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PubMed1992

Neonatal lupus erythematosus syndrome: analysis of C4 allotypes and C4 genes in 18 families.

We examined 18 families with infants who had neonatal lupus erythematosus (NLE) syndrome to determine whether abnormalities in C4 phenotypes and genotypes were an additional risk factor for this syndrome. Fifteen of 18 mothers of infants with NLE (83%) had C4 null allotypes compared with 36% of population controls (p = less than .001). This increased frequency was due mainly to the presence of C4A null allotypes (11/18, 61%). C4 gene abnormalities, i.e., deletion or probable duplication, were present in 100% (16/16) of mothers of infants with NLE. The most common molecular genetic abnormality in mothers of infants with NLE in this study was deletion of C4A genes. Duplication of C4A and C4B loci was also commonly seen. Duplication of C4A genes was detected only in mothers of infants with complete congenital heart block (CCHB), and duplication of C4B was detected only in mothers of infants with dermatitis. No significant increase in C4A or C4B null allotypes or protein deficiencies was noted in mothers of infants with neonatal lupus when compared with anti-Ro(SS-A)-positive mothers delivered of clinically normal infants. Fathers of infants with NLE showed a trend toward increase in C4B null allotypes when compared with population controls (75%, 3/4, p = .06). The two infants with CCHB examined were C4B protein-deficient, in contrast to infants with lupus dermatitis, who had frequent C4B null allotypes but no C4B protein deficiency. C4B null allotypes were not seen in unaffected siblings of infants with NLE and in only 1 of 7 anti-Ro(SS-A)-positive mothers who delivered clinically normal infants. We conclude that inheritance of C4A null allotypes is not predictive of increased risk of neonatal lupus when present in anti-Ro(SS-A)-positive women. Examination of paternal and maternal C4 genes of additional infants with NLE, in particular those with CCHB, and of normal infants born to anti-Ro(SS-A)-positive mothers--and of the normal infants' parents--is required to determine if abnormal C4B genes are a critical factor rendering susceptibility to the NLE syndrome.

Antibodies, Antinuclear↗
PubMed1990

Genetic polymorphisms of HLA class III and GLO1 in Chinese Yao nationality.

Yao is one of the minority nationalities located mainly in the South of China (Guang Xi province). The purpose of this study was to examine HLA class III and GLO1 in Yao nationality to identify the difference between Yao and Han. Han is the major nationality in China. Yao has the lowest C2*C frequency (0.9336) in the world. Before this study the lowest C2*C frequency known was that of the Japanese (0.9386). Gene frequencies in Yao are the following: C2*C = 0.9336, C2*B = 0.0664; BF*S = 0.9071, BF*F = 0.0929; C4A*4 = 0.0253, C4A*3 = 0.6061, C4A*2 = 0.2121, C4A*1 = 0.0152, C4A*Q0 = 0.1414; C4B*3 = 0.0051, C4B*2 = 0.0657, C4B*1 = 0.7071, C4B*92 = 0.0455, C4B*95 = 0.0253, C4B*96 = 0.0253, C4B*12 = 0.0051, C4B*Q0 = 0.1212; GLO1*1 = 0.1161, GLO1*2 = 0.8839. We have compared these data with those reported for Han.

Blood Donors↗
PubMed2000

Octamerization enables soluble CD46 receptor to neutralize measles virus in vitro and in vivo.

A chimeric fusion protein encompassing the CD46 ectodomain linked to the C-terminal part of the C4b binding protein (C4bp) alpha chain (sCD46-C4bpalpha) was produced in eukaryotic cells. This protein, secreted as a disulfide-linked homo-octamer, was recognized by a panel of anti-CD46 antibodies with varying avidities. Unlike monomeric sCD46, the octameric sCD46-C4bpalpha protein was devoid of complement regulatory activity. However, sCD46-C4bpalpha was able to bind to the measles virus hemagglutinin protein expressed on murine cells with a higher avidity than soluble monomeric sCD46. Moreover, the octameric sCD46-C4bpalpha protein was significantly more efficient than monomeric sCD46 in inhibiting virus binding to CD46, in blocking virus induced cell-cell fusion, and in neutralizing measles virus in vitro. In addition, the octameric sCD46-C4bpalpha protein, but not the monomeric sCD46, fully protected CD46 transgenic mice against a lethal intracranial measles virus challenge.

