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PubMed2003

Demonstration of apoptosis-associated cleavage products of DNA, complement activation products SC5b-9 and C3d/dg, and immune complexes CIC-C3d, CIC-IgA, and CIC-IgG in the urine of patients with membranous glomerulonephritis.

AIM: To investigate the involvement of complement activation and apoptosis in the pathogenesis of membranous glomerulonephritis by determining the concentrations of apoptosis-associated 180 bp nucleosomes and complement activation products SC5b-9 and C3d/dg in the urine of patients with membranous glomerulonephritis. METHODS: Morning urine was taken from 15 patients with immunohistologically established membranous glomerulonephritis. Apoptosis-associated 180 bp nucleosomes, complement activation products SC5b-9, C3d/dg, and immune complexes CIC-C3d, CIC-IgA, and CIC-IgG were detected in the urine samples by using antigen-specific enzyme-linked immunosorbent assay. RESULTS: Concentrations of measured parameters were expressed in units of standard deviation, ie, relatively to the average concentrations measured in healthy subjects. We found drastically increased concentrations of apoptosis-associated 180 bp nucleosomes (13.71+/-14.97; p=0.047), complement activation products SC5b-9 (197.07+/-134.88; p=0.003) and C3d/dg (38.70+/-43.35; p=0.048), and immune complexes CIC-C3d (11.01+/-13.39; p=0.74), CIC-IgA (7.93+/-4.38; p=0.001), and CIC-IgG (20.56+/-10.87; p=0.001) in the urine of patients with an active form of membranous glomerulonephritis. All studied molecules were absent, or present in very low concentrations, in healthy subjects and patients with membranous glomerulonephritis in remission. The mean differences between healthy controls and patients with the active disease were statistically significant in all parameters, except CIC-C3d. CONCLUSIONS: There is an association of complement activation and apoptosis with membranous glomerulonephritis. Correlation analysis suggests that the excretion of apoptosis-associated 180 bp nucleosomes, SC5b-9, C3d/dg, and immune complexes containing IgA and IgG in the urine of patients with active membranous glomerulonephritis does not depend solely on the passive transport together with other proteins, but is probably an independent active process.

Adult↗
PubMed1991

The relationship of complement-mediated microvasculopathy to the histologic features and clinical duration of disease in dermatomyositis.

Accumulating evidence indicates that a complement-mediated microvasculopathy may play a pathogenic role in dermatomyositis. In a previous study, we demonstrated neoantigens of the C5b-9 complement membrane attack complex in the muscle microvasculature of childhood and adult cases of dermatomyositis. To further characterize the relationship between the vascular complement deposits and histologic changes, quantitative histopathologic analyses were performed on 39 dermatomyositis biopsy specimens (26 adult, 13 children). There was a significant correlation between the percentage of fascicles with fibers having focal myofibrillar loss, a change seen early in the evolution of ischemic muscle fiber damage, and the percentage of fascicles having capillary deposits of membrane attack complex. Conversely, in biopsy specimens with a higher percentage of fascicles with perifascicular atrophy, membrane attack complex deposits were significantly less common. A fascicle-by-fascicle analysis supported these observations. Patients whose biopsy specimens were negative for microvascular membrane attack complex had clinical weakness for a significantly longer time than those patients with vascular complement deposits. These data support the hypothesis that the complement-mediated vasculopathy is a primary immunopathogenic event in the evolution of muscle lesions in dermatomyositis.

Adult↗
PubMedDate not supplied

The role of complement and activated microglia in the pathogenesis of Alzheimer's disease.

A variety of inflammatory mediators including complement activation products, protease inhibitors, and cytokines are colocalized with beta-amyloid (A beta) deposits in the Alzeimer's disease (AD) brain. Activation products of the early complement components C1, C4, and C3 are always found in neuritic plaques and to a lesser extent in varying numbers of diffuse plaques. In contrast to these findings, no immunohistochemical evidence was obtained for the presence of the late complement components C7 and C9 and the complement membrane attack complex in the neuropathological lesions in AD brains. The mRNA encoding the late complement components C7 and C9 appears to be hardly or not detectable. These findings indicate that in AD the complement system does not act as an inflammatory mediator through membrane attack complex formation, but through the actions of the early complement products. In this review we focus on the role of complement in the pathological amyloid cascade in AD. In our opinion, the early complement activation products play a crucial role as mediators between the A beta deposits and the inflammatory responses leading to neurotoxicity.

Alzheimer Disease↗
PubMed2006

Amyloid myopathy presenting with rhabdomyolysis: evidence of complement activation.

