Decreased levels of complement components C4 and C2 in lupus erythematosus: genetic defect or complement activation?
Explore the source record for details and available documents.
Complement Activation↗
SEARCH · Search PubMed
Results for “Complement C2”
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.
DNA polymorphism of the C2 and factor B genes. Detection of a restriction fragment length polymorphism which subdivides haplotypes carrying the C2C and factor B F alleles.
Factor B and the second component of complement (C2) in man are encoded within the major histocompatibility complex by single loci that are less than 1 kb apart. A 2.3 kb factor B-specific cDNA probe has been used to examine, by Southern blot analysis, the genomic DNA of individuals typed for C2 and factor B by protein electrophoresis. We have identified a restriction fragment length polymorphism using the endonuclease Taq I, which subdivides haplotypes carrying both the common variant of C2 (C2C) and the fast (F) variant of factor B. This DNA polymorphism has been mapped to lie in the C2 gene and represents a new genetic marker not defined by protein electrophoresis. This polymorphism may serve as a useful marker in the genetic analysis of diseases that are related to the major histocompatibility complex.
Alleles↗
[Familial glomerulonephritis and hereditary deficiency of C2].
The association between glomerulonephritis and hereditary C2 complement deficiency has been found in 4 out of 8 children of a family. The hemolytic complement (CH50) was much decreased in homozygot subjects and slightly decreased in heterozygot. C1q, C4, C3, C5, C1s INA were normal, the C2 was found at an intermediate or null rate; CH50 could be reconstitued by purified human C2. The C2 deficiency genes were associated with HLA A10 B18 (father) and HLA A29 B18 (mother) haplotypes but HLA D allels were different on the 2 haplotypes. The C2 deficiency appears to lead to an increased susceptibility to immune-complexe diseases, specially to glomerulonephritis.
Adolescent↗
C2 deficiency vasculitis: complication of enterocolitis, cutaneous ulcers, and neuropsychiatric disorder.
A rare case of systemic vasculitis with second component of complement (C2) deficiency was documented in a patient who developed colonic ulcerations, jejunal edema and dilatation, cutaneous ulcers, peripheral neuropathy, and psychosis. Colonoscopy revealed typical features of ischemic colitis and radiological examination showed ischemic changes in the jejunum and ileum. Histopathological examination of the cutaneous biopsy revealed typical necrotizing vasculitis. It is very likely that multiorgan involvement, including ischemic changes of the intestine, developed secondary to vasculitis associated with C2 deficiency.
Complement C2↗
Homozygous C2 deficiency: association with defective alternative pathway function and immunoglobulin deficiency.
Deficiency in the second component of complement (C2) is the most common homozygous complement deficiency. While approximately half of the affected individuals are apparently healthy, C2 deficiency may be associated with autoimmune diseases and rarely increased susceptibility to infection. We report 5 patients who had homozygous type I C2 deficiency in two families. Three of them suffered from frequent infections. These symptomatic patients had additional risk factors; the index cases in the first and the second family had IgG2 deficiency and IgA deficiency, respectively, and alternative complement pathway hemolytic activity was also low in both of them and in the sibling of the first index case. These results emphasize the probable role of other immunologic defects in the clinical presentation of C2 deficiency.
Child↗
The second component of human complement: detection of two hemolytic forms in plasma by pH variation.
