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PubMedDate not supplied

The contrasting mechanisms of serum resistance of Neisseria gonorrhoeae and group B Neisseria meningitidis.

Neisseria gonorrhoeae and Neisseria meningitidis have evolved intricate mechanisms to evade complement-mediated killing. Sialylation of gonococcal lipooligosaccharide (LOS) results in conversion of previously serum sensitive strains to unstable serum resistance, which is mediated by factor H binding. Porin (Por) is also instrumental in mediating stable serum resistance in gonococci. The 5th loop of certain gonococcal PorlAs binds factor H, which efficiently inactivates C3b to iC3b. Factor H glycan residues may be essential for factor H binding to certain Por1A strains. Por1A strains can also regulate the classical pathway by binding to C4b-binding protein (C4bp) probably via the 1st loop of the Por molecule. Certain serum resistant Por1 B strains can also regulate complement by binding C4bp through a loop other than loop 1. Purified C4b can inhibit binding of C4bp to Por 1B, but not Por1A, suggesting different binding sites on C4bp for the two Por types. Unlike serum resistant gonococci, resistant meningococci have abundant C3b on their surface, which is only partially processed to iC3b. The main mechanism of complement evasion by group B meningococci is inhibition of membrane attack complex (MAC) insertion by their polysaccharide capsule. LOS structure may act in concert with capsule to prevent MAC insertion. Meningococcal strains with Class 3 Por preferentially bind factor H, suggesting Class 3 Por acts as a receptor for factor H.

Blood Bactericidal Activity↗
PubMed1996

Role of complement in glomerular injury.

The alternative and classical pathway of activation enable the complement system to operate in various phases of infection. Both pathways are tightly controlled by membrane-bound and circulating regulatory proteins. The immediate effects of complement activation comprise the direct lysis of target structures, the generation of proinflammatory molecules and the recruitment of circulating leukocytes. In addition, complement is involved in antigen processing and in the regulation of appropriate immune responses. All functions of complement contribute to the development of glomerular injury. The terminal membrane attack complex acts directly on resident glomerular cells, whereas the earlier components are effective via the recruitment of leukocytes. That the early components are critically involved also in the metabolism and clearance of immune complexes is of special relevance to the pathogenesis of certain glomerular diseases. The exact role of complement components produced locally by resident glomerular cells has yet to be determined.

Animals↗
PubMed2005

Decay-accelerating factor in the periovulatory rat ovary.

One of the most prominent inflammatory reactions is the activation of the complement system. The activated complement system does not distinguish between pathogens and the host cell. In order to prevent autologous complement-mediated attack, host cells express a variety of both membrane-bound and fluid-phase complement regulatory proteins which control activity of the complement cascade by acting on convertase enzymes or the membrane-attack complex. Although the process of ovulation is facilitated by the inflammatory reaction, this reaction has the potential to cause serious damage to growing follicles, ovulated follicles, and other important ovarian tissues. This study was undertaken to characterize the expression and regulation of decay-accelerating factor (DAF), a complement regulator, as a potential mediator of ovarian tissue protection from ovulatory inflammation. DNA microarray and Northern blot analyses showed that an ovulatory gonadotropin stimulus dramatically yet transiently induced DAF mRNA expression in the immature rat ovary. Northern blot and PCR analyses revealed that of the three known DAF isoforms, glycosylphosphatidylinositol (GPI)-, soluble-, and transmembrane-(TM) DAF, GPI-DAF was the predominant form. In situ hybridization localized GPI-DAF mRNA expression in the theca-interstitial cells of the periovulatory ovary. Neither the anti-progestin RU486 nor the cyclooxygenase inhibitor indomethacin significantly inhibited human chorionic gonadotropin (hCG)-induced GPI-DAF mRNA expression in vivo. In vitro theca cell culture studies indicated that hCG induces GPI-DAF mRNA expression through the protein kinase A pathway. This study suggests that gonadotropin-induced GPI-DAF may be involved in the protection of ovarian tissues from the potential attack by the complement system activated by the inflammatory response associated with ovulation.

Animals↗
PubMed1985

Complement activation and attack on autologous cell membranes induced by streptolysin-O.

