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PubMed1970

The fixation of complement and the activated first component (C1) of complement by complexes formed between antibody and divalent hapten.

Hapten-antibody complexes prepared at equivalence with the bivalent hapten bis-DNP-octamethylene-diamine and purified rabbit anti-DNP antibody were fractionated by Sepharose gel-filtration and the fractions examined by electron microscopy. Individual fractions were tested for whole-complement fixation and C1 fixation. Dimer forms did not show this type of biological activity, while fractions containing tetramers and larger polymers exhibited both C and C1 fixation, which could be inhibited by prior exposure of the complexes to the univalent hapten epsilon-DNP-caproic acid. The dose-response result indicated that the C-fixation observed was not due to interpolymeric cooperative effects. It was concluded that in the generation of biological activity by soluble antigen-antibody complexes made with complement-fixing antibody, quaternary structural changes following specific combination with antigen may be as important as any tertiary structural alterations that occur in the individual immunoglobulin molecule.

Animals↗
PubMed1999

Complement regulators C1 inhibitor and CD59 do not significantly inhibit complement activation in Alzheimer disease.

Proteins characteristic of activated complement are associated with Alzheimer disease (AD) lesions. The classical complement pathway can be activated only when the influence of such endogenous regulators as C1-inhibitor (C1-inh) and CD59 are overcome. We used the techniques of reverse transcriptase-polymerase chain reaction and Western blotting to assess the mRNA and protein levels of C1-inh and CD59 in AD and control brains in comparison with levels of the complement components with which they interact. The inhibitors were only slightly upregulated and then only in heavily affected areas of AD brain such as the entorhinal cortex, hippocampus, midtemporal gyrus and midfrontal gyrus. The ratio of AD to control mRNAs in these four areas was 1.17 for C1-inh and 1.12 for CD59, compared to 3.06 for C1r, 2.67 for C1s, 2.35 for C5, 2.56 for C6, 2.42 for C7, 5. 08 for C8 and 16.3 for C9. Peripheral organ expression of C1-inh and CD59 mRNAs was no different in AD than controls but was slightly upregulated in infarcted heart tissue. Again, the increase was small compared with that of the competitive complement components. These data indicate that the forces which upregulate and activate complement in AD and myocardial infarction are not effectively suppressed by the endogenous regulators, C1-inh and CD59.

Adult↗
PubMed1989

Deficiency of the first component of human complement.

C1 deficiency results from an absence or lowering of the level of one or more of the proteins C1q, C1r and C1s, which are the subcomponents of the C1 complex of the classical pathway of the serum complement system. The major clinical pattern shown in such deficiency states is an inability to deal effectively with immune complexes, resulting in the typical symptoms associated with immune-complex-related diseases and a great susceptibility to recurrent bacterial infections. Both acquired and genetic deficiencies of the C1 subcomponents have been reported; the possible genetic deficiencies appear quite rare, with only 14 reports of C1q deficiency (involving 24 people) and six reports of C1r/C1s deficiency (involving 11 people) appearing in the literature to date.

Complement Activation↗
PubMed1990

Specific, sensitive, precise, and rapid functional chromogenic assay of activated first complement component (C1) in plasma.

We present a new functional assay for the first complement component (C1) in plasma, based on its activation by inhibition of the C1-esterase inhibitor (C1-inh) when monospecific antiserum to C1-inh is added to the plasma. After maximal activation, we can determine the concentration of activated C1 by using an amidolytic rate assay with a chromogenic substrate. We have optimized the assay conditions with respect to incubation time, concentration of antiserum to C1-inh, ionic strength, and pH. Our method determines specifically the concentration in plasma of free activated C1, not complexes of activated C1 with C1-inh, and is not influenced by the concentration of C1-inh in the test sample. Concentrations of C1 correlated significantly with activities determined by a hemolytic assay (r = 0.55, t = 4.09, P less than 0.001). The estimated interassay CV was 5% and the intra-assay CV was 1%. The sensitivity, imprecision, and practical test performance of our assay are superior to those of conventionally used hemolytic assays.

Adult↗
PubMed1996

Proteolytic cleavage of MHC class I by complement C1-esterases--an overlooked mechanism?

The complement C1-esterases have been shown to cleave the MHC class I molecules, which are important participants in the activation of T lymphocytes, between the alpha 2- and the alpha 3-domain of the heavy chain. The possible involvement of the C1-esterases in the regulation of peripheral self-tolerance is discussed. It is hypothesized that the C1-esterase-mediated cleavage of the MHC class I molecules either induces: a soluble fragment of the outer two domains of the MHC class I molecule, in association with beta 2-microglobulin, to bind to the T cell receptors and prevent the cells from being activated, or produces a change in the exposure of the alpha 3-domain that remain on the cell surface, acting as mediator of a 'veto signal' that prevents these cells from being activated.

Complement C1s↗
PubMed1985

Effector functions of a monoclonal aglycosylated mouse IgG2a: binding and activation of complement component C1 and interaction with human monocyte Fc receptor.

