozygotes for HLA-DR3 and DR7 was consistent with recessive inheritance of the major histocompatibility complex-linked susceptibility gene for gluten-sensitive enteropathy. On the other hand, by odds ratio analysis and from the sum of DR3 and DR7 homozygotes compared with DR3/DR7 heterozygotes, there was an increase in heterozygotes and a decrease in homozygotes suggesting the presence of modifying phenomena.

Celiac Disease↗
PubMed1985

C4 allotypes and HLA-DR antigens in the family of a patient with C4 deficiency.

Major histocompatibility complex (MHC) haplotypes, including HLA-A, -B, -C and -DR and complotypes (BF, C2, C4A and C4B) were determined in a large family with inherited C4 deficiency. The propositus, a 12-year-old girl with complete C4 deficiency and SLE, had the MHC haplotypes HLA-A2,Cw3,-B40,-DR6,BFS,C2C,C4AQO,C4ABQO inherited from her father and HLA-A30,-B8,-DR3,BFF1,C2C,C4AQO,C4BQO from her mother. These haplotypes were identified in several of the healthy relatives, who were thus shown to be carriers of C4 deficiency. Most of the other haplotypes found in the family were not considered to be unusual in the general population. The complete absence of C4 in the patient was confirmed by studies of Chido and Rodgers antigens in the plasma and on the erythrocytes, the absence of plasma C4d fragments and by studies of C4 chain antigens by immunoblotting technique. The results of the genetic analysis, together with the findings in other cases of C4 deficiency, supports the possibility that complete C4 deficiency in itself predisposes to development of SLE without contribution of other MHC gene products.

Alleles↗
PubMed1986

Interaction of culture-derived macrophages with the fibroblast-binding domain of fibronectin is a necessary but inefficient signal for fibronectin enhancement of CR1-mediated phagocytosis.

Human plasma fibronectin (Fn) enhances ingestion of opsonized particles through its interaction with phagocytic cells. To better characterize the site or sites on Fn responsible for this effect, we subjected Fn to limited proteolytic cleavage by chymotrypsin and used affinity and gel filtration chromatography to isolate a 110,000 dalton cell-binding fragment, a 60,000 dalton fragment that bound both heparin and gelatin, and 50,000 and 45,000 dalton fragments that bound to gelatin but not heparin. The cell-binding fragment mediated adhesion and spreading of fibroblasts on glass slides, whereas the heparin-gelatin and gelatin-binding fragments failed to cause fibroblast spreading. At high concentrations, the cell-binding fragment doubled phagocytosis of C4b-coated sheep erythrocytes by human monocyte-derived macrophages, whereas equal concentrations of the other fragments had minimal enhancing effect on phagocytosis. Interestingly, the effect of the cell-binding fragment on CR1-mediated phagocytosis was always less than the effect of intact Fn, even when a 40-fold higher molar concentration of the cell-binding fragment was used. Fab of a monoclonal anti-Fn, HFn 7.1, which recognizes the 110,000 dalton cell-binding fragment of Fn and inhibits fibroblast binding, blocked enhancement of CR1-mediated phagocytosis by intact Fn. Fab of Fn 8, a monoclonal anti-Fn that binds the heparin-gelatin-binding fragment, failed to inhibit the Fn effect. These data suggest that interaction of the macrophage with the cell-binding domain of Fn is critical for the Fn effect on CR1-mediated phagocytosis. In addition, there may be other domains of the Fn molecule that have a role in augmenting the Fn-phagocyte interaction.

Antibodies, Monoclonal↗
PubMed1990

C4 null alleles in childhood onset systemic lupus erythematosus. Is there any relationship with renal disease?

C4 genotyping was performed in 38 unrelated patients with systemic lupus erythematosus (SLE) aged 2-16 years at onset. Null alleles were found in 68% of patients. Ten patients had one null allele at the C4A locus and 11 others had one null allele at the C4B locus. One patient was homozygous for C4A*Q0, 2 homozygous for C4B*Q0 and 1 heterozygous C4A*Q0/B*Q0. The last patient was C4A*Q0B*Q0/B*Q0. Three patients, being heterozygous C2 deficient, had thus a combined C2 and C4 deficiency. A significant increase in C4 null alleles in SLE patients has been reported by different authors who have suggested that the C4 null alleles confer susceptibility to SLE. However, when considering only the 20 patients of French descent, no differences in gene frequencies were found between this group and the French population. Disease patterns were compared in patients with or without null C4. Renal involvement was more frequent in the C4A*Q0 or C4A*Q0/C4A*Q0 patients than in the patients without null C4 (9/11 vs 3/12). These data suggest that differences between these results and those of others might be due to clinical heterogeneity of the disease, as exemplified by the frequency of renal involvement in the different groups. In susceptible individuals the absence of one C4A gene product may predispose the patient to renal involvement.

Adolescent↗
PubMed1985

Amino acid sequence studies of human C4b-binding protein: N-terminal sequence analysis and alignment of the fragments produced by limited proteolysis with chymotrypsin and the peptides produced by cyanogen bromide treatment.