Streptolysin-O damages mammalian membranes through generation of large transmembrane channels formed by membrane-inserted polymers of the toxin (S. Bhakdi et al., Infect. Immun. 47:52-60, 1985). We here report that the native toxin binds naturally occurring human serum immunoglobulin G antibodies to form immune complexes with potent complement-activating capacity. Nanomolar concentrations of toxin added to antibody-containing serum cause rapid consumption of C4 and C5 hemolytic activity and 30 to 90% C3 conversion within 10 to 60 min at 37 degrees C. After binding to target membranes, streptolysin-O polymers serve as foci for antibody-dependent complement activation, which proceeds to completion with the formation of terminal C5b-9 complexes on the autologous cells. The binding and insertion of a primarily water-soluble bacterial product into a host cell membrane has thus been shown to generate a stable and hyperactive focus for activation of and self-attack by the complement system. We suggest that this process perpetuates local tissue damage, deviates host complement action away from the invading bacteria, and may possibly play a role in the pathogenesis of poststreptococcal disease.

Antigen-Antibody Complex↗
PubMed1995

Expression of complement regulatory proteins on human eggs and preimplantation embryos.

PROBLEM: To investigate the relation between the complement system and reproduction, expression of complement regulatory proteins (C3b receptors and inhibitor of the membrane attack complex) were screened on unfixed human eggs and preimplantation embryos. METHODS: Unfixed unfertilized oocytes and preimplantation embryos obtained from an in vitro fertilization program were stained by indirect immunofluorescence using monoclonal antibodies raised against membrane cofactor protein, (MCP or CD46), decay accelerating factor (DAF or CD55), protectin (CD59), human C3b/C4b receptor (CR1 or CD35), and major histocompatibility complex class I antigen (MHC class I). RESULTS: CD55 and CD59 were both expressed by the plasma membrane of unfertilized oocytes and pre-implantation embryos. CD46 was not expressed by unfertilized oocytes but appeared at the 6-to-8 cell stage embryo when human gene expression first occurs. CD35 and MHC class I antigens were not expressed at all on oocytes and preimplantation embryos. CONCLUSIONS: Selective expression of complement regulatory proteins (DAF and protectin) associated with the lack of MHC class I antigens may represent an immune protective mechanism by which human oocytes and preimplantation embryos escape complement-mediated damage during their travel through the female genital tract. Furthermore, participation of these complement regulatory proteins including MCP in cell to cell interaction during fertilization and/or implantation cannot be excluded.

Antibodies, Monoclonal↗
PubMed2006

Alternative roles for CD59.

CD59 was first identified as a regulator of the terminal pathway of complement, which acts by binding to the C8/C9 components of the assembling membrane attack complex (MAC), to inhibit formation of the lytic pore. Structurally, CD59 is a small, highly glycosylated, GPI-linked protein, with a wide expression profile. Functionally, the role of CD59 in complement regulation is well-defined but studies have also shown clear evidence for signalling properties, which are linked to its glycophosphatidyl inositol (GPI) anchor and its location within lipid rafts. Cross-linking of CD59 using specific monoclonal antibodies drives both calcium release and activation of lipid-raft associated signalling molecules such as tyrosine kinases. These observations clearly show that CD59 exhibits roles independent of its function as a complement inhibitor. In this review, we examine the progression of research in this area and explore the alternative functions of CD59 that have recently been defined.

Animals↗
PubMed2004

Production of recombinant C5a from rainbow trout (Oncorhynchus mykiss): role in leucocyte chemotaxis and respiratory burst.

Activation of the complement system can lead to the formation of the membrane attack complex, in which the component C5 is cleaved into C5a and C5b fragments. The C5a anaphylatoxin is a very potent pro-inflammatory molecule that induces chemotaxis and respiratory burst processes in a variety of mammalian leucocytes. While C5a has been well studied in mammals, little is known about the structure and function of C5a in teleost fish or other non-mammalian species. In the present study, we have produced and purified recombinant rainbow trout C5a (rtC5a), and we have shown that it plays an important role in inducing leucocyte migration as well as in triggering the respiratory burst of peripheral blood (PBLs) and head kidney leucocytes (HKLs). When the carboxy-terminal Arg was removed from rtC5a, its ability to induce cell migration and superoxide production remained intact. Interestingly, we show that leucocytes migrating towards rtC5a attached to the plate with a well-spread circular morphology, whereas those migrating towards activated trout serum displayed more irregular and dendritic-like shapes. Our data suggest that the basic mechanisms of action of the C5a anaphylotoxin have remained conserved for more than 300 million years.

