PubMed Health⌕ Search

SEARCH · PubMed Health

Results for “Complement Pathway, Alternative”

Explore indexed PubMed citations for clinical trials, systematic reviews and public health research. Read source abstracts and follow each citation to its original PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 1,621 records · Page 90Linked to original sources
PubMed1986

Serotherapy of primary rat mammary carcinoma: inhibition by ethylenedinitrilotetraacetic acid but not by [ethylenebis(oxyethylenenitrilo)]tetraacetic acid.

We reported inhibition of growth of primary rat mammary carcinomas after infusions of tumor-bearer plasma absorbed with Protein A-Sepharose or inactivated CNBr Sepharose. Absorbed plasmas were depleted of the third component of complement (C3) (other complement components defined similarly) and C5 but not C1, C4, or C2. These results suggested that activation of the alternative pathway of complement might be involved in the observed antitumor effects. To test this concept sera were treated with ethylenedinitrilotetraacetic acid or [ethylenebis(oxyethylenenitrilo)]tetraacetic acid before absorption with Protein A-Sepharose. Ethylenedinitrilotetraacetic acid, by chelating calcium and magnesium, prevents activation of both the alternative and classical complement pathways. [Ethylenebis(oxyethylenenitrilo)]tetraacetic acid, by chelating calcium but not magnesium, permits activation of the alternative pathway but inhibits activation of the classical complement pathway. Sera in the presence or absence of chelating agent were absorbed with Protein A-Sepharose twice at room temperature. After absorption calcium was added to the sera. Rats were treated by i.v. injection of sera twice a week for 2 weeks. Measurements of tumor size were made weekly for 5-7 weeks and then tumor weight was determined. Groups were compared both for size of index and total tumors. The results can be summarized as follows: tumor-bearer sera before absorption did not inhibit the growth of rat primary mammary carcinomas; tumor-bearer sera after absorption with Protein A-Sepharose showed significant consumption of C3 and did inhibit tumor growth; tumor-bearer sera absorbed in the presence of ethylenedinitrilotetraacetic acid did not show a decrease in C3 functional activity and did not inhibit tumor growth; tumor-bearer sera absorbed in the presence of [ethylenebis(oxyethylenenitrilo)]tetraacetic acid did show a decrease in C3 functional activity and did inhibit tumor growth; sera from normal adult female rats after absorption with Protein A-Sepharose did inhibit tumor growth. The results are consistent with a role for the alternative pathway of complement in the inhibition of growth of rat primary mammary carcinomas observed after treatment with absorbed sera.

Animals↗
PubMed1983

Diethylcarbamazine dependent, complement mediated, adherence and cytotoxicity of cells on microfilariae of Litomosoides carinii.

Diethylcarbamazine (DEC) induced dose dependent adherence of normal spleen cells from Mastomys natalensis to microfilariae of L. carinii in the presence of serum from Mastomys infected with L. carinii or normal serum. The effect could be also induced, using fresh, normal human serum and human blood leucocytes. The responsible serum factor was heat labile (56 degrees C, 30 min) and was eliminated from the sera by pretreatment with Inulin. The activity could be reconstituted by normal serum. Cell adhesion was inhibited by 0.004 MEDTA while 0.004 M EGTA had only a weak inhibitory effect. The addition of Mg++ led to high adherence rates in the presence of EGTA. The data indicate that DEC activates complement on the surface of the larval sheath by the alternate pathway. Adherent Mastomys cells or human cells had a cytotoxic effect on the larvae. The death of the microfilariae did not depend on the loss of the larval sheath.

Animals↗
PubMed2001

Interaction of poly(2-acrylamido 2-methylpropane sulfonate)-grafted polystyrene beads with cationic complement proteins.

Influence of various biomaterials on the complement system in serum has been intensively studied by many research groups, since activation of the complement pathway in vivo has been known to give rise to some pathological conditions, such as inflammation and anaphylaxis. Much effort has been devoted to develop new materials that do not activate or deteriorate the complement system. The present work is aimed at revealing the mode of reactions of anionic poly(2-acrylamido 2-methylpropane sulfonate) grafted on polystyrene bead (PAMPS-g-bead) with serum complement. Complement activity assay, determination of complement proteins levels, and immunoblot analysis were carried out for sera pretreated with PAMPS-g-beads. The results clearly showed that, when PAMPS-g-beads were incubated with serum, those beads adsorbed several complement proteins, i.e. C1q, factor D, factor P, C6, and C8, but the generation of activation fragments of complement components was not observed. Especially, factor D was most effectively removed from serum, resulting in potential inhibition of the alternative pathway. A larger amount of PAMPS-g-beads was needed to decrease the serum CH50 level. That may be caused by removal of C6. Although some polyanions, such as dextran sulfate, were reported to activate the complement system, the obtained results indicate that the PAMPS-g-bead is not an activator of the complement pathway, but acts as an adsorbent of complement components. One possible clinical application of the PAMPS-g-beads is adsorption of serum factor D by extracorporeal treatment of patients with renal failure with a high level of factor D, because the increased quantity of factor D in serum may cause consistent activation of the alternative pathway.