Animals↗
PubMed2005

Two divergent isotypes of the fourth complement component from a bony fish, the common carp (Cyprinus carpio).

Duplication and diversification of several complement components is a striking feature of bony fish complement systems. It gives an interesting insight into an evolutionary strategy for the possible enhancement of the repertoire of innate immunity. The present study is aimed at examining diversity in bony fish C4, a member of the thioester-containing complement components. Two diverged cDNA sequences sharing only approximately 32% identity at the amino acid level were isolated from the common carp and designated C4-1 and C4-2. C4-1 and C4-2 share a number of C4-like structural signatures, such as the thioester site and a disulfide-linked three-chain structure. Interestingly, they differ at the residue corresponding to the thioester-catalytic histidine, as seen in the human C4A and C4B isotypes, suggesting their distinct substrate specificities in the binding reaction of the thioester. Phylogenetic analysis indicates that the divergence of C4-1 and C4-2 predated the separation of the cartilaginous and bony fish lineages. Genomic Southern hybridization suggests the presence of single copy genes each encoding C4-1 and C4-2 in the carp genome. An activation fragment, C4a, was shown to be released from each isotype in carp serum activated via the classical and/or lectin pathways. Synthetic peptides representing a putative C2 binding site on C4-1 and C4-2 inhibited the classical pathway-mediated hemolytic activity of carp serum in a dose-dependent manner. The results suggest that C4-1 and C4-2 represent two major lineages of C4 that are present in carp serum, have distinct binding specificities, and are functional in the classical/lectin pathways of complement activation.

Amino Acid Sequence↗
PubMed1987

There are two C4 genetic loci and a null allele in the chimpanzee.

Genetic polymorphism in C4 in the chimpanzee was studied by agarose gel electrophoresis of desialated plasma and development of patterns by immunofixation with antiserum to human C4 and by a C4-sensitive hemolytic overlay. In general, immunofixation patterns showed multiple partially overlapping bands of which only the most cathodal had strong hemolytic activity. In analogy to human C4, the latter were designated C4B, whereas those detected by immunofixation which had little hemolytic activity were designated C4A. Chimp C4A and C4B reacted with human and mouse (monoclonal) anti-C4B and human anti-Ch1 but neither reacted with monoclonal anti-C4A or human anti-Ch2, Ch3, Rg1, or Rg2. On sodium dodecyl sulfate polyacrylamide gel electrophoresis, the alpha chain of C4B showed a slightly lower apparent relative mass than that of C4A at around Mr 93,000. There were three C4A variants and two C4B variants inherited in families as autosomal codominant traits, as C4A-C4B cosegregating pairs with no detectable crossing-over. These pairs were inherited with chimpanzee leukocyte antigen types C2 and BF variants without detectable crossing-over. Half-null C4 haplotypes with C4B QO were observed in family studies. Nine BF, C2, C4A, C4B allelic haplotypic combinations (complotypes) were identified among presumably unrelated chimpanzees.

Alleles↗
PubMed1989

C4A gene deletion and HLA associations in black Americans with systemic lupus erythematosus.

In North America and European Caucasoids with systemic lupus erythematosus (SLE) there is an increased frequency of a C4A, CYP21A gene deletion, largely associated with the HLA-B8,DR3,C4A*QO extended haplotype. There have been no consistent HLA associations reported for SLE in blacks, although an increased frequency of serologically determined C4A null alleles has been reported in two studies. We studied 79 black American SLE patients and 68 black controls by restriction fragment length polymorphism analysis to determine if a C4A gene deletion was a genetic risk factor for SLE. Moreover, the nature of the deletion and any HLA phenotypic associations were sought. Nineteen of 79 (24%) patients compared to 5 of 68 (7.4%) controls had a phenotypic C4A,CYP21A gene deletion (P = .005; RR = 4). A homozygous deletion in four patients gave a genotypic frequency of 23/158 (14.5%) SLE patients vs 5/136 (3.7%) controls (P = .001; RR = 4.5). The deletion was associated with HLA-DR2 (P = .03) and HLA-DR3 (P = .03). Moreover, all subjects with the deletion had HLA-DR2 or DR3 (P = 7.7 x 10(-6). HLA-B44 was also associated with the deletion (P = .02), and eight of the nine HLA-B44 positives also carried HLA-DR2. HLA-B8 approached significance (P = .08) and was always accompanied by HLA-DR3. Finally, this black population demonstrated a unique C4B gene size polymorphism with 80% C4B "short" as compared to the 40% C4B "short" frequency reported in whites. We conclude that a large C4A,CYP21A gene deletion, particularly associated with the HLA-B44, -DR2, and -DR3 alleles, is the strongest genetic risk factor thus far identified for SLE susceptibility in black Americans. Furthermore, the unique preponderance of the C4B "short" gene form may be a factor in the actual formation of the deletion.