Animals↗
PubMed2006

A novel interpretation of immune redundancy and duality in reperfusion injury with important implications for intervention in ischaemic disease.

The majority of ischaemia related injury occurs upon tissue reperfusion. Knock-out mouse models have recently shed light on the underlying molecular mechanisms, and suggest that this may be the result of an innate autoimmune response. Based on these new findings we present a novel model of immune redundancy and duality in reperfusion injury. Natural antibody, mannan-binding lectin and toll-like receptor 4 are three pre-formed innate immune receptors that recognise pathogenic molecular patterns. Removing either significantly ameliorates reperfusion injury. We propose that these three receptors serve as key parallel recognition elements that respond to the same or similar ischaemic neo-antigens, of which at least one may have a lipopolysaccharide-like motif. This would fit both with the ligand preference of the three receptors, and the observation that giving monoclonal antibody to lipopolysaccharide reduces reperfusion injury. The consequent injury caused by receptor activation appears to be mainly related to the complement anaphylatoxins, and less to phagocytes, oxidative radicals, and the membrane attack complex. C5a levels in particular are predictive of overall injury, and we suggest this anaphylatoxin causes most of reperfusion injury via both direct toxic effects and a generalised immune activation. The former is illustrated by the recent observation that excess C5a alone can cause cardiac dysfunction. As for the latter, there is evidence that adaptive immunity (especially CD4+ cells) and other serum cascades (coagulation and kallikrein) are involved, and may have been recruited by complement. Furthermore, excess C5a can cause innate immune overactivation that paralyses neutrophils, reduces complement lytic function, and leads to systemic inflammation. This is analogous to what happens in sepsis, and would explain the passive role in IRI of normal immune effectors. Finally, there is a duality complement's function in reperfusion, as some elements are conductive of damage, whilst others may help inflammatory resolution. Most important among the latter are the opsonins, like C3b and apparently C1q, which help macrophages clear apoptosing cells before they undergo secondary necrosis. This model has important implications for clinical interventions. Firstly, redundancy means that inhibiting multiple receptors may achieve a larger mortality reduction than the small and inconsistent one seen in the published monotherapy trials. Secondly, duality means that a non-specific inhibition of complement would reduce both injury and resolution. Therefore, a specific inhibition of the lectin pathway and/or an inhibition of the downstream effectors upon which the receptors converge (e.g. C5a) seem to be a better interceptive strategy.

Animals↗
PubMed2000

Preconditioning reduces myocardial complement gene expression in vivo.

This investigation examined the effect of preconditioning in an in vivo model of ischemia-reperfusion injury. Anesthetized New Zealand White rabbits underwent 30 min of regional myocardial ischemia followed by 2 h of reperfusion. Hearts preconditioned with two cycles of 5 min ischemia-10 min reperfusion (IPC) or with the ATP-sensitive K (K(ATP)) channel opener, diazoxide (10 mg/kg), exhibited significantly (P < 0.05) smaller infarcts compared with control. These treatments also significantly (P < 0.001 to P < 0.05) reduced C1q, C1r, C3, C8, and C9 mRNA in the areas at risk (AAR). The K(ATP) channel blocker 5-hydroxydecanoate (5-HD; 10 mg/kg) attenuated infarct size reduction elicited by IPC and diazoxide treatment. 5-HD partially reversed the decrease in complement expression caused by IPC but not diazoxide. There were no significant differences in complement gene expression in the nonrisk regions and livers of all groups. Western blot analysis revealed that IPC also reduced membrane attack complex expression in the AAR. The data demonstrate that preconditioning significantly decreases reperfusion-induced myocardial complement expression in vivo.

Animals↗
PubMed1998

Could synergistic interactions among reactive oxygen species, proteinases, membrane-perforating enzymes, hydrolases, microbial hemolysins and cytokines be the main cause of tissue damage in infectious and inflammatory conditions?