At age of 57 years, a man experienced an episode of rhabdomyolysis. On that occasion muscle biopsy was not performed, however monoclonal gammopathy of undetermined significance (MGUS) was diagnosed. Further he developed a moderate proximal muscle weakness with CK level persistently elevated (1000-1200U/l). When he came to our observation, at age 67, a muscle biopsy revealed an amyloid myopathy and multiple myeloma was at the same time disclosed. Terminal complement complex C5b9 (membrane attack complex) deposits were found in the vessel walls and muscle fibers surface depicted by amyloid. Our case suggests to keep in mind the possibility that amyloid myopathy may begin as an isolate episode of rhabdomyolysis. The detection of complement complex C5b9 suggests that complement cascade is implicated in the muscular damage of amyloid myopathy.

Aged↗
PubMed1983

Localization of the membrane attack complex (MAC) in experimental immune complex glomerulonephritis.

The role of the membrane attack complex (MAC) as a mediator of renal tissue injury was evaluated in rats affected by bovine serum albumin (BSA)-induced immune complex glomerulonephritis. Immunofluorescence studies revealed concurrent deposits of IgG, BSA, C3, and the MAC along glomerular capillary walls, although the MAC manifested a more restricted distribution than that observed for immune complexes. Immunoelectron microscopic techniques were utilized to demonstrate immune complexes, C3, and the MAC within dense deposits in the subepithelial aspect of the basement membrane. Visceral epithelial foot processes were fused in areas overlying large dense deposits and exhibited intense staining for the MAC, lesser reactivity for C3 but IgG was absent from the foot process membranes. Smaller granular deposits of immune complexes, C3, and the MAC were observed in the subendothelial region of the lamina rara interna and the lamina densa. Immune complexes may activate the classical complement pathway causing diffuse injury to the glomerular basement membrane (GBM), allowing subepithelial accumulation of complexes. These observations implicate the MAC as a mediator of GBM and juxtaposed podocyte membrane injury, thereby contributing to disruption of the glomerular filtration barrier. IgG and C3 were demonstrated within tubulointerstitial regions on the surface of collagen fibers in close proximity to the tubular basement membrane (TBM) of proximal convoluted tubules. Within the TBM, C3 localization was prominent with diminished reactivity for the MAC, but IgG was not detectable. The demonstration of C3 and scant MAC deposits in the TBM of nonimmunized control rats without evidence of interstitial IgG and C3 deposits suggests that both nonimmune and immune processes play a role in the pathogenesis of extraglomerular lesions. Evidence derived from these morphologic studies indicates that the MAC is associated with injury to the GBM, foot process membranes of visceral epithelium, and the TBM. Further experiments designed to selectively enhance or inhibit the deposition of MAC and assess consequent renal dysfunction are required to substantiate hypotheses concerning the in vivo membranolytic potential of the MAC in experimental immune complex glomerulonephritis.

Animals↗
PubMed1990

The complement-inhibitory activity of CD59 resides in its capacity to block incorporation of C9 into membrane C5b-9.

A human E membrane protein that inhibits lysis by the purified human C5b-9 proteins was isolated and characterized. After final purification, the protein migrated as an 18- to 20-kDa band by SDS-PAGE. Elution from gel slices and functional assay after SDS-PAGE (nonreduced) confirmed that all C5b-9 inhibitory activity of the purified protein resided in the 18- to 20-kDa band. Phosphatidylinositol-specific phospholipase C digestion of the purified protein abolished 50% of its C5b-9 inhibitory activity, and removed approximately 15% of the protein from human E. Western blots of normal and paroxysmal nocturnal hemoglobinuria E revealed an absence of the 18- to 20-kDa protein in the paroxysmal nocturnal hemoglobinuria E cells. The identity of this E protein with leukocyte Ag CD59 (P18, HRF20) was confirmed immunochemically and by N-terminal amino acid sequence analysis. A blocking antibody raised against the purified protein reacted with a single 18- to 20-kDa band on Western blots of human erythrocyte membranes. Prior incubation of human E with the F(ab) of this antibody increased subsequent lysis by the purified human C5b-9 proteins. Potentiation of C5b-9-mediated lysis was observed when erythrocytes were preincubated with this blocking antibody before C5b-9 assembly was initiated, or, when this antibody was added after 30 min, 0 degrees C incubation of C5b-8-treated E with C9. Chicken E incubated with purified CD59 were used to further characterize the mechanism of its C-inhibitory activity. Preincorporation of CD59 into these cells inhibited lysis by C5b-9, regardless of whether CD59 was added before or after assembly of the C5b-8 complex. When incorporated into the membrane, CD59 inhibited binding of 125I-C9 to membrane C5b-8 and reduced the extent of formation of SDS-resistant C9 polymer. The inhibitory effect of CD59 on 125I-C9 incorporation was most pronounced at near-saturating input of C9 (to C5b-8). By contrast, CD59 did not inhibit either C5b67 deposition onto the cell surface, or, binding of 125I-C8 to preassembled membrane C5b67. Taken together, these data suggest that CD59 exerts its C-inhibitory activity by limiting incorporation of multiple C9 into the membrane C5b-9 complex.

