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PubMed1989

Lysis of sensitized sheep erythrocytes in human sera deficient in the second component of complement.

Analysis of C-dependent lysis of sensitized SRBC by C2-deficient sera (C2D) led to the characterization of a C2 bypass pathway. Lysis in the total hemolytic C assay by C2D sera was Ca2+-dependent and required a high concentration of hemolysin to sensitize E. Selective component depletion indicated a requirement for C1 and C4 of the classical pathway (CP) and proteins B, P, and probably D of the alternative pathway (AP). Total hemolytic C could be restored to normal in these C2D sera by utilizing heavily sensitized E or by the addition of a supranormal concentration of B. This system most closely resembles a pathway described by J. E. May and M. M. Frank which requires antibody, C1, and the AP but not C4 or C2. It differs in its requirement for C4. We hypothesize that this pathway represents vestiges of a more primitive C pathway. It becomes evident and possibly clinically important in the setting of C2 deficiency, by allowing C activation, other than the AP, and perhaps in normal individuals, by damaging microorganisms that have evolved means to inhibit early components of the CP.

Adult↗
PubMed1976

Inherited structural polymorphism in human C2: evidence for genetic linkage between C2 and Bf.

Structural variation in the second component of human complement was identified in about 4% of serum samples from random unrelated individuals of all the major races. Three forms of C2 have been identified by isoelectric focusing in polyacrylamide gel and development of patterns in agarose gel containing antibody-sensitized sheep red cells and C2-deficient serum: C2 C (common), C2 A (acidic), and C2 B (basic). The C2 variants were shown to be inherited as autosomal codominant traits, and suggestive evidence for close linkage between C2 and Bf was obtained.

Complement C2↗
PubMed1979

Hereditary C2 deficiency associated with non-systemic glomerulonephritis.

A patient with non-systemic idiopathic glomerulonephritis was found to have a complete deficiency of C2, the second component of complement. The clinical course, histological findings and serological abnormalities are reported in detail. The renal disease was a mild glomerulonephritis with mesangial and subendothelial immune deposits comprising IgG, IgM and C3, increased mesangial matrix without significant cell proliferation. An immunogenetic analysis of the patient's family was carried out. It was demonstrated that the homozygous C2 deficiency was associated with heterozygotism for HLA-A, B and D. Only one of the C2 deficient genes was associated with the expected HLA-A10, B18 haplotype and the propositus was HLA-D2 negative. This report confirms the fact that non-systemic glomerulonephritis should be included in the variety of immunological disorders associated with a complement deficient state. However, C2 deficiency does not seem to be related specifically to a given histological variety of glomerulonephritis.

Adult↗
PubMed1981

The bovine complement system.

Methods were developed for titrating bovine C3b-inactivator, C2, C3 and C4 by non-hemolytic means, and for assaying by hemolysis all the components of the bovine classical complement system except C2. All components were detected at serum dilutions above 1:1000, and some at dilutions above 1:100,000. C1, C4, C5, C7 and C9 titers were very high in adult bovine serum, and C2 and C8 were relatively low. C1, C2, and C8 were quite heat-labile at 56 degrees C, and C7 was moderately so, while C3 amd C6 titers increased after heating due to inactivation of a heat-labile inhibitor. Fetal bovine serum contained approximately 1-3% of adult levels of conglutinin, C1 and C6, and 5-50% of adult levels of the remaining components except C3. C3 antigen was found, but C3 functional activity was undetectable in most fetal bovine sera, though present at low levels in a few.

Animals↗
PubMed1989

Human major histocompatibility complex contains a minimum of 19 genes between the complement cluster and HLA-B.

A 600-kilobase (kb) DNA segment from the human major histocompatibility complex (MHC) class III region was isolated by extension of a previous 435-kb chromosome walk. The contiguous series of cloned overlapping cosmids contains the entire 555-kb interval between C2 in the complement gene cluster and HLA-B. This region is known to encode the tumor necrosis factors (TNFs) alpha and beta, B144, and the major heat shock protein HSP70. Moreover, a cluster of genes, BAT1-BAT5 (HLA-B-associated transcripts) has been localized in the vicinity of the genes for TNF alpha and TNF beta. An additional four genes were identified by isolation of corresponding cDNA clones with cosmid DNA probes. These genes for BAT6-BAT9 were mapped near the gene for C2 within a 120-kb region that includes a HSP70 gene pair. These results, together with complementary data from a similar recent study, indicated the presence of a minimum of 19 genes within the C2-HLA-B interval of the MHC class III region. Although the functional properties of most of these genes are yet unknown, they may be involved in some aspects of immunity. This idea is supported by the genetic mapping of the hemopoietic histocompatibility locus-1 (Hh-1) in recombinant mice between TNF alpha and H-2S, which is homologous to the complement gene cluster in humans.

