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PubMed1989

Measurement of complement proteins C2 and B in systemic lupus erythematosus and septic shock.

We developed sensitive radioassays to quantitate the homologous complement proteins C2 and B, in intact form, in sera from patients with diseases associated with hypocomplementemia. In a study of systemic lupus erythematosus (SLE) patients, we found a subset of patients (6/40) with low C2 concentrations, though overall, C2 concentration was not related to disease activity. Protein B concentration was increased in 23/40 SLE patients, apparently not due to a generalized acute phase response. Among patients with both gram-negative and gram-positive septic shock, C2 and B concentrations were low in a subset of patients with pre-existing cirrhosis, suggesting hepatic hyposynthesis of these proteins may be important in their prognosis and predisposition to severe infections.

Biomarkers↗
PubMed1992

Production and interferon-gamma-mediated regulation of complement component C2 and factors B and D by the astroglioma cell line U105-MG.

In this paper, we demonstrate the synthesis of the complement component C2 and factors B and D by the human astroglioma cell line U105-MG. All three components were structurally and antigenically similar to their serum counterparts, as determined by biosynthetic labelling studies or Western blot analysis. Northern blot analysis demonstrated that the mRNAs of all three components had the same apparent sizes as the equivalent mRNAs from hepatocyte and monocyte cell lines. Interestingly, U105-MG cells produce two C2 transcripts with sizes of approximately 2.8 and 2.3 kb. Interferon-gamma (IFN-gamma) enhanced the expression of C2 and factor B mRNA and protein in a dose- and time-dependent fashion, while factor D expression was refractory to IFN-gamma. IFN-gamma appeared to predominantly enhance the expression of the large (2.8 kb) C2 transcript. Kinetic studies demonstrated peak C2 and factor B expression in 48 h in response to IFN-gamma, similar to the acute-phase response of factor B in serum. These data are the first to demonstrate the synthesis of C2 and factor D by astroglioma cells. Combined with previous reports documenting the synthesis of C3 by astrocytes, our data suggest that endogenous synthesis of complement proteins, and particularly of alternative pathway activation components (C3, factors B and D), may play an important role in host defence in the central nervous system.

Astrocytoma↗
PubMed1979

Limited proteolysis of complement components C2 and factor B. Structural analogy and limited sequence homology.

A method is described for the simultaneous purification of milligram quantities of complement components C2 and Factor B. Both products are homogeneous by the criteria of polyacrylamide-gel electrophoresis and N-terminal sequence analysis. Component C2 is cleaved by serine proteinase C1s at an X-Lys bond to give fragment C2a (approx. mol.wt. 74000) and fragment C2b (approx. mol.wt. 34000). The two fragments can be separated by gel filtration without the need for reducing or denaturing agents. Fragment C2b represents the N-terminal end of the molecule. Similar results were seen on cleavage of Factor B by Factor D in the presence of component C3. Again two non-covalently linked fragments are formed. The smaller, fragment Ba (approx. mol.wt. 36,000),) has threonine as the N-terminal residue, as does Factor B; the larger, fragment Bb (approx. mol. wt. 58000), has lysine as the N-terminal residue. A similar cleavage pattern is obtained on limited proteolysis of Factor B by trypsin, suggesting an Arg-Lys-or Lys-Lys bond at the point of cleavage. Although component C2 and Factor B show no apparent N-terminal sequence homology, a limited degree of sequence homology is seen around the sites of proteolytic cleavage.

Amino Acid Sequence↗
PubMed1987

Effect of histamine on the gene expression and biosynthesis of complement components C2, factor B and C3 in mouse peritoneal macrophages.

The gene expression and biosynthesis of C2, factor B and C3 have been investigated in vitro in mouse resident peritoneal macrophages after incubation with histamine. C2- and factor B-specific mRNA and the amount of the immunoprecipitated C2 and factor B were decreased by 10(-4) M and 10(-8) M histamine. These effects can be abrogated by the H2 antagonist cimetidine and mimicked by the H2 agonists impromidine and 4-methylhistamine. Since the H1 antagonist chlorpheniramine and the H1 agonists PEA and 2-methylhistamine have little effect on C2 and are ineffective on factor B, a strong H2 receptor dependence of the inhibition of C2 and factor B gene expression and biosynthesis is suggested. Conversely, the C3 gene expression and biosynthesis can be influenced through both H1 and H2 receptors, e.g. elevated by histamine + cimetidine, PEA and 2-methylhistamine through H1 receptors, and inhibited by histamine + chlorpheniramine, impromidine and 4-methylhistamine through H2 receptors. The data obtained by quantification of C2, factor B and C3 mRNA concentration of peritoneal macrophages suggest that the regulation of biosynthesis of these complement components by histamine in mouse peritoneal macrophages is under pretranslational control.