Biocompatible Materials↗
PubMed1978

Hereditary C2 deficiency and systemic lupus erythematosus associated with severe glomerulonephritis.

Although an unusually high incidence of immunological diseases has been described in patients with hereditary C2 deficiency, the severity of these illnesses has been relatively mild, suggesting that blocking complement activation beyond C4 may protect against significant complement-mediated inflammation. This report describes studies in a C2-deficient patient with severe systemic lupus erythematosus (SLE) and diffuse proliferative glomerulonephritis. An immunopathological study of the kidney revealed the deposition of properdin, properdin factor B, C3 and C5 in a pattern similar to immunoglobulin G deposits. Serum properdin and properdin factor B levels were low at various times during the patient's course. In vitro complement fixation studies showed C3 fixation by glomerular deposits could occur via the alternative pathway. Studies of the immune deposits in the patients' skin revealed similar results. These studies suggest that inflammation may be effectively mediated via the alternative complement pathway in the C2 deficiency-lupus syndrome.

Adolescent↗
PubMed1996

Mesophilic Aeromonas sp. serogroup O:11 resistance to complement-mediated killing.

The complement activation by and resistance to complement-mediated killing of Aeromonas sp. strains from serogroup O:11 were investigated by using different wild-type strains (with an S-layer characteristic of this serogroup) and their isogenic mutants characterized for their surface components (S-layer and lipopolysaccharide [LPS]). All of the Aeromonas sp. serogroup O:11 wild-type strains are unable to activate complement, which suggested that the S-layer completely covered the LPS molecules. We found that the classical complement pathway is involved in serum killing of susceptible Aeromonas sp. mutant strains of serogroup O11, while the alternative complement pathway seems not to be involved, and that the complement activation seems to be independent of antibody. The smooth mutant strains devoid of the S-layer (S-layer isogenic mutants) or isogenic LPS mutant strains with a complete or rather complete LPS core (also without the S-layer) are able to activate complement but are resistant to complement-mediated killing. The reasons for this resistance are that C3b is rapidly degraded, and therefore the lytic membrane attack complex (C5b-9) is not formed. Isogenic LPS rough mutants with an incomplete LPS core are serum sensitive because they bind more C3b than the resistant strains, the C3b is not completely degraded, and therefore the lytic complex (C5b-9) is formed.

Aeromonas↗
PubMed1994

Familial hemolytic-uremic syndrome and homozygous factor H deficiency.

Inherited hemolytic-uremic syndrome (HUS) is unusual. We report the occurrence of HUS in two siblings; one died at an early age while the other (the proband) has presented with three episodes of HUS since the age of 19 years. The finding of a persistently low serum C3 level in this patient led to a thorough evaluation of her complement cascade and a family investigation. The proband and her asymptomatic younger sister were found to have very low serum levels (5% of normal) of factor H, a regulatory protein of the alternative complement pathway. Both patients had low levels of serum C3, factor B, CH50 and VAH50, reflecting persistent alternative pathway activation. The father and mother both had half-normal serum factor H levels but an otherwise normal complement profile. Other members of the extended pedigree were also found to have half-normal serum factor H levels. In conclusion, in this family, factor H deficiency appears to be associated with HUS and is transmitted as an autosomal recessive trait. Persistent C3 hypocomplementemia in the setting of familial and/or recurrent HUS should be a clue to a possible inherited complement deficiency.

Adult↗
PubMed1991

Molecular basis of the enhanced susceptibility of the erythrocytes of paroxysmal nocturnal hemoglobinuria to hemolysis in acidified serum.

