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PubMed2001

The human complement C9 gene: structural analysis of the 5' gene region and genetic polymorphism studies.

C9 is the last of the human complement components creating the membrane attack complex. The single chain serum protein is encoded by a gene located on chromosome 5p13 that is composed of 11 exons. With the aid of inverse PCR, the hitherto unknown regions flanking exon 1 and the 3' part of exon 11 (3'UTR) have been sequenced. A computer-based analysis of the 300-bp region located just upstream of the AUG start codon showed homologies to known DNA modules which affect the transcriptional regulation of certain genes. The most striking of these is a sequence that may substitute the missing TATA box in initiating C9 transcription. In the 3'UTR, three successive polyadenylation signals were found. Although the C9 protein is invariant, four different single nucleotide polymorphisms (SNPs) have been observed at the DNA level by exon-specific PCR and direct sequencing. None of them changes the amino acid composition of the mature protein. Due to a C --> T transition in exon 1 at cDNA position 17, the fifth amino acid of the leader peptide may be either an arginine or a tryptophane. Using either PCR/ RFLP analysis (exons 1 and 11) or allele-specific PCR (intron 1 and exon 4), each polymorphism can be characterized without sequencing. All of the exon 1, intron 1 and exon 11 variants could be detected in small population samples of European, Thai or South American Indian origin. In contrast, the exon 4 C variant was observed only once in a European. The first three SNPs can be combined to designate eight different 'C9 alleles'. Of these, six have actually be found. These data provide strong evidence that several mutation and recombination events occurred in the course of C9 gene evolution.

3' Untranslated Regions↗
PubMed1994

Complement, neutrophils and free radicals: mediators of reperfusion injury.

Myocardial ischemia of sufficient duration produces irreversible myocardial injury and cell death. Associated with the direct ischemic insult, there is the indirect attack on the jeopardized tissue through activation of the complement system. The latter, occurring in response to ischemia, facilitates neutrophil-endothelial cell interactions, neutrophil migration into and across the vascular wall, along with the formation of cytotoxic oxygen metabolites and release of proteolytic enzymes. The neutrophil dependent actions participate in extending the tissue injury beyond that due to ischemia alone. The invading neutrophils injure the myocardial vasculature and sarcolemma through the generation of oxygen free radicals. Components of the complement system can damage tissue indirectly through formation of neutrophil chemoattractants as well as directly through assembly of the "membrane attack complex." Pharmacologic interventions that prevent complement activation, modulate neutrophil function or scavenge oxygen radicals, can reduce the extent of myocardial injury associated with ischemia reperfusion. The inflammatory reaction of cell injury mediated by neutrophil invasion of the affected tissue is an important site for pharmacologic intervention. Specific adhesive glycoprotein receptors are expressed on the neutrophil in conjunction with corresponding endothelial cell ligands. Recognition of these events has led to the development of specific antibodies having the potential to prevent cell-cell interactions essential for promoting and maintaining the inflammatory response. Therefore, neutrophil-independent extension of irreversible cell death that occurs upon reperfusion, is additive to the component of cell death attributed to the ischemic interval. As is the situation with any organ, function and cellular viability are dependent upon a blood supply, which if interrupted for a sufficiently long period, will lead to irreversible cellular changes and necrosis. Reperfusion is essential for arresting the otherwise progressive injury due to ischemia. The accelerated inflammatory response upon reperfusion contributes to an extension of the injury, a phenomenon known as "reperfusion" or "reoxygenation" injury.

Animals↗
PubMed1995

Limitation of reperfusion injury by a monoclonal antibody to C5a during myocardial infarction in pigs.