Cell Line↗
PubMedDate not supplied

Major histocompatibility complex genes in a Mexican family with deficiency of the second component of the complement system.

Hereditary deficiency of the second component of the complement system is an uncommon condition that has been reported so far mostly in Caucasians. We describe a Mexican patient with undetectable C2 levels and absence of complement hemolytic activity. Major histocompatibility complex (MHC) genes in his family showed that the proband had the MHC haplotypes HLA-A25, B18, DR2, DQ1, SQ042/HLA-A24, B18, DR2, DQ1, SQ042. A strong genetic linkage of the deficiency of the second component of the complement gene and the HLA antigens A25, B18, and DR2, is well established in Caucasian populations. This suggests that the probable origin of the deficiency in our patient was admixture with Caucasian ancestors.

Complement C2↗
PubMed1979

Mapping of the structural gene for the second component of complement with respect to the human major histocompatibility complex.

Families have been HLA typed, and allotypes of the second component of complement and properdin factor B determined. The lod score for the C2 structural gene and HLA-B from the study of 11 families and 55 informative meioses was 14.39 at maximum likelihood estimate of the recombination fraction of .02. This is related to other estimates of the distance between these two genes. The relative kinetic activities of the C2 allotypes were studied and no differences were demonstrated. No crossovers between Bf and C2 were observed.

Adult↗
PubMed2002

A single amino acid substitution in DNA-PKcs explains the novel phenotype of the CHO mutant, XR-C2.

We recently described a CHO DSBR mutant belonging to the XRCC7 complementation group (XR-C2) that has the interesting phenotype of being radiosensitive, but having only a modest defect in VDJ recombination. This cell line expresses only slightly reduced levels of DNA-PKcs but has undetectable DNA-PK activity. Limited sequence analyses of DNA-PKcs transcripts from XR-C2 revealed a point mutation that results in an amino acid substitution of glutamic acid for glycine six residues from the C-terminus. To determine whether this single substitution was responsible for the phenotype in XR-C2 cells, we introduced the mutation into a DNA-PKcs expression vector. Whereas transfection of this expression vector significantly restores the VDJ recombination deficits in DNA-PKcs-deficient cells, radioresistance is not restored. Thus, expression of this mutant form of DNA-PKcs in DNA-PKcs- deficient cells substantially recapitulates the phenotype observed in XR-C2, and we conclude that this single amino acid substitution is responsible for the non-homologous end joining deficits observed in XR-C2.

3' Flanking Region↗
PubMed1975

Complement fixation by rheumatoid factor.

The capacity for fixation and activation of hemolytic complement by polyclonal IgM rheumatoid factors (RF) isolated from sera of patients with rheumatoid arthritis and monoclonal IgM-RF isolated from the cryoprecipitates of patients with IgM-IgG mixed cryoglobulinemia was examined. RF mixed with aggregated, reduced, and alkylated human IgG (Agg-R/A-IgG) in the fluid phase failed to significantly reduce the level of total hemolytic complement, CH50, or of individual complement components, C1, C2, C3, and C5. However, sheep erythrocytes (SRC) coated with Agg-R/A-IgG or with reduced and alkylated rabbit IgG anti-SRC antibody were hemolyzed by complement in the presence of polyclonal IgM-RF. Human and guinea pig complement worked equally well. The degree of hemolysis was in direct proportion to the hemagglutination titer of the RF against the same coated cells. Monoclonal IgM-RF, normal human IgM, and purified Waldenström macroglobulins without antiglobulin activity were all inert. Hemolysis of coated SRC by RF and complement was inhibited by prior treatment of the complement source with chelating agents, hydrazine, cobra venom factor, specific antisera to C1q, CR, C5, C6, or C8, or by heating at 56 degrees C for 30 min. Purified radiolabeled C4, C3, and C8 included in the complement source were bound to hemolysed SRC in direct proportion to the degree of hemolysis. These data indicate that polyclonal IgM-RF fix and activate complement via the classic pathway. The system described for assessing complement fixation by isolated RF is readily adaptable to use with whole human serum.

Animals↗
PubMed1980

Effect of aspirin on complement in vivo.

Following ingestion of aspirin (1 g) complement consumption could be demonstrated in 18/20 healthy volunteers. A slight to moderate decrease of whole complement activity (CH50) and of the components C1, C4 and C2 was found. In addition, reduced levels of the C1 inactivator (C1 IA) were measured in 19/20 probands. The drop in C titers and C1 IA was only detectable within a short period of time and 30 min after ingestion of the drug the titers were usually returning to normal. In view of these findings, the possible role of complement in adverse reactions to aspirin is discussed.

