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PubMed2003

Functional properties of the sex-hormone-binding globulin (SHBG)-like domain of the anticoagulant protein S.

Protein S (PS) possesses a sex-hormone-binding globulin (SHBG)-like domain in place of the serine-protease domain found in other vitamin K-dependent plasma proteins. This SHBG-like domain is able to bind a complement fraction, C4b-binding protein (C4b-BP). To establish whether the PS SHBG-like domain can fold normally in the absence of other domains, and to obtain information on the specific functions of this region, we expressed the PS SHBG-like domain alone or together with its adjacent domain EGF4. The folding of the two recombinant modules was studied by analyzing their binding to C4b-BP. The apparent dissociation constants of this interaction indicated that both recombinant modules adopted the conformation of native PS, indicating that the PS SHBG-like region is an independent folding unit. We also obtained the first direct evidence that the SHBG-like domain alone is sufficient to support the interaction with C4b-BP. In addition, both recombinant modules were able to bind Ca2+ directly, as shown by the migration shift in agarose gel electrophoresis in the presence of Ca2+, together with the results of equilibrium dialysis and the functional effect of Ca2+ on the C4b-BP/PS interaction, confirming the presence of one Ca2+ binding site within the SHBG-like domain. Neither recombinant module exhibited activated protein C (aPC) cofactor activity in a clotting assay, suggesting that the PS SHBG-like region must be part of the intact molecule for it to contribute to aPC cofactor activity, possibly by constraining the different domains in a conformation that permits optimal interaction with aPC.

Anticoagulants↗

PubMed1990

Human non-lineage antigen, CD46 (HuLy-m5): purification and partial sequencing demonstrates structural homology with complement-regulating glycoproteins.

CD46, until recently known as HuLy-m5, is a non-lineage restricted surface antigen ubiquitously expressed by almost all human cells except erythrocytes. The CD46 antigen is identified by the E4.3 monoclonal antibody (mAb) and exists at the surface of human peripheral blood lymphocytes (PBLs) as two acidic, non-disulfide bonded chains, alpha and beta, of Mr 66,000 and 56,000. Receptor density analysis showed that CD46 was of moderately low abundance on PBLs with 7.5 x 10(3) molecules present on each cell. The two chains of CD46 were purified (144,000-fold) by immunoaffinity-chromatography with E4.3 mAb from the plasma membranes of a human spleen infiltrated with chronic myelogenous leukemia cells. Amino acid sequence analysis of the NH2-terminal of both alpha and beta chains yielded the same sequence; XEEPPQ/TFEAMELIGKPKPYYEIGE. Peptide mapping studies confirmed that both CD46 chains were closely related, except for one peptide fragment. This amino acid sequence is identical to that of the NH2-terminal of the recently cloned membrane co-factor protein (MCP), a membrane protein that binds the C3b and C4b fragments of complement and acts as a co-factor for I protein-mediated decay of the complement convertases. CD46 shares a cross-reactive epitope with some primate retroviruses, and this may indicate that some retroviruses mimic the mechanisms used by autologous human cells to evade complement-mediated immune clearance.

Amino Acid Sequence↗

PubMed1992

Properdin factor B and complement factor C4 allotypes in rheumatoid arthritis: results of a follow-up study.

The association between allotypes of properdin factor B (Bf), the fourth component of complement (C4A and C4B), and rheumatoid arthritis (RA), was investigated in a well-characterized cohort of RA patients who were followed from an early phase of the disease for a mean duration of 6 years. The frequencies of probable heterozygous C4AQ0 and of C4A3 were lower in RA patients compared to controls, irrespective of the presence of DR4 [relative risk (RR): 0.52 and 0.49, respectively, 95% confidence intervals (95% CI): 0.34-0.80 and 0.29-0.82]. The frequency of C4A4 was higher in RA patients compared to controls (RR: 1.86, 95% CI: 1.03-3.35), especially in DR4 positive RA patients compared to DR4 positive controls (RR: 2.58, 95% CI: 1.07-6.25), indicating a positive association of this allotype with RA additional to DR4. Bf and C4B allotypes were comparable in RA patients and controls. We did not find significant differences in Bf and C4 allotype frequencies in RA patients subdivided according to severity of the disease into a mild group and a progressive group. Because of inconsistent results in all studies on Bf and C4 allotypes, we conclude that C4 and Bf allotypes do not seem to have an important independent effect on determining disease susceptibility.