The second component of human complement (C2) in pseudoglobulin prepared from normal plasma eluted as a single peak at high conductivity (30 mS) and pH 4.5 from the cationic exchangers S-Sepharose or Mono S in the Fast Protein Liquid Chromatography (FPLC) System. The C2 was stable at pH 4.5 and 0 degrees C if enzyme inhibitors were used and the pH was raised to 6.0 after elution from the columns. After rechromatography on Mono S in the FPLC System at the median isoelectric point of 5.5 or pH 6.0, the C2 eluted as two distinct hemolytic forms: the first peaked at 16 mS, the second at 30 mS. The two forms of C2 did not correlate with the allotypic variant of C2 in individual, normal human plasmas. After elution at pH 4.5 from S-Sepharose and rechromatography at pH 5.5 or 6.0 on Mono S, the hemolytic activities of the two forms in individual plasmas eluted in 3 patterns: 1) high activity at 16 mS, low activity at 30 mS; 2) low activity at 16 mS, high activity at 30 mS; 3) high activity at 16 mS, high activity at 30 mS. The specific activities of both forms were approximately the same; both eluted the same after gel filtration at pH 5.5, and both had the same pattern on SDS-PAGE and immunoblots. The pattern of elution was characteristic for each individual plasma, and the first hemolytic form appeared to elute independent of the second form. At pH 4.5, C2 was completely separated from Factor B, a functionally and structurally similar protein of the alternative complement pathway, whereas at pH 5.5 or 6.0, the two proteins eluted together. From these results, the two forms of hemolytic C2 can be purified for structural and functional analyses.
Chromatography, Ion Exchange↗
Serologic studies in a family with heterozygous C2 deficiency.
Twelve family members of a patient with systemic lupus erythematosus (SLE) and heterozygous deficiency of the second component of complement (C2) were studied. Histocompatibility (HLA) typing was determined for A, B, and DR and MB antigens. Serum samples were tested for a variety of antinuclear antibodies (ANA), lymphocytotoxic antibodies and rheumatoid factors, and C2 levels were determined by hemolytic titration. Inheritance of C2D, the gene coding for C2, was limited to the haplotype HLA-A25, B18, DR2. Low but significant titers of ANA, rheumatoid arthritis nuclear antigen (RANA) and/or rheumatoid factors were found in eight of the nine adult family members without association with HLA haplotype. The sister of the proband had persistently strongly positive LE cell preparations for more than a decade and had joint pains while taking sulfa drugs. The son of the proband had leukemia. All other family members were healthy. We conclude that the increased incidence of rheumatic disease in persons with C2D deficiency is multifactorial and requires environmental factors or other hereditary factors unrelated to the HLA-A25, B18, DR2 haplotype. The C2D gene is clearly not associated with positive ANA tests or immunoprecipitins to RANA.
Adult↗
A molecular map of the human major histocompatibility complex class III region linking complement genes C4, C2 and factor B.
Four human complement genes, which have previously been mapped between HLA-D and HLA-B on chromosome 6, have now been aligned on a 98-kilobase (kb) section of the chromosome on the basis of four overlapping cosmid clones of genomic DNA. The C2 and factor B genes, less than 2 kb apart, are about 30 kb from two C4 genes separated from each other by about 10 kb.
Chromosome Mapping↗
Prevalence of a mutation causing C2 deficiency in systemic lupus erythematosus.
OBJECTIVE: In an effort to establish whether a 28 base pair (bp) deletion in the gene for the 2nd component of complement (C2) constitutes a significant genetic risk factor for systemic lupus erythematosus (SLE), we determined the frequency of this mutation in SLE and control populations. The MHC associations of this mutation were also established. METHODS: Polymerase chain reaction (PCR) was used to amplify DNA, and the wild type and mutant alleles were distinguished by gel electrophoresis. RESULTS: Among 122 Caucasoid patients with SLE, 2 homozygous and 2 heterozygous carriers of the 28 bp deletion were found, giving a gene frequency of 0.0246. In contrast, 6 of 427 North American Caucasoid controls were heterozygous for the 28 bp deletion, giving a gene frequency of 0.0070 (p < 0.05). Carriers of the 28 bp deletion in C2 frequently carried the DRB1*1501 allele. The 28 bp deletion in C2 was not found in 194 African-American controls or in 127 African-American patients with SLE. CONCLUSIONS: A direct assay for the most common form of C2 deficiency established that the 28 bp deletion in the C2 gene is significantly more common in Caucasoid patients with SLE compared to controls (p < 0.05). When only heterozygous carriers of the 28 bp deletion were enumerated, they were not found more frequently in the Caucasoid population with SLE compared to controls.
Base Sequence↗
C4 complement allotypes in juvenile dermatomyositis.