The complement system has been implicated in reperfusion injury during acute myocardial infarction. We therefore attempted to reduce reperfusion injury with a monoclonal antibody (MAb) to the complement component, C5a. In 13 control pigs and 9 pigs pretreated with this MAb, ischemia was induced by a 50-min occlusion of the left anterior descending coronary artery, followed by 3 h of reperfusion. Infarct area (as percent of risk area) was reduced from 58 +/- 5% in controls to 38 +/- 7% (P < 0.05) in MAb-treated animals. Heart rate-systolic blood pressure product, left ventricular (LV) first derivative of pressure, LV end-diastolic pressure, and coronary blood flow were similar (P > 0.05) in the two groups. At 15 min of reperfusion, immunoreactive factor Bb began to increase significantly (P < 0.05) in regional coronary venous plasma, consistent with activation of the alternative complement pathway. The anti-C5a MAb did not attenuate formation of the membrane attack complex (C5b-9) as assessed by a hemolytic complement assay. Myocardial myeloperoxidase activity, a marker of tissue neutrophil concentration, was similar in the risk regions of the two groups, suggesting that neutrophil infiltration was unaltered by the MAb. However, in vitro the MAb (15 and 30 micrograms/ml) reduced C5a-stimulated neutrophil aggregation (67.4 and 70.9%), chemotaxis (52.5 and 81.4%), degranulation (66.7 and 75.8%), and superoxide generation (26.7 and 100%). In conclusion, myocardial infarction-reperfusion is associated with activation of the alternative complement pathway. Furthermore, a MAb to C5a that inhibits neutrophil cytotoxic activity, but neither the membrane attack complex nor myocardial neutrophil accumulation, decreases infarct size in pigs. These data suggest an important role of the alternative complement pathway and C5a in the propagation of ischemia cardiac damage during reperfusion.

Animals↗
PubMed1992

Identification of the disulfide bonds in human plasma protein SP-40,40 (apolipoprotein-J).

SP-40,40, a human plasma protein, is a modulator of the membrane attack complex formation of the complement system as well as a subcomponent of high-density lipoproteins. In the present study, the positions of the disulfide bonds in SP-40,40 were determined. SP-40,40 was purified from human seminal plasma by affinity chromatography using an anti-SP-40,40 monoclonal antibody and reversed-phase, high-performance liquid chromatography (HPLC). The protein was digested with trypsin and the fragments were separated by reversed-phase HPLC. The peptides containing disulfide bonds were fluorophotometrically detected with 4-(aminosulfonyl)-7-fluoro-2,1,3-benzoxadiazole (ABD-F). The peptides containing more than two disulfide bonds were further digested with Staphylococcus aureus V8 protease and lysylendopeptidase, and the fragments were isolated by HPLC. The amino acid compositions and the amino acid sequences of the peptides containing only a disulfide bond were determined. Disulfide bonds thus determined were between Cys58(alpha)-Cys107(beta), Cys68(alpha)-Cys99(beta), Cys75(alpha)-Cys94(beta), and Cys86(alpha)-Cys80(beta). Since there was no free sulfhydryl groups in the SP-40,40 molecule, Cys78(alpha) and Cys91(beta) should also be linked by a disulfide bond. It is notable that all of the disulfide bonds in SP-40,40 are not only formed by inter-chain pairing, but also appear to form an antiparallel ladder-like structure between the two chains. The unique structure could be related to the functions of SP-40,40.

Amino Acid Sequence↗
PubMed2006

Inflammation, anti-inflammatory agents and Alzheimer disease: the last 12 years.

Two basic discoveries have spurred research into inflammation as a driving force in the pathology of Alzheimer disease (AD). The first was the identification of activated microglia in association with the lesions. The second was the finding that rheumatoid arthritics were relatively spared from the disease. These findings spurred the first pilot trial of a classical NSAID in the treatment of AD. This trial showed promise for indomethacin as a useful therapeutic agent but appropriate follow up trials have not been done. However, more than 20 epidemiological studies have since been conducted showing a sparing effect for antiinflammatories in AD, including four which specifically addressed the use of classical NSAIDs. Other key findings linking inflammation to AD pathology are the identification of activated complement fragments, including the membrane attack complex, as well as inflammatory cytokines in association with the lesions. In vitro, activated microglia release factors which are toxic to neurons, and these can be partially blocked by NSAIDs. Future directions should include a search for other inflammatory mediators in AD and exploitation of current knowledge to improve available treatments.

Alzheimer Disease↗
PubMed1992

Bullous pemphigoid autoantibodies reactive with intracellular basal keratinocyte antigens: studies of subclass distribution and complement activation.

Using immunofluorescence (IF) and monoclonal antibodies (MoAbs) to IgG subclasses, terminal complement components, and S-protein/vitronectin, we have extended recent observations concerning reactivity of bullous pemphigoid autoantibodies with intracellular antigens located on the polar tips of basal human keratinocytes (HuK). Using three purified bullous pemphigoid IgG fractions, autoantibody reactivity with these intracellular antigens was present in all four IgG subclasses. When skin sections were used as substrate, an identical IgG subclass distribution of autoantibodies for each bullous pemphigoid IgG fraction was observed, but reactive with the basement membrane zone. All three bullous pemphigoid IgG preparations contained IgG subclass autoantibodies capable of complement fixation. Each IgG fraction resulted in fixation of all of the terminal complement components (C5, C6, C7, C8, and C9) and assembly of the membrane attack complex (MAC) on the polar tips of basal HuK. S-protein/vitronectin was not bound in a similar fashion. Normal IgG fractions yielded consistently negative reactions. Thus, bullous pemphigoid autoantibodies, fixed to polar tips of basal HuK, are found in all four IgG subclasses and will activate complement resulting in generation of MAC.

