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PubMed1976

Cold activation of complement i. presence of coagulation-related activator.

Determination of the complement titer in the serum and plasm of 120 patients with chronic liver diseases showed that in eight (7%) patients with cirrhosis of the liver, chronic active or chronic inactive hepatitis complement in the serum was less than half in the plasma. The dissociation of complement serum and plasma was due to cold activation of the classical pathway of complement in vitro since serum drawn from these patients at 37 degrees C lost hemolytic activity in 4 hours when transferred to a cold environment. Neither HB antigen nor cryoglobulin participated in this phenomenon. The activation of complement in the cold could be prevented by increasing the ionic strength, or by adding vitamin E or, to a lesser extent its vehicle HCO-60, while heparin, Trasylol, soybean trypsin inhibitor, or hirudin had no effect. Trans-AMCHA prevented activation in one case. It is speculated that a factor appearing as a result of blood clotting is able to activate the classical pathway of complement in the cold; it is probably not related to Hageman factor (factor XII), factor VII, thrombin, kallikrein.

Antithrombins↗
PubMed1990

Reactivity of alpha 1-antitrypsin mutants against proteolytic enzymes of the kallikrein-kinin, complement, and fibrinolytic systems.

Increased extracellular proteolysis because of unregulated activation of blood coagulation, complement, and fibrinolysis is observed in thrombosis, shock, and inflammation. In the present study, we have examined whether the plasma kallikrein-kinin system, the classical pathway of complement, and the fibrinolytic system could be inhibited by alpha 1-antitrypsin reactive site mutants. Wild-type alpha 1-antitrypsin contains a Met residue at P1 (position 358), the central position of the reactive center. It did not inhibit plasma kallikrein, beta-factor XIIa, plasmin, tissue-type plasminogen activator (t-PA), or urokinase. In contrast, these serine proteases were inhibited by alpha 1-antitrypsin Arg358. For the inhibition of C1s, a double mutant having Arg358 and a Pro----Ala mutation at P2 (position 357) was required. This double modification was made because C1-inhibitor, the natural inhibitor of C1s, has Arg and Ala residues at positions P1 and P2. Plasminogen activator inhibitor 1, the natural inhibitor of t-PA, also has Arg and Ala residues at positions P1 and P2. In a purified system, alpha 1-antitrypsin Ala357-Arg358 was 150-fold less efficient against C1s than C1-inhibitor and 27,000-fold less efficient against t-PA than plasminogen activator inhibitor-1. In plasma, 2.3 microM alpha 1-antitrypsin Ala357-Arg358 reduced by 65% the formation of a complex between kallikrein and C1-inhibitor following activation of the intrinsic pathway of blood coagulation by kaolin. Furthermore, after supplementation by 2.0 microM alpha 1-antitrypsin Ala357-Arg358, zymographic analysis showed that the majority of the free t-PA of normal plasma formed a bimolecular complex with the double mutant. In contrast, 3.4 microM alpha 1-antitrypsin Ala357-Arg358 did not prevent the activation of the classical pathway of complement observed when normal serum is supplemented with anti-C1-inhibitor F(ab')2 fragment. These results demonstrate that alpha 1-antitrypsin Ala357-Arg358 has therapeutic potential for disorders with unregulated activation of the intrinsic pathway of blood coagulation and the fibrinolytic system; however, the double mutant is not an efficient inhibitor for the classical pathway of complement.

Amino Acid Sequence↗
PubMed1988

Structure-function relationships in the inhibitory effect of heparin on complement activation: independency of the anti-coagulant and anti-complementary sites on the heparin molecule.

