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PubMed1978

Remissions induced in hereditary angioneurotic edema with an attenuated androgen (danazol): correlation between concentrations of C1-inhibitor and the forth and second components of complement.

Serum concentrations of antigenic and functional C1-INH increased in patients in whom remissions from attacks of HANE were induced with danazol. The levels of C4 were directly related to serum concentrations of C1-INH antigens up to a concentration of about half the C1-INH found in normal plasma; at this point, the C4 concentrations were in the normal range and no longer correlated well with C1-INH concentration. Serum C2 levels correlated less well with C1-INH concentration. In normal serum there was a poor correlation between C1-INH, C4, and C2 levels, suggesting that C1-INH is normally present in excess of the amount needed for normal C4 levels. The increments in serum C1-INH were related to the dose of danazol.

Angioedema↗
PubMed1986

Functional analysis of activated C1s, a subcomponent of the first component of human complement, by monoclonal antibodies.

Three mouse monoclonal antibodies (M365, M81, and M241) directed against human C1s were used to analyze the structure of C1s related to the enzymatic activity. M365 and M81 recognized different epitopes on the heavy chain of C1s and could bind to C1s, as well as to C1s. The C4 cleaving activity of C1s was completely blocked by M81 and was partially blocked by M365. Although the C2 cleaving activity of C1s was partially inhibited by M81, no blocking was observed with M365. Both antibodies had no effect on the esterolytic activity of C1s. These results indicate that the C4 and C2 binding sites on C1s reside in the heavy chain, and they are distinct from each other. M241 could bind only to C1s, an active form of C1s. After reduction of C1s, M241 could not react with either heavy or light chain of C1s. The esterolytic activity of C1s was markedly reduced by M241. Furthermore, M241 blocked not only the cleavage of C4 and C2 by C1s but also the complex formation of C1s and C1 inactivator. From these observations, we suggest that M241 reacts with the active site of C1s, and both heavy and light chains of C1s participate in the composition of the active site.

Antibodies, Monoclonal↗
PubMed1996

Rhodobacter capsulatus CycH: a bipartite gene product with pleiotropic effects on the biogenesis of structurally different c-type cytochromes.

While searching for components of the soluble electron carrier (cytochrome c2)-independent photosynthetic (Ps) growth pathway in Rhodobacter capsulatus, a Ps- mutant (FJM13) was isolated from a Ps+ cytochrome c2-strain. This mutant could be complemented to Ps+ growth by cycA encoding the soluble cytochrome c2 but was unable to produce several c-type cytochromes. Only cytochrome c1 of the cytochrome bc1 complex was present in FJM13 cells grown on enriched medium, while cells grown on minimal medium contained at various levels all c-type cytochromes, including the membrane-bound electron carrier cytochrome cy. Complementation of FJM13 by a chromosomal library lacking cycA yielded a DNA fragment which also complemented a previously described Ps- mutant, MT113, known to lack all c-type cytochromes. Deletion and DNA sequence analyses revealed an open reading frame homologous to cycH, involved in cytochrome c biogenesis. The cycH gene product (CycH) is predicted to be a bipartite protein with membrane-associated amino-terminal (CycH1) and periplasmic carboxyl-terminal (CycH2) subdomains. Mutations eliminating CyCH drastically decrease the production or all known c-type cytochromes. However, mutations truncating only its CycH2 subdomain always produce cytochrome c1 and affect the presence of other cytochromes to different degrees in a growth medium-dependent manner. Thus, the subdomain CycH1 is sufficient for the proper maturation of cytochrome c1 which is the only known c-type cytochrome anchored to the cytoplasmic membrane by its carboxyl terminus, while CycH2 is required for efficient biogenesis of other c-type cytochromes. These findings demonstrate that the two subdomains of CycH play different roles in the biogenesis of topologically distinct c-type cytochromes and reconcile the apparently conflicting data previously obtained for other species.

Amino Acid Sequence↗
PubMed1976

80% of patients with intrinsic asthma are homozygous for HLA W6. Is intrinsic asthma a recessive disease?

Of 26 patients with intrinsic asthma, 21 (81%) were homozygous for the histocompatibility antigen HLA-W6. Also, half the patients had complement defects, in particular low levels of C2. This is the first indication of a strong genetic component in intrinsic asthma, apart from that already known from family studies. These findings suggest that intrinsic asthma may be a recessive disease.