Animals↗
PubMed1986

Guinea pigs with inherited deficiencies of complement components C2 or C4 have characteristics of immune complex disease.

Guinea pigs genetically deficient in the second (C2) or fourth component of complement (C4) generally appear healthy in contrast to humans with a C2 or C4 deficiency. However, upon investigation of these genetic deficiencies in guinea pigs for signs of dysregulation in the humoral immune system and especially autoantibodies, many complement-deficient guinea pigs (greater than 50%) had elevated levels of serum IgM and higher concentrations of anti-hapten (dinitrophenyl) antibodies as signs of polyclonally stimulated antibody synthesis. In addition, a significant number of the complement-deficient animals, on average 30%, had IgM rheumatoid factors in their sera compared with less than 1% of the normal animals. These observations, therefore, indicate that guinea pigs, genetically deficient in C2 or C4, show characteristics of immune complex disease in general.

Aging↗
PubMed1991

Transcriptional termination between the closely linked human complement genes C2 and factor B: common termination factor for C2 and c-myc?

We have demonstrated, using a combination of nuclear run-off and poly(A) site competition assays, that transcriptional termination occurs between the closely spaced human complement genes, C2 and Factor B, soon after the C2 poly(A) site. A comparison of the C2 termination signal with a functionally similar sequence downstream of the human alpha 2 globin gene reveals that both signals function in an orientation dependent manner, with subfragments of the whole signal displaying partial effects. In the case of the C2 termination sequence a protein binds within it, and is partially responsible for the termination effect. We further demonstrate that the same (or closely related) protein binds to the ME1a1 site in the murine c-myc promoter, which has been implicated in c-myc attenuation. We suggest that the termination/pause sequences positioned downstream of a gene's poly(A) site may constitute the general signals that elicit transcriptional termination in genes transcribed by RNA polymerase II.

Base Sequence↗
PubMed1988

Radioassays for quantitation of intact complement proteins C2 and B in human serum.

Availability of polyclonal and monoclonal antibodies recognizing determinants on the major cleavage fragments of complement proteins C2 and B enabled development of sensitive radioassays which can be used to quantitate the intact proteins in human sera. Changes in C2 and B concentrations indicative of classical or alternative pathway activation, or both, were seen in normal serum after incubation with complement activators. We determined the normal range (mean +/- 2 SD) of C2 concentration to be 11-35 micrograms/ml in 32 healthy individuals, and that of protein B to be 74-286 micrograms/ml. Sera from patients with systemic lupus erythematosus (SLE), septic shock, infections, and following orthopedic surgery were then assayed. Mean protein B concentration was significantly higher in SLE sera (P = 0.002) and in the infected and post-operative (acute-phase) sera (P less than 0.001), and the mean C2 concentration in the septic shock group (P less than 0.001) was significantly lower than the mean of healthy individuals. Intact C2 was not detected in known C2-deficient individuals. These assays allow parallel quantitation of the structurally and functionally homologous proteins of the classical (C2) and alternative (B) pathways, which is of interest in patients with genetic and acquired hypocomplementemia.

Adult↗
PubMed1991

Site-directed mutagenesis of the region around Cys-241 of complement component C2. Evidence for a C4b binding site.

We probed the functional significance of the region around Cys-241 in human C2 by testing the hemolytic activity of a series of mutant rC2. Mutant C2 cDNA were constructed by oligonucleotide-directed site-specific mutagenesis and expressed transiently in COS cells. Wild-type rC2 had threefold higher specific hemolytic activity than native serum C2. Substitution of Gly, Ala, or Ser for Cys-241 resulted in a slightly, but significantly, increased activity. In addition, I2 had no effect on the activity of these mutant C2. Substitution of Lys for Gln-243 increased the hemolytic activity by more than two-fold. Increased activity in all cases was due to slower decay rates of the C3 convertase. Finally, substitution of Leu or Ala for Asp-240 or Ser-244, respectively, resulted in more than 100-fold decrease of hemolytic activity. The results suggest that residues 240 to 244 of human C2 represent an important structural determinant of the C4b binding site of C2a. They also confirm that Cys-241 is the residue responsible for the increased activity of C2 reacted with I2.

Amino Acid Sequence↗
PubMed1991

Association of major histocompatibility complex class III complement components C2, BF, and C4 with Brazilian paracoccidioidomycosis.

A genetic influence of the major histocompatibility complex (MHC) on the susceptibility and the development of the different clinical forms of paracoccidioidomycosis (PCM) has been postulated. In the present investigation allotypes of MHC-coded class III gene products (complement components C2, BF, C4A, and B) were determined in 69 Brazilian PCM patients and 225 healthy control individuals matched for ethnic and geographic origin. The frequency of the non-expressed C4B allele (C4B*Q0) was significantly elevated in comparison to the controls (p less than 0.01; Fisher's exact test). Three out of 69 patients had a complete C4B deficiency as against 2 among 223 control individuals. The C4A*Q0 allele was also more frequent in the patients. Other C4 alleles were not seen to differ between the two groups. The analysis of BF allotypes showed a non-significant predominance of the rarer allele BF*S07 in the patients, whereas no difference in the distribution of C2 alleles was seen. The data on MHC class III association may support the hypothesis of immune response modulation in PCM and suggest a functional genetic role of complement action against the fungus and in the outcome of PCM infection. We conclude that MHC class III products, especially C4B*Q0, are associated with chronic uni- or multifocal PCM and may influence the course of the infection.

