Classical complement pathway in HIV infection.
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Acquired Immunodeficiency Syndrome↗
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Isolation and characterization of a novel plasma protein which binds to activated C4 of the classical complement pathway.
We report here the isolation and partial characterization of a previously unrecognized protease-sensitive plasma protein identified during the development of a novel protocol for the purification of the second component of human complement (C2). This new protein is physicochemically similar to C2. It coprecipitates with C2 on polyethylene glycol fractionation and specifically binds, like C2, to Sepharose-bound iC4/C4b. Binding occurs both in the presence and absence of C2. The purified protein has a chain structure similar to C2 as determined by sodium dodecyl sulfate-gel electrophoresis in the presence or absence of reducing agent and has a molecular mass of 120 kDa, only somewhat greater than C2 at 95 kDa. Both proteins radioiodinate under similar conditions to the same specific activities with each of two different methods that yield 10-fold disparate results. Quantitative Mancini analysis identifies 300 micrograms/ml of the 120-kDa protein in plasma and serum. The protein is present at normal concentrations in serum from individuals genetically deficient in C2, has no C2 functional activity, and is not cleaved as is C2 when serum complement is activated. Potent monospecific polyclonal anti-serum to each do not cross-immunoprecipitate using standard gel techniques. However, these anti-sera identify epitopes in common by Western blotting. The data presented indicate that the 120-kDa protein is a distinct plasma component and suggest that the protein is not an "immature" form of C2. Initial experiments to delineate a functional role for the 120-kDa protein have demonstrated a consistent inhibition of C1 site generation on EAC4b which is dose-dependent and reversible. Thus, this protein appears to be a new complement regulatory factor.
Blood Proteins↗
Activation of the classical complement pathway in human serum by a small oligosaccharide.
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Ant Venoms↗
Activation of the classical complement pathway in brain tissue of Alzheimer patients.
Positive immunohistochemical staining of Alzheimer brain tissue was obtained with antibodies to proteins associated with classical, but not the alternative, complement pathway. Clq, C3d, C4d are fractions of complement proteins that bind to tissue when the classical complement pathway is activated. Antibodies to these fractions stained senile plaques, dystrophic neurites and some neurofibrillary tangles. C5b-9 is the membrane attack complex which promotes cell lysis when assembled on the plasma membrane. An antibody to a neoantigenic site on this complex stained dystrophic neurites and many neurofibrillary tangles, but not extracellular amyloid. Properdin and fraction Bb of factor B, two proteins that bind to tissue when the alternative complement pathway is activated, were not detected immunohistochemically.
Aged↗
Activation of the classical complement pathway by mannose-binding protein in association with a novel C1s-like serine protease.
Serum mannose-binding protein (MBP) is a C-type lectin that binds to terminal mannose and N-acetylglucosamine moieties present on surfaces of certain pathogens and activates the classical complement pathway. In the present study, we describe the mechanism underlying the activation triggered by MBP. The human serum MBP fraction was obtained by sequential affinity chromatography on mannan-Sepharose, anti-IgM-Sepharose and anti-MBP-Sepharose in the presence of calcium ions. This fraction contained a C1s-like serine protease as assessed by C4 consumption. The C1s-like serine protease, designated MBP-associated serine protease (MASP), was separated from MBP by rechromatography on anti-MBP-Sepharose in the presence of ethylenediaminetetraacetic acid. MASP exhibited both C4- and C2-consuming activities. The molecular mass of MASP was estimated to be 83 kD with two polypeptides of heavy (66 kD) and light (L) (31 kD) chains linked by disulfide bonds. The serine residue responsible for protease activity is located on the L chain. Reconstitution experiments using MASP and MBP revealed that combination of the two components restores C4- and C2-activating capacity on mannan. Based on analyses of molecular size, antigenicity, and 11 NH2-terminal amino acid sequences of the L chain, we conclude that MASP is a novel protein different from C1r or C1s. Our findings are not in accord with a proposed mechanism by which MBP utilizes the C1r2-C1s2 complex to initiate the classical complement pathway.
Amino Acid Sequence↗
High doses of intravenous immunoglobulin do not affect the recognition phase of the classical complement pathway.