Twenty probands with juvenile dermatomyositis and their relatives were studied to determine the inherited segregation patterns of class I, II, and III HLA region markers including C4A, C4B, Bf, and C2 complement polymorphisms. The extended haplotype B8, DR3, C4A*Q0, C4B*1, C2*C, and Bf*S was present in 13 of the 20 probands. Three other probands also carried a haplotype with a null allele for C4A and two further probands carried a null allele for C4B; only two probands had no detectable C4 null allele. These data confirm previous studies showing high frequencies of B8 and DR3 in patients with juvenile dermatomyositis, but show that there is a higher association with null alleles of C4. This suggests that the C4 genes are either themselves the disease-susceptibility genes or are in very strong linkage disequilibrium with such genes.
Adolescent↗
A hypocomplementemic vasculitic urticarial syndrome. Report of four new cases and definition of the disease.
We describe four new patients with a unique syndrome of persistent urticaria, with leukoclastic angiitis, severe angioedema, occasional life-threatening laryngeal edema, arthritis, arthralgia, neurologic abnormalities and pronounced persistent hypocomplementemia. The complement abnormalities involved markedly reduced levels of the Clq subunit of the first component of complement (Cl) in the presence of near normal levels of Clr and Cls subunits of Cl; modest to marked depletion of the fourth component of complement (C4), the second component of complement (C2) and the third component of complement (C3); and normal levels of the fifth through ninth components of complement (C5 through C9) and properdin factors B and D. A striking serologic abnormality found in all patients was the presence of low molecular weight (7S) proteins which precipitated with Clq in agarose gels; these previously were shown to be comprised at least in part of immunoglobulin G. The present experience is offered to help to define the clinical, histopathologic and serologic characteristics of this entity, designated hypocomplementemic vasculitic urticarial syndrome, and to emphasize its distinctiveness and prevalence.
Adult↗
Hereditary C2 deficiency associated with immune complex disease.
A patient presenting with a syndrome probably due to immune complex deposition was investigated and found to possess an inherited C2 complement deficiency. Family studies indicated that the deficiency was transmitted as an autosomal recessive trait. HLA typing for the HLA-A and HLA-B specificities and HLA-D specificities indicated a close linkage between the HLA and C2 genes, as has been described elsewhere. The HLA-A and B locus specificities HLA-AW25 and HLA-B18 were coded for by each of the two chromosomes carrying the C2(0) gene. However, the two chromosomes differed at the HLA-D locus, as one coded for HLA-DW2 whilst the other did not. This case, therefore, provides a unique haplotype and may be of importance in mapping the C2(0) locus, as it suggests that the gene order on chromosome 6 is HLA-D, C2(0), HLA-B, HLA-A. Extensive complement component assays indicated that utilization of complement in the patient was occurring via the alternate complement pathway. It is suggested that, as a result of the C2 deficiency, infections with viruses and other agents could lead to an immune complex disease due to an impaired capacity to effectively eliminate circulating complexes.
Adult↗
Simple method for preparing the cellular intermediate EAC14, and its use for estimation of the second component of complement.
Sensitized erythrocytes carrying the first and fourth components of complement (EAC14) were prepared by incubating optimally sensitized sheep erythrocytes with normal serum appropriately diluted in Mg2+-free diethylbarbiturate buffer containing Ca2+. EAC14 cells so prepared were found to be suitable for use in estimating the second component of complement (C2) in human serum, and the method is described here.
Animals↗
Level of complement activity and components C1, C4, C2, and C3 in complement response to bacterial challenge in malnourished rats.
In experimentally induced malnutrition in rats, there was no significant difference between the measured level of complement activity of the classical pathway (50% hemolytic complement [CH50]) and that of the alternative pathway (ACH50), although the levels of complement components C1, C4, C2, and C3 were depressed significantly. The complement activity showed a temporary elevation with a peak at 2 or 3 days after bacterial challenge with Staphylococcus aureus in rats, and we call this the complement response. After 3 days, CH50 and C3 in the malnourished rats and ACH50, CH50, and C3 in the well-nourished rats showed a significant increase, and C1, C4, and C2 in both groups tended to elevate. On the basis of these observations, the significance of the elevation of C3 in the complement response to bacterial infection showed a strong influence by enhancing the activation of both the classical and the alternative pathways, since C3 is known to be the junction of both complement pathways. In this way, C3 responded to an earlier stage than did the other components and may contribute to maintaining the body defense system against infection.