Adolescent↗
PubMed1990

Translational regulation of complement protein C2 expression by differential utilization of the 5'-untranslated region of mRNA.

A recently isolated cDNA for human complement protein C2, C2HL5-3, has an unusually long 5'-untranslated region (UTR) containing four open reading frames upstream of the authentic initiation codon. Here we report that deletion of the 5'-UTR of C2HL5-3 resulted in a 10-fold enhancement in the translational efficiency of C2 in transient eukaryotic cellular assays. Elimination of the open reading frames in the 5'-UTR by site-directed mutagenesis of the initiation codons did not affect C2 synthesis in this assay system, indicating that other structural elements in this region are responsible for translational control. We also show that several C2 mRNAs of varying length in the 5'-UTR, including an alternative C2 mRNA expressing a considerably shorter 5'-UTR, are present in the liver and that the shorter C2 mRNA is the only C2 message found in U937 cells. These results suggest that tissue-specific utilization of alternative transcriptional start sites results in differential translational efficiencies of C2 and may provide insights into the tissue- and stimulus-specific regulation of eukaryotic gene expression.

Base Sequence↗
PubMed1986

The functional inhibition of activated C1 inhibitor in normal human serum causes spontaneous consumption of the complement components C2, C3, C4, and factor B.

The human complement components C1r, C1s, C4, C3, factor B, and/or activated C1INH were functionally blocked in normal human serum (NHS) and EGTA- or EDTA-treated NHS by polyclonal monospecific Fab'-fragments to the individual components. The results of inhibition experiments are compatible with the formation of a classical pathway fluid-phase C3 convertase (C4b2a) spontaneously generated by the inhibition of activated C1INH. This process in both NHS and EGTA-NHS was accompanied by the consumption of C2, C4, C3, and factor B but only by poor enhancement of C5 conversion. Blocking subcomponent C1r, completely inhibited spontaneous activation of the complement components, indicating that the control of C1r hydrolysis is the essential role of activated C1INH as a regulator of C1 activation in NHS. Non-complement serum proteases were inactive during the initiation of the activation process. The presence of blood cells during functional inhibition of activated C1INH in NHS slightly decreased the consumption of C3 but not of C2 and C4.

Angioedema↗
PubMed1988

Effect of histamine on the gene expression and secretion of complement components C2, factor B and C3 in murine macrophages--an opposite signal processing via H1 and H2 receptors.

The effect of histamine on the gene expression, biosynthesis and secretion of C2, factor B and C3 was studied in mouse resident and starch elicited peritoneal macrophages. Measuring the quantity of specific mRNAs and biosynthetically labelled proteins a down-regulation of the biosynthesis of C2, factor B and C3 via H2 receptor was found. On the contrary, histamine displayed no visible H1 receptor mediated influence on the biosynthesis of C2 and factor B. However, via H1 receptor a considerably up-regulation of C3 gene expression and biosynthesis was demonstrated. The data suggest a distinct signal processing mechanism acting on H1 and H2 receptors resulting in opposite effects on the transcriptions of C3 gene in macrophages.

Animals↗
PubMed1987

Determination of the complement component C2 by ELISA in human serum and bronchoalveolar lavage fluids.

In order to measure the concentration of the human complement component C2 in various biological fluids, an enzyme linked immunosorbent assay (ELISA) was developed. This assay was highly sensitive and allowed to detect as few as 400 pg of C2 in a sample volume of 150 microliters (i.e. 2.6 ng/ml). This is a 10- to 15-fold increase in sensitivity with regard to the conventional hemolytic test. As assessed by an immunoblot analysis, our anti-C2 antiserum was able to detect native C2 as well as the cleavage fragments C2a and C2b generated upon complement activation through the classical pathway. Thus, complement activation involving the classical pathway can easily be evidenced by comparing functional (hemolytic) and immunochemical (ELISA) C2 assays which respectively do not and do reveal activated C2. When C2 was assayed in either normal human serum or bronchoalveolar fluids, in both ELISA and hemolytic tests, a highly significant correlation was observed between the two assays (P less than or equal to 0.01). The specific C2 activity (i.e. functional hemolytic activity/ng C2 assayed in ELISA) was higher in serum than in bronchoalveolar lavage fluids from both normal volunteers and patients with pulmonary diseases.

Adult↗