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PubMed2005

The role of c5b-9 terminal complement complex in activation of the cell cycle and transcription.

Activation of the complement system plays an important role in innate and acquired immunity. Activation of complement and subsequent formation of C5b-9 channels on the surface of cellular membranes leads to cell lysis. When the number of channels assembled on the surface of nucleated cells is limited, C5b-9 does not cause lysis, but instead can induce cell-cycle progression by activating signal transduction pathways, transcription factors, and key components of the cell-cycle machinery. Cell-cycle induction by C5b-9 is dependent on the activation of phosphatidylinositol 3-kinase and the ERK1 pathway in a Gi protein-dependent manner. Cell-cycle activation is regulated, in part, by activation of proto-oncogene c-jun and AP1 DNA binding activity. C5b-9 induces sequential activation of CDK4 and CDK2, leading to G1/S-phase transition and cellular proliferation. RGC-32 is a novel gene whose expression is induced by C5b-9. RGC-32 may play a key role in cell-cycle activation by increasing cyclin B1-CDC2 activity. C5b-9-mediated cell-cycle activation plays an important role in cellular proliferation and protection from apoptosis.

Animals↗
PubMed1997

The immunofluorescent profile of dermatomyositis: a comparative study with lupus erythematosus.

We have demonstrated a role for microvascular injury mediated by the membrane attack complex of complement (C5b-9) in the genesis of cutaneous lesions of dermatomyositis (DM) (1). The purpose of this study is to revisit the immunofluorescent (IF) profile of DM, to further investigate the role of C5b-9 in the pathogenesis of cutaneous lesions, and to see if any features of the IF profile reliably distinguish DM from LE. Lesional skin biopsies from 24 patients with clinical findings characteristic of DM were received in formalin and in Michel's transport medium. Conventional light microscopy, and IF studies with antibodies monospecific for IgG, IgA, IgM, C3, fibrin and C5b-9 were performed. The control group comprised biopsies from 31 patients with well-documented LE. A positive lupus band test (LBT) correlated highly with a diagnosis of LE, with a sensitivity of 64.5% and a specificity of 95.6% (p=0.001). The LBT was most sensitive in the setting of DLE and SLE and was least sensitive in the setting of SCLE. The finding of vascular C5b-9 deposition correlated with a diagnosis of DM versus LE (p=0.001) although the false positive rate was 21.4%. The false negative rate was reduced when vascular C5b-9 was seen in the absence of antibodies to Ro, La, or RNP. While a negative LBT correlated with a diagnosis of DM (p=0.001), the specificity was only 64.5%. However, when it was seen in concert with C5b-9 along the DEJ, specificity was increased to 80.6% (p=0.001). The presence of C5b-9 in vessels and along the DEJ in concert with a negative LBT was predictive of DM (p=0.001) with a specificity of 93.5%, sensitivity of 78.3%, a false positive rate of 10% and a false negative rate of 14.7%. The combination of a negative LBT, vascular C5b-9 deposition and negative serology for Ro, La, and RNP was a predictor of DM versus LE with a sensitivity of 90.5%, a specificity of 96.8%, a false positive rate of 5% and a false negative rate of 6.2% (p=0.001). The IF profile of DM in lesional skin comprises a negative LBT, deposition of C5b-9 within vessels and along the DEJ, and variable keratinocyte decoration for IgG and C5b-9. The most statistically powerful predictor of DM is the combination of a negative LBT with vascular C5b-9 deposition and negative serology for antibodies to Ro, La, Sm, and RNP. Demonstration of a negative LBT in all but 1 case of DM suggests that the DEJ is not a primary site for antigen-antibody interaction. We postulate that the aforementioned IF findings reflect humorally mediated injury of endothelium and keratinocytes, effected by C5b-9.

Adult↗
PubMed1993

Molecular mechanisms of invasion by Entamoeba histolytica.