Antibodies, Monoclonal↗
PubMed1994

Recombinant soluble CD59 inhibits reactive haemolysis with complement.

Three soluble forms of membrane attack complex inhibitory factor (MACIF or CD59) were prepared using recombinant baculovirus-infected insect cells. They consisted of 70, 77 and 86 amino acids, starting from the amino terminus of naturally occurring CD59, and were designated recombinant (r) CD59 70, 77 and 86, respectively. All three rCD59 lacked a glycosyl-phosphatidylinositol (GPI) anchor, unlike membrane CD59 which has a GPI anchor at the anchor at the carboxyl terminus (77th amino acid). Their activities in inhibiting complement activation were assayed with C5b-7 intermediate cells and C8 and C9 components. The inhibitory activity of rCD59 70 was as high as that of rCD59 77 and twice that of rCD59 86. In addition, it was one-fourth and one-hundredth lower than the activities of urine and erythrocyte CD59, respectively. However, when assayed in the presence of human serum at a final concentration of 50% (v/v), the activities of both urine and erythrocyte CD59 were greatly decreased to to one-tenth of that of rCD59 70. Purified rCD59 70 molecules were all glycosylated, but rCD59 77 and 86 were mixtures of glycosylated and non-glycosylated molecules. The inhibitory activities of rCD59 77 and 86 were the same for the glycosylated and non-glycosylated forms. These results suggest that the soluble rCD59 provide a means for elucidating the biological roles of CD59.

Amino Acid Sequence↗
PubMed1995

The influence of tumour necrosis factor-alpha, interleukin-1 beta and interferon-gamma on the expression and function of the complement regulatory protein CD59 on the human colonic adenocarcinoma cell line HT29.

CD59 is a 18-25 kDa glycoprotein which, by inhibiting the formation of the membrane attack complex, protects homologous cells from complement mediated damage. We have described recently the expression and complement regulatory function of CD59 on colonic adenocarcinoma cells both in vivo and in vitro. In this study we have examined the influence of cytokines on the expression and complement regulatory function of CD59 on the colonic adenocarcinoma cell line HT29. CD59 expression on the HT29 cells was up-regulated after stimulation by mononuclear cells activated by mixed lymphocyte reaction and by culture supernatants from activated mononuclear cells. Similarly, a dose-dependent increase in CD59 expression was observed after stimulation with both tumour necrosis factor-alpha and interleukin-1 beta. A dose-dependent increase in the level of CD59 expression was also seen using low concentrations of interferon-gamma (IFN-gamma), while CD59 expression on cells cultured with high IFN-gamma concentrations was comparable to non-stimulated cells. Cytokine treated cells were more resistant to lysis by homologous complement than non-stimulated cells, and the increase in CD59 expression was shown to be partially responsible for this. The present data strengthen the role of CD59 as a possible participant in tumour escape.

Adenocarcinoma↗
PubMed1995

Chimeras of human complement C9 reveal the site recognized by complement regulatory protein CD59.

CD59 antigen is a membrane glycoprotein that inhibits the activity of the C9 component of the C5b-9 membrane attack complex, thereby protecting human cells from lysis by human complement. The complement-inhibitory activity of CD59 is species-selective and is most effective toward C9 derived from human or other primate plasma. By contrast, rabbit C9, which can substitute for human C9 in the membrane attack complex, mediates unrestricted lysis of human cells. To identify the peptide segment of human C9 that is recognized by CD59, rabbit C9 cDNA clones were isolated, characterized, and used to construct hybrid cDNAs for expression of full-length human/rabbit C9 chimeras in COS-7 cells. All resulting chimeras were hemolytically active, when tested against chicken erythrocytes bearing C5b-8 complexes. Assays performed in the presence or absence of CD59 revealed that this inhibitor reduced the hemolytic activity of those chimeras containing human C9 sequence between residues 334-415, irrespective of whether the remainder of the protein contained human or rabbit sequence. By contrast, when this segment of C9 contained rabbit sequence, lytic activity was unaffected by CD59. These data establish that human C9 residues 334-415 contain the site recognized by CD59, and they suggest that sequence variability within this segment of C9 is responsible for the observed species-selective inhibitory activity of CD59.