The mechanisms of cellular damage caused by infectious and inflammatory processes are complex and are still not fully understood. There is, however, a consensus that reactive oxygen species (ROS) generated by phagocytes migrating to injured tissues might be the main agents responsible for cellular damage in inflammatory processes. However, because both activated phagocytes and catalase-negative, peroxide-producing, toxigenic bacteria (Streptococci, Clostridiae) secrete a near-identical array of proinflammatory agonists, including reactive oxygen species (ROS), and because these microbial species might kill their targets by a synergism among several of their secreted enzymes (a multicomponent system), we postulated that activated phagocytes might also function in the same way. Using radiolabeled targets, in culture, we demonstrated that subtoxic amounts of a variety of oxidants (H2O2, radicals produced by xanthine-xanthine-oxidase, peroxyl radical, NO) acted synergistically with subtoxic amounts of a large series of membrane-perforating agents (microbial hemolysins, phospholipases, fatty acids, cationic proteins, proteinases, bile salts, the attack complex of complement, the xenobiotics, lindane, ethanol, methanol) to kill cells in culture and to release large amounts of arachidonic acid and metabolites. Membrane perforators might act primarily to overcome the potent antioxidant systems present in all mammalian cells and scavengers of ROS and inhibitors of the additional agonists might act to abolish the synergism among ROS and the membrane-damaging agents. It is also proposed that protection against tissue damage in vivo should also include 'cocktails' of appropriate antagonists. It is enigmatic that those publications which do describe both in-vitro and in-vivo models proposing that a synergism among a multiplicity of agonists might truly represent the mechanisms by which tissues are injured, in vivo, are hardly ever quoted in the current literature.

Animals↗
PubMed1995

CD59: its role in complement regulation and potential for therapeutic use.

CD59 regulates complement activation cascade at the final step, inhibiting formation of membrane attack complex (MAC). This protein, being anchored to the cell membrane via glycosyl phosphatidyl inositol (GPI), is expressed ubiquitously on cells which are in contact with body fluids containing components. Recently, MAC formation has been reported to play an important role in pathogenesis of inflammatory diseases such as ischemia or autoimmune diseases. In this review, we describe the structure and biological activities of CD59, the pathogenic role of MAC formation, and discuss application of soluble molecules of CD59 for therapeutic use.

Animals↗
PubMed1998

The complement regulatory proteins CD46 and CD59, but not CD55, are highly expressed by glandular epithelium of human breast and colorectal tumour tissues.

Three of the proteins protecting cells from autologous lysis by complement are: membrane cofactor protein (MCP; CD46), an inhibitor of the membrane attack complex formation (CD59), and decay accelerating factor (DAF; CD55). We have investigated the expression of these proteins in breast and colorectal carcinoma by immunohistochemistry and immunoblotting of breast tissue for CD46. CD46 was consistently and strongly expressed in the epithelial compartment in 26/28 ductal carcinomas of the breast, 9/9 fibroadenomas, and 9/11 cases of control non-neoplastic breast tissue. CD59 showed a similar degree of expression in the fibroadenomas (9/9), but was less strongly expressed in carcinomatous (22/28) and control (5/11) tissues. In marked contrast, no CD55 expression was detected in tissue from 15 ductal carcinomas. Immunoblotting of breast tissue for CD46 showed the same size of the molecule as for lymphocytes. It had however considerably stronger expression in tumour tissue than in non-neoplastic tissue. CD46 and CD59 were either lacking or only weakly expressed in the epithelial component of control colorectal mucosa: 2/15 and 5/15, respectively. In contrast, tissue samples from colorectal adenocarcinomas showed clear staining for both CD59 (10/18) and, more markedly, CD46 (15/18). There was no association between the pattern or intensity of CD46 and CD59 expression and tumour differentiation. As the complement regulatory proteins CD46 and CD59 are also strongly expressed by trophoblast at the feto-maternal tissue interface, these results support the concept that similar mechanisms are employed both by the genetically dissimilar fetus and certain tumours to evade immune attack by their host.

Adenocarcinoma↗
PubMed2007

The C-terminus of complement factor H is essential for host cell protection.

