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PubMed1983

Solubilization of immune complexes and inhibition of immune precipitation in SLE sera.

The ability of serum to in vitro process immune complexes both preformed (ICSC) and during their formation (ICPIC) has been evaluated in 37 patients affected by systemic lupus erythematosus (SLE). ICSC was found to be significantly lower in these patients than in normal controls (p less than 0.001), and strictly related to the phase of the disease. Correlations were evidenced between ICSC and haemolytic activity of the classical and alternative pathways of complement, levels of the complement components C3 and C4, and incidence of circulating immune complexes. Low values of ICPIC were demonstrated almost only in sera of patients with active SLE; in fact, ICPIC was impaired in 6 sera only, and five of them were collected in the acute phase. All sera with decreased ICPIC also displayed a very low level of the C4 complement component.

Antigen-Antibody Complex↗

PubMed1993

Differential expression of complement C3 and C4 in the human kidney.

Complement activation is associated with a variety of immunologically-mediated renal diseases. Proximal tubular epithelial cells in situ constitutively express messenger RNA for C4 of the complement system. These same epithelial cells in culture have been reported to contain message for C3 and to secrete this protein when stimulated by IL-2. The present study compared the in situ localization of C3 and C4 message in parallel in a variety of renal biopsy and nephrectomy specimens. All adequate tissue samples (n = 23) had C4 mRNA throughout in the cortical tubular epithelium. Although C3 message was also expressed in tubular epithelial cells, there was much greater variation in its distribution. mRNA for C3 was not detected in histologically normal specimens (n = 4) either by in situ or Northern hybridization. Focal C3 message correlated with focal histologic abnormalities (e.g., focal glomerulosclerosis), while more generalized C3 signal occurred in specimens with more diffuse inflammatory processes (e.g., SLE). Infiltrating inflammatory cells and cells of the glomeruli were uniformly negative for C3 (and C4) message. Tubular C3 and C4 mRNA appeared to be translated, since selected specimens showed cytoplasmic staining by monoclonal antibodies to C3c and C4c. These observations are consistent with the hypothesis that local production of inflammatory mediators could induce C3 synthesis in the renal interstitium, with the possibility that subsequent complement activation could enhance the pathogenic process.

Complement C3↗

PubMed1999

[Complement and serum immunoglobulins in homozygous and heterozygous sickle cell anemia in Senegal].

Sickle cell disease is an hereditary hemoglobinopathy syndrome which provokes deglobulization crisis and infectious complications. These infectious diseases may be due to a permanent activation of the immune system. The aim of our study was to explore alternative pathway by measuring C3 complement and the classical pathway by C4 complement. The level of immunoglobulins IgA, IgG and IgM was also measured in the subjects sera. Thirty homozygous sickle cell anemia (SS), 25 heterozygous (AS) and 34 controls subjects (AA) were recruited in the Hôpital d'Enfants Albert Royer (HEAR), Fann hospital and Centre National de Transfusion Sanguine (CNTS). Radial Immunodiffusion (RID) technics using specific antisera for C3c, C4c, IgA, IgG and IgM were used in our study. Homozygous SS proved an increase level of IgA (50%, p < 0.003) and IgG (47%, p < 0.003), unlike of IgM level. The C3c complement decrease significantly in (27%) of homozygous SS patients (p < 0.0005) unlike of C4c level. This low level of C3 and IgG in sickle cell homozygous patients can explain the higher susceptibility to infection in these patients. Normal level of C4 and low level of C3 show activation of alternative pathway. Heterozygous AS showed a normal level of C4, C3 and immunoglobulins. Our results suggests a direct involvement of the complement system in sickle cell disease and the depletion of C3 registered was a possible cause of increased susceptibility to infections in patients with homozygous sickle cell anemia.

Adolescent↗

PubMed1977

Linkage between the gene (or genes) controlling synthesis of the fourth component of complement and the major histocompatibility complex.

In an attempt to map the gene (or genes) controlling the synthesis fo the fourth component of complement (C4), we performed linkage studies in a family with hereditary C4 deficiency. The proband, a seven-year-old boy with lupus erythematosus, consistently lacked deteftable serum C4 by both functional and protein measurements. The complement defect was transmitted as an autosomal recessive disorder. Eight of 15 family members were considered to be heterozygotes, seven because of low C4 levels and one because of genetic data (obligate heterozygote). The gene (or genes) coding for C4 deficiency appeared to be linked to the major histocompatibility complex (A2,B12,DW2 on the maternal side and A2,BW15,LD108 on the paternal side) and to other markers known to be in close proximity to the histocompatibility complex on chromosome 6 (phosphoglucomutase-3, glyoxalase-1 and properdin factor B).

