Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Complement C4b”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 1,441 records · Page 80Linked to original sources
PubMed1989

Isolated pulmonary hypertension in the grandchild of a kindred with scleroderma (systemic sclerosis): "neonatal scleroderma"?

We report a small kindred in which the father and daughter with positive antinuclear antibodies (ANA) (proband) had diffuse cutaneous and visceral scleroderma (systemic sclerosis, SSc), antitopoisomerase autoantibodies and shared the HLA-A23 C- B- DR5 DRw52 DQw3 haplotype. The ANA- granddaughter (daughter of the proband) was noted to have severe isolated pulmonary hypertension within the first 6 months of life, and had the other maternal HLA-A1 Cw8 B14 DR1 DQw1 haplotype, which included a B1, B2 duplication of the C4B allele. All 3 members shared DRw52. The possibility that neonatal pulmonary hypertension represents an isolated autoimmune disease or a hitherto undescribed neonatal syndrome is proposed and the immunogenetic autoantibody implications are discussed.

Antibodies, Antinuclear↗
PubMed1989

Molecular cloning of the cDNA coding for proline-rich protein (PRP): identity of PRP as C4b-binding protein.

Proline-rich protein (PRP) is a plasma protein with a high proportion of proline residues and possessing lipid-binding properties. In order to clarify its structure, a human liver cDNA library was screened using anti-PRP antiserum. Several overlapping phage cDNA clones were isolated and the total nucleotide sequence of the cDNA, 2178 bp in length, was analyzed. The amino acid composition of PRP deduced from the cDNA was essentially the same as that reported for PRP. In a homology search, the cDNA sequence was almost completely the same as the previously reported cDNA sequence of C4b-binding protein. Furthermore, the reported molecular weights of the two proteins under both reduced and unreduced conditions were quite alike. These findings indicate that PRP is identical with C4bp.

Amino Acid Sequence↗
PubMed1993

Protein S levels during the normal menstrual cycle and during estrogen therapy for premature ovarian failure.

Protein S levels have been reported to be decreased in pregnancy and with oral contraceptive use. This study monitored the effects of estrogen shifts on protein S levels. Four patients with premature ovarian failure were treated with either oral or transdermal patch estrogen replacement. Blood drawn on days 1, 14, and 28 of therapy was analyzed for estradiol, estrone, free and total protein S, and C4b-binding protein (C4b-BP) levels. Similar studies were performed on six normally cycling control patients and seven postmenopausal women. In healthy females, total levels of protein S fell from 22.1 +/- 0.73 micrograms/mL on day 1 to 19.2 +/- 1.29 micrograms/mL on day 14 (p < 0.023). Free protein S levels declined from 6.45 +/- 0.70 micrograms/mL to 5.59 +/- 0.69 micrograms/mL (p < 0.016). C4b-BP levels did not change during the normal menstrual cycle. Baseline total protein S (44.1 +/- 7.0 micrograms/mL) and C4b-BP (193 +/- 18%) levels were elevated in patients with premature ovarian failure. On oral therapy, there was a strong, negative correlation (r = -0.979, p < 0.021) between C4b-BP and estradiol levels. C4b-BP levels did not change in patients with the patch. Both estrogen therapies produced similar declines (44 to 26 micrograms/mL) in total protein S levels. In all cases, total protein S levels changed as a reciprocal function of estradiol. C4b-BP (128 +/- 6.5%) and total protein S (32.2 +/- 3.0 micrograms/mL) levels were higher in postmenopausal women than in nonmenopausal females. Free protein S levels in postmenopausal women (9.6 +/- 0.6 micrograms/mL) were normal.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1995

The Ser 460 to Pro substitution of the protein S alpha (PROS1) gene is a frequent mutation associated with free protein S (type IIa) deficiency.

A Ser 460 to Pro mutation of protein S (PS), involving a T to C transition in exon XIII of the protein S alpha (PROS1) gene and known as the Heerlen polymorphism, was found in 16 of 85 symptomatic patients with PS deficiency (18.8%) and only 1 of 113 healthy subjects (0.8%). Another frequent polymorphism was described in exon XV of the PROS1 gene, in the codon for Pro 626 (CCA/CCG). We found that Heerlen polymorphism was associated with allele CCA and not with allele CCG, suggesting a probable transmission by a common ancestor. Most subjects bearing the Ser 460 to Pro mutation were deficient in free PS, but had normal total PS levels. Normal levels of the C4b-binding protein (C4b-BP) isoform containing a beta chain (C4b-BP beta +) ruled out increased C4b-BP beta + as a cause of the free-PS deficiency. The binding curves of the mutated (Heerlen) PS on C4b-BP immobilized on microplates were biphasic, suggesting that one molecule of C4b-BP can bind two molecules of Heerlen PS. Because normal PS binds to C4b-BP with 1:1 stoichiometry, this may explain the free-PS deficiency observed in patients carrying the Ser 460 to Pro mutation.