Adult↗

PubMed1990

Genesis by meiotic unequal crossover of a de novo deletion that contributes to steroid 21-hydroxylase deficiency.

The HLA-linked human steroid 21-hydroxylase gene CYP21B and its closely homologous pseudogene CYP21A are each normally located centromeric to a fourth component of complement (C4) gene, C4B and C4A, respectively, in an organization suggesting tandem duplication of a ca. 30-kilobase DNA unit containing a CYP21 gene and a C4 gene. Such an organization has been considered to facilitate gene deletion and addition events by unequal crossover between the tandem repeats. We have identified a steroid 21-hydroxylase [steroid, hydrogen-donor:oxygen oxidoreductase (21-hydroxylating), EC 1.14.99.10] deficiency patient who has a maternally inherited disease haplotype that carries a de novo deletion of a ca. 30-kilobase repeat unit including the CYP21B gene and associated C4B gene. This disease haplotype appears to have been generated as a result of meiotic unequal crossover between maternal homologous chromosomes. One of the maternal haplotypes is the frequently occurring HLA-DR3, B8, A1 haplotype that normally carries a deletion of a ca. 30-kilobase unit including the CYP21A gene and C4A gene. Haplotypes of this type may possibly act as premutations, increasing the susceptibility of developing a 21-hydroxylase deficiency mutation by facilitating unequal chromosome pairing.

Adrenal Hyperplasia, Congenital↗

PubMed1981

Binding of fluid-phase complement components C3 and C3b to human lymphocytes.

It is known that a population of B-lymphocytes has receptors for the third component of complement, C3, and that these lymphocytes may be identified by their ability to form rosettes with sheep erythrocytes coated with covalently bound fragments of complement component C3. Human tonsil lymphocytes, enriched for B-cells, form rosettes with sheep erythrocytes coated with antibody and complement components C1, C4b and C3b (EAC143b cells). Fluid-phase C3 will inhibit rosette formation between EAC143b and human tonsil lymphocytes over the same concentration range as fluid-phase C3b. C3 is not cleaved to C3b during incubation with lymphocytes or with lymphocytes and EAC143b cells. Fluid-phase 125I-labelled C3 and 125I-labelled C3b bind to lymphocytes in a specific manner. The characteristics of binding of both radioiodinated C3 and radioiodinated C3b are very similar, but the binding oc C3 is again not a result of cleavage to C3b. Salicylhydroxamic acid does not inhibit binding of 125I-labelled C3 to tonsil lymphocytes at concentrations that completely inhibit binding of 125I-labelled C3 to EAC142 cells via the nascent binding site of C3b. It is concluded that C3 and C3b share a common feature involved in binding to lymphocytes bearing receptors for the third component of complement.

Animals↗

PubMed1990

Restriction fragment length polymorphism of complement C4 in Japanese patients with rheumatoid arthritis and normal Japanese.

Restriction fragment length polymorphism (RFLP) of the two genes for complement C4A and C4B was studied in 56 Japanese patients with rheumatoid arthritis (RA) and 161 normal individuals. HindIII digestion revealed six common patterns, from which the segregation of three common RFLP-types were deduced; 32-15 kb, 32-25 kb, and 32-20-13-6.5 kb. The last type showed positive associations with C4B5 and HLA-DR4. In the RA patients, an increase of this type was found as well as a decrease of the 32-15 kb/32-25-15 kb heterozygotes.

Arthritis, Rheumatoid↗

PubMed1976

A new activity of complement component C3: cell-bound C3b potentiates lysis of erythrocytes by C5b,6 and terminal components.

EAC4b,3b (sheep erythrocytes carrying rabbit antibody and guinea pig complement component fragments C4b and C3) adsorb human C5b,6 reversibly; the avidity of binding varies inversely with ionic strength. We believe that the receptor of C5b,6 is contributed by the cell-bound C3b because the binding capacity of EAC4b,3b varies with C3b multiplicity and can be blocked with rabbit antibody to guinea pig C3. The fixation of C5b,6 to the erythrocyte-bound C3b serves to concentrate C5b,6 on the cell surface; as a consequence, the hemolytic efficiency of C5b,6 is almost 100 times greater when assayed with EAC4b,3b than with plain erythrocytes. This potentiation represents a hitherto unrecognized function of cell-bound C3b.