Black People↗
PubMed1990

Molecular characterisation of C4 null alleles found in Felty's syndrome.

A higher prevalence of C4B null alleles is found in Felty's syndrome. The molecular basis of C4 null alleles was investigated by studying restriction fragment length polymorphisms (RFLPs) obtained with C4 and 21-hydroxylase (21-OH) DNA probes and by pulsed field gel electrophoresis in 30 subjects with Felty's syndrome. C4A null alleles were found in 10 subjects, and in five of these were associated with a deletion that included C4A and adjacent 21-OHA gene sequences. A 6.4 kilobase C4B-5'-specific Taq I fragment usually provided a reliable guide to the presence of a C4A deletion but unusually in one instance this fragment was found to be a marker of a functioning C4A gene. A C4B null allele was found in 17 subjects and was associated with a deletion involving C4B and 21-OHA gene sequences on only two occasions. There were no instances in which deletion of the 21-OHB gene occurred.

Alleles↗
PubMed2006

Structure of complement component C2A: implications for convertase formation and substrate binding.

C2a provides the catalytic center to the convertase complexes of the classical and lectin-binding pathways of complement activation. We determined two crystal structures of full-length C2a, with and without a pseudo ligand bound. Both structures reveal a near-active conformation of the catalytic center of the serine protease domains, while the von Willebrand factor A-type domains display an intermediate activation state of helix alpha7 with an open, activated metal-ion-dependent adhesion site. The open adhesion site likely serves to enhance the affinity for the ligand C4b, similar to "inside-out" signaling in integrins. Surprisingly, the N-terminal residues of C2a are buried in a crevice near helix alpha7, indicative of a structural switch between C2 and C2a. Extended loops on the protease domain possibly envelop the protruding anaphylatoxin domain of the substrate C3. Together with a putative substrate-induced completion of the oxyanion hole, this may contribute to the high substrate specificity of the convertases.

Amino Acids↗
PubMed1997

Combined heterozygous deficiency of the classical complement pathway proteins C2 and C4.

Genetic deficiencies of components of the classical pathway of complement activation are associated with an increased risk for the development of autoimmune and immune complex-mediated diseases. In the present study we report on the molecular and clinical features associated with combined heterozygous C4 and C2 deficiency in 15 individuals investigated within six families. Approximately 30% of the individuals manifested SLE or another autoimmune condition. Heterozygous C2 deficiency was related to a 28-bp deletion in the C2 gene (C2 deficiency type I), in most cases within the HLA-A25 B18 C2Q0 BfS C4A4B2 DR2 haplotype. Among 13 partial C4-deficient haplotypes transmitted, 8 carried C4A*Q0 alleles and 5 C4B*Q0 alleles. In seven cases the C4A*Q0 alleles were associated with a deletion of the C4A/CYP21P genes within the HLA-B8 C2C BfS C4AQ0B1 DR3 haplotype. In three cases, the C4B*Q0 allele was associated with a deletion of the C4B/CYP21P genes within the HLA-B18 C2C BfF1 C4A3BQ0 DR3 haplotype. In the other cases, C4A*Q0 or C4B*Q0 was dependent on as yet uncharacterized defects in the C4 gene or in C4 gene expression. In view of the relatively high frequency of heterozygous C4 deficiency in the normal Caucasian population, the expected frequency of the combined deficiency should approximate 0.001.

Adult↗
PubMed1982

C3 convertase of human complement: enhanced formation and stability of the enzyme generated with nickel instead of magnesium.