Treatment of human C4b-binding protein (C4BP) with cyanogen bromide gave five major peptides and limited proteolysis with chymotrypsin yielded two fragments. The yields, apparent mol. wts and N-terminal amino acid sequences of these peptides and fragments indicates that in dissociating conditions, after reduction of disulphide bonds, C4BP is composed of only one type of polypeptide chain of approx. 70,000 mol. wt. The amino acid sequence data obtained, which accounts for over 55% of the total sequence, allows an alignment of the cyanogen bromide peptides. In addition the amino acid sequence data indicates that the 70,000-dalton polypeptide chain of C4BP contains nine internal homology regions, each 60 amino acids long, which would account for 540 of the expected 600 amino acids in C4BP. Similar internal homology regions are found within the Ba region of factor B [Morley and Campbell, EMBO J. 3, 153-157 (1984)] and it is of interest that the regions found in C4BP are homologous to those found in Ba.

Amino Acid Sequence↗
PubMed1992

Organization of C4 and CYP21 loci in gorilla and orangutan.

The standard human haplotype contains two C4 and two CYP21 loci arranged in the order C4A ... CYP21P ... C4B ... CYP21 and intercalated between the class I and class II loci of the HLA complex. The C4A gene is 22 kilobases (kb) long; the C4B gene is either 22 kb or 16 kb long. The CYP21P is a pseudogene characterized by an eight base pair (bp) deletion in exon 3 and other defects; the CYP21 is a functional gene. The standard chimpanzee haplotype is arranged in the same way as the standard human haplotype, except that both C4 genes are of the short variety; like the human gene, the chimpanzee CYP21P gene contains the 8 bp deletion. In the present study we demonstrate that a representative gorilla haplotype also consists of two short C4 genes and two CYP21 genes, neither of which, however, has the characteristic 8 bp deletion. On the other hand, the single characterized orangutan haplotype is organized in the following way: C4A ... CYP21 ... C4A ... CYP21 ... C4B ... CYP21. The first two C4 genes are of the long variety, the third gene is short. None of the defects characterizing the human CYP21P gene is present in any of the three orangutan genes. These conclusions are based on the analysis of overlapping clones isolated from cosmid libraries of the indicated species. The observed haplotype organization of the four primate species can be explained by expansion and contraction of the C4-CYP21 region through unequal homologous crossing-over, which preserves the differentiation of the C4 genes into the A and B categories but otherwise homogenizes these genes, as well as the CYP21 genes, within a given species. The 8 bp deletion in the CYP21P gene is postulated to have occurred before the separation of the lineages that led to modern humans and chimpanzees, but after the separation of these two lineages from the lineage that led to modern gorillas. The 6 kb insertion generating the long C4 gene is postulated to have occurred before the separation of the orangutan, gorilla, chimpanzee, and human lineages.

Animals↗
PubMed1991

Protein C, protein S and C4b-binding protein in severe infection and septic shock.

We measured concentrations of the natural anticoagulant protein C; its cofactor, protein S; and the carrier protein C4b-binding protein (C4BP), in 24 patients with severe infection and 13 with septic shock. Decreased antithrombin III levels were found in 16 of 24 infection patients and all shock patients; high thrombin-antithrombin (TAT) complexes were present in 16 of 24 infection and 12 of 13 shock patients. Protein C concentrations were significantly reduced compared to healthy blood donors, to 60 +/- 14% (infection) and 47 +/- 20% (septic shock) (mean +/- 1 SD). Total protein S levels were not reduced (119 +/- 36.7 and 88 +/- 20.0%, normal value 96 +/- 15%). Free protein S was also normal (27 +/- 9.4 and 30 +/- 8.7%, normal value 29 +/- 9%). The percentage free of total protein S was normal in shock patients (35 +/- 8.5%), but significantly reduced in patients without shock (23 +/- 5.3%). C4BP was significantly higher than normal in the latter group (135 +/- 43%), but not in the shock group (118 +/- 40%), possibly due to increased consumption. Thus, no deficiency of total or free protein S was found in these patients, who had evidence of activated coagulation but no clinical DIC.

Bacterial Infections↗
PubMedDate not supplied

Protein C pathway impairment in nonsymptomatic cigarette smokers.