When incubated in acidified serum, the erythrocytes of paroxysmal nocturnal hemoglobinuria (PNH) are hemolyzed through activation of the alternative pathway of complement (APC), but normal erythrocytes are resistant to this process. PNH cells are deficient in decay-accelerating factor (DAF), a complement regulatory protein that inhibits the activity of both the classical and the alternative pathways. However, deficiency of DAF alone does not account entirely for the aberrant effects of acidified serum on PNH cells. Recently, we have shown that PNH erythrocytes are also deficient in another complement control protein called membrane inhibitor of reactive lysis (MIRL) that restricts complement-mediated lysis by blocking formation of the membrane attack complex (MAC). To determine the effects of the DAF and MIRL on susceptibility to acidified serum lysis, PNH cells were repleted with the purified proteins. DAF partially inhibited acidified serum lysis by blocking the activity of the amplification C3 convertase. MIRL inhibited acidified serum lysis both by blocking the activity of the MAC and by inhibiting the activity the C3 convertase. When DAF function was blocked with antibody, normal erythrocytes became partially susceptible to acidified serum lysis. By blocking MIRL, cells were made completely susceptible to lysis, and control of C3 convertase activity was partially lost. When both DAF and MIRL were blocked, the capacity of normal erythrocytes to control the activity of the APC and the MAC was destroyed, and the cells hemolyzed even in unacidified serum. These studies demonstrate that DAF and MIRL act in concert to control susceptibility to acidified serum lysis; of the two proteins, MIRL is the more important. In addition to its regulatory effects on the MAC, MIRL also influences the activity of the C3 convertase of the APC. Further, in the absence of DAF and MIRL, the plasma regulators (factor H and factor I) lack the capacity to control membrane-associated activation of the APC.

Animals↗
PubMed1999

Immunohistologic evaluation of mechanisms mediating hyperacute lung rejection, and the effect of treatment with K76-COOH, FUT-175, and anti-Gal column immunoadsorption.

Although most investigators agree that lung dysfunction occurs rapidly in various pig-to-primate hyperacute lung rejection (HALR) models, the basic mechanisms mediating this phenomenon remain in question. Here we describe an immunohistochemical method for assessment of mechanisms driving HALR. Using an established model wherein piglet lungs are perfused ex vivo with human blood, six experimental groups (K76 COOH; FUT-175; K76 with FUT; anti-alpha-Gal column adsorption; column with FUT; and column with K76) and two control groups (unmodified human blood; autologous pig blood) were studied. Each lung was biopsied serially during perfusion, and assessed using an immunohistochemical technique, with vWF staining as an internal control to quantitate binding of human IgM, IgG, C3, C5b-9, properdin, and C1q. The effect of each treatment and subsequent lung perfusion on IgG and IgM anti-alpha-Gal titers(by ELISA) and on pig endothelial cell cytotoxicity were correlated with histologic findings. We found that [1] the classical complement activation pathway was activated, as has been shown for other pig organs in primate or human blood environments [2]; alternative complement pathway activation is also seen, which has not been described for other organs in pig-to-primate models, but only in the context of classical pathway activation; and [3] anti-Gal column absorption, pharmacologic inhibition of complement, or combination therapy each was associated with histologic evidence of partial protection, consistent with what would be predicted for each intervention. Further, immunohistologic differences correlated with physiologic outcomes [8] and with antibody assay results, and revealed that treatments used were incompletely effective. Our data suggest that more complete inhibition of antibody- and complement-driven pathways than was achieved in these experiments will be necessary to prevent the antibody and complement-mediated facets of hyperacute lung rejection. This immunohistologic technique may also help us identify additional pathogenic mechanisms important to eventual clinical application of pig-to-human lung xenografts.

Acute Disease↗
PubMed1989

Analysis of the complement C3 fragments associated with hemodialysis membranes.

During hemodialysis with cuprophan membranes, bioactive peptides are generated because the alternative pathway of complement is activated. When cellulose acetate membranes are employed, complement activation is attenuated. The molecular basis for this improved biocompatibility is unknown. It has been postulated, however, that the complement activating potential of dialysis membranes is influenced by the availability of free hydroxyl groups which would provide an acceptor site for activated C3. To investigate this hypothesis, the forms of C3 associated with cellulose acetate and cuprophan membranes have been analyzed. By Western blot, the predominant form of C3 present on both types of membranes is C3c, a degradation product of C3 that lacks the thiolester necessary for covalent bonding. Minimal amounts of C3d (the region of C3 which contains the thiolester) were observed on both membranes; however, by ELISA, there was no difference in the amount bound to cellulose acetate compared to cuprophan. Further, membrane-associated C3d could be removed by urea, suggesting that it was not bound covalently. These studies indicate that the complement activating potential of dialysis membranes is not determined primarily by the availability of potential covalent binding sites for activated C3b.

Blotting, Western↗
PubMed1991

[Diversity of complement activation by lentinan, an antitumor polysaccharide, in gastric cancer patients].