Animals↗

PubMed1983

Effect of radiographic contrast media on complement components C3 and C4: generation of C3b-like C3 and C4b-like C4.

Various water soluble iodinated radiographic contrast media (RCM) have been studied for their effect on complement components C3 and C4, purified and in serum. Hepatotropic RCM, and at higher concentration also some nephrotropic RCM, were found to exert a direct effect on purified C3 and C4. RCM treated human C3 and C4 are characterized by (a) loss of haemolytic function, (b) retention of activity in the formation of fluid phase C3 convertases and (c) an antigenic relationship to activated C3 and C4 (C3b and C4b, respectively). This direct alteration of C3 and C4 can probably also occur in serum since loss of haemolytic function is observed at similar RCM concentrations after incubation of serum and of purified components. It is concluded that RCM treated C3 and C4 represent altered forms of these components that resemble C4b and C3b in activity and conformation (C3b-like C3 and C4b-like C4). The alteration is probably caused by binding of RCM, exerting a mild denaturing effect. C3b-like C3 is a potential activator of the alternative pathway, and both C3b-like C3 and C4b-like C4 are known to be cleaved by serum inactivators. A possible pathological significance of the generation of C3b-like C3, C4b-like C4 and their split products remains to be evaluated.

Animals↗

PubMed1987

Human complement factor I: analysis of cDNA-derived primary structure and assignment of its gene to chromosome 4.

Factor I is a serine proteinase of complement which together with one of several specific cofactors cleaves activation products of the third and fourth components of complement (C3b and C4b) and modulates the activity of C3 convertase. A heterodimer glycoprotein (Mr = 88,000), factor I is synthesized as a single-chain precursor, prepro-I, which undergoes intracellular proteolytic processing. The human hepatoma line HepG2, however, secretes predominantly the single-chain precursor pro-I. In order to determine the molecular basis for this apparent processing defect, factor I cDNA clones were isolated from a HepG2 mRNA-derived library. Sequencing of the largest insert, HI1971, revealed that it contains 14 base pairs of 5' untranslated region, the complete coding sequence for the 583-residue prepro-I (NH2-signal peptide-heavy chain-linking peptide-light chain-COOH), two polyadenylation signals within the 200-base pair 3' untranslated region, and a portion of poly(A) tail. Analysis of the derived protein structure 1) reveals a mosaic multidomain structure of the heavy chain; 2) demonstrates structural similarity between intracellular conversion of pro-I and activation of other serine proteinase zymogens; and 3) indicates that the light chain of factor I resembles most closely the active subunit of tissue plasminogen activator among all serine proteinases and factor D among complement proteinases. Furthermore, this protein sequence was compared to the sequences of factor I cDNA clones isolated from normal human liver libraries and found to be identical. By exclusion, this defines as cellular the basis for the inefficient processing of pro-I by the HepG2 line. Chromosomal localization by the somatic cell hybrid method maps the factor I gene to chromosome 4.

Amino Acid Sequence↗

PubMed1984

Complement phenotypes in glomerulonephritis: increased frequency of homozygous null C4 phenotypes in IgA nephropathy and Henoch-Schönlein purpura.

Polymorphism of three complement genes (C4A, C4B, and BF) located within the major histocompatibility complex was studied in 48 biopsy-proven IgA nephropathy patients and nineteen patients with Henoch-Schönlein purpura (HSP). Polymorphism was determined by immunoelectrophoretic techniques and functional activity using an overlay of sheep cells in agarose and C4 deficient sera. The subjects were divided into four large groups according to the presence or absence of a C4 null allele (a gene producing no identifiable gene product): group 1 (no null variants), group 2 (one C4A null variant), group 3 (one C4B null variant), and group 4 (two null variants at either the C4A or C4B locus, that is, homozygous null). Patients had a significantly increased frequency of group 4 phenotypes (homozygous null): (12 of 67 patients, 17.8%) as compared to controls (4 of 102 patients, 3.9%, P = 0.0031). Both IgA (P = 0.045) and HSP patients (P = 0.003) had a greater frequency of a C4 homozygous null phenotype. The serum C4 concentration was higher in patients than in controls (740 mg/ml and 576 micrograms/ml, respectively, P = less than 0.001) whether evaluated together or by C4 phenotypic group. The association between the presence of IgA nephropathy or HSP with a homozygous C4 null phenotype is of unknown significance but suggests a predisposition to development of HSP or IgA nephropathy for individuals with the C4 homozygous null phenotype.