Carrier Proteins↗
PubMed2002

Structure-function studies of the receptors for complement C1q.

C1q is an essential component of the phylogenetically ancient innate complement (C) system and is crucial to our natural ability to ward off infection and clear toxic cell debris (e.g. amyloid fibrils, apoptotic cells). Several candidate C1q receptors [C1q receptor for phagocytosis enhancement (C1qRp), complement receptor (CR) 1, calreticulin (CRT), binding protein for the globular head of C1q (gC1qbp)] have been described, and the aim of this review is to shed light on their structure-function relationships. One cell-surface molecule, C1qRp, has emerged as a defence collagen receptor for C1q, as well as mannose-binding lectin (MBL) and surfactant protein A. C1qRp (also known as the AA4 antigen in rodents) is the antigen recognized by a pro-adhesive monoclonal antibody called mNI-11 and antibodies against CD93, but recent results failed to confirm C1q binding activity. CR1 (CD35), a multifunctional receptor both in its ligand specificity and in its C regulation activities, is found on circulating monocytes and neutrophils, but the major site of expression is B-lymphocytes. As a receptor, CR1 binds to C1q, other C opsonins (C4b, C3b, iC3b) and MBL, and as such, has been involved in promoting phagocytosis. Several studies support a role for the cell surface receptor for the collagenous domains of C1q (cC1qR; also known as CRT). CRT belongs to the family of heat-shock proteins, the most abundant and ubiquitous soluble intracellular proteins. Though CRT does not have a transmembrane domain, it seems to mediate phagocytosis of the apoptotic cells through association with CD91. A 33 kDa protein interacts with the globular head of C1q and, logically, has been termed gC1qbp. This protein is located in mitochondria, suggesting that gC1qbp is not a cell-surface receptor itself.

Animals↗
PubMed1992

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

We have studied the behaviour of total protein S, free protein S, protein C and C4b-binding protein fifteen neonates with severe infections, eight with septic shock and in a group of ten healthy newborns. Protein C was decreased in shock and septic patients, but only the shock group showed significant differences compared to normal neonates. Total protein S was normal in both groups of patients, although free protein S had significantly lower values in shock and nonshock infants. C4b-binding protein was higher than normal in septic and shock patients compared to the control group. Decreased values of protein C and free protein S can be explained by the activation of coagulation and their subsequent consumption. On the other hand, the increased levels of C4b-binding protein can affect the distribution of protein S in plasma, producing a shift in protein S to the complexed inactive form. These findings can contribute to an increased risk of microthrombosis during neonatal sepsis.

Carrier Proteins↗
PubMed1993

The thioester and isotypic sites of complement component C4 in sheep and cattle.

The region inclusive of the thioester and the isotype-determining sites of the sheep C4 genes from a single animal was amplified by polymerase chain reaction (PCR). Two bands, at 880 base pairs (bp) and 1000 bp, were resolved by agarose gel electrophoresis. Four different clones were obtained for the 880 bp (type 1) product and two from the 1000 bp (type 2) product. Two of the type 1 clones (type 1H) and both type 2 clones (type 2H) code for the PCPVIH sequence at the isotypic site whereas the other two type 1 clones (type 1D) code for the PFPVMD sequence. By restriction mapping and Southern blot analysis, there appears to be four C4 gene loci for the sheep: two type 1H, one type 1D, and one type 2H. The type 1H and type 2H genes are likely to code for proteins with C4B-like properties whereas the type 1D genes for proteins with C4A-like properties. The same region of the sheep C4 genes of nine other breeds of sheep are also amplified by PCR and analyzed by restriction mapping and Southern hybridization. Each of the sheep has type 1H, type 2H, and type 1D genes and appears to have four C4 gene loci except for the Orkney, which may have five. A single band of 880 bp was obtained from the PCR product from the genomic DNA of a single cow. Five different clones were identified, two of which code for the PFPVMD sequence and three for the PCPVIH sequence at the isotypic site, which is consistent with previous finding that C4 proteins with A- and B-like activities could be purified from the plasma of the same animal. Comparison of the nucleotide sequences of the isotype-determining region of the sheep and cattle C4 genes with those of the primates and mouse suggests that the C4A-like genes evolved independently in the primates and the ungulates.

Amino Acid Sequence↗
PubMed1985

Adrenal 21-hydroxylase cytochrome P-450 genes within the MHC class III region.