Lentinan, a pure polysaccharide, augments many immune responses in vivo but not in vitro. Therefore reaction with any factor is thought to be required for triggering of immunopotentiation by lentinan. To clarify the role of complement in this effect, we investigated whether lentinan could activate alternative pathway of complement or not and the relation with the immunopotentiation in 13 gastric cancer patients. C3, C3a, C5 and C5a levels as parameters of complement activation and interleukin-2 producing activity as parameter of immunopotentiation were assayed before and immediately after intravenous injection of lentinan. Among these complement components, remarkable change was observed only in C3a level. C3a level elevated to more than 1000ng/ml from less than 300ng/ml. And according to the degree and continuation of the elevation, these patients were classified into 3 types-(1) every time little elevation, (2) first remarkable and thereafter little elevation and (3) continuous remarkable elevation. Such an elevated C3a level returned to the level before lentinan injection within one day. When C3a level elevated to more than 1000ng/ml, leukocyte counts of peripheral blood decreased significantly and interleukin-2 producing activity increased concomitantly. Thus, there was diversity in response to lentinan and complement activation was suggested to have contribution in immunopotentiation by lentinan.

Adjuvants, Immunologic↗
PubMed1992

Plasmodium berghei: sporozoites are sensitive to human serum but not susceptible host serum.

Human complement was activated by rodent malaria, Plasmodium berghei, sporozoites through the alternative pathway, as revealed by C3 deposition on sporozoites using the fluorescent antibody technique. Sporozoites exposed to fresh human serum decreased in infectivity to HepG2 cells, but those exposed to heated or C3-deficient human serum showed normal infectivity to HepG2 cells. In contrast, C3 deposition was not observed on the sporozoites treated with mouse or rat serum even in the presence of specific polyclonal anti-sporozoite antibody. However, following treatment with trypsin (250 micrograms/ml), 81% of salivary gland sporozoites and 49% of oocyst sporozoites became reactive with mouse serum, and reactive sporozoites deposited mouse C3 on their surface in the presence of 30 mM EGTA and 1 mM Mg2+ without antibody. Concomitantly some sporozoites lost reactivity to anti-circumsporozoite protein monoclonal antibody. These results suggest that P. berghei sporozoites possibly express surface molecules that regulate the complement activation pathway of susceptible hosts but not of nonhosts, and that the putative structures consist of protease-sensitive molecule(s) which are closely associated with the circumsporozoite protein.

Animals↗
PubMed1984

Local opsonization by secreted macrophage complement components. Role of receptors for complement in uptake of zymosan.

We have examined the role of macrophage (M phi plasma membrane receptors for the cleaved third complement component (iC3b; CR3) and mannosyl, fucosyl terminated glycoproteins (MFR) in uptake of unopsonized zymosan. Monoclonal antibodies against CR3, M1/70 (Mac-1) and MO1, each inhibited approximately 50% of uptake of 125I-zymosan by murine and human M phi, respectively. Yeast mannan inhibited 0-50% of zymosan uptake in various M phi, in parallel with their expression of MFR. We demonstrated that M phi were the source of C3 in our assay and that the activity of other components of the complement system, namely a C3 convertase, factor I, and a factor I cofactor were also present in serum-free cultures of human monocytes. Macrophage C3 was deposited rapidly, within 10 min, on the zymosan particles and mediated binding, ingestion, and stimulation of superoxide release in BCG-activated and thioglycollate-elicited peritoneal M phi via CR3. Local secretion of complement proteins by M phi themselves can therefore opsonize pathogens and cells able to activate the alternative pathway and effect their destruction.

Animals↗
PubMed1978

Oxygen radicals mediate endothelial cell damage by complement-stimulated granulocytes. An in vitro model of immune vascular damage.

During hemodialysis, alternative pathway complement activation leads to pulmonary sequestration of granulocytes, with loss of pulmonary vascular endothelial integrity and, at times, protein-rich pulmonary edema. An in vitro model of this phenomenon was constructed utilizing 51Cr-labeled human umbilical vein endothelial cell cultures. In this system, granulocytes, when exposed to activated complement (C), induce endothelial damage; this injury is mediated primarily by oxygen radicals produced by the granulocytes. C5a appears to be the C component responsible for granulocyte-induced cytotoxicity; studies with cytochalasin B-treated granulocytes suggest that close approximation of the granulocytes and endothelial cells is necessary for maximal cell injury.

Blood Vessels↗
PubMed2001

Complement-regulator factor H and related proteins in otitis media with effusion.