We have recently found that intravenous immunoglobulin (IVIg) prevents deposition of C3 and C4 fragments onto antibody sensitized erythrocytes. To find out if such an effect results from the blockade of the recognition phase of the classical complement cascade, we investigated the ability of human serum containing high concentrations of IVIg to deposit the recognition subunit of the first complement component (C1q) onto targets. Normal human serum supplemented in vitro with IVIg did not demonstrate reduced C1q binding to targets as determined by radiolabeled antihuman C1q antibody uptake. Similarly, methylamine-treated normal human serum to which IVIg was added was equally effective in terms of C1q binding as the same serum without IVIg. At increasing doses of sensitizing antibody, C1q uptake decreased proportionally; however, at all antibody dilution points C1q uptake was not significantly different in the serum with IVIg in comparison with normal serum. Serum from a patient treated with IVIg did not differ in its capacity to deposit C1q from the same patient's serum before therapy. Our data suggest that IVIg does not interfere with the recognition step of classical complement pathway. This is a US government work. There are no restrictions on its use.
Complement C1↗
Anticomplementary activity of boswellic acids--an inhibitor of C3-convertase of the classical complement pathway.
Boswellic acids (BA), an anti-inflammatory and anti-arthritic principle/s of Boswellia serrata, were found to possess anticomplementary activity. It inhibits the in vitro immunohaemolysis of antibody-coated sheep erythrocytes by pooled guinea-pig serum. The reduced immunohaemolysis was found to be due to inhibition of C3-convertase of the classical complement pathway. The threshold concentration for inhibiting C3-convertase was found to be 100 micrograms. However, higher concentrations of BA showed constant inhibitory effects on immunohaemolysis. BA also exhibited weak inhibitory effects on individual components of the complement system. In vivo administration of BA also showed the inhibitory effect on guinea-pig serum.
Animals↗
Repressed classical complement pathway activities and clinical correlations in chronic lymphocytic leukaemia.
Haemolytic activities of the classical and alternative complement pathways, and levels of C1, C4, C3, factor B and C1 inhibitor (C1-INH) were measured in 137 serum samples of 69 patients with chronic lymphocytic leukaemia (CLL). In most sera IgG, IgA and IgM concentrations were determined as well. Clinical correlations of these laboratory parameters have been studied. C1 and C4 activities were found to be depressed in almost 50% of the sera tested, and hypogammaglobulinaemia was observed with a similar frequency. Low C1 and C4 levels were found mainly in the early stages of the disease. A strong association between the occurrence of infections and hypogammaglobulinaemia was observed, although low immunoglobulin levels frequently occurred in patients without a history of infections. Low C1 and C4 levels were significantly correlated with the incidence of infections, too, and this correlation was observed mostly in the early stages of the disease. The reason for this is not known. The present results suggest that not only low immunoglobulin levels but low C1 and/or C4 levels may contribute to the increased susceptibility to infections in patients with chronic lymphocytic leukaemia.
Complement Activation↗
Activation of classical complement pathway by naturally occurring heteroantibodies in normal rabbit serum. Effect on subpopulations of human lymphoid cells.
Heteroantibodies present in normal rabbit serum (NRS) are toxic to human B lymphocytes, T lymphocytes, and monocytes. Even NRS, which exhibits little back ground cytotoxicity for human lymphoid cells in conventional HLA or B-cell lymphocytotoxic assays, can be shown to contain considerable activity by making two modifications in usual procedures: by washing cells in saline or balanced salt solutions devoid of protein or sugar substances, and by increasing incubation time for 1 h to 3--4 h. Using such modifications, the cytotoxic activity of NRS towards human lymphoid cells was investigated and was found to involve activation of the classical complement pathway rather than activation of the alternate complement pathway. Residual unwanted background cytotoxicity of NRS toward human lymphoid cells can be decreased without loss of desired complement activity either by heating NRS for 15 min at 50 degrees C or by mixing NRS with small amounts of normal human serum.
Animals↗
Classical pathway complement activation in association with paraproteinaemia.
Five of twenty-three patients with paraproteinaemia (two IgM, three IgG) have been shown to exhibit marked classical pathway complement activation. The mechanisms of hypocomplementaemia proposed for the five patients are cryoglobulinaemia in one and in vivo immunoglobulin aggregation in the other four. Three further patients had a low C1q and three a low C3 unassociated with any other complement abnormality. No association with any particular IgG subclass or obvious clinical abnormality existed in association with hypocomplementaemia.