Fluid phase heparin inhibits formation of the classical and alternative pathway C3 convertase of complement in assays performed either with purified complement proteins or in whole serum. Experiments using oligosaccharides of homogeneous mol. wt obtained by mild nitrous hydrolysis of heparin, demonstrated that the inhibitory activity of heparin increased exponentially with mol. wt for fragments containing between 4 and 14 saccharidic units and that fragments of mol. wt above 4700 (greater than 14 saccharidic units) had a similar anti-complementary activity to that of native heparin. Fragments of homogeneous mol. wt (octasaccharides) separated by ion exchange chromatography on the basis of negative charges, exhibited increasing inhibitory activity with increasing sulfate content. Over-sulfation of fragments of defined mol. wt resulted in a constant enhancement of the relative capacity of each fragment species to inhibit formation of the classical and alternative pathway C3 convertases. A synthetic pentasaccharide representing the minimal critical sequence responsible for the binding of heparin to anti-thrombin III exhibited a similar inhibitory capacity on formation of the C3 convertases as another synthetic pentasaccharide that was devoid of anti-Xa activity. These studies contribute to define a minimal structure of the heparin molecule with C3b- and C4b-binding capacity and definitively establish the independency of the anti-coagulant and anti-complementary sites on the heparin molecule.

Blood Coagulation↗
PubMed1997

Complement and complement deficiencies.

The complement system provides a first line of defense and mediates a large variety of cellular and humoral interactions within the immune response, including chemotaxis, phagocytosis, cell adhesion, and B-cell differentiation. The system involves more than 30 serum components and numerous cell surface regulators and receptors. Similar to the blood clotting system, complement activation is initiated through a series of complex activation cascades involving enzymatic cleavage. Three independent complement activation cascades, the classical, the alternative, and the lectin pathway, have been described. The liver is the main site of biosynthesis for most of the serum components of complement and diseases of the liver can lead to alterations of the normally stable plasma levels of complement. Deficiencies of single components can lead to a broad variety of secondary diseases, caused by either imbalanced activation or defects in the humoral or cellular response to microbial infections.

Complement C3a↗
PubMed1998

Complement-inhibiting cucurbitacin glycosides from Picria fel-terrae.

Four cucurbitacin glycosides were isolated from Picriafel-terrae and identified by MS and NMR spectroscopy as picfeltarraenin IA (1), picfeltarraenin IB (2), picfeltarraenin IV (4), and a new compound picfeltarraenin VI (3) (picfeltarraegenin I 3-O-beta-D-xylopyranoside). All four compounds acted as inhibitors on both the classical and alternative pathways of the complement system, with compound 3 exhibiting the highest inhibitory activity (IC50 29 +/- 2 microM and 21 +/- 1 microM, respectively). Compounds 1-4 showed no antiviral, antibacterial, or antifungal activities. Picfeltarraenin IA and IB were tested in an in vitro human tumor cell line panel, but displayed no cytotoxic activity.

Anti-Infective Agents↗
PubMed2003

Inhibition of C1q-beta-amyloid binding protects hippocampal cells against complement mediated toxicity.

Activation of complement by beta-amyloid (A beta) contributes to the pathology of Alzheimer's disease (AD). Here, we show that C1-Inhibitor (C1-Inh) protects cultured rat hippocampal cells against beta-amyloid induced complement lysis indicating a classical pathway-mediated activation mechanism. We report on screening of compound libraries to identify compounds that inhibit C1q binding to beta-amyloid. Characterization of these compounds revealed that C1q possessed distinct binding sites for beta-amyloid and antibodies. One selected compound protected cultured hippocampal cells against complement-dependent beta-amyloid toxicity. These results provide evidence that complement has the potential to damage hippocampal cells, and C1q is a relevant target to suspend this deleterious mechanism in Alzheimer's disease.

Amyloid beta-Peptides↗
PubMed1987

Synergistic complement lysis by monoclonal antibodies to the human leukocyte common antigen requires both the classical and alternative pathways.