Chromosome Mapping↗

PubMed1986

HLA and narcolepsy in a German population.

In this paper the first MHC data including HLA-A, B, C, DR, DQ and complement BF, C4A, C4B determinants in German narcoleptics are presented together with the first family studies in European Caucasoids. 57 out of 58 unrelated patients (98.3%) were positive for DR2 and DQw1, respectively. In contrast to all other reports, one patient with typical signs of narcolepsy was found to be DR2/DQw1 negative. Data showing significant increase in the frequency of B7, and normal frequencies of B35 were discordant with data from Japanese patients. Definition of the extended DR2 linked haplotypes, deduced from 6 families, revealed that 5 out of 12 were DQw1, DR2, BFS, C4B1, C4A3, B7 (Cw7), while 11/12 had DR2, DQw1, BFS, C4A3, C4B1 in common. In one multiple case family two genotypically different DR2 haplotypes were identified in affected siblings. Results from the family study were concordant with a dominant mode of inheritance with incomplete penetrance of a hypothetical disease susceptibility gene.

Complement C4↗

PubMed1986

Relationship between C4 null genes, HLA-D region antigens, and genetic susceptibility to systemic lupus erythematosus in Caucasian and black Americans.

The complement components C4A, C4B, and factor B, and the HLA-A, B, C, DR, DQ, and DRw antigens were analyzed in 103 patients (66 Caucasian, 37 black) with systemic lupus erythematosus (SLE) and 98 control subjects (63 Caucasian, 35 black). Only the C4A null (silent) allele was significantly increased in SLE (0.254 versus 0.095 in Caucasians, p = 0.033; 0.200 versus 0.071 in blacks, p = 0.046). The absence of any detectable C4A gene products (homozygous C4A null or C4A*Q0,Q0) was found in 11.1 percent of Caucasian patients but in no control subjects (p = 0.006 with relative risk of 16.86). HLA-DR2 was significantly associated with Caucasian SLE (R2 = 0.63, p less than 0.0012). Multivariate analysis demonstrated that the HLA-DR2 antigen and C4A null allele contributed independently to the risk of SLE (relative risk 3.0 and 3.2, respectively); when HLA-DR2 and the homozygous C4A null phenotype were present together, the relative risk of SLE was 24.9. Both HLA-B8 and HLA-DR3 were increased in SLE, but these antigens are in linkage disequilibrium with the C4A null allele; the presence of HLA-B8 or DR3 did not contribute further to the risk of SLE. It is concluded that the HLA-DR2 antigen and the C4A null allele are independent and additive risk factors for development of SLE.

Adolescent↗

PubMed1989

Pulsed field gel electrophoresis identifies a high degree of variability in the number of tandem 21-hydroxylase and complement C4 gene repeats in 21-hydroxylase deficiency haplotypes.

The human steroid 21-hydroxylase gene, CYP21B, and its closely homologous pseudogene, CYP21A, are each normally located centromeric to a complement C4 gene C4B and C4A respectively, in an organization suggesting tandem duplication of a CYP21 + C4 unit. Such an organization has been considered to facilitate gene deletion and addition events by unequal crossover between the tandem repeats. However, the large size (approximately 30 kb) of the individual CYP21 + C4 repeat units together with the difficulty in identifying reliable CYP21A- and CYP21B-specific markers has prevented direct monitoring of gene organization on individual haplotypes by conventional Southern analyses. In the present investigation we have sought to clarify the CYP21 and C4 gene organization in members of 32 British 21-hydroxylase deficiency families by employing additional experimental approaches, notably a long-range restriction mapping approach, which permits assessment through a VNTR type of analysis, of the number of CYP21 and C4 units on individual haplotypes. Our results show that there is a very high frequency (33%) of 21-hydroxylase deficiency haplotypes where functional CYP21B gene sequence has been removed as a consequence of CYP21 + C4 gene deletion while several haplotypes show evidence of gene addition. In each case that we have investigated the gene deletion and gene addition haplotypes differ in length from conventional haplotypes by integral multiples of approximately 30 kb, which strongly supports the involvement of unequal crossover mechanisms. Additionally, the comparatively frequent occurrence of CYP21 fusion genes which contain both CYP21A- and CYP21B-associated markers is suggested by the combined data from Southern analyses, long-range restriction mapping and characterization of selected regions of CYP21 genes which have been amplified in vitro.