Amino Acid Sequence↗
PubMed1997

A mechanism of acquired resistance to complement-mediated lysis by Entamoeba histolytica.

Some Entamoeba histolytica strains resist complement-mediated lysis by serum. Susceptible and resistant strains activate the complement system equivalently, but resistant amebas evade killing by membrane attack complexes. Our objective was to determine the mechanism by which trophozoites of E. histolytica resist lysis by human serum. Amebas were made resistant to lysis by incubation with increasing concentrations of normal human serum. The possibility that resistant cells ingest membrane attack complexes was explored by subcellular fractionation of susceptible and resistant trophozoites treated with sublytic concentrations of human serum containing radiolabeled C9. In both cases, most of the label was in the fractions containing plasma membrane. The susceptible strain consistently showed more label associated with these fractions than the resistant strain. Thus, the possibility that the membrane attack complexes were released to the medium was explored. Both resistant and susceptible trophozoites release to the medium similar amounts of material excluded by Sepharose CL-2B in the presence or absence of normal human serum. Labeled C9 elutes together with the main bulk of proteins from the medium: this indicates that it is not in vesicles or high molecular weight aggregates. Coincubation of susceptible amebas with lysates of resistant trophozoites confers resistance to susceptible cells within 30 min. Resistance to lysis by serum can also be acquired by susceptible amebas after coincubation with lysates from human erythrocytes or after feeding them with whole human red blood cells. Resistant but not susceptible trophozoites show intense immunofluorescent staining on their surface with anti-human erythrocytic membrane antibody. These results suggest that amebas acquire resistance to lysis by serum by incorporating into their membranes complement regulatory proteins.

Animals↗
PubMed1995

The contribution of terminal complement components to acute and hyperacute allograft rejection in the rat.

Acute rejection and antibody-mediated hyperacute allograft rejection are affected by activation of the complement cascade. Split products of early complement components influence the localization, activation, and effector functions of platelets, granulocytes, monocytes, and lymphocytes, while the formation of membrane attack complex (C5b-C9) can lead to rapid cell destruction. Therefore, we compared acute and Ab-mediated hyperacute allograft rejection in a recently described model of C6 deficient PVG (C-) (RT1c) rats and their normal counterpart PVG (C+) (RT1c) rats. Cardiac allografts from fully MHC disparate ACI donors were heterotopically grafted into naive and skin graft sensitized PVG (C-) and PVG (C+) rats. ACI cardiac allografts were rejected acutely (8.3 +/- 2 days; n = 7) by naive PVG (C+) recipients, but survived significantly longer in PVG (C-) recipients (22 +/- 10 days; n = 10). Presensitized PVG (C+) rats rejected ACI cardiac allografts hyperacutely in 6.1 +/- 2.4 hr (n = 5). In contrast, ACI cardiac allografts transplanted into presensitized (PVG (C-) rats had markedly longer survival of 91 +/- 14 hr (n = 5). The alloantibody responses of naive PVG (C+) and PVG (C-) recipients 7 days after cardiac allografting, and of presensitized PVG (C+) and PVG (C-) recipients at time of cardiac allografting were not significantly different as measured by flow cytometry against ACI lymphocytes. Immunofluorescence demonstrated deposition of IgM, IgG and C3 in ACI allografts in PVG (C-) as well as in PVG (C+) recipients. Deposition of C6 was only found in grafts rejected by PVG (C+). The significantly longer survival of ACI cardiac allografts in C6-deficient PVG (C-) rats indicates that the membrane attack complex contributes to acute as well as antibody-mediated hyperacute allograft rejection.

Acute Disease↗
PubMed1982

Terminal membrane C5b-9 complex of human complement: transition from an amphiphilic to a hydrophilic state through binding of the S protein from serum.