In a previous study we isolated a series of rat monoclonal antibodies to the human leukocyte common (LC) antigen and demonstrated that synergistic complement lysis was possible between IgG2b antibodies which recognised different epitopes. In this report we have examined the mechanisms that were involved in synergistic lysis. We found that the number of C1q binding sites increased from 30,000 to 40,000/cell using a single antibody to 90,000/cell when two IgG2b antibodies to different epitopes were used together. The affinity of C1q binding also increased approx. 3-fold for the synergistic pair, and there was a similar increase in the rate of C1 activation. Combinations of an IgG2b with IgG1 or IgG2a gave much smaller increases in the amount of C1q bound and in the rate of C1 activation. Despite the large number of C1q molecules bound with the optimal synergistic pair and the increased rate of C1 activation, lysis was inefficient in serum depleted of Factor D, suggesting a requirement for the alternative pathway. This is the first demonstration of the need for the alternative pathway in complement lysis by monoclonal antibodies.

Animals↗
PubMedDate not supplied

Chimeric CD46/DAF molecules reveal a cryptic functional role for SCR1 of DAF in regulating complement activation.

Chimeric proteins using membrane cofactor (CD46) and decay accelerating factor (DAF or CD55) were generated to further investigate the functional domains involved in the regulation of human serum complement. Following activation of the classical pathway, the isolated substitution of CD46 SCR III (x3DAF) exhibited a modest regulatory activity comparable to that of CD46. The isolated substitution of CD46 SCR IV (x4DAF), and the combined CD46 SCR III+IV substitutions (x3/4DAF) were essentially as efficient as DAF. No regulation of C3b deposition was observed with the combined CD46 SCR I+II substitutions (x1/2DAF). When tested after activation of the alternative pathway, both the x3DAF and x3/4DAF chimeras failed to regulate C3b deposition, while the x4DAF chimera still displayed some activity. In contrast to that observed following classical pathway activation, the x1/2DAF chimera exhibited a similar efficiency to wild type CD46 and DAF in controlling C3b deposition. Using SCR specific antibodies, the regulatory activity of the x1/2DAF chimera against the alternative pathway was mapped to the first three distal SCR (i.e. DAF 1, DAF 2 and CD46 III). These data demonstrate that several combinations of SCR domains from two related complement regulators can result in functional molecules, and reveal a novel and cryptic functional role for DAF SCR1.

Animals↗
PubMed1976

Genetic loci of components of the classical and alternate pathway of complement activation: a new dimension of the immunogenetic linkage group (HLA) on chromosome 6 in man.

In this review, a working hypothesis is put forward that functional cooperation of various types of cells and proteins in immune recognition, mediation and response is maintained by a common chromosomal region which evolved over millions of years from a common ancestor by gene duplication. In brief, the known functions of the H-2 complex are discussed (susceptibility and resistance to viral infection, immune response genes, T-B cell interaction as non-self recognition and response). The addition of loci of the classical and alternate pathway of complement activation to the HLA region (i.e., C2, C4 and the Bf system) is reviewed with respect to functional relationship to immune recognition and mediation mechanisms. As expected according to this hypothesis, genes for late-acting components (C3, C5, C7 and C8 in man, C5 in mice) have so far not proved to be linked to HLA.

Animals↗
PubMed2003

Inactivation of porcine endogenous retrovirus by human serum as a function of complement activated through the classical pathway.

BACKGROUND: The clinical use of organs and cells of pig donors as a source of tissue for xenotransplantation and extracorporeal therapies has been problematic due to the risk for zoonotic infection of porcine endogenous retroviruses (PERV). METHODS: The effect of human serum on PERV was evaluated using an infectivity assay and virolysis assay. Cell-free PERV infection to human 293 cells was determined by the presence of proviruses 5 days post-infection by a highly sensitive nested PCR, and the lysis of PERV virions was determined by the reverse transcriptase activities released into the supernatant. RESULTS: Treatment of PERV-PK, the culture supernatant of a pig kidney cell line containing the virus titer of 10(2.8) TCID(50) units/ml, with a quarter volume of human serum completely inactivated the infectivity. This activity was heat-labile and sensitive to an anti-complement agent, nafamostat mesilate, and a Ca(2+)-chelator, EGTA, indicating the crucial involvement of complement activated through the classical pathway. Since a synthetic galactosyl alpha1-3 galalactose (Galalpha1-3Gal) largely absorbed the activity from the serum, natural antibodies to the Galalpha1-3Gal epitopes are likely to trigger the complement activation. CONCLUSION: Cell-free PERV seems no longer be infectious in human serum. This greatly encourages the clinical application of pig tissues in particular for extracorporeal therapies such as a bioartificial liver, in which pig cells do not come in direct contact with a recipient.