Adrenal Hyperplasia, Congenital↗

PubMed1995

Immunopathogenesis of inflammatory myopathies.

Immune-mediated mechanisms appear to play a primary role in the pathogenesis of polymyositis (PM) and dermatomyositis (DM). The serum of patients with active DM has high levels of circulating complement fragments C3b, C4b, and C5b-9 membranolytic attack complex (MAC) and demonstrates a very high C3 uptake in an vitro assay system. The MAC and the immune complex-specific C3bNEO fragment are deposited on the endomysial capillaries early in the disease and lead sequentially to loss of capillaries, muscle ischemia, muscle fiber necrosis, and perifascicular atrophy. In contrast, in PM the muscle fiber injury is initiated by sensitized CD8+ cytotoxic T cells that recognize heretofore unknown and probably endogenous muscle antigens in the context of major histocompatibility complex (MHC) class I expression. A restricted (oligoclonal) pattern of T-cell receptor with prominence of Va1, Vb6, and Vb15 genes is noted within the endomysial infiltrates suggesting that the T-cell response is antigen driven. In both PM and DM, intercellular adhesion molecule (ICAM)-1 and vascular cell adhesion molecule (VCAM)-1 are upregulated in the endomysial endothelial cells and function as ligands for the leukocyte integrins leukocyte function-associated antigen (LFA)-1 and very late activating antigen (VLA)-4, allowing activated lymphocytes to adhere to the endothelial cells and migrate to the muscle fibers. Among viruses, only the retroviruses human immunodeficiency virus (HIV) and human T-cell lymphotropic virus (HTLV)-1 have been convincingly shown to trigger PM, which is mediated by nonviral-specific, cytotoxic CD8+ cells. The treatment of inflammatory myopathies remains empirical. Many patients respond to steroids to some degree and for some period of time. Azathioprine, methotrexate, cyclosporine, cyclophosphamide, and plasmapheresis can be of mild to moderate benefit. High-dose intravenous immunoglobulin (IVIg) is a promising therapeutic modality for some patients resistant to therapies. In a controlled study, IVIg was effective in DM not only in improving the clinical symptoms but also in reversing the underlying immunopathology. The role of IVIg in PM and IBM is under study in control trials.

Atrophy↗

PubMed1993

Altered CYP21 genes in HLA-haplotypes associated with congenital adrenal hyperplasia (CAH): a family study.

Disorders of the CYP21 gene, which is located within the major histocompatibility complex on the short arm of chromosome 6, are the leading causes of congenital adrenal hyperplasia (CAH). The coding gene and a highly homologous pseudogene are tandemly arranged with the two genes for the fourth component of complement (C4A and C4B). To analyse the prevalence rates of mutations of the CYP21 genes and the segregation of the CYP21 genes with their corresponding human leucocyte antigen (HLA)-haplotypes, 21 families with one or two children with the severe form of 21-hydroxylase deficiency were studied. Mutations of the CYP21 gene on their corresponding HLA-haplotype were detected by hybridisation of polymerase chain reaction (PCR)-amplified genomic DNA with sequence-specific oligonucleotides and solid phase direct sequencing. Our study has shown the following. (1) A single basepair mutation (A-->G or C-->G) within the second intron is the most frequent mutation leading to impaired 21-hydroxylase activity. This mutation is only detected in HLA-haplotypes associated with the salt-wasting form of CAH. (2) A large deletion of part or all of the CYP21 gene is associated with the HLA-haplotype A3, BW47, C6, DR7, DR53, DQ2 but is also observed in other HLA-haplotypes and can be detected by a simple rapid PCR restriction fragment length polymorphism method. (3) Two alleles of the coding CYP21 gene differing in a leucine codon within the first exon, (formerly described as a mutation associated with 21-hydroxylase deficiency) have been found with an equal distribution in patients with 21-hydroxylase deficiency, non-disease HLA-haplotypes and the local healthy controls.