The membrane-damaging C5b-9(m) complex of complement is a cylindrically structured, amphiphilic molecule that is generated on a target membrane during complement attack. Isolated C5b-9(m) complexes are shown here to possess the capacity of binding a protein, termed "S"-protein, that is present in human plasma. Binding of this protein apparently shields the apolar surfaces of C5b-9(m), since the resulting "SC5b-9(m)" complex is hydrophilic and no longer aggregates in detergentfree solution. Dispersed SC5b-9(m) complexes exhibit an apparent sedimentation coefficient of 29S in sucrose density gradients, corresponding to a molecular weight of approximately 1.4 million. SDS PAGE analyses indicate binding of 3-4 molecules of S-protein per C5b-9(m) complex. These data are consistent with a monomer nature and molecular weight of 1-1.1 million of the C5b-9(m) complex. Ultrastructural analysis of SC5b-9(m) shows preservation of the hollow cylindrical C5b-9(m) structure. Additional material, probably representing the S-protein itself, can be visualized attached to the originally membrane-embedded portion of the macromolecule. The topography of apolar surfaces on a molecule thus appears directly probed and visualized through the binding of a serum protein.

Complement System Proteins↗
PubMed1989

Peripheral nerve vasculitis: immune characterization of the vascular lesions.

Quantitative immunohistochemical analyses were performed on 22 nerve biopsy specimens from patients with systemic vasculitis (n = 14) or isolated vasculitis of peripheral nerve (n = 8). In the vascular lesions the cellular infiltrates were composed primarily of T cells (71 +/- 18%; mean +/- SD) and macrophages (27 +/- 17%), and the majority of the T cells (65 +/- 20%) were cytotoxic/suppressor CD8 cells. B cells were seen in only 4 cases and constituted less than 2% of all cells. Natural killer cells and polymorphonuclear leukocytes were rare, and a leukocytoclastic response was not observed. Fourteen biopsy specimens had vascular deposits of immunoglobulins G and M and complement components C3 and C5b-9 membrane attack complex, while 4 had only the latter. The fact that the immunoglobulin and complement deposits were seen only in vessels that had corresponding intense cellular infiltrates suggests an important, but perhaps not primary, role for immune complexes in causing the vascular lesions. Statistical analysis revealed striking similarities in the lesions of patients with isolated nerve vasculitis and those with systemic vasculitides, suggesting a common pathogenic mechanism. Collectively, our observations suggest an important role for a T-cell-dependent cell-mediated process as a primary mechanism of vessel injury in peripheral nerve vasculitis.

Biopsy↗
PubMed1993

Acute renal failure and degenerative tubular lesions associated with in situ formation of adenovirus immune complexes in a patient with allogeneic bone marrow transplantation.

We describe the development of acute renal failure and degenerative tubular lesions associated with local immune deposits in a patient with allogeneic bone marrow transplantation. A 21-year-old man with an acute myelocytic leukemia received a bone marrow graft from a cousin mismatched for a single HLA-DR locus antigen. Hemorrhagic cystitis due to adenovirus type 11 infection occurred 26 days after transplantation, and 17 days later the patients developed acute renal failure. A study of renal tissue obtained by needle biopsy showed degenerative and necrotic lesions, especially in the distal part of the nephron. By electron microscopy adenovirus type 11 particles were found in the nuclei of tubular cells and in cellular debris in tubular lumina. By immunofluorescence technique, granular immune deposits containing adenovirus type 11 related antigen(s), immunoglobulins, C3, and membrane attack complex (MAC) C5b-9 of the complement system were detected along the tubular basement membranes but not in glomeruli. The patient's IgG did not bind to normal human kidneys. These findings suggest that adenovirus type 11 directly induced acute tubular damage, and that the tubular immune deposits were formed "in situ" by viral antigens and circulating viral antibody.

Acute Kidney Injury↗
PubMedDate not supplied

Sulfonated dextran inhibits complement activation and complement-dependent cytotoxicity in an in vitro model of hyperacute xenograft rejection.

In the present study, we demonstrate that a substituted soluble dextran derivative bearing 73% carboxylic groups and 15% benzylamide sulfonate groups, termed CMDBS25, inhibits complement activation and complement-mediated damage in an in vitro model of xenogeneic rejection. Incubation of porcine aortic endothelial cells with normal human serum resulted in time-dependent complement consumption as assessed by C3a generation in the fluid phase and deposition of activated complement fragments C3, C5 and of C5b-9 on target cells. The presence of C5b-9 membrane attack complex was associated with 51Cr release from prelabelled endothelial cells. The addition of 5-25 mg of CMDBS25/ml under the experimental conditions used, inhibited complement activation and C3a generation in a dose-dependent fashion. CMDBS25 (25 mg/ml) totally suppressed iC3b, C5 and C5b-9 cytolytic complex deposition on cells and inhibits by 42% lysis of target endothelial cells. Native dextran had no effect. Our observations document the anti-complementary properties of sulfonated dextran derivatives and their potential as therapeutic agents for the prevention of complement-dependent hyperacute xenograft rejection.