Increased risk of thrombosis in cigarette smokers implies the existence of an underlying prethrombotic state. It is known that oxidative damage to the endothelium surface occurs in chronic smokers. Protein C activation takes place mostly on the endothelium of small vessels and the anticoagulant activity of protein C requires the presence of lipid membranes that are vulnerable to oxidation. Our objective was to analyze the relationship between smoking and plasma levels of activated protein C, protein C zymogen, activated protein C complexed with serpins, total and free protein S, C4b-binding protein, and thrombomodulin, as well as fibrinogen, fibrinopeptide A, and protease-cleaved antithrombin III. Of the 189 plasma donors used in this study 83 were nonsymptomatic smokers (age range 20-44 years, women/men ratio = 1.13) and 106 were healthy nonsmokers (age range 22-59 years, women/men ratio = 1.36). Smokers had 23.3% lower circulating activated protein C than nonsmokers (p = 0.003) and the differences were more pronounced in males than in females. Protein C levels were also significantly lower in smokers than in nonsmokers (p = 0.034). Correlations were negative between the intensity of smoking and circulating activated protein C levels (r = -0.31, p = 0.004) and between smoking and the ratio of activated protein C to protein C zymogen (r = -0.37, p = 0.001). Positive correlations were found between smoking intensity and fibrinogen (r = 0.21, p = 0.042), or fibrinopeptide A (r = 0.219, p = 0.034). Other parameters tested did not show a statistically significant dose-response for the number of cigarettes smoked. Cigarette smoke dose-dependent hypercoagulability due to acquired activated protein C deficiency could contribute to the increased risk of thrombosis in smokers.

Adult↗
PubMed1989

Characterization of the baboon erythrocyte C3b-binding protein.

E from primates demonstrate type 1 CR (CR1) with binding specificities for C3b and C4b. In the present study we characterized the E C3b-binding protein of baboons. We showed that three out of four mouse mAb and one polyclonal antiserum, raised against human E CR1, cross-reacted with baboon E. In addition, one anti-human CR1 mAb (1B4) and a polyclonal anti-human CR1 inhibited the binding of C3b opsonized immune complexes to baboon E. Finally, a mAb to human CR1 (E11) recognized epitopes on E of a variety of nonhuman primates, including baboons. SDS-PAGE analysis of biochemically purified baboon E membrane fractions reactive with E11 demonstrated a 65-kDa protein as a major component. Affinity absorption and elution experiments verified this protein to be E11 reactive as well as a C3b binding protein. E surface radiolabeling, followed by C3i affinity purification, confirmed that this 65-kDa protein is the only C3b-binding protein present on the baboon E membrane. We postulate that the baboon E 65-kDa protein is the equivalent of the human E CR1. In addition, there appear to be antigenic similarities between the baboon E 65-kDa protein and the human E CR1.

Animals↗
PubMed1985

Family studies of IgA deficiency.

Seventeen immunoglobulin A (IgA)-deficient subjects and other members from 13 families were examined at HLA-A, B and DR, C4A, C4B, and Bf loci. Of the 29 independent haplotypes in the IgA-deficient subjects, 22 included deletions, duplications, or defects at the C4 or 21-hydroxylase loci. It is suggested that there may be a gene regulating serum IgA concentrations in this same region of chromosome 6. Three main supratypes explain most of the previously reported HLA associations with IgA deficiency. These are A1, Cw7, B8, C4AQ0, C4B1, BfS, DR3, Bw65(14), C4A2, C4B1/2, BfS, and Bw57(17), C4A6, C4B1, BfS. All three are proposed to carry a gene for IgA deficiency, while other supratypes carrying the same B allele generally do not. Other supratypes possibly associated with IgA deficiency were also identified. A survey of about 150 individuals with at least 1 of the 3 main supratypes revealed only 2 IgA-deficient subjects, and these were among the 20 that had 2 of these supratypes. This suggests the possibility of a recessive mode of inheritance, with penetrance determined by another factor which is not major histocompatibility complex-linked. All the supratypes found in this group of IgA-deficient subjects would then carry the putative recessive allele for IgA deficiency.

Alleles↗
PubMed1997

7E3 F(ab')2, a monoclonal antibody to the platelet GPIIb/IIIa receptor, protects against microangiopathic hemolytic anemia and microvascular thrombotic renal failure in baboons treated with C4b binding protein and a sublethal infusion of Escherichia coli.

We have used our previously described baboon model of infusion of both a sublethal dose of Escherichia coli and C4b binding protein to assess the impact of inhibiting platelet function with the F(ab')2 fragment of the monoclonal antibody 7E3, directed against the platelet glycoprotein (GP)IIb/IIIa receptor, on the characteristic microvascular changes. At a dose of 0.25 to 0.35 mg/kg bolus plus an infusion of 0.25 to 0.35 mg/kg over 6 hours, c7E3 F(ab')2 had only a minimal impact on fibrinogen consumption and delayed but did not prevent, the development of thrombocytopenia. Treatment with 7E3 F(ab')2, however, produced significant protection from the development of microangiopathic hemolysis and renal insufficiency. Histologic examination supported these observations, with treated animals having fewer schistocytes on blood smear and less evidence of ischemic renal changes. Treated animals also had more rapid recovery of peripheral white blood counts, suggesting a possible protective effect of treatment on ischemic damage to the bone marrow. These data indicate that potent inhibition of platelet function via GPIIb/IIIa receptor blockade can decrease ischemic organ damage in this animal model that has features similar to those found in diffuse intravascular coagulation, hemolytic uremic syndrome, and thrombotic thrombocytopenic purpura.

Anemia, Hemolytic↗