Child, Preschool↗

PubMedDate not supplied

Serial study of the complement fractions C3, C4 and C3PA in allergic children.

The C3, C4 and C3PA complement fractions were dosed by radial immunodiffusion in the serum of 25 children with ages from 4 to 9 years in a non symptomatic period comprehending 10 atopic asthmas (40,0% of the cases) 8 non atopic asthmas (32.0%) and 7 urticarias (28,0%). The quantitative dosage of the studied fractions was carried out in a serial form 7, 14, 30 and 45 days after the first determination, what made a total of 116 dosages of C3, 112 of C4 and 114 of C3PA. Globally, no differences were verified in the averages and standard deviations of the complement fractions studied in the various pathological situations considered. The complement anomaly more frequently observed was the C4 increase in 37,8% of the assays in patients with atopic asthma, 16,2% of the assays in patients with non-atopic asthma and in 33,3% of the assays in urticaria cases. The other complement fractions studied showed inconstant variations in some cases. The serial study demonstrated in the same patient, variations larger than 2 standard deviations in 25,8% of the assays for C3, 25,0% for C4 and 27,2% for C3PA, what may possibly indicate the great instability of the complement system which depends on a function, consumption or activation and synthesis relation, having to be taken into consideration in those assays comprehending the quantitative study of the seric complement fractions.

Asthma↗

PubMed1983

Selective depression of the C4 component of complement: evidence for an association with genetic deficiency of C4 and dermatologic diseases.

Thirty-four patients with selective low serum C4 levels were found among 1,731 patients studied in a hospital-based routine clinical immunology laboratory. A high incidence of dermatologic diseases, particularly discoid lupus erythematosus and angioedema/urticaria, was present among patients with selective low C4. Although evidence for activation of C4 was present in patients' sera, studies to determine the presence of known activation mechanisms of complement were negative. Genetic C4 typing in four pedigrees showed that all propositi carried the null allele B*QO. It is postulated that the selective C4 depression in these patients is related to the skin lesions and this partial genetic deficiency.

Aged↗

PubMed1972

Role of antibody and complement in the immune clearance and destruction of erythrocytes. I. In vivo effects of IgG and IgM complement-fixing sites.

A model which permits evaluation in molecular terms of the role of antibody and of complement in the immune destruction of erythrocytes was established in the guinea pig. IgM and IgG immunoglobulins were isolated from rabbit anti-guinea pig erythrocyte antisera and were used to sensitize (51)Cr-labeled guinea pig erythrocytes. The average number of complement-fixing sites per erythrocyte formed by antibody was determined for each of the various preparations by the Cla fixation and transfer test. The rate of clearance and of organ localization was determined for cells sensitized with either IgM or IgG antibodies, and dose-response curves were established in normal guinea pigs and guinea pigs with a genetically controlled, complete absence of the fourth component of complement (C4). At least 60 complement-fixing sites per cell were required for accelerated clearance of IgM-sensitized erythrocytes. The bulk of cells with IgM sites were cleared by the liver within 5 min after injection and were then slowly returned to the circulation where they survived normally. There was no accelerated clearance whatsoever of IgM-sensitized erythrocytes in C4-deficient guinea pigs. As few as 1.4 IgG complement-fixing sites per cell resulted in decreased erythrocyte survival. There was no evidence of immediate tissue sequestration and release. Progressive trapping and destruction of erythrocytes by the spleen was responsible for most of the clearance of IgG-sensitized cells. Clearance of IgG-sensitized cells was markedly impaired in guinea pigs with C4 deficiency; however, there was some decrease over normal survival. The data indicate that IgG and IgM antibodies interact with complement in vivo by mechanisms which are qualitatively or quantitatively different and produce different biologic effects.

Anemia, Hemolytic↗

PubMed1986

Analysis of synthetic sites of fourth and fifth components of serum complement system in allogeneic bone marrow chimaeras.