Amebiasis is the third leading cause of death due to parasitic disease. Adherence to and contact-dependent killing of host cells requires the galactose-inhibitable lectin, a heterodimeric glycoprotein composed of heavy and light subunits. The cysteine-rich extracellular domain of the heavy subunit has identity with beta 1 integrins, complement receptor CD59, and complement components C8 and C9; the light subunit sequence is unlike any other sequenced protein. Monoclonal antibodies to the cysteine-rich domain identify pathogenic-specific domains, have adherence-inhibitory and -enhancing properties, block contact-dependent cytotoxicity, and abrogate complement C5b-9 resistance. The purified lectin has galactose-binding activity and confers C5b-9 resistance to susceptible amebae. The accumulated evidence points to the same cell surface galactose-inhibitable lectin as a mediator of two activities required for invasion: adherence and complement resistance.

Animals↗
PubMed2002

Herpes simplex virus 1 infected neuronal and skin cells differ in their susceptibility to complement attack.

Herpes simplex virus type 1 (HSV-1) infection in neurons is lifelong and generally asymptomatic. Reactivation of this latent infection results in skin blistering whereas the respective peripheral neurons are rarely affected. Why the neuronal cells are spared while the skin cells are sacrificed is not well understood. In the present study our aim was to study whether neuronal and skin cells differ in their ability to control complement attack during HSV-1 infection. Human embryonal skin (HES) cells and neuronal Paju cells were infected by HSV-1 in vitro. Both types of infected cells activated complement but were initially resistant to membrane attack complex (MAC) deposition. During the first hours of infection the expression of the endogenous complement regulators decay accelerating factor (DAF) and CD59 increased on both HES and Paju cells. By 12 hr the infected HES cells had lost their ability to control complement attack. The expression of DAF and CD59 decreased and the cells became targets for MAC attack. In contrast, complement regulator expression on the Paju cells did not decrease below the initial level and complement C5b-9 deposition was found only on 10% of the Paju cells at 12 hr. The results suggest that HSV-infected neuronal cells are better than skin cells in protecting themselves against complement attack. This may contribute to the persistence of a latent HSV-1 infection in neuronal cells for prolonged periods.

CD55 Antigens↗
PubMed1986

Synthesis of complement components C5, C6, C7, C8 and C9 in vitro by human monocytes and assembly of the terminal complement complex.

Monocytes cultured under serum-free conditions secreted protein which bound covalently and non-covalently to agarose beads, an activator of the alternative pathway of complement. There was a significantly binding of monoclonal anti-C3c antibodies, polyclonal anti-C5, anti-C6, anti-C7, anti-C8, and anti-C9 antibodies, and of a monoclonal antibody against a neoantigen of polymerized C9 to agarose beads incubated with the monocytes for 24, 48, 72 or 96 h. From these results, we conclude that monocytes produce C5, C6, C7, C8 and C9 that assemble as the terminal complement complex on the surface of the agarose beads. Activation by agarose of the alternative pathway with generation of particle bound C3 and C5 convertases is a prerequisite for the subsequent formation of the terminal complement complex. Whether SC5b-9 or the membrane attack of complement (C5b-9) is formed on the beads will be examined.

Antibodies, Monoclonal↗
PubMed2002

Complement activates the c-Jun N-terminal kinase/stress-activated protein kinase in glomerular epithelial cells.

In the rat passive Heymann nephritis model of membranous nephropathy, complement C5b-9 induces sublethal glomerular epithelial cell (GEC) injury and proteinuria. C5b-9 activates cytosolic phospholipase A(2) (cPLA(2)), and products of cPLA(2)-mediated phospholipid hydrolysis modulate GEC injury and proteinuria. In the present study, we demonstrate that C5b-9 activates c-Jun N-terminal kinase (JNK) in cultured rat GECs and that JNK activity is increased in glomeruli isolated from proteinuric rats with passive Heymann nephritis, as compared with control rats. Stable overexpression of cPLA(2) in GECs amplified complement-induced release of arachidonic acid (AA) and JNK activity, as compared with neo (control) GECs. Activation of JNK was not affected by indomethacin. Incubation of GECs with complement stimulated production of superoxide, and pretreatment with the antioxidants, N-acetylcysteine, glutathione, and alpha-tocopherol as well as with diphenylene iodonium, an inhibitor of the NADPH oxidase, inhibited complement-induced JNK activation. Conversely, H(2)O(2) activated JNK, whereas exogenously added AA stimulated both superoxide production and JNK activity. Overexpression of a dominant-inhibitory JNK mutant or treatment with diphenylene iodonium exacerbated complement-dependent GEC injury. Thus, activation of cPLA(2) and release of AA facilitate complement-induced JNK activation. AA may activate the NADPH oxidase, leading to production of reactive oxygen species, which in turn mediate the activation of JNK. The functional role of JNK activation is to limit or protect GECs from complement attack.