We demonstrate that nickel++ (Ni) can replace Mg in the formation of the C3b,Bb enzyme, and that Ni is more efficient in enzyme formation than Mg. C3b-bearing sheep erythrocytes (EC3b) were used to measure radiolabeled Factor B uptake and C3 convertase activity. Up to nine times more Factor B was specifically bound to EC3b in the presence of Ni than in the presence of Mg under identical conditions. To form one effective hemolytic site (1 Z) per EC3b cell with Ni, three times less Factor B, 12 times less Factor D, and 66 times less metal ion were required than when using Mg. The C3b,Bb formed with Ni (C3b,Bb(Ni)) had a 5 to 10 times longer half-life at different temperatures than the enzyme formed with Mg (C3b,Bb(Mg)). Native properdin stabilized C3b,Bb(Ni) to the same extent as C3b,Bb(Mg) (four to five times) and Factor H accelerated similarly the decay of both enzymes. Ni could also replace Mg in the formation of the C4b,2a enzyme. C4b,2a formation was measured by using C1 and C4b-bearing sheep erythrocytes (EAC1,4b) and native C2. To form 1 Z per EAC1,4b cell with Ni, two times less C2 and 60 times less metal ion were required than when using Mg. The half-life of the C4b,2a formed with Ni was two times longer than that formed with Mg. Decay of both C3b,Bb and C4b,2a enzymes formed either with Mg or with Ni was unaffected by EDTA. These results show that Ni is more efficient than Mg in the generation of both enzymes and suggest that Ni binds to the Mg-binding sites of the enzymes with a higher affinity than Mg.

Complement Activating Enzymes↗
PubMed1995

Tyrosine is a potential site for covalent attachment of activated complement component C3.

Activation of C3 results in the generation of metastable C3b, which has been shown to preferentially react with the hydroxyl groups of carbohydrates and with specific serine and threonine residues in proteins. In this study we have examined the reactivity of metastable C3b with the third type of hydroxyl group present in proteins, tyrosine (Tyr). The results demonstrated that Tyr reacts with the thioester of metastable C3b and that this reactivity was 11-fold better than that of threonine, 47-fold better than serine and 50-fold better than the reactivity of carbohydrates. Model peptides containing Tyr showed even higher reactivity than free Tyr, demonstrating that incorporation into peptide structures does not block C3b attachment. The site of attachment was found to be in the alpha'-chain of C3b and the bond was hydroxylamine sensitive, indicating an ester linkage. The stability of the C3b-Tyr complex was measured under physiological conditions (pH 7.4, 37 degrees C) and compared to the stability of other C3b complexes. C3b-Tyr decayed 50% in 19 hr at 37 degrees C, but C3b bound to a Tyr-containing peptide was more stable, exhibiting a t1/2 of 53 hr. The ester linked complexes C3b-IgG and C3b-glycerol were less stable each exhibiting a t1/2 of approximately 8 hr. As yet, only two specific C3b attachment sites on proteins have been identified, Ser1217 in C4b and Thr144 in IgG1. The present evidence demonstrates that Tyr residues are highly reactive and that the C3b-Tyr linkage is stable. The findings suggest that complexes involving tyrosine residues as the site of attachment will also be found.

Amino Acid Sequence↗
PubMed1976

Interaction of C-reactive protein with lymphocytes and monocytes: complement-dependent adherence and phagocytosis.

The serum constituent C-reactive protein (CRP), which activates the classical complement (C) pathway when reacting with its substrates, was examined for its ability to mediate reactions of opsonic adherence and phagocytosis. Erythrocytes coated with C-polysaccharide (CPS) and reacted with CRP (E. CPS-CRP) failed to adhere to B cells and displayed only minimal adherence to monocytes. However, upon the addition of absorbed C or purified C components these cells were found to possess the cleavage products C4b and C3b, which in turn resulted in attachment of these cells to both human B lymphocytes and peripheral blood monocytes. E. CPS-CRP treated with C in the absence of antibody were readily phagocytosized by glass-adherent human monocytes. The phagocytosis of E. CPS-CRP-C was not only mediated by CRP but also required the presence of CRP on the surface of the red cells. The extent of ingestion was proportional to the amount of CRP on the red cell intermediate and was reduced by blocking monocyte receptors with aggregated human gamma-globulin (HGG) at concentrations which did not impair the uptake of other particles. The mediation by CRP of reactions of opsonic adherence and phagocytosis as outlined in these studies points to a significant role for CRP in reactions of host defense and inflammation.