Genes encoding several serum complement components and the gene(s) for steroid 21-hydroxylase (21-OH) have been located in the class III region of the major histocompatibility complex (MHC). All these genes are highly polymorphic in man, and these polymorphisms have been used to draw conclusions about the structure and function of these genes. For example, electrophoretic polymorphisms of the fourth component of complement (C4) have been shown to be controlled by two closely linked genes, which also control expression of the red cell antigens Rodgers and Chido. Steroid 21-OH deficiency (D) can occur in several forms which differ in severity, and because of 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-OH D 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-OH and C4 loci and perhaps the HLA-B gene as well. To test this hypothesis and identify the 21-OH gene, a cDNA clone was isolated which 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 gene. These experiments showed that at least one structural gene for the cytochrome P450 specific for 21-hydroxylation is located in the MHC, probably very near the C4 genes, and a mutation in this gene results in 21-OH D. Cosmid clones have been used to locate the 21-OH genes both in man and mouse. In both species, there are two 21-OH 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-OH D on the Bw47 haplotype, but the gene 3' of the C4A gene is deleted in hormonally normal individuals on the A1;B8;C4AQO;C4B1;DR3 haplotype. Thus the 21-OH B gene is normally active in man, but the 21-OH A gene is not.

Adrenal Glands↗
PubMed1984

Extended haplotypes of chromosome 6 in adult rheumatoid arthritis.

In 46 patients with rheumatoid arthritis (RA) the allele C4B*3 occurred in 6 patients, while among 350 normal controls, it occurred 6 times (P less than 0.00002). Among 9 white and 1 black families, each of which had 2 or more members with RA, there were 36 haplotypes associated with RA. An extended haplotype (specific HLA-B, DR, complotype haplotypes in significant linkage disequilibrium) containing C4B*3: HLA-B15, DR4, BF*S, C2*C, C4A*3, C4B*3, was found twice (P less than 0.001) among whites with the disease-associated chromosomes.

Adult↗
PubMed1987

The study of a French family with two duplicated C4A haplotypes.

The finding of two duplicated C4A haplotypes in a normal French family led to a detailed study of their C4 polymorphism. The father had an extremely rare A*6A*11, B*QO haplotype inherited by all of his children and the mother had the more common A*3A*2, B*QO haplotype. Two HLA identical daughters only have four C4A alleles. The father's A11 allotype expresses Ch:1 (Chido) rather than Rg:1 (Rodgers) and represents a new Ch phenotype Ch:1,-2,-3,-4,-5,-6. In order to clarify the genetic background in this unusual family, DNA studies of restriction fragment length polymorphisms (RFLPs) were undertaken. The father's rare haplotype, which expresses two C4A allotypes, results from a long and a short C4 gene normally associated with the A*6, B*1 that also exhibits the Bg/II RFLP. As it travels in an extended MHC haplotype HLA A2, B57(17), C2*C, BF*S, DR7 that is most frequently associated with A*6, B*1, we postulate that the short C4B has been converted in the alpha chain region to a C4A gene which produces a C4A protein. This report of a short C4A gene is the first example in the complex polymorphism of C4.

Alleles↗
PubMed2003

C4b-binding protein (C4BP) activates B cells through the CD40 receptor.

We demonstrate that the alpha chain of human C4b binding protein (C4BP) binds directly to CD40 on human B cells at a site that differs from that used by CD40 ligand. C4BP induces proliferation, upregulation of CD54 and CD86 expression, and IL4-dependent IgE isotype switching in normal B cells but not in B cells from patients with CD40 or IKKgamma/NEMO deficiencies. Furthermore, C4BP colocalized with B cells in the germinal centers of human tonsils. These observations suggest that C4BP is an activating ligand for CD40 and establish a novel interface between complement and B cell activation.

Antigens, CD↗
PubMed1990

Relative electrophoretic migration distances for the classification of C4 allotypes.

For the definition of common C4 allotypes relative electrophoretic migration (RM) values were determined. A set of standard C4 variants were investigated by prolonged agarose gel electrophoresis and subsequent immunofixation with specific antiserum. RM distances were measured by laser densitometry. Using an arbitrary standard of 100 units for the migration distance between the C4B 1 and C4A 3 bands a total deviation of +/- 6.45% in more than 108 single determinations was found. The common C4 alleles used for standardization were C4A*6, C4A*4, C4A*3, C4A*2, C4B*5, C4B*3, C4B*2, C4B*1. In addition, side by side comparison and admixture of known variants will be necessary for the differentiation of some of the closely migrating allotypes. RM values are now available for eight alleles frequently found in all populations for future comparison and designation of newly discovered C4 allotypes.