Aglycosylated monoclonal anti-DNP mouse IgG2a produced in the presence of tunicamycin was compared with the native monoclonal IgG2a with respect to its ability to interact with the first component of complement, C1, and to compete with human IgG for binding to human monocyte Fc receptors. The aglycosylated IgG2a was found to bind subcomponent C1q with an equivalent capacity to the native IgG2a, but the dissociation constant was found to be increased three-fold. When activation of C1 by the glycosylated and aglycosylated IgG2a was compared, the rate of C1 activation by the aglycosylated IgG2a was reduced approximately three-fold. In contrast aglycosylation was accompanied by a large decrease (greater than or equal to 50-fold) in the apparent binding constant of monomeric IgG2a to human monocytes. The data suggest that the aglycosylated IgG2a has a structure which differs in the CH2 domain from the native IgG2a, and that the heterogeneous N-linked oligosaccharides of this monoclonal IgG2a which occur at a conserved position in the CH2 domain play a role in maintaining the integrity of its monocyte-binding site. This lack of monocyte binding may result either from a localized conformational change occurring in a single CH2 domain or from an alteration in the CH2-CH2 cross-domain architecture which is normally structured by a pair of opposing and interacting oligosaccharides. The minimal changes in C1q binding and C1 activation suggest that the oligosaccharides are, at most, indirectly involved in these events.

Animals↗
PubMed1981

Conformational changes of the subunits C1q, C1r and C1s of human complement component C1 demonstrated by 125I labeling.

C1s and C1r proenzymes and enzymes (C1s, C1r) and C1q were labeled with 125I. The distribution of the 125I label between H- and L-chain of C1s was only slightly dependent on the state of activation of C1s, and approx. 90% of the label was found in the H-chain. In the C1r proenzyme molecules 50% of the label was incorporated into the H-chain. The C1r H-chain label was reduced to 10% on activation of C1r to C1r, while the L-chain label increased to 90% of the total label. The presence of either C1s, C1q or C1qs during labeling reduced the C1r H-chain level, although C1r remained in the proenzyme form. The presence of C1s or C1rs enhanced the 125I uptake of C1q in Ca2+ or EDTA medium. This was unexpected because one would have anticipated a diminution of the C1q label due to the apposition of C1r and C1s, similarly as it occurs during C1rs complex and C1s dimer formation for the H-chain label of C1s. The results show that C1r and C1q alter their conformation during activation and C1 complex formation.

Calcium↗
PubMed1977

Complement C1-inactivator in the serum of patients with malignant disease.

Complement C1-inactivator (C1-IA) in serum was determined in 423 individuals. The normal range for the concentration of C1-IA in serum was calculated from values in 94 blood donors and the concentrations in the sera of 329 patients were determined in relation to this range. A significant correlation was found between widespread malignant neoplastic disease and increased quantity of C1-IA in serum. Determination of C1-IA may be used to evaluate the extent to which a malignant disease is disseminated.

Complement C1 Inactivator Proteins↗
PubMed1985

Antibody density on rat red cells determines the rate of activation of the complement component C1.

It is a common observation that there is variability in the rate of activation of C1, the first component of complement, when bound to immune complexes. The cause of this variation has been investigated with experiments designed to assess separately the effect of antibody, antigen and C1 density. Using 125I-labeled C1 and a rat monoclonal antibody specific for the class I antigen, it has been found that the rate of activation is primarily dependent on antibody density on the cell surface and not on antigen or C1 density. This finding supports the suggestion that direct contact between the C1r2C1s2 subcomponent of C1 and antibody may be required for potentiation of C1 activation.

Animals↗
PubMed1980

The relationship between the binding ability and the rate of activation of the complement component C1.

The strength of the bond between C1 and C1 binders (as measured by C1q binding) has been correlated with the ability of the binders to activate C1. The rate of activation of C1 has been studied by following the extent of hydrolysis of the C1r and C1s subcomponents, using a purified preparation of C1 labelled with 125I. The rate of activation of C1 was not correlated with the binding strength between C1q and the C1 binders. Immune complexes were found to activate C1 rapidly, whereas glutaraldehyde-aggregated IgG failed to activate faster than the spontaneous activation seen on incubation of C1 alone; the strength of the bond between C1q and the binders was similar in the two cases. It is suggested that an interaction other than the binding between C1q and C1 binders is necessary for activation of C1. C1 bound to immune complexes was not activated in the presence of C1 inhibitor, indicating that the inhibitor can prevent the hydrolysis of C1r under the test conditions.

Antigen-Antibody Complex↗
PubMed1982

Modulation of lymphocyte proliferative responses to mitogens and antigens by complement components C1, C4 and C2.