Animals↗
PubMed1986

Activation of complement by myelin: identification of C1-binding proteins of human myelin from central nervous tissue.

Myelin isolated from central nervous tissue activates the classic pathway of complement by directly activating C1. Activation of C1 can proceed to form membrane attack complex, C5b-9, in the myelin. Such an interaction between myelin and complement may be important in diseases involving myelin damage, in view of the role of complement in membrane attack and inflammation. To identify the C1-activating protein, myelin was subjected to sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and Western blot. The blots were incubated with C1 or with whole serum complement, followed by immunostaining for C1 or C3, respectively. A duplicate strip was stained with amido black or anti-myelin antibody to visualize the myelin proteins. The results showed that two major protein bands were capable of activating C1. An approximately 56-58-kilodalton band comigrated with the W2 protein and an approximately 45-47-kilodalton band migrated along with, but slightly behind, the W1 Wolfgram doublet.

Complement Activating Enzymes↗
PubMed2004

The membrane attack complex, C5b-9, up regulates collagen gene expression in renal tubular epithelial cells.

Evidence suggesting a direct role for proteinuria in the pathogenesis of renal tubulointerstitial fibrosis is accumulating. However the mechanism by which proteinuria leads to injury is unknown. In proteinuric states complement proteins are filtered through the glomerulus and could contribute to the tubular damage. The aim of this study was to investigate the role of complement activation in the progression of interstitial fibrosis. To determine whether complement activation may be responsible for the pro-fibrotic response that occurs in the tubulointerstitial compartment we stimulated primary cultures of proximal tubular epithelial cells with membrane attack complex, C5b-9. This led to increased mRNA concentrations of both collagen type IV and its intracellular chaperone, Heat Shock Protein 47 (HSP47). To determine whether this occurred in vivo Adriamycin was used to induce proteinuria in female Balb/c mice. The expression of collagen type IV and HSP47 was increased in proteinuric mice compared to control mice. In proteinuric mouse kidney, C3 was deposited at sites of tubulointerstitial injury and there was a relationship between C3 deposition and immunochemical staining for collagen type IV and HSP47. In situ hybridization suggested that the renal tubular epithelium was actively expressing HSP47 mRNA and, by implication, excess collagen. These observations support the hypothesis that complement activation on tubular epithelial cells can directly increase the pro-fibrotic process associated with tubulointerstitial damage.

Albuminuria↗
PubMedDate not supplied

Complement resistance of tumor cells: basal and induced mechanisms.

Clinical and experimental studies have suggested that complement may play a role in tumor cytotoxicity. However, the efficiency of complement-mediated tumor cell lysis is hampered by various protective mechanisms, which may be divided into two categories: basal and induced mechanisms. The basal mechanisms are spontaneously expressed in cells without a need for prior activation, whereas the induced mechanisms develop in cells subjected to stimulation with cytokines, hormones, drugs or with sublytic doses of complement and other pore-formers. Membrane-associated complement regulatory proteins, such as CD55 (DAF, Decay-Accelerating Factor), CD46 (MCP, Membrane Cofactor Protein), CD35 (CR1, Complement Receptor type 1) and CD59, which serve as an important mechanism of self protection and render autologous cells insensitive to the action of complement. appear to be over-expressed on certain tumors. Furthermore, tumor cells secrete several soluble complement inhibitors. Tumor cells may also express proteases that degrade complement proteins, such as C3, or ecto-protein kinases which can phosphorylate complement components, such as C9. Besides this basal resistance, nucleated cells resist, to some extent, complement damage by removing the membrane attack complexes (MAC) from their surface. Several biochemical pathways, including protein phosphorylation, activation of G-proteins and turnover of phosphoinositides have been implicated in resistance to complement. Calcium ion influx and activation of protein kinase C (PKC) and of mitogen-activated protein kinase (MAPK) have also been demonstrated to be associated with the complement-induced enhanced resistance to lysis. The complete elucidation of the molecular mechanisms involved in basal and induced tumor cell resistance will enable the development of strategies for interfering with these evasion mechanisms and the use of the cytotoxic complement system against tumor cells.

Animals↗