Complement C4↗
PubMed1988

Major histocompatibility complex markers in patients with nomifensine-induced immune hemolytic anemia.

To evaluate a possible role of major-histocompatibility-complex (MHC)-related immune-response genes for the selective production of drug-induced antibodies, HLA class I (ABC), class II (DR, DQ), class III (BF, C2, C4A, C4B) as well as glyoxalase-1 allotypes were investigated in 26 patients with nomifensine-induced immune hemolytic anemia. No statistically significant deviations of MHC antigen frequencies were noted. The possible implications of these findings are discussed.

Adult↗
PubMed1996

Effect of repetitive high-dose treatment with soluble complement receptor type 1 and cobra venom factor on discordant xenograft survival.

Hyperacute xenograft rejection may be modified by the activation and depletion of complement (C) using cobra venom factor (CVF). This method of prolonging xenograft survival is toxic and associated with systemic inflammation, which may potentially contribute to the pathologic features of delayed xenograft rejection. Soluble complement receptor type 1 (sCR1) inhibits both the classical and alternative C pathways and thus limits the production of proinflammatory products such as the anaphylatoxins. Hence, we investigated the effects of various sCR1 and CVF regimens, and combinations thereof, in the discordant guinea pig-to-Lewis rat cardiac xenograft model. Mean graft survival time (MST) was significantly prolonged with repetitive dosing (MST=22 hr) or continuous infusion of sCR1 (MST=32 hr) as compared with unmodified controls (MST=15 min). However, sCR1 did not prevent intragraft deposition of C3 or neutrophil infiltration and resulted in only partial inhibition of C-mediated hemolytic activity in vitro. Grafts in rats treated with a single dose of CVF (MST=67 hr) or repetitive doses of CVF (MST=69 hr) survived significantly longer than those treated with sCR1 alone, and lacked C3 deposition or neutrophil accumulation. Sera from these animals were completely depleted of C-mediated hemolytic activity. Animals treated with a single dose of CVF, or sCRI plus a single dose of CVF (MST=64 hr), had similar xenograft survival times. However, immunohistologic studies showed that addition of sCR1 to a single dose of CVF resulted in decreased macrophage activation and reduced levels of cytokines (tumor necrosis factor-alpha and interleukin-1beta) within xenografts as compared with that in recipients treated with CVF alone. Such decreased macrophage activation may result from the binding of C4b by sCR1, since combination therapy was associated with decreased intragraft C4b as compared with either therapy alone. High doses of sCR1 were well tolerated by rats and significantly prolonged discordant xenograft survival (MST=32 hr), although not to the same extent as CVF. The modification of the intragraft immune responses seen with CVF/sCR1 combination therapy may augment further therapeutic manipulations to achieve discordant xenograft survival without the attendant toxicity associated with repeated CVF administration.

Animals↗
PubMed1996

Incomplete functional deficiencies of the fourth (C4) and second (C2) components of complement in a patient with linear frontoparietal scleroderma and his family. Deficiencies determined by a gene not linked to human leukocyte antigen system.

BACKGROUND: In a previous study, a patient suffering from linear frontoparietal scleroderma and some of his family members were found to have an incomplete functional deficiency of the second component (C2) of complement (C). In this study, the proband and the rest of his family members were investigated for functional deficiencies of C2 and the fourth component of C (C4). A search for null alleles of C2 (C2*Q0) and C4 (C4*Q0) was made to find out whether their occurrence is responsible for incomplete functional deficiencies. HLA analysis was performed to find out whether deficiencies are linked to HLA alleles known to be associated with C4*Q0 and C2*Q0. Possible large deletions at C4 and 21-hydroxylase (21-OH) gene loci were also investigated in some family members. OBSERVATIONS: The proband had a combined functional deficiency of C4 and C2. Some of his family members had a partial functional deficiency of C4, some of C2 and some of C4 and C2; none had null alleles of C2 (C2*Q0), factor B (B*Q0) or C4B (C4B*Q0). C4*Q0 or functional C4 deficiency in this family was not associated with HLA-A1;B8;DR3 alleles. C2 deficiency was also not associated with HLA antigens known to be associated with type I and II C2 deficiencies. No gene deletion or unusual polymorphism at C4A and 21-OHA loci could be seen by restriction fragment length polymorphism (RFLP) studies. CONCLUSIONS: Combined and isolated partial functional deficiencies of C4 and C2 observed in the proband and many of his family members were not caused by C activation or null alleles. They were not linked to HLA system and were reminiscent of those observed previously in a family in which C4 deficiency was determined by a gene not linked to the HLA system.