Complement is a powerful self-amplifying system of innate immune defense with the capacity to eliminate microbes directly. Factor H is a central regulator in plasma which protects host tissue from complement mediated damage. Here we characterize the relevance of surface attached factor H, and study the regulatory activity of factor H on endothelial cells. Although these cells expressed membrane bound regulators, cell bound factor H contributed substantially to complement regulatory activity at the cell surface. Blockade of the C-terminus of factor H with monoclonal antibodies inhibited cell binding of this soluble regulator and resulted in enhanced complement activation on the cells. In the absence of factor H, increased deposition and slower inactivation of C3b resulted in higher amount of membrane attack complexes on the cell surface. When the membrane regulators CD55 and CD59 were removed by enzymatic treatment, complement mediated cell lysis was enhanced in the absence of factor H. Importantly, inhibition of the C-terminus did not compromise the regulatory function of factor H in fluid phase. Altogether these data point to a highly relevant, yet so far underestimated role of factor H for complement control at cellular surfaces, and reveal a decisive role of the factor H C-terminus in host cell recognition and protection.

Antibodies, Monoclonal↗
PubMed1993

Levels of complement regulatory molecules in lung cancer: disappearance of the D17 epitope of CD55 in small-cell carcinoma.

The levels of complement-regulatory molecules (complement receptor type one [CR1], decay-accelerating factor [DAF], membrane cofactor protein [MCP], and an inhibitor of membrane attack complex [CD59]) in lung cancer cells were analyzed to investigate the relation between their expression and histological subtypes, and the possibility of homologous complement deposition on cancer cells. In 25 cell lines (10 adenocarcinoma, 3 large-cell carcinoma, 7 small-cell lung cancer [SCLC], and 5 squamous cell carcinoma), flow cytometric analysis revealed that MCP was expressed in all cell lines, whereas none of the cell lines was CR1-positive. CD59 was detected in all cells. The DAF epitope defined by IA10 was expressed in all cells except one large cell carcinoma cell line. However, another epitope for anti-DAF monoclonal antibody, D17, was not detected in 5 (71.4%) SCLC and in 4 (22.2%) non-small-cell lung cancer. This disparity was seen in most cell lines, irrespective of histological subtypes. The loss of D17 reactivity seemed to be pertinent to malignant phenotype, because most of the normal pulmonary cells possessed the D17 epitope. Furthermore, a cell line lacking DAF (IA10-/D17-) allowed alternative pathway-mediated homologous complement (C3) deposition after pretreatment with anti-MCP antibody. This raises a new possibility for immunotargeting of cancer. These cell lines should be useful in studying the biology of lung cancer.

Antigens, CD↗
PubMed2002

Brain edema after intracerebral hemorrhage: the effects of systemic complement depletion.

The complement cascade is activated after experimental intracerebral hemorrhage (ICH) and may play an important, role in edema formation. This study investigated the effects of systemic complement depletion on brain edema formation following ICH. Thirty-six pentobarbital-anesthetized Sprague-Dawley rats were used. Treatment animals were complement-depleted with cobra venom factor (CVF) while controls received an equal volume of saline injection (i.p.). In both treatment and control rats, autologous blood (100-microL) was infused stereotactically into the right basal ganglia. Rats were sacrificed one and three days later for brain water and ion content measurements and immunohistochemical studies. Immunohistochemistry was used to detect complement C3d, C5a, and C9. Western blot analysis was applied for C9 semiquantitation. Perihematomal brain edema was reduced by systemic complement depletion at one and three days. The water content of the cerebellum (a tissue distant from the hematoma site) was unaffected by complement depletion. Immunocytochemistry found complement depletion significantly reduced perihematomal C9 deposition, C3d production, and C5a positive cell accumulation. In conclusion, complement depletion by CVF attenuates brain edema in ICH perhaps by inhibiting the inflammatory response and membrane attack complex (MAC) formation.

Animals↗
PubMed2005

Terminal complement components mediate release of von Willebrand factor and adhesion of platelets in arteries of allografts.

