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The second component of human complement (C2) was purified by a combination of euglobulin precipitation, ion-exchange chromatography, (NH4)2SO4 precipitation and affinity chromatography. The final product was homogeneous by the criterion of polyacrylamide-gel electrophoresis and represents a purification of about 4000-fold from serum with 15-20% yield. Component C2 comprises a single carbohydrate-containing polypeptide chain, with an apparent mol.wt. of 102000; alanine is the N-terminal amino acid. The molecule is rapidly cleaved by activated subcomponent C1s with the loss of haemolytic activity to yield two fragments with apparent mol.wts. of 74000 and 34000. These fragments are not linked by disulphide bonds and can be easily separated. A second protein isolated during the purification of component C2 was identified by its haemolytic and antigenic properties as complement Factor B, the protein serving an analogous function to component C2 in the alternative pathway. The protein, which is also a single carbohydrate-containing polypeptide chain, has an apparent mol.wt. of 95000 and threonine as N-terminal amino acid. The amino acid analyses of component C2 and Factor B are compared.
EDTA plasma from patients with hereditary angioedema (HAE), the genetic deficiency of C1-inhibitor, when incubated at 37 degrees produces a kinin-like activity which can induce contraction of oestrus rat uterus. The second component of complement (C2) has previously been suggested to be the source of this kinin-like activity, with the implication that C2-kinin is a normal product of complement activation. Our results show that purified human C2 is cleaved rapidly to C2a and C2b when added to HAE plasma, but not normal plasma or plasma from a danazol-treated HAE patient. However, the addition to HAE plasma of C2 at 20 X normal plasma concentration had no effect on the kinin activity generated on incubation at 37 degrees. In the presence of soya bean trypsin inhibitor, the rate of C2 cleavage and products were unaltered but no kinin activity was generated. C2 was cleaved by purified C1s to C2a and C2b. Incubation of C2 with trypsin resulted in cleavage to C2a and C2b followed by more extensive cleavage of both C2a and C2b. Kallikrein cleaved C2 to C2a and C2b but plasmin had no effect on C2. In no case was kinin activity generated. When C2 was cleaved by C1s to C2a and C2b then incubated with trypsin, kallikrein, or plasmin, no kinin activity was generated: only trypsin cleaved the C2 fragments further. The results suggest that C2 is not the source of the kinin-like activity generated in hereditary angioedema plasma.
Complement components Bf, C2 and C6 have been typed in various Micronesian, Polynesian, Melanesian and Indian populations of the Western Pacific. BfS and BfF gene frequencies are heterogeneous throughout the region but the number of alleles in the Bf system is restricted. C2 is also restricted with the C22 gene frequency from 0-1.3% in all groups except Fijian Indians where it is 4.8%. The C6A and C6B frequencies of Polynesians, Melanesians and Fijian Indians are within the narrow range of frequencies reported for these alleles from other parts of the world. In the Micronesians of Nauru, a third polymorphic allele (C6Nauru) occurs together with a number of rare alleles (C6R). The Nauruan C6 gene frequencies are C6A 44.6%, C6B 45.2%, C6Nauru 6.7% and C6R 3.5% C6Nauri is present in low frequencies in most other Western Pacific populations and C6R variants occur in Polynesians.
Genetic deficiency of the second component of complement (C2) is the most common complement-deficiency state among Western Europeans and is frequently associated with autoimmune diseases. To examine the molecular basis of this deficiency, we established cultures of blood monocytes from four families with C2-deficient members. Using a hemolytic-plaque assay, [35S]methionine metabolic labeling of proteins in tissue culture and immunoprecipitation, RNA extraction and Northern blot analysis, and DNA restriction-enzyme digestion and Southern blot analysis, we found that C2 deficiency is not due to a major gene deletion or rearrangement but is the result of a specific and selective pretranslational regulatory defect in C2 gene expression. This leads to a lack of detectable C2 mRNA and a lack of synthesis of C2 protein. The approach used in this study should prove useful in examination of other plasma protein deficiencies, especially those in which the deficient gene is normally expressed in peripheral-blood monocytes or tissue macrophages and in which ethical considerations preclude the use of liver or other tissue for study.
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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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.