Antigens, Differentiation↗
PubMedDate not supplied

Levels of SC5b--9 complement complex in plasma and synovial fluid of patients with rheumatic disease.

Activation of the terminal complement pathway leads to formation of the C5b--9 complex. The main effects of C5b--9 generation are tissue injury by cell lysis or by stimulation of proinflammatory mediators. In a study carried out in 42 patients, using polyclonal antibodies against C5b--9 neoantigens and C9 in an ELISA assay, we found significantly higher levels of SC5b--9 complex in plasma from the 18 patients with active systemic lupus erythematosus than those found in 10 healthy controls (p less than 0.005). In the 18 patients presenting rheumatoid arthritis and the 6 with progressive systemic sclerosis the plasma levels of SC5b--9 complex did not differ significantly from those in controls. The SC5b--9 levels found in the synovial fluid samples from the 16 rheumatoid arthritis patients were higher than the corresponding plasma ones. The ratio between synovial fluid and plasma levels was 1.2. Immunoperoxidase staining for C5b--9 was intense in three rheumatoid synovial membranes and absent in two normal synovial membranes obtained during meniscectomy. Increased levels of plasma and synovial fluid SC5b--9 reflect pathologic systemic or local activation of the complement carcase in systemic lupus erythematosus and respectively rheumatoid arthritis. Synovial membrane deposits of C5b--9 are indicative for the lytic and proinflammatory effects of complement activation.

Adolescent↗
PubMed1987

Terminal complement complex in plasma from patients with systemic lupus erythematosus and other glomerular diseases.

To evaluate terminal complement pathway activation in plasma from patients with systemic lupus erythematosus (SLE) and primary glomerular diseases, we developed an enzyme-linked immunosorbent assay (ELISA) for measuring the terminal complement complexes (TCC). The method is based on a sandwich technique using rabbit antibodies against native human C5, C7 and C9. To avoid interference by native components, we equilibrated plasma specimens with 5% polyethylene glycol buffer. The precipitates were measured by ELISA. TCC was detectable in all 14 normal controls (0.48 +/- 0.06 AU/ml; mean +/- s.e.m.). TCC levels were elevated in 18 of 54 patients with SLE (0.89 +/- 0.07 AU/ml; P less than 0.01) and in eight of 11 patients with membranoproliferative glomerulonephritis (MPGN) (3.15 +/- 0.62 AU/ml; P less than 0.01). However, only one of six patients with membranous nephropathy and none of 13 with mesangial proliferative glomerulonephritis showed high values. In SLE, TCC was correlated with circulating immune complexes and inversely with CH50, C3, C4, C5 and alternative complement pathway activity (AH50), and showed significantly high values even in normal CH50 cases (n = 34; P less than 0.01). In MPGN, TCC was inversely correlated with CH50, AH50, C3, C5 and C9. These results suggest that the classical pathway plays an important role for TCC generation in SLE and that the alternative pathway does in MPGN.

Adolescent↗
PubMed1989

Early ultrastructural alterations in adult dermatomyositis. Capillary abnormalities precede other structural changes in muscle.

In 6 adults with dermatomyositis, minimally weak or nonweak muscles that showed inconclusive light-microscopic alterations were examined by electron microscopy. In all 6 specimens, this revealed pathologic changes in endomysial capillaries. The endothelial cells harbored microtubular inclusions and microvacuoles in all cases; pale swollen endothelial cells were observed in 3 specimens. There were no significant ultrastructural changes in the muscle fibers. In all cases, a small proportion of muscle capillaries were immunoreactive for complement membrane attack complex neoantigens. The findings imply that in adult dermatomyositis capillary injury precedes muscle fiber damage and infiltration by inflammatory cells, and that the microvasculature is an early and specific target of the disease process in muscle.

Adult↗
PubMed2003

ONO-6818, a novel, potent neutrophil elastase inhibitor, reduces inflammatory mediators during simulated extracorporeal circulation.