Animals↗
PubMed1991

Detection of the membrane inhibitor of reactive lysis (CD59) in diseased neurons of Alzheimer brain.

The membrane inhibitor of reactive lysis (MIRL) protects host cells from complement-mediated lysis. It was detected immunohistochemically in tangled neurons and dystrophic neurites of Alzheimer disease (AD) tissue in a pattern highly similar to that observed for the membrane attack complex of complement, C5b-9. MIRL was also detected in cultured IMR-32 neuroblastoma cells. The mRNA for MIRL was detected in RNA extracts of both AD and normal brain. These data provide the first evidence of brain neuronal expression of MIRL and its upregulation in neurons exposed to complement attack. They are consistent with the previously advanced hypothesis that complement-mediated neuronal injury may play a role in AD.

Alzheimer Disease↗
PubMed1989

Inhibition of acute passive transfer experimental autoimmune myasthenia gravis with Fab antibody to complement C6.

The role of the lytic complement C5b-9 membrane attack complex (MAC) in acute passive transfer experimental autoimmune myasthenia gravis (EAMG) produced in rats was investigated by in vivo inhibition of MAC formation with anti-C6 Fab. Anti-C6 Fab totally inhibited in vitro serum hemolytic activity, but did not consume or inhibit early complement pathways. Injection of rats with 0.12 mg/ml anti-C6 Fab reduced serum C6 to 8% and inhibited the muscle weakness, electrophysiologic abnormalities and loss of acetylcholine receptor (AChR) associated with acute EAMG. This level of C6 inhibition reduced the total serum complement hemolytic activity to 29% of normal but did not reduce the serum levels of complement components C3, C5, or C7. Treatment of rats with lower amounts of anti-C6 Fab (0.08 mg/ml) also inhibited clinical and electrophysiologic signs of EAMG, however, the lower amount of anti-C6 did not prevent the loss of muscle AChR. Both the higher and the lower amount of anti-C6 Fab inhibited the accumulation of macrophages at muscle motor end-plates. The inhibition by anti-C6 indicates that muscle weakness and electrophysiologic abnormalities associated with EAMG are dependent on the complement MAC, and that muscle weakness results from tissue injury in addition to loss of muscle membrane and AChR.

Animals↗
PubMed1985

The membrane attack complex of complement: lipid insertion of tubular and nontubular polymerized C9.

The membrane-restricted photoactivatable carbene generator 3-(trifluoromethyl)-3-(m-[125I]-iodophenyl)diazirine [Brunner, J., & Semenza, G. (1981) Biochemistry 20, 7174-7182] was used to label the subunits of the membrane attack complex of complement (C5b-9). C5b-9 complexes either were assembled from serum on erythrocyte membranes or were reconstituted from purified components on liposomes. After irradiation, most of the probe is bound to C9 independent of the membrane system used, indicating that the wall of the transmembrane channel is predominantly composed of C9. No difference was observed whether polymerized C9 was in the tubular or nontubular form [Podack, E. R., & Tschopp, J. (1983) J. Biol. Chem. 257, 15204-15212], showing that tubule closure is not essential for successful lipid insertion. The same label distribution between the two forms of polymerized C9 was obtained by analyzing zinc-polymerized C9 in the absence of C5b-8. Since the photoreactive probe reacted with at least two distinct polypeptide segments within C9, lipid interaction does not occur via a single segment of hydrophobic amino acids.