BACKGROUND: Both humoral and cellular immune responses can cause arterial injury in organ transplants, but the manifestations of these different inflammatory mechanisms have not been dissected fully. The present study was designed to define the effects of the terminal complement components on arterial injury in vivo. METHODS: The authors have developed congenic rat strains with a C6 deficiency. The absence of C6 terminates the cascade of complement after C5 cleavage and prevents the assembly of the membrane attack complex. Hearts were transplanted from PVG.1A (RT1) rats to major histocompatibility complex-incompatible C6-deficient (C6-) or C6-sufficient (C6+) PVG.1U (RT1) rats. RESULTS: PVG.1A (C6-) cardiac grafts were rejected acutely (6-7 days) by untreated PVG.1U (C6+) recipients but survived significantly longer in PVG.1U (C6-) recipients (8 to >30 days). Arteries of cardiac allografts in C6+ recipients demonstrated extensive endothelial injury evidenced by release of von Willebrand factor (vWF) and accompanied by platelet aggregation. In contrast, vWF was retained in Weibel-Palade storage granules of arterial endothelial cells in cardiac allografts that were rejected by C6- recipients. In the absence of C6, intimal alterations were limited to lifting of endothelial cells from supporting stroma by infiltrating mononuclear cells, duplicating the clinical lesion described as endotheliitis or intimal arteritis. Delaying graft rejection with a short course of cyclosporine did not decrease vWF release and platelet aggregation in PVG.1U (C6+) recipients. CONCLUSIONS: Mononuclear cell infiltration of the arterial intima occurs in the absence of C6, but C6 deficiency limits the release of vWF from arterial endothelial cells.

Animals↗
PubMed2000

Evidence for activation of the alternate complement pathway in patients with juvenile rheumatoid arthritis.

OBJECTIVE: Complement activation has been shown to occur in patients with juvenile rheumatoid arthritis (JRA). Since the two pathways of complement are activated by different stimuli (the alternate pathway by microbial products and IgA, and the classical pathway by immune complexes), we decided to study the relative contribution of the two pathways of complement activation in patients with JRA. METHODS: In 56 patients with JRA, plasma levels of C3 and C4 were measured by turbidimetric assays, and those of C4d, factor Bb and sC5-9 complex by solid-phase enzyme immunoassays. Levels beyond the mean +/- 2 S.D. of normal were considered abnormal. RESULTS: Plasma C3 and C4 levels were decreased in one patient each. The C4d values were increased in 17 patients, whereas levels of factor Bb were elevated in 42 patients and levels of sC5-9 complex were elevated in 51 patients. The values of factor Bb and sC5-9 had a linear correlation (r = 0.75), but there was no significant correlation between C4d and sC5-9 levels (r = 0.36). CONCLUSION: Complement activation in JRA is initiated predominantly by the alternate pathway and culminates in the formation of terminal membrane attack complex.

Adolescent↗
PubMed1994

Immunohistological studies of complement activation after xenogeneic perfusion of a working heart model.

Transplantation of organs from one species to another leads to immediate hyperacute rejection. Activation of complement is one important factor involved in this process. Whether complement activation is induced by preformed natural antibodies (PNAbs) via the classical pathway or by an "activator surface" via the alternative pathway is unclear. In order to simulate the relevant clinical situation of animal donor/human recipient we perfused working porcine hearts ex vivo with human blood. This also offered the possibility to study the process of complement activation in a precisely defined system with human complement proteins. PNAb titer and complement lytic activity of the plasma were measured. Immunohistological stainings for IgG, IgM, C1q, C4, C3d, C5-9, factor B, and properdin were performed on tissue sections of the left ventricle. PNAb titer almost totally disappeared within the first 5 min of perfusion. Complement lytic activity of the classical pathway decreased similarly within the first 3 h of xenogeneic and autologous perfusion from 70% to 40%. More detailed immunohistological studies revealed positive staining for C3d on endothelium and myocardium of ex vivo perfused xenogeneic hearts. Complement-induced cytotoxicity was proven by the presence of C5-9 (membrane attack complex). However, hardly any C1q and C4 could be found in the ex vivo xenogeneic perfused hearts. Staining for factor B was positive and proved activation via the alternative pathway. Beyond that, the presence of properdin binding even indicated an upregulation of the alternative pathway C3 convertase.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