Journal Article↗
PubMed1979

Complement fixation in acute serum sickness: assembly of glomerular-bound C3-convertase.

Complement (C) fixing properties of glomerular immune deposits were studied in vitro in two groups of rabbits with acute serum sickness (ASS). Deposits were studied early in decomplemented (cobra venom factor-treated) rabbits (Group I) and during the evolution of the nephritis in non-decomplemented rabbits (Group II). Following perfusion of kidneys of animals from Group I (which contained no autologous C3) with rabbit serum deficient in factor B (classical pathway) or serum pre-treated with Mg++EGTA (alternative pathway), fixation of C3 was observed in both systems. No C3 deposition was found when EDTA-rabbit serum was used. When kidney sections obtained from serial biopsies and autopsy material from Group II (which contained rabbit C3-C3rb) were incubated with purified factors B and D, followed by either purified human C3 (C3hu) or EDTA-guinea-pig serum (C3gp), fixation of C3hu or C3gp to early C3 deposits was observed. When sections were pre-incubated with heat-inactivated rabbit serum (source of C3b-inactivator), C3 fixation was substantially reduced. Little or no C3 fixation was found after incubation of sections with human or guinea-pig serum depleted of factor D (classical pathway). Thus, in ASS, glomerular complement deposition appears to be predominantly dependent on the activation of the alternative pathway (C3b-feedback) which is progressively lost during the evolution of the nephritis.

Animals↗
PubMed2006

Classical complement activation and acquired immune response pathways are not essential for retinal degeneration in the rd1 mouse.

Misregulation of the innate immune response and other immune-related processes have been suggested to play a critical role in the pathogenesis of a number of different neurodegenerative diseases, including age related macular degeneration. In an animal model for photoreceptor degeneration, several genes of the innate and acquired immune system were found to be differentially regulated in the retina during the degenerative process. In addition to this differential regulation of individual genes, we found that in the rd1 retina a significantly higher number of genes involved in immune-related responses were expressed at any given time during the degenerative period. The peak of immune-related gene expression was at postnatal day 14, coinciding with the peak of photoreceptor apoptosis in the rd1 mouse. We directly tested the potential involvement of acquired and innate immune responses in initiation and progression of photoreceptor degeneration by analyzing double mutant animals. Retinal morphology and photoreceptor apoptosis of rd1 mice on a SCID genetic background (no mature T- and B-cells) or in combination with a RAG1 (no functional B- and T-cells) or a C1qalpha (no functional classical complement activation pathway) knockout was followed during the degenerative process using light microscopy or TUNEL staining, respectively. Although complement factor C1qalpha was highly up-regulated in the rd1 retina concomitantly with the degenerative process, lack of this protein did not protect the rd1 retina. Similarly, retinal degeneration and photoreceptor apoptosis appeared to proceed normally in the rd1 mouse lacking functional B- and T-cells. Our results suggest that both, the classical complement system of innate immunity and a functional acquired immune response are not essential for the degenerative process in the rd1 mouse retina.

Animals↗
PubMed1980

Effect of intravenously injected killed pneumococci on leukocytes, complement, and phagocytosis in rabbits.