Animals↗
PubMedDate not supplied

Cellular and molecular biology of membranous nephropathy.

There have been dramatic increases in the understanding of the molecular mechanisms involved in membranous nephropathy (MN) over the past 2 decades. Most of these have come directly from studies carried out in the Heymann nephritis models of MN in rats, which closely simulate the clinical and pathologic features of the human disease. Once considered a prototypical example of circulating immune complex trapping in glomeruli, we now recognize that MN develops, in both the rat and man, consequent to an autoimmune process involving antibodies directed to antigens on the foot processes of podocytes that form subepithelial immune deposits. Proteinuria is a consequence of sublytic complement C5b-9 attack on podocytes. The podocyte response to sublytic C5b-9 includes up-regulated expression of genes for production of oxidants, proteases, prostanoids, growth factors, CTGF, transforming growth factor (TGF) and TGF receptors leading to overproduction of extracellular matrix components that result in 'spike' formations. Other podocyte changes including detachment, apoptosis and alterations in cell cycle regulatory proteins favoring hypertrophy over proliferation also contribute to proteinuria and to development of glomerular sclerosis. Finally, progression of chronic proteinuric MN to chronic kidney disease (CKD) and renal failure likely results in part from additional effects of sublytic C5b-9 on proximal tubular epithelial cells, resulting in interstitial inflammation and fibrosis with a fall in glomerular filtration rate (GFR). Expanded understanding of the molecular pathophysiology of MN has important implications for monitoring disease activity, predicting disease course and designing new approaches to therapy for this common glomerular disease.

Animals↗
PubMed1988

The C8-binding protein of human erythrocytes: interaction with the components of the complement-attack phase.

C8-binding protein is an intrinsic membrane protein of the human erythrocyte. It inhibits the complement (C5b-9)-mediated lysis in a species-restricting manner. In the present study we incorporated C8bp, isolated from human erythrocytes, into sheep erythrocytes (SRBC). SRBC, normally sensitive to lysis by human C5b-9, became insensitive to lysis. Furthermore, we found that C8bp is incorporated into the membrane-attack complex C5b-9, most probably by interacting with C8, since C8bp has an affinity for C8, particularly for the C8 alpha-gamma-subunit. Antibodies to C8bp react with the C8 alpha-subunits and with C9, pointing to the possibility of a partial homology between these proteins.

Animals↗
PubMed1998

X-linked vacuolated myopathy: membrane attack complex deposition on the surface membrane of injured muscle fibers is not accompanied by S-protein.

We have studied the expression of S-protein on the muscle from patients with X-linked vacuolated myopathy [characterized by the deposition of the complement C5b-9 membrane attack complex (MAC) over abnormal muscle fibers] and controls by immunocytochemistry and immunoblotting. No expression was detected on muscle from controls and patients with X-linked vacuolated myopathy. These findings suggest that S-protein does not render the MAC inactive in X-linked vacuolated myopathy. This situation may be due to the fact that the pathways of MAC activation and the expression of S-protein in X-linked vacuolated myopathy are different from the ones observed in ischemic and/or necrotic, or immune diseases. These results emphasize the role of the membrane complement regulatory proteins (i.e., CD59) in X-linked vacuolated myopathy.

Adult↗
PubMed1998

Temporal induction of clusterin in the peri-infarct zone after experimental myocardial infarction in the rat.