Asthma↗
PubMed1984

Phenotypic genetics of complement components.

Both charge and size-dependent electrophoretic techniques have been used to investigate genetic polymorphisms of complement proteins. Of the seventeen complement proteins, ten have been shown to have genetic variants and only one (C9) has been extensively investigated without revealing variants. These investigations give information on the numbers of cistrons and their linkage relations. They demonstrate or confirm the linkage of C2, Factor B and C4 to the MHC. In the cases of both human and mouse C4, it has been shown that the loci are (usually) duplicated. C4 in humans is extremely polymorphic and exhibits a number of strong allelically associated haplotypes. Some of these have only one expressed C4 gene and are associated with disease susceptibility. C8 has at least two cistrons coding for associating subunits. C6 and C7 are linked in several species and sometimes C7 is duplicated. This gene pair is discussed in relation to natural selection and gene conversion.

Animals↗
PubMed1989

Regulation of human and murine complement: comparison of 5' structural and functional elements regulating human and murine complement factor B gene expression.

The serine protease complement factor B (Bf), an acute phase plasma protein, is a component of the alternative pathway of complement activation. Previous studies revealed that several cytokines including IFN-gamma and IL-1 are involved in mediating acute phase Bf expression. To determine the molecular details of Bf expression we isolated, sequenced and characterized the 5' flanking regions of the human and murine Bf genes. In both species the Bf transcriptional start site in liver was located less than 400 bp 3' to the polyadenylation site of the upstream C2 gene. This upstream intergenic region contained greater than 65% nucleotide homology between species. Within this region, an IRS and three heat shock consensus elements were found in the murine sequence in an identical position to that of the human. To examine the functional details of Bf expression, a series of mouse and human Bf promoter-chloramphenicol acetyltransferase (CAT) chimeric gene constructs were transfected into mouse L or human HepG2 cells. Analysis of expression of these fusion gene constructs revealed that 1) cis-acting DNA sequences identified, at least in part, in the 3' untranslated region of the C2 gene (within the 400 bp upstream of the Bf cap site) mediate responsiveness to IL-1 and IFN-gamma, 2) the responsiveness to each mediator appears to be conferred by separate upstream regions similar in position and homologous in man and mouse, and 3) the IL-1 responsive region in both species appears to have the characteristics of an enhancer element. The results of this analysis suggest a selective pressure to conserve the intergenic sequence between C2 and Bf genes and that further studies of these sequences will be useful in elucidating mechanisms controlling the acute phase response.

Animals↗
PubMed2006

Homozygosity for the IgG2 subclass allotype G2M(n) protects against severe infection in hereditary C2 deficiency.

Homozygous C2 deficiency (C2D) is the most common deficiency of the classical complement pathway in Western countries. It is mostly found in patients with autoimmune disease or susceptibility to bacterial infections and in healthy persons. We wished to assess to what extent other immunological factors might explain differences of susceptibility to infections in C2D. For this reason, 44 Swedish patients with C2D were stratified with regard to the severity of documented infections. Investigations of IgG subclass levels, IgG subclass-specific GM allotypes, concentrations of factor B, properdin, and factor H, and polymorphisms of mannan-binding lectin and the Fc receptors FcgammaRIIa and FcgammaRIIIb were performed. Homozygosity for the G2M*n allele, which is known to promote Ab responses to polysaccharide Ags, was strongly associated with the absence of severe infections (p < 0.001) in the patients, suggesting a major protective role. The combination of mannan (or mannose)-binding lectin and C2 deficiency was found to be a minor susceptibility factor for invasive infection (p = 0.03). Low concentrations of IgG2 and factor B might sometimes contribute to susceptibility to infection. Other factors investigated did not appear to be important. In conclusion, the findings indicated that efficient Ab responses to polysaccharides are protective against severe infection in C2D. Implications with regard to vaccination should be considered.

Adult↗
PubMed2001

An assay for the mannan-binding lectin pathway of complement activation.