A pneumococcal infection may be lethal in the absence of overwhelming pulmonary involvement, and death may occur even after the organisms have been killed with antibiotics. The mechanism of death is not understood but may be related to circulating pneumococcal products. For investigating the effects of nonviable pneumococci on several host defense mechanisms, rabbits were injected intravenously with 4 X 10(8) colony-forming units of killed sonified type 13 or type 29 pneumococci. Blood was sampled periodically for the next 24 h, and the following were measured: (i) circulating levels of leukocytes; (ii) activity of the classical and alternate complement pathways; and (iii) ability of the serum to opsonize pneumococci for ingestion and killing by polymorphonuclear leukocytes. Saline-injected control rabbits showed no change in any of the functions. Nonimmune rabbits injected with either pneumococcal serotype showed progressive and profound leukopenia, no change or an increase in classical and alternate complement pathway activity, and a profound reduction in the serum-opsonizing capcity for pneumococci of the same serotype as that used in the injection. The opsonizing capacity remained normal for the other serotype. When a previously immunized animal was injected, the opsonizing capacity for the homologous organism remained intact, but leukopenia nervertheless occurred.

Animals↗
PubMed1988

Complement activation in cardiopulmonary bypass, with special reference to anaphylatoxin production in membrane and bubble oxygenators.

Complement activation by cardiopulmonary bypass (CPB) was studied in 82 patients divided into membrane (MOG) and bubble oxygenator groups (BOG). The influence of primed homologous to circulating autologous blood volume (H/A) ratio was also evaluated. C4a increased very slowly during CPB in both groups, maintaining slightly higher levels in the BOG than in the MOG, with the exception of a marked initial rise in the BOG with a high H/A ratio (greater than or equal to 20%). Anaphylatoxin C3a levels increased more steeply in the BOG than in the MOG. An obvious rise in anaphylatoxin C5a production was observed in the BOG alone. The influence of high H/A ratio perfusion on complement activation was milder in the MOG than in the BOG. In 20 monkeys (Macaca fascicularis), continuous intraaortic infusion with bubbled autologous blood increased C4a and C3a levels, while autologous blood extracorporeally contacted with nylon increased C3a levels alone. In vitro studies revealed that human immunoglobulin fractions denatured by oxygen bubbling produced C4a, C3a, and C5a in a dose-dependent manner, although human albumin treated identically as human immunoglobulin did not produce these complements. It was thus inferred that (1) during CPB, complement is predominantly activated via the classical pathway in the BOG and via the alternative pathway in the MOG; (2) higher anaphylatoxin levels in the BOG than in the MOG are related to mode and grade of blood trauma; (3) anaphylatoxin level differences in both groups tend to increase with high H/A perfusion; and (4) immunoglobulin-free sera may reduced classical pathway activation.

Animals↗
PubMed1991

The complement system in HIV disease.

Different aspects of the relationship between the HIV infection and the complement system were studied. 1. No significant differences were found between seronegative controls, asymptomatic, and symptomatic (ARC, AIDS) HIV-seropositive patients in the plasma levels of complement components C4, Bf, and C3. 2. Using sensitive ELISA assays, a significant increase was observed in the levels of protein-protein complexes which are formed at the activation of the classical (C1r-C1s-C1-INH) and alternative (C3b-Bb-P) pathways, indicating that both complement pathways are activated in the HIV disease. No significant differences were found, however, in the levels of these complexes between the groups of asymptomatic and symptomatic HIV-infected patients. 3. Artificial immune complexes of synthetic peptides representing some immunodominant epitopes of HIV envelope (gp120, and gp41) proteins, and human polyclonal anti-HIV IgG were found to weakly activate both the classical and alternative complement pathways. 4. An elevated percentage of the lymphocytes carrying a complement activation fragment, C3d, was detected in the blood of HIV seropositive patients as compared to the seronegative controls. No significant positive correlation was found between the percentage of these cells and that of any T cell subsets tested.

Complement Activation↗
PubMed2003

Complement membrane attack complexes in pathologic disc tissues.