Adrenal Hyperplasia, Congenital↗

PubMed2000

Molecular, serological and genetic studies on two new HLA-DRB1 alleles--HLA-DRB10704 and HLA-DRB11507.

Two new HLA-DRB1 alleles (DRB1*0704 and DRB1*1507) were detected during routine polymerase chain reaction (PCR)-based typing of two Caucasoid bone marrow panel donors due to apparent DRB1* "blanks" being associated with unexpected DRB4, DRB5 and DQB1 alleles. HLA-DRB1*0704 differed from DRB1*0701 by five consecutive nucleotides at positions 217 to 221 of exon 2 encoding two amino acids substitutions of tyrosine to asparagine at codons 77 and valine to tyrosine at codon 78. DRB1*1507 differed from DRB1*1501 by a single nucleotide at position 127 encoding an amino acid substitution of phenylalanine to tyrosine at codon 47. Their specificities were unequivocally assigned by serology as HLA-DR7 and DR15, respectively, and family and population studies allowed their likely HLA-A,B,C,DR,DQ and complement (Bf, C4A, C4B) bearing haplotypes to be identified. No further examples were found in 19,113 HLA-DR,DQ typed donors from the Welsh Bone Marrow Donor Registry indicating that both these alleles have a phenotype frequency of <0.01% and a gene frequency of <0.00003.

Alleles↗

PubMed2001

Binding of human C4BP to the hypervariable region of M protein: a molecular mechanism of phagocytosis resistance in Streptococcus pyogenes.

The amino-terminal hypervariable region (HVR) of streptococcal M protein is required for the ability of this virulence factor to confer phagocytosis resistance. The function of the HVR has remained unknown, but the finding that many HVRs with extremely divergent sequences bind the human complement regulator C4b-binding protein (C4BP) has suggested that this ligand may play a role in phagocytosis resistance. We used the M22 system to study the function of bound C4BP and provide several lines of evidence that C4BP indeed contributes to phagocytosis resistance. First, the ability of anti-HVR antibodies to cause opsonization correlated with their ability to inhibit binding of C4BP. Secondly, a short deletion in the HVR eliminated C4BP binding and also reduced the ability of M22 to confer phagocytosis resistance. Thirdly, the addition of an excess of pure C4BP to a phagocytosis system almost completely blocked the effect of opsonizing anti-HVR antibodies. Together, our data indicate that binding of C4BP to the HVR of M22 plays an important role in phagocytosis resistance, but other properties of M22 also contribute. This study provides the first molecular insight into the mechanisms by which the HVR of an M protein confers phagocytosis resistance.

Amino Acid Sequence↗

PubMed1992

Genetic risk factors for perinatally acquired HIV-1 infection.

This study evaluates genetic influence on susceptibility to perinatal HIV-1 infection among 106 Black infants from New York and San Francisco born to mothers infected with HIV-1. Genes tested by molecular techniques are HLA class II loci DRB1, DPB1 and DQA1; HLA class III loci complement C4A and C4B; alpha and beta interferons; and the constant region of the T-cell receptor beta chain. Of the 106 infants analysed, 54 are infected with HIV and 52 remain uninfected at age 15 months and older. Genotypes in the HLA region appear to influence risk of HIV infection. Specifically, infants with the amino acid sequence -asp-glu-ala-val- at DPB1 positions #84-87 are more likely to be infected (P = 0.001) and infants with the allele DQA1*0102 are less likely to be infected (P = 0.031). Combinations of these two risk factors show a strong dose response (P = 0.0005). HLA DPB1 and DQA1 may play a direct role in immune response associated with HIV-1 infection, or the critical region may be located between these two genes. Characterisation of other class II HLA genes in these infants will allow more precise determination of the role of HLA loci in susceptibility to HIV-1 infection.

Alleles↗