The mannan-binding lectin (MBL) pathway of complement activation has been established as the third pathway of complement activation. MBL is a carbohydrate-binding serum protein, which circulates in complex with serine proteases known as mannan-binding lectin associated serine proteases (MASPs). When bound to microorganisms, the MBL complex activates the complement components C4 and C2, thereby generating the C3 convertase and leading to opsonisation by the deposition of C4b and C3b fragments. This C4/C2 cleaving activity is shared with the C1 complex of the classical pathway of complement activation. Therefore, in a generally applicable complement activation assay specific for the MBL pathway, the activity of the classical pathway must be inhibited. This can be accomplished by exploiting the finding that high ionic strength buffers inhibit the binding of C1q to immune complexes and disrupt the C1 complex, whereas the carbohydrate-binding activity of MBL and the integrity of the MBL complex is maintained under hypertonic conditions. In the assay described here, the specific C4b-depositing capacity of the MBL pathway was determined by incubating serum diluted in buffer containing 1 M NaCl in mannan-coated microtiter wells before the addition of purified C4. The interassay coefficient of variation in the ELISA version was 7.3%. As expected no activity was found in MBL-deficient serum. When 100 normal serum samples were analysed we found that the MBL level correlated with the amount of C4b deposited on the mannan-coated surface. However, we also found a threefold variation in C4b-depositing capacity between individuals with similar MBL concentrations. The assay permits for the determination of MBL complex activity in serum and plasma samples and may thus be used to evaluate the clinical implications of complement activation via this pathway.

Carrier Proteins↗
PubMed1975

EAC4 and EAC14 production without purified Ci.

EAC4 and EAC14 of high activity were prepared by treating sensitized red cells with human or guinea pig serum in the presence of TTHA, a chelating agent whid at low pH to maximize C1 and C4 activity and to minimize C3 contamination. Cells prepared with guinea pig complement were contaminated with C2, which could be decayed away at 37 degrees C. Cells sensitized with IgG antibody were more reactive than those sensitized with whole serum or with IgM, and preparations made with TTHA-complement were more reactive than those prepared with purified C1 plus EDTA-complement. EAC14 stored at 0 degrees C for 3 weeks lost very little activity.

Animals↗
PubMed2001

Ethnic diversity of class III genes in autoimmune disease.

One may wonder why the genes for the class III region are even situated in the human Major Histocompatibility Locus (MHC). However, on closer inspection we find that the genes for the complement components, tumor necrosis factor (TNF) and others may play an important role in host immune defenses. Thus, this region on chromosome six may be more appropriately thought of as an immune response area. Accordingly, there is a high degree of polymorphism in many genes within the MHC, the most notable being the HLA genes. In the class III region C2, factor B (Bf) and C4 are polymorphic in as many populations studied to date. The purpose of this review will be to briefly describe the class III region, identify the genetic polymorphism found in various ethnic groups and define their roles in autoimmune diseases.

Autoimmune Diseases↗
PubMed1982

Complement-mediated inhibition of immune precipitation. I. Role of the classical and alternative pathways.

This study has examined the mechanisms involved in complement-mediated inhibition of immune precipitation using radiolabelled BSA and rabbit anti-BSA. Purified proenzyme C1 was capable of maintaining the complexes in soluble form during the first few minutes of reaction whereas immune precipitation was immediate in the presence of purified C1q or C1 + EDTA (ethylenediamine tetra-acetate). In C1q deficient serum, initial immune aggregation was followed by partial solubilization of the formed precipitate similar to that obtained with normal human serum in the presence of Mg EGTA. In C2 deficient serum precipitation occurred at a slow rate. Repletion of the deficient component (C1q or C2 respectively) restored fully inhibition of precipitation. These experiments establish a critical role for the classical pathway, in this phenomenon. By contrast the role of the alternative pathway in maintaining complexes in solution was less important; only partial and delayed precipitation occurred in sera depleted of factor D (RD) or factor B (RB). B and D restored normal complement activity to depleted sera. No precipitation was detected in a reagent depleted of properdin (RP). The mechanisms of inhibition of precipitation are therefore distinct from those responsible for solubilization of an immune precipitate, which is largely dependent on the alternative pathway.

Animals↗
PubMed1984

Prevention of immune precipitation by purified classical pathway complement components.

The role of the classical pathway of complement in the prevention of immune precipitation has been investigated using purified complement components and immune complexes (IC) consisting of rabbit anti-BSA and BSA. C1 reduced the rate of immune precipitation. As C1q, EDTA treated C1 or C1-inhibitor treated C1 were unable to retard the precipitation of IC, it was concluded that the intact C1 molecule was required for this function. Use of phenylmethylsulphonyl fluoride and benzamidine showed that the enzymatic site on C1 was not required for this activity. C4 and C2 did not affect immune precipitation significantly when C1 was present at the concentrations present in serum. When C3 was added to C1, C4 and C2 precipitation of IC did not occur. These data demonstrate that classical pathway activation alone is sufficient for the prevention of immune precipitation.