Alleles↗
PubMed1978

The sequential appearance of Ia-like antigens and two different complement receptors during the maturation of human neutrophils.

Ia antigens and two different types of complement (C) receptors appeared on membrane surfaces in a distinct sequence during the maturation of human neutrophils. Taking advantage of the finding that neutrophil celll density increased with maturation, density gradient centrifugation was used to separate neutrophils into fractions that were greatly enriched in cells representing individual stages of differentiation. Myeloblasts, the earliest cells recognized in the myeloid series of both normal and myelogenous leukemic individuals, expressed Ia determinants, whereas Ia determinants were absent or diminished on the majority of promyelocytes and completely undetectable on more mature granulocytes. Double marker studies demonstrated that Ia determinants were lost from the membrane of developing myeloid cells before the appearance of any type of C receptor. In the next phase of maturation defined by surface markers, neutrophils acquired a CR2-type C receptor (C3d receptor) that was similar in specificity to CR2 of B lymphocytes. This stage of maturation approximately corresponded to the myelocyte-metamyelocyte stage defined by standard morphologic criteria, and preceded the third stage of surface marker maturation when developing neutrophils began to express CR1-type C receptors (immune adherence, C4b-C3b receptors) in addition to CR2. In the final stage of surface marker-defined maturation, CR2 was lost from high density polymorphonuclear neutrophils and CR1 was maximally expressed. Normal blood polymorphonuclear neutrophils contained only 17% of CR2-bearing cells and these were shown to be of lower density than the majority of neutrophils that expressed only CR1. There was some variation in the correlation of surface marker expression and maturation stage defined by morphologic criteria, but in all cases the sequence of marker appearance was the same: Ia leads to CR2 leads to CR1CR2 leads to CR1.

Binding Sites↗
PubMed1988

Evidence for a C4b binding site on the C2b domain of C2.

We raised murine mAb against human C protein C2. The representative mAb 3A3.3 (IgG1 kappa) recognized an epitope on the C2b domain of C2, as determined by binding and inhibition of binding radioassays. The hemolytic activity of purified human C2 and of C2 in normal human serum was inhibited by the mAb. The rate of decay of the C3-convertase at 30 degrees C was not affected by the mAb. C2 binding to EAC4b was inhibited by intact IgG and the Fab fragment of the mAb; 50% inhibition required 1 microgram/ml of either. The data suggest the presence of a C4b-binding site on the C2b domain of C2 and that the mAb recognizes an epitope at, or adjacent to, this site. The C2b portion of the C2 molecule may be important in assembly of the classical pathway C3-convertase.

Animals↗
PubMed2006

Deficiency of functional mannose-binding lectin is not associated with infections in patients with systemic lupus erythematosus.

Infection imposes a serious burden on patients with systemic lupus erythematosus (SLE). The increased infection rate in SLE patients has been attributed in part to defects of immune defence. Recently, the lectin pathway of complement activation has also been suggested to play a role in the occurrence of infections in SLE. In previous studies, SLE patients homozygous for mannose-binding lectin (MBL) variant alleles were at an increased risk of acquiring serious infections in comparison with patients who were heterozygous or homozygous for the normal allele. This association suggests a correlation between functional MBL level and occurrence of infections in SLE patients. We therefore investigated the biological activity of MBL and its relationship with the occurrence of infections in patients with SLE. Demographic and clinical data were collected in 103 patients with SLE. Functional MBL serum levels and MBL-induced C4 deposition were measured by enzyme-linked immunosorbent assay using mannan as coat and an MBL- or C4b-specific monoclonal antibody. The complete MBL-dependent pathway activity was determined by using an assay that measures the complete MBL pathway activity in serum, starting with binding of MBL to mannan, and was detected with a specific monoclonal antibody against C5b-9. Charts were systematically reviewed to obtain information on documented infections since diagnosis of SLE. Major infections were defined as infections requiring hospital admission and intravenous administration of antibiotics. In total, 115 infections since diagnosis of lupus, including 42 major infections, were documented in the 103 SLE patients (mean age 41 +/- 13 years, mean disease duration 7 +/- 4 years). The percentage of SLE patients with severe MBL deficiency was similar to that in 100 healthy controls: 13% versus 14%, respectively. Although deposition of C4 to mannan and MBL pathway activity were reduced in 21% and 43% of 103 SLE patients, respectively, neither functional MBL serum levels nor MBL pathway activity was associated with infections or major infections in regression analyses. In conclusion, SLE patients frequently suffer from infections, but deficiency of functional MBL does not confer additional risk.

Adult↗