STUDY DESIGN: Complement membrane attack complexes were located in lumbar spine disc tissues by immunohistochemistry. Their occurrence was compared in control discs obtained from organ donors (CD), discs showing a normal macroscopic anatomy, samples of intervertebral disc herniations (DH), and intervertebral discs found to be degenerated by discography, but not herniated (DD). OBJECTIVE: To look for a possible role of complement activation, specifically complement membrane attack complexes, an end product of the classic immune complex-mediated complement activation pathway, in disc pathophysiology. SUMMARY OF BACKGROUND DATA: Recent immunohistochemical and biochemical studies suggest a possible role for immune complexes, as observed by immunohistochemical location and biochemical assay of immunoglobulins M and G in intervertebral disc pathophysiology. Immune complexes may trigger complement activation and ultimately cell lysis. There are, however, currently no reports on complement activation in disc tissues, although immune (antigen-antibody) complexes have been demonstrated. Such immune complexes have been reported to occur on or near to disc cells in DH tissues. METHODS: Thin frozen sections of disc tissue from CD (n = 9 discs), DH (n = 58 discs), and DD (n = 11 discs) were cut and then immunostained with a monoclonal antibody to the complement membrane attack complex (C5b-9) using avidin-biotin complex (ABC) immunostaining. The presence or absence of complement membrane attack complex immunoreactivity was compared in the various subtypes of DH and also with preoperative duration of radicular pain. RESULTS: Complement membrane attack complexes could be observed in none of the CDs studied. In contrast, in more than one third of both the DH (21/58, 36.2%) and the DD (4/11, 36.4%), immunoreactivity to complement membrane attack complexes could be observed in disc cells. In DD discs, immunoreactivity to complement membrane attack complexes was most often present in anulus fibrosus samples (5/13, 38.5%). With respect to subtype of DH, complement membrane attack complexes were observed in 19 of 36 sequestrated discs (52.8%), 1 of 16 extrusions (6.3%), and 1 of 6 protrusions (16.7%). Complement membrane attack complexes were more often present with shorter pain duration (P= 0.03), but showed no relation to age. Disc cells often showed a heavy staining pattern for complement membrane attack complexes, suggesting an abundance of these complexes lodged in the membrane of the cells. CONCLUSIONS: The predominant presence of complement membrane attack complexes in sequestrated disc tissue could suggest a role in DH tissue-induced sciatica. Possibly immune (antigen-antibody) complexes, reported in previous studies, trigger the classic pathway of complement activation, with complement membrane attack complexes as the final product. Complement membrane attack complexes also appear to have some as yet undefined role in degenerated nonherniated disc tissue, with a predominant presence in the anulus fibrosus cells of such discs.

Adult↗
PubMedDate not supplied

[Levels of various components of the classical and alternative pathways of complement activation in diabetes mellitus patients].

The state of the complement system was studied in 91 patients with insulin dependent and in 47 patients with non-insulin dependent diabetes. A study was made of the quantity of hemolytically effective molecules of some components C2, C4, C3, C5 of classic and factors B and D of alternative pathway of activation. Complement components were studied for control in 51 healthy blood donors. Antigens B8 and B18 of the HLA-histocompatibility system were studied in parallel in 24 patients and 21 donors. A significantly raised level of components C3 and C4, factors B and D was revealed in the patients with insulin dependent diabetes as compared to the controls (p less than 0.05). In non-insulin dependent diabetes C4, factors B and D were significantly raised and the level of C5 was lowered (p less than 0.05). In the patients with insulin dependent diabetes having antigens B18 the level of C3 was raised and the level of C4 was lowered as compared to the controls. The level of factors B and D was also lower than that in the diabetic patients. An analysis of the content of the complement components in 31 diabetic patients with diabetic nephropathy indicated a decrease in the levels of components C3 and C5 and an increase in the content of C4 (p less than 0.001) as compared to the normal. Diabetes was accompanied by considerable variations as compared to normal values characterizing the state of the complement system and reflecting, to a certain extent, the main features of the pathogenesis of disease.

Complement C2↗