Complement C1↗
Classical complement pathway activation in membranoproliferative glomerulonephritis.
Levels of components of the classical and alternative complement pathways and the activity of the C3 nephritic factor (C3NeF) were measured in serum specimens from patients with type I (subendothelial deposits) and type II (intramembranous dense deposits) membranoproliferative glomerulonephritis (MPGN) and the results compared with the levels in normal subjects. Although C3 and C5 concentrations were comparably depressed in type I and type II, the levels of Clq and C4 were lower in type I and the correlation coefficients between Clq vs. C4 and C4 vs. C3 were higher than in type II. The profile was highly suggestive of classical pathway activation. In contrast, in type II MPGN, factor B levels were lower and C3NeF activity was more frequently detectable and higher. A feature of interest was that type I, as compared to type II, was characterized by significantly lower serum concentrations of properdin, higher and more significant correlation coefficients between serum properdin concentrations and those of Clq, C4 and C3, and consistent glomerular deposition of properdin. The involvement of properdin in type I may reflect recruitment of a pathway resembling the C1 bypass mechanism, said to involve C1, properdin, factor B and C3-9.
Adult↗
The cold activation of the classical complement pathway: The cause of the differences between plasma and serum complement in liver cirrhosis.
The mechanism responsible for making the differences between plasma and serum complement (CH50) was studied on eight patients with hepatitis-B(s) antigen negative alcoholic liver cirrhosis. CH50 and C4 activities of the sera of all patients were equal to those of the corresponding EDTA-plasma, when sera wre separated after clotting the blood at 37 degrees C. CH50 and C4 activities of the sera, prepared at 21 degrees C or 4 degrees C, from four of eight patients were very low. When serum from one of these four patients was added to normal human serum, C4 activity of the serum mixture markedly decreased at 4 degrees C but not at 37 degrees C. The inactivation of C4 was prevented by adding EDTA or heparin to the serum mixture. These results indicated that very low complement in the sera, prepared at 21 degrees C or 4 degrees C, of the four cases were due to the cold activation of the classical complement pathway.
Cold Temperature↗
Determination of C4b.C4-bp complex formed by the activation of classical complement pathway using an enzyme-linked immunosorbent assay.
We developed a quantitative enzyme-linked immunosorbent assay (ELISA) for the detection of C4b.C4-bp complex by incubating the sample on anti-C4-bp-coated plate and then developing with HRP-labeled anti-C4. The amount of C4b.C4-bp complex, generated in vivo by the interaction of purified C4b with C4-bp or normal human serum with aggregated human IgG, was measured by the ELISA. The complex, however, rapidly decreased in serum by the action of factor I. Six out of the 100 plasma samples from patients with various diseases were found positive in the ELISA. One plasma sample from a patient with SLE showed high level of C4b.C4-bp complex with decreased levels of factor I, C4, C4-bp and CH50. These results suggest that the detection of C4b.C4-bp complex is useful for monitoring the diseases in which the classical pathway activation is expected.
Arthritis, Rheumatoid↗
Serum amyloid P component binds to histones and activates the classical complement pathway.
Two members of the pentraxin family of proteins, C-reactive protein (CRP) and serum amyloid P component (SAP), bind to chromatin and may be involved in the solubilization and clearance of nuclear material. Previous studies demonstrated that CRP binding to chromatin is mediated by histones. SAP differs from CRP in being able to bind to DNA, but SAP binding to histones has not been reported. CRP is an activator of the classical C pathway, and C-dependent cleavage of chromatin in the presence of CRP and serum has been shown. Oligomers of SAP have recently been found to bind to C1q and consume total C and C4, indicating that SAP can activate C as well. The present study examined CRP and SAP binding to histones H1 and H2A and C activation after binding. SAP binding to histones H1 and H2A was observed as well as SAP binding to chromatin. In contrast to CRP, SAP binding to chromatin did not require H1. SAP partially inhibited CRP binding to chromatin and to H1. However, neither pentraxin inhibited binding of the other to H2A. Binding of either CRP or SAP to H2A activated C in SAP-depleted serum leading to the deposition of C4 and C3. C activation required C1q and produced C4d indicating that it occurred through the classical pathway. These findings demonstrate that CRP and SAP share histone as well as chromatin binding, and that both pentraxins can activate the classical C pathway after ligand binding.
