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PubMed1981

Quantitation of C2 by rocket immunoelectrophoresis in 120 pathological sera.

A potent monospecific anti-C2 was used for quantitation of serum C2 by rocket immunoelectrophoresis (RIE). This ready procedure was compared to the one-step hemolytic titration utilizing C2-deficient human serum. RIE detected 4 nanograms C2 in 5 microliters samples. Using highly purified C2 as a reference, C2 concentration in pooled normal human sera was estimated around 50 micrograms/ml by both test systems. The reliability of RIE was assessed when immunochemical and hemolytic determinations were comparatively performed in 120 pathological sera. The correlation coefficient was significant (r = 0.69) and only 8 sera were found outside the expected range, exhibiting an abnormally high C2 protein. They were obtained from 6 patients with cryoglobulinemia associated connective tissue disease and 2 with acute glomerulonephritis. These occasional findings suggested the possibility of an activation of C2 hemolytic activity without simultaneous loss of C2 protein. In 16 sera of individuals with familial C2 deficiency (r = 0.83) and 29 sera of patients with angioneurotic edema (r = 0.72), RIE provided an extremely simple and reliable alternative to the time consuming hemolytic titration of C2.

Animals↗
PubMed1999

IgG and complement-mediated tissue damage in the absence of C2: evidence of a functionally active C2-bypass pathway in a guinea pig model.

In vitro complement-mediated lysis of heavily sensitized sheep erythrocytes by C4-deficient (C4D) guinea pig and C2-deficient (C2D) human sera was demonstrated some years ago. It was postulated that these "complement-bypass" pathways resulted from activation of C1 and components of the alternative pathway. We used normal, C2D, and C4D guinea pigs in a Forssman shock model to test the in vivo relevance of the C2- and C4-bypass pathways of complement activation. High concentrations of both anti-Forssman Ab and C2D or C4D guinea pig serum induced efficient lysis of sheep erythrocytes in vitro. The most efficient lysis was observed when IgG Ab and C2D guinea pig serum were used. Blocking either the classical pathway (treatments with EGTA-Mg2+ or soluble recombinant complement receptor type 1 (sCR1)) or the alternative pathway (treatment with heating at 50 degrees C, sCR1, or soluble recombinant CR1 lacking the first of the four long homologous repeat sequences (sCR1[desLHR-A])) inhibited lysis; both pathways were required for lysis of sheep erythrocytes by C2D and C4D guinea pig sera. i.v. injection of anti-Forssman Ab in normal guinea pigs resulted in rapid death from pulmonary shock, whereas C4D guinea pigs had no adverse effect. Surprisingly, C2D guinea pigs either died in a delayed fashion or had a sublethal reaction. sCR1 treatment prevented Forssman shock in both normal and C2D guinea pigs, whereas sCR1[desLHR-A] prevented Forssman shock only in C2D animals. Our results suggest that the C2-bypass pathway occurs in vivo to produce tissue damage. Activation of complement in the absence of C2 appears to be far more efficient than in the absence of C4.

Anaphylaxis↗
PubMed2000

Binding of immune complexes to erythrocyte CR1 (CD35): difference in requirement of classical pathway components and indication of alternative pathway-mediated binding in C2-deficiency.

Deficiency of complement components within the classical pathway is associated with increased risk for immune complex disease. However, C2-deficient individuals often have a mild disease and about 50% are healthy. To study the importance of the different components for immune complex clearance, bovine serum albumin (BSA)/anti-BSA complexes were opsonized in human serum and the binding to erythrocyte complement receptor type 1 (CR1, CD35) was measured in vitro. In C2-depleted serum the complexes were opsonized and bound to CR1 but the reaction needed a longer opsonization time than in normal human serum (NHS). In contrast, serum reagent lacking C1q, C4 or C3 did not promote binding in this assay system. We also demonstrated that elevated levels of factor B could restore binding of complexes to erythrocytes in C2-depleted serum via alternative pathway activation. These results indicate that in spite of lack of a complete classical pathway, C2-deficient individuals could retain some immune complex opsonizing activity via the alternative pathway. This finding could contribute to the understanding of differences in association between complement deficiency and immune-complex disease.