Aspirin↗
PubMed1983

In vitro alternative and classical activation of complement by extracts of cotton mill dust: a possible mechanism in the pathogenesis of byssinosis.

Extracts of cotton mill dust (CDE) were shown to activate complement by the classical and alternative pathways. Activation of the classical pathway, presented in this study for the first time, was verified by C1 consumption, C2 destruction, and C4 conversion tests. The component of cotton dust that causes complement activation precipitated in the presence of 20% saturated ammonium sulfate. The data presented suggest that endotoxin is not the principal complement-activating component, as complement activation could not be correlated to endotoxin concentrations of extracts of various parts of the cotton plant. Proteolytic enzymes were also eliminated as possible causative agents of complement cleavage since CDE did not cleave purified C3 in the absence of other complement components. Polyvinylpolypyrrolidone failed to remove the complement-activating component in CDE demonstrating that polyphenolic tannins are not the causative agents. Involvement of complement activation in the pathogenesis of byssinosis could explain in part the mechanism and symptoms of the acute byssinotic reaction.

Byssinosis↗
PubMed1988

Patients with CLL and hypocomplementaemia have an impaired serum bactericidal activity against the Salmonella minnesota Re mutant.

The bactericidal effect of 25 serum samples from 23 patients with chronic lymphocytic leukaemia (CLL) against the Salmonella minnesota S form and Re mutant has been studied. No killing of the S form was observed in any of the sera tested, whereas a normal bactericidal effect was found against the Re mutant (group 1) in 17/25 sera of CLL patients. By contrast, in 8 serum samples from 6 CLL patients no killing or a markedly delayed killing of the Re strain was observed (group 2). Significant differences in the complement levels were found between the sera of group 1 and group 2. In group 1 mostly normal or elevated complement levels were observed, while in group 2 levels of C4 and C2 were found to be strongly decreased. A significant correlation was found between the bactericidal effect on the one hand and the C4 and C2 levels on the other.

Blood Bactericidal Activity↗
PubMed1990

[Hereditary angioneurotic edema. Management in pediatric surgery].

Hereditary angioneurotic oedema is an autosomal dominant disorder associated with serum deficiency of functionally active C1 inhibitor protein (type 1) or normal serum level of functionally deficient C1-inhibitor (type 2). These biochemical abnormalities induce a complement activation which leads to episodic swelling of interstitial tissues usually of the abdominal viscera and of the upper airway with resultant asphyxia. Vasoactive peptides from the degradation of component C2 of the complement along with an activation of basophils by chemotactic substances from the degradation of C3 and C5 are the main mechanisms involved in vasodilatation and swelling. Attacks of angioneurotic oedema, sometimes fatal when involving the upper airway, can occur during any but usually during ear-throat-nose, dental or facial surgery. This article describes the pathophysiology and the main features of the disease in children. It reviews the different treatments used to avoid attacks or to cure an attack of angio-oedema once it has begun, both during planed surgery and during emergency surgery.

Adolescent↗
PubMed1976

The complement profile in babesiosis.

Rats have been infected with Babesia rodhaini, a protozoan agent that induces immune complex disease. Assays for complement have revealed depletion of C2, C3, C4, C5, and whole complement in the course of infection. No evidence of depletion in the alternative (properdin) pathway was found. These findings are consistent with the conclusion that the classical complement pathway is activated during the course of the protozoan infection.

Animals↗
PubMed1988

Pulmonary alveolar type II epithelial cells synthesize and secrete proteins of the classical and alternative complement pathways.

The serum complement system is a major mediator of inflammation reactions. Two of the complement proteins, the third (C3) and fifth (C5) components, are precursors of potent phlogistic molecules, C3a and C5a. C5a has potent chemotactic activity and plays an active role in pulmonary inflammation. We present evidence suggesting that several complement proteins, including C5, are synthesized locally in the lung in alveolar type II epithelial cells. Lung tissue from normal mice synthesized and secreted C5 protein similar to the C5 protein in mouse serum, whereas lung tissue from C5-deficient mice did not. Lung tissues from both normal and C5-deficient mice synthesized C3. Rat lung tissue synthesized and secreted C5, as well as C2, C4, C3, and factor B. Cultures of type II cells (95% type II cells, 5% macrophages) regularly synthesized all these proteins. In contrast, cultures of macrophages alone synthesized large amounts of C2 and factor B, and in some experiments C3 and C4, but never C5. The C5 synthesized by the rat cells was slightly larger than serum C5 (200 kD compared with 180 kD) and was not processed to the two-chain molecule seen in serum. Rat lung tissue and purified type II cells contained C5 mRNA with the same molecular mass as the C5 mRNA in rat liver and in mouse lung and liver. Human type II cells also synthesized C5, as well as C2, C4, C3, and factor B. Human pulmonary macrophages synthesized only C2, factor B, and, in some experiments, C3. Synthesis of complement proteins in cells that line the alveolar wall may provide a local source of these proteins for inflammatory responses in the lung. Local synthesis of complement proteins could be regulated independently of the synthesis in the liver.