C-Reactive Protein↗
PubMed1989

Low incidence of null alleles of the fourth component of complement (C4) in elderly people.

Allotype frequencies of three complement proteins (C2, factor B, and C4) encoded on the sixth chromosome were tested in 150 "young" (under 53 yrs) and 131 "old" (over 62 yrs) healthy Hungarian individuals. In women, we found significant differences in BF*F allotype frequencies between the two age groups. A marked decrease of null alleles for C4 was observed especially in men. In the "old" age group, the total frequency of the non-expressed, "null" (Q0) alleles of the C4 protein dropped to almost one third of the "young" ones. The decrease was even larger (a 5.5-fold decrease in the incidence) among men. The relative risk of those having C4B*Q0 allele not to survive a "critical age period" of 53-62 yrs for males and 58-62 yrs for females was calculated to be 12.4 and 2.85, respectively. Our data substantiate the view that the expected life time is genetically determined and it can be forecast partly by the analysis of the antigens encoded on the sixth chromosome.

Adult↗
PubMed1990

The effect of ethnicity on major histocompatibility complex complement allotypes and extended haplotypes in patients with systemic lupus erythematosus.

Previous studies of patients with systemic lupus erythematosus (SLE) have shown an increased frequency of certain major histocompatibility complex (MHC) markers, including HLA-DR2, DR3, and C4AQ0 (C4A-null), in Caucasian patients. However, most of these studies were of randomly selected, unrelated patients; families were not included, and haplotypes were not determined. In order to define more accurately the possible role of MHC genes in lupus susceptibility, HLA-A, B, C, and DR, as well as BF, C2, C4A, C4B, and GLO, markers were determined in 62 Caucasian patients of known ethnic background, and in the members of their families. The distributions of extended haplotypes (fixed combinations of HLA-B, DR, and complotype alleles), fragments thereof, and individual alleles were determined in SLE patients and controls. The MHC distributions in all patients were compared with haplotypes in a normal Caucasian population. There were no statistically significant differences between the frequencies of any MHC marker, fragment, or extended haplotype in the patients compared with the controls. The patients were categorized into 2 groups of European ancestry (English/Irish; other Europeans), and each group was compared with a group of ethnically matched controls. There was a statistically significantly increased frequency of the alleles C4AQ0 and DR3 and the complotype SC01 in SLE patients of English/Irish descent as compared with ethnically matched controls. The increase in C4AQ0 and DR3 could be accounted for by the fact that they were part of the extended haplotype [HLA-B8;SC01;DR3] and/or its fragment (SC01;DR3). No increase in any MHC marker was observed in the other patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Complement System Proteins↗
PubMed2001

The endogenous retroviral insertion in the human complement C4 gene modulates the expression of homologous genes by antisense inhibition.

Intron 9 contains the complete endogenous retrovirus HERV-K(C4) as a 6.4-kb insertion in 60% of human C4 genes. The retroviral insertion is in reverse orientation to the C4 coding sequence. Therefore, expression of C4 could lead to the transcription of an antisense RNA, which might protect against exogenous retroviral infections. To test this hypothesis, open reading frames from the HERV sequence were subcloned in sense orientiation into a vector allowing expression of a beta-galactosidase fusion protein. Mouse L cells which had been stably transfected with either the human C4A or C4B gene both carrying the HERV insertion (LC4 cells), and L(Tk-) cells without the C4 gene were transiently transfected either with a retroviral construct or with the wild-type vector. Expression was monitored using an enzymatic assay. We demonstrated that (1) HERV-K(C4) antisense mRNA transcripts are present in cells constitutively expressing C4, (2) expression of retroviral-like constructs is significantly downregulated in cells expressing C4, and (3) this downregulation is further modulated in a dose-dependent fashion following interferon-gamma stimulation of C4 expression. These results support the hypothesis of a genomic antisense strategy mediated by the HERV-K(C4) insertion as a possible defense mechanism against exogenous retroviral infections.