Clusterin, a glycoprotein with potent cellular cohesive properties, is induced in many organs at times of tissue injury or remodeling. After renal infarction, for example, clusterin is localized to tubular epithelial cells in the peri-infarct zone. The purpose of this study was to examine the spatial and temporal expression of cardiac clusterin after myocardial infarction. Sprague-Dawley rats underwent permanent coronary ligation or sham operation. Hearts were harvested at 6 hours and at 2, 14, and 28 days after infarction. Cardiac clusterin expression was examined by immunohistochemistry and in situ hybridization. Left ventricular clusterin staining was evident at 6 hours and 2 days after myocardial infarction, although not at later time periods. Clusterin was localized to peri-infarct zone myocytes and endothelial cells of this region, and local synthesis of clusterin by myocytes was confirmed by in situ hybridization. Clusterin was not present in inflammatory cells or in left ventricular tissue distant from the infarct. The distribution of clusterin was different from the membrane attack complex of complement (C5b-9), with the latter being present diffusely throughout the infarct zone. Although the role of cardiac clusterin is not known, we speculate that clusterin's cohesive properties serve to promote myocyte interactions that are perturbed in the peri-infarct zone after myocardial infarction.

Animals↗
PubMed1997

Mixed connective tissue disease. A clinical, histologic, and immunofluorescence study of eight cases.

A study of the cutaneous eruptions of eight patients with mixed connective tissue disease (MCTD) was performed to better characterize its dermatopathology and to explore a role for the membrane attack complex of complement C5b-9 in lesional pathogenesis. Nine lesional skin biopsies were obtained from eight patients with MCTD and analyzed by conventional light microscopy. Direct immunofluorescence (IF) and indirect IF using a monoclonal antibody to C5b-9 were applied in six and five cases respectively. The biopsied cutaneous eruptions were characterized clinically as photo-distributed erythematosus annular and/or papulosquamous lesions mimnicking subacute cutaneous lupus erythematosus (SCLE) in five of eight patients as an ill-defined, telangiectatic, scaly patch on the face in one patient, palpable purpura in one patient, and dorsal hand blisters resembling porphyria cutanea tarda (PCT) in another. With the exception of the latter two patients, the histology appeared similar, comprising a cell poor and/or lichenoid interface dermatitis with suprabasilar exocytosis around necrotic keratinocytes in the absence of deep periadnexal or perivascular extension or conspicuous follicular plugging, a pattern similar to that of SCLE. However, the lesions differed from SCLE by virtue of vasculopathic alterations comprising vascular ectasia, hypovascularity, and/or luminal thrombosis confined to the superficial vascular plexus and a sclerodermoid tissue reaction, the latter seen in two cases. One biopsy showed a pustular leukocytoclastic vasculitis (LCV). In another case, a biopsied hand blister demonstrated a PCT-like appearance histologically, namely, pauci-inflammatory subepithelial blister formation with hyalinization of dermal papillae capillaries accompanied by an LCV. There was nuclear keratinocyte decoration with IgG and C5b-9 in all cases studied, accompanied by a positive lupus band test in two cases and homogenous deposition of immunoreactants along the dermoepidermal junction and within vessels in the PCT-like eruption. Granular vascular decoration with immunoreactants including C5b-9 was seen in two LCV cases and in two biopsies from rashes clinically mimicking SCLE. Although the epidermal pathology of MCTD mimicks that of SCLE, a concomitant vasculopathy paralleling that seen in skin lesions of dermatomyositis distinquishes the dermatopathology of MCTD from that of SCLE. Corroborating the role of microangiopathy in the pathogenesis of the skin lesions of MCTD was the demonstration of C5b-9 in blood vessels. The deposition of C5b-9 in keratinocytes may explain the pattern Of IgG decoration of keratinocytes; the formation of plasmalemmal pores may permit binding of immunoglobulin to antigens in the nucleus and/or cytosol. The C 5b-9 complex may be the effector mechanism of epithelial and/or endothelial cell injury in MCTD or may serve to augment the effects of antibody-dependent cellular cytotoxicity.

Adult↗
PubMed2005

Both apoptosis and complement membrane attack complex deposition are major features of murine acute graft-vs.-host disease.