Animals↗
Immunoglobulin G independent activation of the classical complement pathway by monosodium urate crystals.
10 mg of monosodium urate crystals reduced the CH50 of 1 ml of human serum by 57% after 30 min at 37 degrees C. C1, C4, and C3 depletion of 52, 68, and 46% were typical of classical pathway activation. C1 binding and activation occurred when urate crystals were incubated with isolated precursor C1, and required the intact macromolecule, C1qrs. Activation of isolated C1 by urate crystals was not diminished by F(ab')2 anti-Fc under conditions in which C1 activation by aggregated immunoglobulin (G) was blocked by the F(ab')2 antibody.
Complement Activation↗
Activation of the classical complement pathway by Fc fragment of human IgA.
Intact Fcalpha fragments from five human IgA myeloma proteins were produced by two different methods, high temperature trypsinolysis and IgA protease digestion. Three of the Fcalpha fragments activated the classical pathway as determined by the titers of the individual complement components. Two other fragments did not fix complement by either pathway.
Complement System Proteins↗
Lysis of RNA tumor viruses by human serum: direct antibody-independent triggering of the classical complement pathway.
In earlier studies we found that human serum, but not serum from multiple other species, inactivated and lysed oncornaviruses from a number of diverse sources in the apparent absence of antibody. A detailed analysis of the role of the human complement (C) system in mediating this lytic process indicates that human C1q interacts directly, in the absence of immunoglobulin, with oncornaviruses. Binding of C1 via C1q in this manner leads to activation of C1r, C1s, and thus of the classical C pathway. Integrity of the classical pathway is an absolute requirement for lysis although activation of the alternative pathway considerably amplifies the amount of lysis obtained, possibly through involvement of the C3b-dependent feedback mechanism. Activation of C is accompanied by deposition of C components on the viral surface and lysis on completion of the C reaction sequence. Thus in this system, the C1q subunit of C1 subserves a specific recognition function normally associated with antibody. This ability of human serum to inactivate oncornaviruses may represent a natural defense mechanism operative in vivo which deters expression of intact oncornaviruses in human malignancies.
Cell Survival↗
Neutrophil activation after burn injury: contributions of the classic complement pathway and of endotoxin.
We attempt to elucidate the mechanisms of neutrophil (PMN) activation after burn injury. We previously reported prolonged elevations of PMN cell surface complement (C) opsonin receptor levels after burn trauma with a corresponding period of depressed PMN chemotaxis to C5a, which suggests that the C product, C5a, was responsible for PMN activation. However, a lack of direct correlation of C activation with C receptor levels soon after injury raised the possibility of a second PMN-activating substance. We therefore investigated the effect of endotoxin (LPS) on the expression of the C receptors (CR1 and CR3) by normal human PMNs. Concentrations from 0 to 50 ng/ml of LPS 026:B6 caused a dose response increase in the PMN surface expression of CR1 and CR3 as assessed by monoclonal antibody binding and indirect immunofluorescence. The relative CR1-dependent fluorescence rose from a mean of 50 to 385 and CR3 from 50 to 300. Chelation by ethylenediaminetetra acetic acid (EDTA) did not influence this dose response, thus ruling out the possibility of C activation by LPS--an inference supported by the lack of complement activation observed with these concentrations of LPS in normal serum. A similar dose response was obtained in the absence of other cell types or serum, which implies a direct effect that mimicked that of C5a. To determine the mechanism of the later, prolonged C activation after burn injury, we next examined C activation products in 22 patients with burn injuries. Elevations of plasma C3a desArg were present and persisted for 50 days. Elevations were at maximum levels on days 9 through 13 postburn (mean +/- standard error of mean [SEM], 496 +/- 47 ng/ml versus normal 113 +/- 32; p less than 0.01). These were accompanied by elevations of C4a desArg (917 +/- 154 ng/ml versus normal 424 +/- 50; p less than 0.01), which are indicative of classic pathway activation. Finally, we examined PMN function, phagocytosis and percentage killing of Staphylococcus aureus, and found PMN function to be unaltered in the 22 patients. Thus PMN activation after burn injury appears to be caused by LPS soon after injury and by C5a later after injury and affects only selected PMN functions.
Adolescent↗