Antigen-Antibody Complex↗
PubMed1994

Complement profiles in human skin lymph during the course of irritant contact dermatitis.

Using microsurgery a superficial peripheral lymph vessel draining the skin of the upper and medial part of the foot was cannulated on the lower leg of two healthy human volunteers. An irritant contact dermatitis was induced 2 days later by the application of 10% sodium lauryl sulphate to the drained skin area. After a further 3 days the spontaneously regressing skin reaction was treated with clobetasol propionate. Lymph was continuously collected in two aliquots per day for 7 days. The levels of total protein, of albumin and globulins, and of complement components of the classical, the alternative and the lytic pathway as well as the C4A and C4B gene products and the regulatory proteins FB, C1INH, C4BP, FH and FI were determined by ELISA and radial immunodiffusion techniques. Postoperatively, the levels of complement proteins and globulins in the lymph were 5-10 times lower than those in normal human serum, but increased during the course of the skin reaction, while the irritant contact dermatitis did not induce a change in their plasma concentration. In comparison to the baseline, the mean values for C1q, C1r, C2, C5, C6, C7, C8, C9, FB, C1INH, C4BP, FH and FI exhibited a 3-5-fold increase, C3, total C4, albumin and the alpha 1-globulin fraction a 6-9-fold increase, and C1s, C4A, C4B, FB and alpha 2-, beta- and gamma-globulins a 10-20-fold increase.(ABSTRACT TRUNCATED AT 250 WORDS)

Albumins↗
PubMed1980

Mechanism of lethal effect of human serum upon Leishmania donovani.

In order to gain greater understanding of potential host defense mechanisms against Leishmania donovani, we examined the effect of nonimmune, human serum upon promastigotes and amastigotes. Fresh sera were found to be lethal for promastigotes, but had no detectable effect on amastigotes. Serum exposed promastigotes became immotile, did not take up neutral red dye, appeared to be disrupted, and failed to recover after further incubation in fresh media. Heat labile components were required for promastigote killing since heat-inactivated serum (56 degrees C, 30 min) agglutinated but did not kill them. Sera that lacked either the 5th or 6th complement (C) component had no effect when used alone, but when used together, were lethal, indicating that activation of the membrane attack complex (C5b-C9) ws necessary for the lethal effect. The mode of C activation was determined by using serum with complete, selective, deficiency of C2, and normal serum chelated with Mg-EGTA. The C2-deficient serum killed promastigotes only after the addition of purified C2, and Mg-EGTA chelated serum had no detectable lethal effect. Thus, promastigotes appeared to activate C through the classical pathway. Human IgG and IgM, detected with 125I-anti-human antibody, bound to promastigotes. Removal of antibody from serum by absorption with promastigotes eliminated the lethal effect. The effect was restored by addition of heat-inactivated serum to absorbed serum. We conclude that promastigotes bind antibody and are killed by activation of the membrane attack complex of C through the classical pathway.

Animals↗
PubMed1984

Antibody-dependent alternative pathway killing of Haemophilus influenzae type b.

The bactericidal activities of human complement and human antibody directed against specific Haemophilus influenzae type b cell surface determinants were investigated. Strain Eagan, a laboratory isolate, and strain Kn, a clinical isolate, were used as the test organisms and gave qualitatively similar results. In the absence of antibody, both isolates were resistant to killing by 60% agammaglobulinemic serum (AGS) containing normal complement levels. The addition of affinity-purified immunoglobulin G anticapsular antibody was bactericidal with 15% AGS as the complement source. Bactericidal activity was also demonstrated with this antibody when the complement source was AGS-Mg-EGTA [ethylene glycol-bis(beta-aminoethyl ether)-N,N-tetraacetic acid], C2-deficient human serum (alternative complement pathway), or AGS in which factor D and properdin had been selectively inactivated (classical pathway). Immunoglobulin G fractions from a human serum pool or from serum from an adult who had recovered from H. influenzae type b (Kn) sepsis were absorbed to remove anticapsular antibody. The absorbed fractions containing noncapsular antibodies also activated complement-dependent bactericidal activity. But, in contrast to the results with anticapsular antibody, noncapsular antibodies did not elicit alternative pathway bactericidal activity. Incubation of cells of H. influenzae type b in C2-deficient serum or AGS-Mg-EGTA did not cause complement consumption (total hemolytic complement and C3). The addition of immunoglobulin G anticapsular antibody (but not noncapsular antibody) increased consumption of total complement and C3, paralleling the results of the bactericidal assays. These studies demonstrated an absolute requirement for anticapsular antibody in alternative pathway activation and killing of H. influenzae type b.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1997