The parent-into-F1 mouse model (P-->F1) of acute graft-vs.-host disease (GVHD) is a useful model of human acute GVHD because it allows the study of the T cell contribution to pathology without the complicating effects of conditioning regimens. To determine the similarity of this model to human GVHD, we assessed injury in organs typically involved in human acute GVHD (skin, liver) and less typically involved organs (spleen, kidney, lung). Mice were assessed histologically at early (2 weeks), intermediate (3 months) and late (6 month) time points. Based on the emerging roles of Fas ligand killing and complement deposition in allograft rejection, we correlated the amount of tissue specific TUNEL positive apoptosis and deposition of complement (C5b-9) with histopathologic changes. Our results indicate a striking similarity histologically between acute GVHD occurring in this model and in humans following bone marrow transplant. Moreover, C5b-9 deposition and apoptotic cell accumulation were found to parallel tissue injury in major organs of acute GVHD mice, although not all organs exhibited the same kinetic pattern. These results indicate a role for both adaptive immunity and innate immunity in this model of GVHD and support its use in modeling human acute GVHD in the nonmyeloablative setting.

Animals↗
PubMed1986

Activated terminal complement in cerebrospinal fluid in Guillain-Barré syndrome and multiple sclerosis.

A quantitative enzyme-linked immunosorbent assay was used to measure the concentration of fluid-phase complement C5b-9 complexes (SC5b-9) in the cerebrospinal fluid (CSF) of 14 patients with acute monophasic Guillain-Barré Syndrome (GBS), 21 patients with multiple sclerosis (MS), and 11 patients with noninflammatory central nervous system (CNS) diseases. SC5b-9 complexes were detected in the CSF of 13 of 14 patients with acute GBS (mean, 3.08 micrograms/ml; range, 0 to 7.1 micrograms/ml) and 16 of 21 patients with MS (mean, 1.83 micrograms/ml; range, 0 to 7.5 micrograms/ml). In the control group of patients with noninflammatory CNS diseases, SC5b-9 was not detected in eight of 11 and was present in low concentrations in the remaining three patients (mean, 0.28 micrograms/ml; range, 0 to 1.7 micrograms/ml). The finding of SC5b-9 complexes in the CSF of patients with GBS and MS suggests that terminal complement components may participate in the tissue-damaging processes in these diseases.

Complement Activation↗
PubMed1998

Plasma cytokine levels and coagulation and complement activation during use of the extracorporeal liver assist device in acute liver failure.

Multiple organ failure frequently occurs in patients with acute liver failure, and this has been associated with increased cytokine production. Treatment by hemoperfusion with an extracorporeal liver assist device (ELAD) containing human liver-derived cells was performed in 12 patients with acute liver failure. Over the first 6 h, there were significant increases in plasma tumor necrosis factor alpha (TNFalpha; from 114+/-54 pg/ml [mean+/-SEM] to 236+/-161 pg/ml, p < 0.05) and interleukin (IL)-6 (260+/-121 pg/ml to 445+/-149 pg/ml, p < 0.05) but not in interferon gamma (IFNgamma). A similar pattern with a small peak increase was observed for complement C5b-9 complex. Plasma C-reactive protein (CRP) and thrombin antithrombin (TAT) III complex showed small peaks after 24 h of ELAD hemoperfusion. No such changes were seen in 12 control patients with acute liver failure who were treated with intensive care alone. These transitory effects, without changes in blood pressure, are likely to be due to the contact of the blood with the dialyzer membrane. There was no evidence of the clearance of cytokines by the ELAD.

Adolescent↗
PubMed1989

Absence of homologous restriction factor does not affect CTL-mediated cytolysis.

Homologous restriction factor (HRF) is a membrane protein of erythrocytes and leukocytes that inhibits the complement (C5b-9)-mediated lysis in a species-restricting manner. HRF has also been reported to inhibit perforin-mediated cytolysis and postulated to play a role in cytotoxic T lymphocyte (CTL) self-protection. We show that paroxysmal nocturnal hemoglobinuria (PNH) erythrocytes, lacking HRF, are no more sensitive to Ca2+-dependent human CTL-mediated lysis than normal erythrocytes. Furthermore, mouse and normal human erythrocytes, as well as PNH erythrocytes, are similarly lysed by isolated murine perforin-containing granules. We conclude that HRF does not inhibit perforin-mediated lysis and therefore is not likely to play a role in CTL self-protection.

Blood Proteins↗