Animals↗
PubMed2006

Low mannose-binding lectin function is associated with sepsis in adult patients.

Mannose-binding lectin (MBL) is an innate immune system pattern recognition molecule that kills a wide range of pathogens via the lectin complement pathway. MBL deficiency is associated with severe infection but the best measure of this deficiency is undecided. We investigated the influence of MBL functional deficiency on the development of sepsis in 195 adult patients, 166 of whom had bloodstream infection and 35 had pneumonia. Results were compared with 236 blood donor controls. MBL function (C4b deposition) and levels were measured by enzyme-linked immunosorbent assay. Using receiver-operator characteristics of MBL function in healthy controls, we identified a level of <0.2 U microL(-1) as a highly discriminative marker of low MBL2 genotypes. Median MBL function was lower in sepsis patients (0.18 U microL(-1)) than in controls (0.48 U microL(-1), P<0.001). MBL functional deficiency was more common in sepsis patients than controls (P<0.001). MBL functional deficient patients had significantly higher sequential organ failure assessment (SOFA) scores and higher MBL function and levels were found in patients with SOFA scores predictive of good outcome. Deficiency of MBL function appears to be associated with bloodstream infection and the development of septic shock. High MBL levels may be protective against severe sepsis.

Adolescent↗
PubMed1999

Modular variations of the human major histocompatibility complex class III genes for serine/threonine kinase RP, complement component C4, steroid 21-hydroxylase CYP21, and tenascin TNX (the RCCX module). A mechanism for gene deletions and disease associations.

The frequent variations of human complement component C4 gene size and gene numbers, plus the extensive polymorphism of the proteins, render C4 an excellent marker for major histocompatibility complex disease associations. As shown by definitive RFLPs, the tandemly arranged genes RP, C4, CYP21, and TNX are duplicated together as a discrete genetic unit termed the RCCX module. Duplications of the RCCX modules occurred by the addition of genomic fragments containing a long (L) or a short (S) C4 gene, a CYP21A or a CYP21B gene, and the gene fragments TNXA and RP2. Four major RCCX structures with bimodular L-L, bimodular L-S, monomodular L, and monomodular S are present in the Caucasian population. These modules are readily detectable by TaqI RFLPs. The RCCX modular variations appear to be a root cause for the acquisition of deleterious mutations from pseudogenes or gene segments in the RCCX to their corresponding functional genes. In a patient with congenital adrenal hyperplasia, we discovered a TNXB-TNXA recombinant with the deletion of RP2-C4B-CYP21B. Elucidation of the DNA sequence for the recombination breakpoint region and sequence analyses yielded definitive proof for an unequal crossover between TNXA from a bimodular chromosome and TNXB from a monomodular chromosome.

Adrenal Hyperplasia, Congenital↗
PubMed1999

Circulating immune complexes and complement C4 null alleles in patients in patients operated on for premature atherosclerotic peripheral vascular disease.

Circulating immune complexes can lead to vascular inflammation and premature atherosclerosis and the fourth component of complement, C4, plays an important role in the removal of immune complexes. The objective of this study was to analyze the relation between circulating immune complexes and C4 null alleles in patients operated on for peripheral vascular disease before the age of 50. The prevalence of circulating immune complexes and null alleles of C4 (C4Q0) was determined in 62 patients with peripheral atherosclerosis requiring surgery before 50 years of age and in a matched control group. C4A and C4B null alleles (C4A*Q0, C4B*Q0) were determined by electrophoresis of plasma, followed by immunofixation. C4A and C4B concentrations were measured by ELISA. Circulating immune complexes were determined by sucrose density gradient centrifugation and gel filtration. There was no difference in the distribution of C4Q0 between patients and controls. The patients had higher prevalences and levels of circulating immune complexes. This was correlated with the presence of C4Q0, especially C4A*Q0. There was an inverse correlation of concentration of circulating immune complexes with C4A levels and with ratio of C4A/B levels. Thus, a significant proportion of patients with premature peripheral atherosclerosis had circulating immune complexes and C4A*Q0 enhanced the propensity to immune complex formation. This might represent one mechanism for vascular damage in this patient group.

Adult↗