Antigen-Antibody Complex↗
PubMed1989

Simultaneous detection of allotypes in native and activated human C2 by isoelectric focusing and silver staining.

A simple and highly sensitive analytical isoelectric focusing (IEF) technique using immunofixation with anti-C2 serum followed by silver staining has been developed in order to study simultaneously the structural polymorphism of both native C2 and C2 activation fragments (C2a MW 74,000 and C2b MW 34,000). Structural C2 polymorphism of C2*B and C2*C allotypes (but not of C2*A1) was found to be associated with the C2a fragment, whereas C2b appears to display no polymorphism. Commercially available IEF gels and C2 antisera gave reproducible allotyping data and make this technique of general use for densitometric analysis of native and activated C2. In vivo C2 activation was studied through C2a/native C2 area ratios obtained by computerized densitometry. Significantly lower ratios were observed in healthy individuals than in patients with systemic lupus erythematosus (SLE), reflecting an abnormally high classical pathway activation of complement in SLE. This methodology may be of value for immunogenetic and functional studies of other complement components.

Alleles↗
PubMed2001

Interallelic complementation at the Drosophila melanogaster gastrulation defective locus defines discrete functional domains of the protein.

The gastrulation defective (gd) locus encodes a novel serine protease that is involved in specifying the dorsal-ventral axis during embryonic development. Mutant alleles of gd have been classified into three complementation groups, two of which exhibit strong interallelic (intragenic) complementation. To understand the molecular basis of this interallelic complementation, we examined the complementation behavior of additional mutant alleles and sequenced alleles in all complementation groups. The data suggest that there are two discrete functional domains of Gd. A two-domain model of Gd suggesting that it is structurally similar to mammalian complement factors C2 and B has been previously proposed. To test this model we performed SP6 RNA microinjection to assay for activities associated with various domains of Gd. The microinjection data are consistent with the complement factor C2/B-like model. Site-directed mutagenesis suggests that Gd functions as a serine protease. An allele-specific interaction between an autoactivating form of Snake (Snk) and a gd allele altered in the protease domain suggests that Gd directly activates Snk in a protease activation cascade. We propose a model in which Gd is expressed during late oogenesis and bound within the perivitelline space but only becomes catalytically active during embryogenesis.

Alleles↗
PubMed1985

Requirement for cations in the stimulation of C2 synthesis by human monocytes.

C2 synthesis by monocytes is stimulated by carbamylcholine acting on nicotinic receptors, phenylephrine acting on alpha 1 adrenergic receptors, and antigen-antibody complexes (IC) acting on Fc receptors. Stimulation of C2 synthesis is reversed by agents which block calcium (LaCl2, CoCl2, verapamil, nifedipidine, diltiazem) and sodium channels (tetrodotoxin) and calmodulin antagonists (trifluoperazine and W7). The changes in intracellular cyclic nucleotide levels that follow these receptor-ligand interactions (decreased cAMP, increased cGMP) do not occur in the presence of calcium and sodium channel blockers. These results suggest that the transmembrane signal which is involved in the stimulation of C2 synthesis is the entry of sodium and calcium ions. Whether this influx occurs by separate channels or a common channel has not been determined. The intracellular events involved in the stimulation of C2 synthesis appear to be calmodulin-dependent.

Antigen-Antibody Complex↗
PubMed1994

Ancestry of SINE-R.C2 a human-specific retroposon.