Complement classical pathway expression by human skeletal myoblasts in vitro.

Human myoblasts express immunological properties in vitro and we have previously reported that they produce Complement (C) components of the alternative pathway. Myoblasts activate the classical pathway but are fully protected against C attack by the expression of major C regulators. In order to fully understand the relationship between myoblasts and C, we here report the biosynthesis of C components of the classical pathway by skeletal muscle cells. Human myoblasts in vitro produced C1q, C1r, C1s, C2 and C4 constitutively and all syntheses were upregulated after stimulation with IFN-gamma. We suggest that human myoblasts may constitute a local source of C and therefore C could be implicated in inflammatory or physiopathological processes developed in skeletal muscle.

Blotting, Western↗
PubMed1989

Control of immune complexes by the classical pathway.

The association between inherited deficiencies of the classical pathway complement components (C1q, C1r, C1s, C4, C2 and C3) and immune complex disease shows that complement is involved in protection against the development of immune complex disease (ICD). This protection is conferred by the ability of the complement system to keep antigen antibody complexes (IC) small and soluble. Two mechanisms exist, prevention of immune precipitation (PIP), which inhibits the formation of large insoluble lattices when IC are formed in the presence of complement (nascent IC), and solubilisation of preformed immune precipitates (SOL). PIP is probably the more important as it is unlikely that, in vivo, IC are ever formed in the absence of complement. PIP displays an absolute dependency upon the classical pathway while SOL is alternative pathway dependent. However, for optimal efficiency SOL requires an intact classical pathway. Thus the classical pathway plays a role in both PIP and SOL. The end result of both processes is the covalent binding of C3b to the IC lattice, which not only keeps IC soluble, but permits binding to CR1 for removal from the circulation. The sera of patients with ICD contain a factor (s) which inhibits PIP. The sera of RA patients inhibits PIP and purified IgM-RF has been shown to inhibit this function. However a second inhibitor of PIP has recently been purified, a glycoprotein (Mr 60 kd) (gp60) which is present in normal serum and in increased concentration in RA sera. Gp60 binds to the Fc piece of IgG, but not to IgA or IgM, and competes with C1q for a binding site on IgG Fc. Thus gp60 appears to act by preventing binding and activation of C1 by IgG containing IC.

Antigen-Antibody Complex↗
PubMed1979

Effects of zinc chloride on guinea pig complement component activity in vitro: concentration-dependent inhibition and enhancement.

We have studied the in vitro effects of zinc chloride on the hemolytic activity of each component of the guinea pig classical complement pathway over a wide range (25 to 500 muM) of zinc concentrations. At high concentrations (>200 muM) the activity of all components was strongly inhibited by this metal. Concentrations of 500 muM inhibited C1 and C5 by 80 and 65%, respectively, whereas all other components were inhibited by more than 94%. Zinc chloride at 25 muM produced more varied effects, with C2, C3, and C6 inhibited by 36, 35, and 55%. C7 and C8 were inhibited by approximately 25%, whereas C1, C4, and C9 were not appreciably affected. The activity of the fifth component, on the other hand, was strongly enhanced by the presence of zinc. Concentrations of 25, 50, and 100 muM zinc chloride produced increases of 92, 44, and 18%, respectively, in C5 titers when present during the activation-binding step of this component. Further studies indicated that the activities of cell-bound complement components were unaffected by zinc treatment after activation and/or binding to the sheep erythrocyte surface had occurred. In addition, zinc did not appear to inhibit by causing irreversible denaturation of either total complement proteins or its various components. Rather, it appears that zinc must be present as a reactant during the activation and/or binding step of each component for inhibition or enhancement to occur.

Animals↗