Synthetic tissue sites for the fourth and fifth components of complement (C4 and C5) have been investigated using allogeneic bone marrow chimaeras in mice. One group of chimaeric mice was prepared by transplanting bone marrow cells from C5-sufficient donor mice into irradiated C5-deficient recipients or vice versa, and another group was prepared by transplanting marrow cells from mice that produce high levels of C4 into irradiated recipients that are characterized by having low levels of C4 or vice versa. In such chimaeras, lymphoid cells and serum immunoglobulin allotypes were shown to be exclusively of donor origin. However, haemolytic activities of sera from the chimaeras were consistently identical with those of normal mice of the recipient strain. Similar results were obtained when the complement component levels of the sera were evaluated by double diffusion assays. C4 or C5 antigens were detected in sera of the chimaeras only when recipients were strains that are characterized by having high C4 level or were C5-sufficient mice, respectively. These findings indicate that circulating C4 or C5 complement components present in the blood are not synthesized primarily by cells that are descendants of bone marrow cells in these chimaeric mice.

Animals↗

PubMed1986

Cold urticaria associated with C4 deficiency and elevated IgM.

Various immunologic abnormalities have been implicated in cold urticaria. This is the first report of cold urticaria associated with C4 deficiency and elevated IgM. A 12-year-old male developed urticaria upon exposure to cold. He denied fever, purpura, hemoglobinuria, Raynaud's disease, or arthralgias. Family history was negative for cold urticaria. Immunologic studies revealed elevated IgM (186 mg/dL) as well as decreased CH100 and C4 (8.0 mg/dL). C1, C2, and C3 were normal. Ice cube skin test was positive, but passive transfer tests were negative. Biopsy was not diagnostic for vasculitis, although it revealed a few immunofluorescent deposits of IgM and C4. Complement genetic studies revealed deficiency of two half-null C4 haplotypes expressed as C4A*3QO and B*2QO.

Child↗

PubMed2003

Complete sequencing and expression of three complement components, C1r, C4 and C1 inhibitor, of the classical activation pathway of the complement system in rainbow trout Oncorhynchus mykiss.

Three complement components, C1r, C4 and C1 inhibitor, of the classical activation pathway have been fully sequenced and their expression investigated in rainbow trout (Oncorhynchus mykiss). Trout C1r cDNA encodes a 707-amino-acid (aa) protein with a theoretical M(r) of 77,200. The trout translation shows highest homology with carp C1r/s, and lower, equal homologies to mammalian C1r and C1s, and MASPs from other vertebrate species. However, phylogenetic analysis and structural features suggest that the trout sequence, together with the two carp sequences, are the orthologues of mammalian C1r. The trout C4 cDNA encodes a 1,724-aa protein with a theoretical M(r) of 192,600. The trout translation shows higher homologies to the carp C4B and medaka C4, but lower homologies to C4 from other species and the carp C4A. It has a predicted signal peptide of 22 aa, a alpha-chain of 773 aa, a beta-chain of 635 aa and a lambda-chain of 288 aa. Trout C1 inhibitor cDNA encodes a 611-aa protein with a theoretical M(r) of 68,700. The trout translation has a C-terminal serpin domain with high homologies with mammalian counterparts (~37% identities), and a longer N-terminus, with no significant homology to other serpins, which contains two Ig-like domains. A molecule containing two Ig-like domains followed by a serpin domain, has also been found in an EST clone from another bony fish, the Japanese flounder. This suggests a unique structural feature of C1 inhibitor in fish. The functional significance of the Ig domains is discussed. The liver is the major site of expression of the three trout complement components, C1r, C4 and C1 inhibitor, although their expression is also detectable in other tissues. The extra-hepatic expression of complement genes may be important for local protection and inflammatory responses. Low-level constitutive expression of the three components was also detectable in a trout monocyte/macrophage cell line RTS-11, but only the expression of C4 could be upregulated by LPS.

Amino Acid Sequence↗

PubMed1989

Molecular basis of complete C4 deficiency. A study of three patients.

The highly polymorphic fourth component of human complement (C4) is usually encoded by two genes, C4A and C4B, adjacent to the 21-hydroxylase (21-OH) genes and is also remarkable by the high frequency of the null alleles, C4A*Q0 and C4B*Q0. Complete C4 deficiency is exceptional because this condition appears only in homozygotes for the very rare double-null haplotype C4AQ0,BQ0. This condition in most cases gives rise to systemic lupus erythematosus and an increased susceptibility to infections. The molecular basis for complete C4 deficiency has not yet been established. Therefore we studied the DNA of three previously described C4 deficient patients belonging to unrelated families by restriction fragment length polymorphism analysis using C4 and 21-OH probes. These studies revealed a deletion of the C4B and 21-OHA genes in two patients and no deletion at all in the third patient. Therefore, complete C4 deficiency as a result of homozygosity for the C4AQ0, BQ0 haplotype is not a consequence of a deletion of the C4 genes. The molecular basis of this genetic abnormality is certainly very complex and may vary also from one case to another.