Otitis media with effusion (OME) is a common disease in childhood. It is characterized by chronic inflammation in which the proinflammatory activity of the complement (C) system is one of the underlying factors. The C system becomes strongly activated in the middle ear effusion (MEE) fluid, but the reasons for this are not known. Here we demonstrate by using complement Bb fragment ELISA that MEE specimens strongly activate the alternative C pathway (AP) in normal human serum (NHS). Some of the MEEs were also found to promote lysis of rabbit erythrocytes by NHS. These findings indicated a disturbance in the fluid-phase regulation of the AP in MEE. The main regulator of the AP, factor H (FH), and proteins structurally related to it (FHL-1, FHR-1, -2, -3, and -4) were present in the MEE fluids of OME patients. Relative to serum, the FHR proteins were more abundant in the MEEs. In addition, we detected the recently discovered 65-kDa FH-related protein FHR-5 in the MEE. The FHR proteins share binding sites with FH in the C3d region of C3b. Thus they may compete with FH in binding to C3b and interfere with the regulatory activity of FH. Consequently, a disturbance in AP control in the MEE may lead to an ongoing excessive C activation and inflammation in OME.

Apolipoproteins↗
PubMed2005

Streptococcal pyrogenic exotoxin B cleaves properdin and inhibits complement-mediated opsonophagocytosis.

Streptococcal pyrogenic exotoxin B (SPE B), a cysteine protease, is an important virulence factor in group A streptococcal (GAS) infection. The reduction of phagocytic activity by SPE B may help prevent bacteria from being ingested. In this study, we investigated the mechanism SPE B uses to enable bacteria to resist opsonophagocytosis. Using Western blotting and an affinity column immobilized with SPE B, we found that both SPE B and C192S, an SPE B mutant lacking protease activity, bound to serum properdin, and that SPE B, but not C192S, degraded serum properdin. Further study showed that SPE B-treated, but not C192S-treated, serum blocked the alternative complement pathway. Reconstitution of properdin into SPE B-treated serum unblocked the alternative pathway. GAS opsonized with SPE B-treated serum was more resistant to neutrophil killing than GAS opsonized with C192S-treated or normal serum. These results suggest that a novel SPE B mechanism, one which degrades serum properdin, enables GAS to resist opsonophagocytosis.

Animals↗
PubMed2002

Development of a novel cytomedical treatment that can protect entrapped cells from host humoral immunity.

Cell therapy is expected to relieve the shortage of donors needed for organ transplantation. When patients are treated with allogeneic or xenogeneic cells, it is necessary to develop a means by which to isolate administered cells from an immune attack by the host. We have developed "cytomedicine," which consists of functional cells entrapped in semipermeable polymer, and previously reported that alginate-poly-L-lysine-alginate microcapsules and agarose microbeads could protect the entrapped cells from injury by cellular immunity. However, their ability to isolate from humoral immunity was insufficient. It is well known that the complement system plays an essential role in rejection of transplanted cells by host humoral immunity. Therefore, the goal of the present study was to develop a novel cytomedical device containing a polymer capable of inactivating complement. In the screening of various polymers, polyvinyl sulfate (PVS) exhibited high anticomplement activity and low cytotoxicity. Murine pancreatic beta-cell line (MIN6 cell) entrapped in agarose microbeads containing PVS maintained viability and physiological insulin secretion, replying in response to glucose concentration, and resisted rabbit antisera in vitro. PVS inhibited hemolysis of sensitized sheep erythrocytes (EAs) and rabbit erythrocytes by the complement system. This result suggests that PVS inhibits both the classical and alternative complement pathways of the complement system. Next, the manner in which PVS exerts its effects on complement components was examined. PVS was found to inhibit generation of C4a and Ba generation in activation of the classical and alternative pathways, respectively. Moreover, when the EAC1 cells, which were carrying C1 on the EAs, treated with PVS were exposed to C1-deficient serum, hemolysis decreased in a PVS dose-dependent manner. These results suggest that PVS inhibits C1 in the classical pathway and C3 convertase formation in the alternative pathway. Therefore, PVS may be a useful polymer for developing an anticomplement device for cytomedical therapy.

Alginates↗
PubMed1973

A new complement-mediated cytolytic mechanism--the C1-bypass activation pathway.

A new cytolytic pathway is described whereby cells sensitized with cytotoxic antibody can be specifically lysed in the complete absence of intact, classical complement pathway function. Evaluation of this model with sera deficient in the 4th (C4), 2nd (C2), and 6th (C6) components of complement has revealed that this new lytic mechanism, termed the C1-bypass activation pathway, is initiated by the antibody-mediated activation of C1. Utilizing components of the previously described alternate complement pathway, this pathway bypasses C4 and C2 to activate the third to ninth components of complement (C3-9) with induction of membrane damage.

Animals↗