BACKGROUND: Among the serine proteases, neutrophil elastase is a powerful cytotoxic enzyme and plays a pivotal role in the inflammatory response associated with cardiopulmonary bypass. This study assesses the effects of the specific inhibition of neutrophil elastase by a novel, potent, low-molecular-weight neutrophil elastase inhibitor, ONO-6818. We hypothesized that ONO-6818 reduces inflammatory mediators and modulates adhesion molecules and the deformability of neutrophils during simulated extracorporeal circulation. METHODS: Simulated extracorporeal circulation was established by recirculating fresh heparinized (3.75 U/mL) human blood for 120 minutes in a membrane oxygenator and a roller pump with and without 1.0 micromol/L of ONO-6818 (n = 9 for control group, n = 7 for ONO-6818 group). The neutrophil adhesion molecules, CD11b and L-selectin, and the cytoplasmic F-actin of neutrophils were measured by flow cytometry. Neutrophil deformability was evaluated using simulated silicon microcapillaries. Neutrophil elastase, interleukin 8, and C5b-9 were measured using enzyme immunoassay. RESULTS: Neutrophil elastase levels were significantly lower in the ONO-6818 group. ONO-6818 significantly reduced interleukin 8 and C5b-9 production. ONO-6818 did not modulate changes of CD11b and L-selectin during recirculation. Cytoplasmic F-actin content and changes of neutrophil deformability did not significantly differ between the groups. CONCLUSIONS: Inhibition of neutrophil elastase activity with ONO-6818 reduces further interleukin 8 production and the formation of the complement membrane attack complex, and this results in a reduction of neutrophil elastase levels during simulated extracorporeal circulation. This study suggests that specific neutrophil elastase inhibition with ONO-6818 is a feasible therapeutic option to attenuate the exaggerated inflammatory response associated with cardiopulmonary bypass.

Actins↗
PubMed2000

Monitoring pig-to-primate cardiac xenografts with live Internet images of recipients and xenograft telemetric signals: histologic and immunohistochemical correlations.

BACKGROUND: Monitoring pig-to-primate cardiac xenografts is often difficult in awake and uncooperative primates. We investigated the possibility of monitoring xenotransplantation through Internet broadcasting of (1) continuous video images of transplant recipients and (2) xenograft telemetric signals detected by an implanted device. The telemetric readings were later compared with histology and immunohistochemistry for signs of rejection. METHODS: Heterotopic baboon-to-baboon (n = 2) and transgenic pig (human complement regulatory proteins CD59/DAF, n = 3; MCP, n = 1)-to-baboon transplants were performed with serial biopsies for hematoxylin-and-eosin staining and immunohistochemical detection of immunoglobulin M (IgM) and complement membrane attack complex (MAC) deposition. Baboon recipients were continuously monitored with a QuickCamPro digital camera, whereas grafts were monitored with a Data Science International implantable telemetric system. Video images and telemetric signals were broadcast over the Internet through a laptop computer. RESULTS: Baboon allografts remained healthy until explant on Day 14, whereas pig xenografts were rejected on Day 5, 6, 7, and 11. Telemetry of allografts and xenografts documented regular rhythm with an average heart rate of 80 to 120, but xenografts developed bradycardia and widened/dampened QRS complexes 24 to 48 hours before graft loss. Continuous video monitoring of recipient activities was vital in differentiating between graft arrhythmias and telemetric artifacts. Allograft biopsies showed little cellular infiltrate, whereas xenograft biopsies showed increasing IgM and MAC deposition, with extensive thrombi and myocardial damage 24 hours before cessation of cardiac activities. CONCLUSIONS: Combined video surveillance of recipient activities and graft telemetric signals is a useful method to continuously monitor abdominal cardiac grafts in large, uncooperative, awake primates. QRS-complex widening associated with progressive bradycardia correlated with histologic and immunohistochemical evidence of xenograft rejection.

Animals↗
PubMed1988

Restriction of cell lysis by homologous complement: II. Protection of erythrocytes against lysis by newly activated complement.

Our previous work revealed that homologous complement (C) was ineffective in lysing antibody-sensitized erythrocytes (EA) even at high concentrations. It was also shown that activation of complement on homologous EA resulted in the binding of C9 and the formation of EA bearing complement proteins C1 through C9 (EAC1-9), yet few hemolytic sites were formed. Instead, as shown here, the formation of homologous EAC1-9 caused the cells to become resistant to lysis even by heterologous complement during a second incubation. In contrast, when homologous EAC1-8 were produced by incubating EA with C9-depleted serum, such intermediates were not protected against lysis by heterologous complement during a second incubation. Furthermore, homologous C9 on EAC1-9 was able to reduce the hemolytic efficiency of heterologous complement without blocking C activation and the formation of new C5b-9 complexes. Protection was not modified when homologous EAC1-9 were produced in one step, by incubation of EA with serum, or sequentially by adding C9 to EAC1-8. The minimum number of 9-sites required to confer a protective effect on EAC1-9 was less than 200 per cell. Thus, in addition to its known effect in heterologous cell killing, homologous C9 is capable of protecting homologous cells against inadvertent complement lysis.