Animals↗
PubMed1983

Complement levels in normal and inflamed aqueous humor.

C2, C6, and C7 were measured by hemolytic assay and Factor B and IgG were measured by radial immunodiffusion in samples of normal and inflamed aqueous humor. Normal aqueous humor was found to contain functional C2, C6, and C7, but the small ratios of aqueous humor to serum measurements suggested that there was relatively little of these complement components in normal aqueous humor when compared to serum. The mean values of C2, C6, C7, and Factor B in aqueous humor and the median ratios of aqueous humor to serum measurements for each complement component were higher in patients with inflamed aqueous humor than in patients with normal aqueous humor. A comparison of the ratios of IgG to each complement component in normal and inflamed aqueous humor suggested that levels of IgG and complement increased proportionately in inflamed aqueous humor. Factor B, a component of the alternative pathway, was not detected in normal aqueous humor but measured in five of six samples of aqueous humor from eyes with anterior chamber inflammation.

Adult↗
PubMed1991

Modulation of complement gene expression by glucocorticoids.

The addition of dexamethasone, prednisolone or cortisol (in order of efficacy) to human monocytes in culture produced dose-related increases in the synthesis rates of the complement components C1 inhibitor (C1-inh), factor B (B) and C2. In contrast, concentrations of C3 and lysozyme in the culture supernatants were decreased. Indomethacin stimulated synthesis of C1-inh, C2 and B, but had little effect on synthesis of C3 or lysozyme. The simultaneous addition of cycloheximide (2.5 micrograms/ml) abrogated the effects of dexamethasone on synthesis of C2, B and C1-inh, but the effect of indomethacin on the synthesis of these components was unchanged. These data suggest that protein synthesis is required for the effects of glucocorticoids on the synthesis of C2, B and C1-inh to occur. Dexamethasone and indomethacin increased the abundances of C1-inh mRNA, B mRNA and C2 mRNA in parallel with changes in the synthesis rates of these proteins. The changes in mRNA abundance were not transcriptional, but were shown to be due to increased mRNA stability. In contrast, dexamethasone decreased the expression of C3 and lysozyme by decreasing the rate of transcription of these genes. Indomethacin had no effect on transcription of the C3 and lysozyme genes. The half-lives of C3 mRNA, lysozyme mRNA and actin mRNA were not altered by dexamethasone or indomethacin. It is concluded that the effects of glucocorticoids on monocyte synthesis of C2, B and C1-inh are due to increased mRNA stability and may be related to inhibition of prostaglandin synthesis, as these effects are similar to those produced by indomethacin. The effects of dexamethasone on the synthesis of C3 and lysozyme differ from those on C2, B and C1-inh as they depend upon a decrease in gene transcription, which is not affected by indomethacin.

Cells, Cultured↗
PubMed1987

Generation of complement anaphylatoxins and C5b-9 by crystalline cholesterol oxidation derivatives depends on hydroxyl group number and position.

Cholesterol crystals activate the human alternative complement pathway. Loss of Factor B hemolytic activity in C2-deficient serum was comparable to that in normal human serum after incubation with cholesterol crystals. Consumption of Factor B hemolytic activity in normal serum incubated with cholesterol occurred in a time- and dose-dependent manner. The reduced capacity of crystals-absorbed serum to activate C2, but not Factor B, on fresh crystals, indicated that cholesterol mediates antibody-dependent classical pathway activation in addition to alternative pathway activation in whole serum. Cholestane triol, an oxidation derivative of cholesterol which bears three hydroxyl groups, cleaved 5-fold more C3 than cholesterol in normal human serum. Three cholesterol derivatives, each bearing two hydroxyl groups, were intermediate activators between cholesterol and cholestane triol. The compounds differed, however, in their complement-activating ability, indicating that hydroxyl position as well as number exerts an influence on complement activation. Measurements of C3adesArg and C5adesArg antigens in cholesterol crystal treated serum revealed that approx. 10% of total serum C3 was cleaved and that, on a molar basis, only 3% C5 cleavage occurred relative to C3 cleavage. For 1 mole of C5a generated, 0.1 moles of fluid-phase C5b-9 was detected. Although the extent of C3 cleavage varied with each cholesterol derivative depending on the position and number of hydroxyl groups, the relative coupling efficiency of C3 and C5 cleavage and C5a and C5b-9 generation was similar for all compounds. The ability of cholesterol and its oxidation products to generate anaphylatoxins and C5b-9 complexes may be of importance in mediating inflammatory processes involved in atherogenesis.

Anaphylatoxins↗