Alleles↗

PubMed1980

Pro-C4 of human plasma: isolation and description of chemical and antigenic properties.

The fourth component of complement (C4) occurs in human plasma as a protein with a three polypeptide chain structure. Lately a single-chain form of C4 has been purified from human plasma by sequential steps of immunoadsorbent chromatography, gel filtration in 6 M guanidine hydrochloride, and gel filtration in 6 M guanidine hydrochloride and 0.015 M dithiothreitol. Single-chain C4, referred to as pro-C4, behaved as a protein of approximately 200,000 daltons upon gel filtration, and was separated from the three chains of C4 on the basis of molecular size. Pro-C4 could be isolated from each of five human plasmas examined and was found to constitute approximately 2% of total, immunoreactive C4. Replicate amino acid analyses of pro-C4 and C4 agreed within 0.5 mol % for all residues except glycine and threonine, which agreed within 0.7 mol percent. Polyacrylamide gel electrophoresis of pro-C4 in the presence of sodium dodecyl sufate in 5% gels under reducing conditions indicated an approximate molecular weight of 202,000. The sum of the molecular weights of the alpha-, beta-, and gamma-chain of C4 is 205,000. After gel electrophoresis, pro-C4 stained positively with periodic acid-Schiff reagent, suggesting the presence of covalently-bound carbohydrate. Competitive inhibition radioimmune assays with pro-C4, purified alpha-, beta-, or gamma-chain, and chain-specific antisera demonstrated the existence of antigenic sites on pro-C4 that are assignable to common determinants on each of the alpha-, beta-, and gamma-chains of C4.

Amino Acids↗

PubMed1995

Studies of group B streptococcal infection in mice deficient in complement component C3 or C4 demonstrate an essential role for complement in both innate and acquired immunity.

Group B streptococci (GBS) cause sepsis and meningitis in neonates and serious infections in adults with underlying chronic illnesses. Specific antibodies have been shown to be an important factor in protective immunity for neonates, but the role of serum complement is less well defined. To elucidate the function of the complement system in immunity to this pathogen, we have used the approach of gene targeting in embryonic stem cells to generate mice totally deficient in complement component C3. Comparison of C3-deficient mice with mice deficient in complement component C4 demonstrated that the 50% lethal dose for GBS infection was reduced by approximately 50-fold and 25-fold, respectively, compared to control mice. GBS were effectively killed in vitro by human blood leukocytes in the presence of specific antibody and C4-deficient serum but not C3-deficient serum. The defective opsonization by C3-deficient serum in vitro was corroborated by in vivo studies in which passive immunization of pregnant dams with specific antibodies conferred protection from GBS challenge to normal and C4-deficient pups but not C3-deficient pups. These results indicate that the alternative pathway is sufficient to mediate effective opsonophagocytosis and protective immunity to GBS in the presence of specific antibody. In contrast, the increased susceptibility to infection of non-immune mice deficient in either C3 or C4 implies that the classical pathway plays an essential role in host defense against GBS infection in the absence of specific immunity.

Animals↗

PubMed1988

[Polymorphism of C4 and factor B in type I diabetes].

The haplotypic frequencies of the fourth component of complement (C4) and factor B (Bf) have been determined in 44 Alsatian type 1 diabetics. An increased frequency of the rare allele Bf F1 (9.1% vs 1.5%) and of the silent alleles of C4 (C4 AQO: 21.6% vers 15.5% -C4 BQO: 29.6% vs 16.0%) was observed in diabetics in comparison to the general population of the same geographic area. A complete HLA haplotype determination has been obtained in 24 type 1 French diabetics. Three haplotypes were associated with the diabetic susceptibility: HLA-A30 CW5 B18 BfF1 C4A3BQO DR3 (18.75% vs 0.86%), HLA-A1 CW7 B8 BfS C4AQOB1 DR3 (15.58% vs 4.17%), HLA-A2 CW3 BW62 BfS C4A3B3 DR4 (6.25% vs 0.45%). The authors suggest that the silent alleles of C4 could modulate the expression of the diabetic susceptibility genes by lowering of the serum C4 hemolytic activity.