Ammonia↗
PubMedDate not supplied

Structural/functional similarity between proteins involved in complement- and cytotoxic T-lymphocyte-mediated cytolysis.

Cytolysis mediated by complement or cytolytic lymphocytes results in the formation of morphology similar lesions in the target membrane. These lesions, formed by the polymerization of C9 or perforin respectively, contribute the major killing action by causing osmotic lysis of the target cell. Following the suggestion of Mayer that the mechanisms of humoral and cell-mediated cytotoxicity might be related, studies into the morphology of the membrane lesions formed, and the proteins responsible for causing the lesions, have shown several similarities. While the lesion caused by natural and T-killer cells is a little larger than that caused by complement, its overall shape is similar and in both cases the cylindrical pore is formed by polymerization of a monomeric subunit, C9 (relative molecular mass, Mr = 71,000) for complement, and perforin (Mr = 66,000) for cell-mediated cytotoxicity. C9 has an absolute requirement for a receptor in the target membrane formed by the earlier membrane attack complex components, C5b, C6, C7 and C8 (ref. 8). For perforin, polymerization in a target membrane requires no receptor, specificity being derived from the specific recognition between killer and target cell. Both proteins can be made to polymerize in vitro by the addition of divalent cations (Zn2+ for C9 (ref. 16) and Ca2+ for perforin) and the resultant complexes closely resemble their physiological counterparts. Antibodies raised against lymphocyte-killed targets have also been shown to cross-react with complement proteins, but the antigenically related proteins were not determined in these studies. We show here using purified proteins that perforin, C9 and complexes involving C7 and C8 share a common antigenic determinant which is probably involved in polymerization.

Amino Acid Sequence↗
PubMed1983

Freeze-fracture analysis of the membrane lesion of human complement.

The structure and membrane insertion of the human C5b-9(m) complex, generated by lysis of antibody-coated sheep erythrocytes with whole human serum under conditions where high numbers of classical ring-shaped lesions form, were studied in single and complementary freeze-fracture replicas prepared by unidirectional and rotary shadowing. The intramembrane portion of the C5b-9(m) cylinder was seen on EF-faces as an elevated, circular structure. In nonetched fractures it appeared as a solid stub; in etched fractures a central pit confirmed the existence of a central, water-filled pore in the molecule. Complementary replicas showed that each EF-face ring corresponded to a hole in the lipid plateau of the PF-face. Etched fractures of proteolytically stripped membranes revealed the extramembrane annulus of the C5b-9(m) cylinder on ES-faces and putative internal openings on PS-faces. Allowing for the measured thickness of deposited Pt/C, the dimensions of EF-face rings and ES-face annuli conformed to anticipations derived from negatively stained preparations. Our results support the concept that the hollow cylindrical C5b-9(m) complex penetrates into the inner leaflet of the target erythrocyte membrane bilayer, forming a stable transmembrane protein channel.

Animals↗
PubMed1989

Immunoelectron microscopic localization of membrane attack complex and hepatitis B e antigen in membranous nephropathy.

Immunoelectron microscopy was used to localize membrane attack complex (MAC) and hepatitis B e (HBe) antigen in renal tissue specimens from a total of 9 patients with membranous nephropathy (MN); 6 with MN associated with a hepatitis B virus (HBV) infection, 2 with idiopathic MN, and 1 with lupus nephritis. All the patients were proteinuric, and 2 patients were classified as stage I-II, 6 as stage II, and 1 as stage IV. MAC, along with IgG and C3, was distributed within the subepithelial electron dense deposits in all the stages. MAC was also stained in the striated membranous structures within the glomerular basement membrane and mesangial matrix of some patients. In HBV-associated MN, HBe antigen was localized in the subepithelial electron dense deposits of 5 patients, while it was absent from the subepithelial deposits in a patient that was sero-positive for hepatitis B s antigen but negative for HBe antigen. This patient also lacked MAC deposition in these loci. These results suggest that MAC is associated with the formation of subepithelial deposits and proteinuria in MN. In HBV-associated MN, HBe antigen-antibody immune complex makes up the subepithelial deposits and is likely to activate the terminal components of complement in situ.

Complement Membrane Attack Complex↗