We have reported previously that a retroposon, containing a variable number of tandemly repeated nucleotide sequences, is present in the third intron of the human C2 gene. This element, termed SINE-R.C2, is a member of a large retroposon family derived from the endogenous retrovirus HERV-K10 and estimated to include a few thousand copies per haploid human genome. In the present study we analyzed genomic DNA from 175 humans from several ethnic groups including Americans of European and African descent, Chinese, Africans, Australians, Pacific Islanders, Japanese, and Koreans. They all contained SINE-R.C2, as indicated by Southern blotting. However, SINE-R.C2 was absent from the genome of nonhuman primates, although SINE-R-type elements were present in chimpanzees and gorillas and the HERV-K10 genome was apparently present in all primates except for New World monkeys. These results indicate that HERV-K10 was inserted into the genome after the divergence of New World monkeys; the prototype SINE-R element, after divergence of orangutans; and SINE-R.C2, after the split between humans and chimpanzees.

Animals↗
PubMed1993

Structure of the human C2 gene.

A human genomic cosmid clone, S22A, was used to characterize the structure of the human C2 gene. Eighteen exons spanning 18 kb of DNA were mapped by nucleotide sequencing of exon-containing subclones and by Southern blotting. Introns vary in length between 83 bp and 4.4 kb and all intron/exon boundaries follow the AG/GT consensus rule for splicing. Exon 1 encodes 270 bp of the 5'-untranslated region of the C2 cDNA C2HL5-3 and 15 amino acids of the leader peptide. The three short consensus repeats of C2b are encoded by the single exons 2, 3, and 4, respectively. The von Willebrand factor type A-like domain of C2a is encoded by exons 6-10 and the serine protease domain by exons 11-18. Exons 5 and 15 appear to be unique to the C2 and factor B genes.

Amino Acid Sequence↗
PubMed1980

Depletion of C2 and C4 in sera from hamsters bearing herpes simplex type 2-induced tumors.

Total hemolytic complement activity (CH50) was compared in sera from normal and tumor-bearing hamsters. CH50 ranged from 160-216 in normal animals and from 82 to 152 in tumor-bearing animals. Preliminary screening assays indicated that of 9 complement components assayed, only C2 and C4 showed differences in titer in both normal and tumor-bearer sera. In an expanded study, examination of sera from 12 normal and 14 tumor-bearing hamsters showed that the mean C4 and C2 levels were approximately 88 and 70% below those seen in normal sera, respectively.

Animals↗
PubMed2004

Identification of HIV-1 protease cleavage site in human C1-inhibitor.

We have investigated the ability of HIV-1 protease to cleave human complement proteins of the classical complement pathway: C1q, C2 and C4 as well as the regulatory protein, C1-inhibitor. Purified complement proteins were incubated with recombinant HIV-1 protease in vitro and analyzed by SDS-PAGE and immunoblotting assay. The only cleavage site was found in N-terminal region of C1-inhibitor, and it was located between residues Leu-32 and Phe-33 as determined by amino acid sequence analysis of the 85 kDa proteolytic fragment after 12 Edman degradation cycles. The HIV-1 protease cleavage sites were not found in C1q, C2 and C4 protein. HIV-1 protease-susceptible site in N-terminal region of C1-inhibitor is very close to the cleavage sites of some other proteases that are able to induce N-terminal proteolysis of the protein.

Amino Acid Sequence↗
PubMed1980

The atopic syndrome: in vitro immunological characteristics of clinically defined subgroups of atopic subjects.

Total IgE, selected specific IgE antibody levels, C2 and yeast opsonization were measured in four clinically defined subgroups of atopic patients who had previously been HLA-typed. Each group was characterized by a distinctive mean total IgE level and profile of specific IgE responses. All groups gave comparable levels of IgE antibodies to Timothy grass pollen but in patients initially presenting with infantile eczema and who subsequently developed asthma and/or hay fever, IgE antibodies to bovine milk proteins, egg ovalbumin and cat dander were frequently observed whereas in patients initially presenting with hay fever later in life these antibodies were usually absent. Computer assisted analysis failed to show any association between IgE antibody responses and (a) the HLA phenotypes A1,B8 and A3,B7 (b) C2 levels and (c) the yeast opsonization index.

Adult↗