Alleles↗

PubMed1992

Restriction fragment length polymorphism of the murine C4 and Slp genes: two C4 groups.

We have examined the related H-2 genes coding for the fourth component of complement (C4) and the sex-limited protein (Slp) from 30 inbred mouse strains by Southern blot analysis. With four restriction enzymes, 11 RFLP patterns distributed among 26 different H-2 haplotypes have been identified. Strains of the same serologic H-2 haplotype were found to have identical RFLP patterns. It was confirmed that the number of C4-related genes in most haplotypes is two, Slp and C4; but H-2SWI6 (SWI6) and SWI9, which have the same RFLP pattern, have four and Sw7 has five. Although C4 and Slp have many similarities, they also were found to contain distinctive features: relative to Slp, each C4 allele examined has two insertions totaling 1.1 kb located in introns 14 and 15; and each Slp allele examined, excluding hybrids, has a provirus insertion upstream. No other large deletions or insertions were detected. The RFLP patterns are also due to 10 polymorphic restriction sites, which have been placed on standard maps; two are associated with Slp and eight are associated with C4.Sk strains, the only strains that express low serum levels of C4, have the same RFLP phenotype as Sw14, Sw18, and Swx; Sk may have arisen from a recent common ancestor of these strains. Homologous recombination has been important in the formation of existing C4 alleles. However, based on complete linkage disequilibrium between three RFLP internal to C4, the haplotypes have been divided into two groups that may have functional significance.

Animals↗

PubMed1988

C4 allotyping on plasma or serum: application to routine laboratories.

Allotypes of the fourth component of complement (C4) can be detected by electrophoresis and immunofixation after treatment of EDTA plasma with neuraminidase (NAse). We have assessed the value of additional treatment with carboxypeptidase B (CPseB). Following treatment with CPseB + NAse, each allele is resolved into a single band, permitting clear definition of overlapping bands seen following treatment with NAse alone. More importantly, C4 allotypes can be determined using stored heparinized plasma or serum. Most C4 null alleles can be assigned without requiring family studies. The approach described is suitable for routine use by tissue typing laboratories.

Alleles↗

PubMed1994

Complete inherited deficiency of the fourth complement component in a child with systemic lupus erythematosus and his disease-free brother in a north African family.

Although null alleles of complement C4 genes (C4A*Q0 and C4B*Q0) are frequent in the normal population, the occurrence of two null alleles on the same chromosome is very rare and therefore complete C4 deficiency is exceptional. We describe a 16-year-old North African boy who presented with systemic lupus erythematosus with renal involvement and persistent undetectable classical pathway activity and C4 protein and hemolytic activity in plasma, with normal C3 levels. Similar complement abnormalities were observed in his healthy 12-year-old brother. Complete C4 deficiency was documented in the two brothers by investigation of the family and the lack of C4A and C4B bands upon phenotyping of C4. Southern blot analysis of the C4/CYP21 gene organization in the family indicated that the deficiency resulted from a deletion of the C4B/CYP21A genes associated with nonexpression of a C4A gene. The double-null haplotype was found to be associated with homozygous A2 B17 C2C BFF C4 AQ0 BQ0 DR7 HLA haplotype. Thus, similar C4 deficiencies with HLA identity may lead to different clinical presentations.

Adolescent↗

PubMed1981

Isolation of component C4 of human complement and its polypeptide chains.

Component C4 of human complement was purified from fresh frozen plasma with a yield of 25% using an initial batch separation with quaternary diethyl-(2-hydroxypropyl)aminoethyl--Sephadex followed by column chromatography on DEAE-cellulose and gel filtration in Sephadex G-200. The final product was homogenous according to polyacrylamide gel electrophoresis and immunochemical methods. Low-speed sedimentation-equilibrium analyses revealed a molecular weight of 189,000, using a value of 0.736 ml/g for the partial specific volume. The polypeptide chains of reduced and alkylated C4 were separated on DEAE-Sepharose in the presence of 8 M urea. Gel filtration in Sepharose 4B in 6 M guanidine hydrochloride revealed molecular weights of 88,000, 72,000 and 32,000 for the alpha, beta and gamma chain respectively. The amino acid compositions of component C4 and its constitutive chains were also determined.

Amino Acids↗