Recent data have shown a definite relationship between complement and lymphocytes. Genetic studies have demonstrated close linkage between the genes controlling synthesis of complement components C4 and C2 and the major histocompatibility complex. Working in a complement-free environment, we studied the effect of purified human complement components, individually and in various combinations, upon in vitro proliferative responses of human lymphocytes to mitogens and antigens. It was found that the early complement components C1, C4 and C2, together, modulate lymphocyte responses to these various stimuli. In general, doses up to 1,000 effective molecules of each component per lymphocyte enhanced the cells' responses to both mitogens and antigens. Higher doses, up to 3,000 effective molecules of each per lymphocyte, progressively inhibited the cells' responses to the mitogens whereas responses to the antigens showed continued enhancement. This effect was removed by prior heat-inactivation of the complement. It persisted when the cells were exposed to C1, C4 and C2 for 1 hr, then washed and cultured with mitogen. It required active C1 in the fluid-phase prior to addition of C4 and C2. It correlated with the amount of activated C2 to which the cells were exposed. Enriched populations of T and B cells were affected equally.

Antigens↗
PubMed2001

Detection of complement C1-inhibitor with a piezoelectric immunosensor.

A novel piezoelectric immunosensor has been developed for the detection of human complement C1-inhibitor. Anti-C1-inhibitor antibody was immobilized onto the gold electrodes of a 9 MHz AT-cut piezoelectric crystal. Coating the crystal with polyethyleneimine adhesion, followed by a glutaraldehyde cross-linking method to immobilize antibody showed better results than the physical adsorption method with respect to sensitivity and reproducibility. Under the optimized experimental conditions, the sensor showed good response to the C1-inhibitor in the range from 2.0 x 10(-8) to 1.2 x 10(-6) g. Other proteins in human serum did not remarkably interfere with the detection. The crystals could be regenerated 5 times, when bound materials on the crystal surface were eluted by strong acid and strong alkali solution and subsequently cleaned in an ultrasonic cleaner.

Biosensing Techniques↗
PubMed1996

Protection of porcine endothelial cells from complement-mediated cytotoxicity by the human complement regulators CD59, C1 inhibitor, and soluble complement receptor type 1. Analysis in a pig-to-human in vitro model relevant to hyperacute xenograft rejection.

Inhibition of complement activation is considered a prerequisite to overcome hyperacute xenograft rejection. In the present study, we investigated the efficacy of C1 inhibitor (C1 inh) and recombinant soluble complement receptor type 1 (rsCR1) to protect xenogeneic cells against complement-mediated cytotoxicity in an in vitro xenotransplantation model. The addition of the soluble complement regulators to human serum led to a dose-dependent inhibition of complement-mediated destruction of aortic porcine endothelial cells (PEC). On a molar base, rsCR1 was more efficient than C1 inh. Transfection of PEC with cDNA of human CD59 resulted in several clones where protection against complement-mediated cell destruction correlated with the expression level of the inhibitor. Addition of low concentrations of C1 inh and rsCR1 to a CD59 (human)-positive PEC clone, expressing a suboptimal level of the membrane-bound regulator, resulted in a significant improvement of protection against complement-mediated cell destruction.

Animals↗
PubMed1977

Purification from euglobulin of the first component (C1) of complement and its subcomponents by heparin-sepharose chromatography.

Most of the C1 material of euglobulin was adsorbed to heparin-Sepharose at an ionic strength of 0.265. After desorbtion at an ionic strength of 0.415 the C1 material was found to be purified six to seven-fold. Highly purified subcomponents C1q, C1r and C1s were recovered at DEAE-Sephadex chromatography from such purified C1 material after EDTA-treatment. Tests on isolated C1q, C1r and C1s disclosed in addition to the well known interaction between heparin and C1q an equally strong or even stronger interaction between heparin and C1s. Even C1r was adsorbed to heparin although by somewhat weaker ionic bonds.

Chromatography, DEAE-Cellulose↗
PubMed1988

The distortive mechanism for the activation of complement component C1 supported by studies with a monoclonal antibody against the "arms" of C1q.

A mouse monoclonal antibody (IgG1 isotype) against human C1q (MAb 130) is presented that activates C1 in serum through its antigen-binding sites at an optimal molar ratio of 3 MAbs:1 C1q. The antibody does not inhibit binding of C1q to IgG. Experiments with pepsin- and collagenase-digested C1q showed that MAb 130 binds to the fibril-like strands (arms) of C1q, close to the globular heads. Bivalency of MAb 130 was a requirement for C1-activation, but not for binding to C1q. Increasing the segmental flexibility of the intact antibody by reduction and alkylation destroyed its capacity to activate C1. A MAb against the globular heads of C1q completely inhibited C1-activation by aggregated IgG (AHG), but did not prevent activation by MAb 130. C1, reconstituted by adding C1q-stalks that lack the globular heads to C1q-depleted serum was not activated by AHG, whereas activation by MAb 130 was not affected. Activation of serum-C1 by AHG and MAb 130 was inhibited by addition of excess purified C1-inhibitor in a comparable and dose-dependent manner. Sucrose-gradient analysis indicated a predominance of stable complexes of a single C1q-molecule with three MAbs at the optimal activating ratio. When isolated and added to C1q-depleted serum, these complexes activated C1 efficiently. A mechanism for activation by MAb 130 is proposed that supports the "distortive" model of C1-activation.

Antibodies, Monoclonal↗