Animals↗
Deficiency of the second component of complement. Its occurrence with membranoproliferative glomerulonephritis.
We studied glomerulonephritis in a child with a deficiency of the second component of complement (C2) who was without clinical or serologic evidence of systemic disease. The clinical course was severe, with malignant hypertension and terminal renal failure when the child was 14 years old. Results of histologic studies were typical of membranoproliferative glomerulonephritis with subendothelial deposits. Immunofluorescence microscopy showed diffuse and intense localization of IgG, C1q, and C4 as granular deposits along the glomerular capillary walls and within the mesanguim. Diffuse deposits of C3 were also found along the capillary walls. Nine months after transplantation, the graft biopsy specimen showed glomerular lesions with IgG, C1q, C4, and C3 deposits, which suggests the possibility of a recurrence. The analysis of the previously reported cases of glomerulonephritis with C2 deficiency showed variable, but generally mild, glomerular lesions. Progression of the glomerulonephritis to severe renal insufficiency, as in the present case, is exceptional.
Adolescent↗
Kinin formation in hereditary angioedema plasma: evidence against kinin derivation from C2 and in support of "spontaneous" formation of bradykinin.
Hereditary angioedema (HAE) is due to a functional deficiency of the inhibitor of the activated first component of complement (C1 INH). This abnormality is thought to be responsible for the generation of a kininlike peptide in HAE plasma that is derived from the second component of complement (C2). Specifically, a combination of C2 cleavage by C1s and C2 fragment cleavage by plasmin has been reported to generate a kinin that is distinguishable from bradykinin. We have attempted to generate this peptide by activating the classical complement pathway by incubation of plasma with immune complexes and then adding plasmin or by incubating purified C1s with C4 and C2 and then adding either plasmin or trypsin. We performed a total of 13 experiments, and in no case was a kininlike molecule generated as assessed by contraction of the estrus rat uterus. However, incubation of EDTA-treated HAE plasma at 37 degrees C for time intervals up to 1 hr progressively generated a smooth muscle-contracting activity. This activity was resistant to tryptic digestion but was destroyed after incubation with carboxypeptidase B, an inhibition profile consistent with that of bradykinin. We therefore propose that bradykinin alone, or in combination with other factors heretofore unrecognized, might be responsible for the swelling that is characteristic of hereditary angioedema.
Angioedema↗
Deficiency of C2, the second complement component, in the family of a patient with SLE-like syndrome: the first case of hereditary C2 deficiency in Czechoslovakia.
A family with hereditary C2 deficiency was discovered in Czechoslovakia. The proband is a 47-year-old female with a SLE-like syndrome and zero activity of the classical complement pathway. Functional CH50, C1, C2, and C4 estimations for all family members revealed a homozygous C2 deficiency in both the proband and her elder sister, and several heterozygotic C2-deficient individuals. The defect segregates with haplo-type HLA A25, B18, DR2.
Adult↗
Renal transplantation in a patient with hereditary deficiency of the second component of complement.
The HLA haplotype A 10,B18 has been associated with hereditary deficiency of the second component of complement(C2). In an effort to detect individuals homozygous for C2 deficiency, a thorough audit of HLA serotyping results in 3,100 individuals was performed, and a single patient homozygous for the A10, B18 haplotype was identified. Detailed complement studies in this patient's serum and plasma revealed previously undetected selective absence of C2 antigen and haemolytic activity, and a hereditary basis for this deficiency was indicated by half-normal levels of C2 haemolytic activity in both of his children. The patient was of special interest in that he had previously developed renal failure which was treated by cadaver kidney transplantation. C2 antigen was undetectable in serum and plasma samples taken prior to and up to 9 months following transplantation. This experience suggests that HLA serotyping can be a valuable screening technique for the detection of individuals with C2 deficiency, and that renal transplantation does not reconstitute normal levels of C2.
Adult↗