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PubMed1991

[Cell-associated complement regulatory proteins and their relation to disease processes].

C3-deposition is a key step for activation of the complement system, which involves C9-mediated immunocytolysis, immunoadherence, C3 receptor-mediated phagocytosis, NK potentiation, anaphylatoxin release, and amplification of C3 activation. Foreign material is eliminated even in the preimmune stage by these complement functions. Self cells, on the other hand, must circumvent the C3-attack, so that they express complement regulatory proteins, namely C3b/C4b receptor (CR1, CD35), decay-accelerating factor (DAF, CD55), membrane cofactor protein (MCP, CD46). We herein review the properties of these regulatory proteins and discuss the relationships between disease processes and the aberrance of these regulatory proteins.

Antigens, CD↗

PubMed1981

Stimulation of Ca2+-dependent chemiluminescence in rat polymorphonuclear leucocytes by polystyrene beads and the non-lytic action of complement.

(1) Chemiluminenscence of rat polymorphonuclear leukocytes was stimulated by a phagocytic stimulus, latex beads (diameter = 1.01 micrometer). The maximum chemiluminescent intensity increased with bead concentration in the range 0.2--20 x 10(9) beads/ml. This response was abolished in the absence of extracellular Ca2+ (1 mM EGTA). (2) Chemiluminescence could also be stimulated by the Ca2+ ionophore A23187 in the presence of extra-cellular calcium. (3) Addition of human serum, as a source of complement, to rat polymorphonuclear leukocytes preincubated with anti-5'-nucleotidase serum resulted in a rapid stimulation of chemiluminescence, after a lag of about 40 s. (4) The stimulation of chemiluminescence by antibody plus complement was not the result of cell lysis because (i) no significant release of lactate dehydrogenase was detected at the time of the chemiluminescent response (ii) chemiluminescence was associated with the cells and not the surrounding media (iii) cell lysis did not produce chemiluminescence. (5) Chemiluminescence stimulated by antibody plus complement or by beads was inhibited by the 'calmodulin-blocker', trifluoperazine (50% inhibiton with approximately 20--30 microM). (6) Cu2+ (10(-4) M), which can inhibit C9 action, inhibited the rapid rise in chemiluminescence induced by antibody plus complement, but not the bead-induced chemiluminescence. (7) Depletion of C9 from human serum markedly inhibited the complement induced chemiluminescence response. Addition of purified C9 restored the response. (8) It was concluded that formation of the terminal complement attack complex at the surface of rat polymorphonuclear leucocytes induces a Ca2+-dependent chemiluminescence in the cells, in the absence of cell lysis.

Animals↗

PubMed1993

Potassium cyanide protects Escherichia coli from complement killing by the inhibition of C3 convertase activity.

The exact mechanism by which deposited C5b-9 complexes kill Gram-negative bacteria is unclear. It has been proposed that during complement activation the membrane attack complex triggers an energy dependent process in Gram-negative bacteria that mediates destruction of the inner membrane. This observation in part resulted from the survival of Gram-negative bacteria that were incubated with an uncoupler (DNP) or an inhibitor (KCN) of oxidative phosphorylation during complement activation. In a reexamination of this issue we employed potassium cyanide (KCN) to block energy dependent pathways and observed a dose dependent inhibition of C9 uptake on E. coli J5 during serum incubation, suggesting that cyanide was interfering with complement activation. To verify the effect on complement activation we chose specifically to study the effects of KCN on the C3 convertase of the classical pathway. Sensitized sheep erythrocytes were employed as our model system. This system allowed us to construct a series of stable intermediates that were used to test the effect of cyanide on the formation and activity of precursors of the classical pathway C3 convertase. The data illustrate that the concentrations of potassium cyanide that inhibit complement killing of J5 also inhibit C3 convertase activity on sensitized sheep erythrocytes. The results of this study refute the principal observation made by other investigators, that potassium cyanide protects bacteria from complement killing by inhibiting bacterial energy dependent pathways that spark inner membrane destruction. A better scenario is that the organisms survive because cyanide inhibits complement activation.

Animals↗

PubMed1998

Antisulfatide polyneuropathy: antibody-mediated complement attack on peripheral myelin.

Increased titers of circulating antisulfatide antibodies are consistently associated with a variety of chronic axonal and demyelinating polyneuropathy syndromes. Previous studies have shown that the pattern of antisulfatide binding to neural tissues correlates with the type of neuropathy. This suggests a possible role for antisulfatide antibodies in inducing peripheral nerve dysfunction, although their exact contribution to the pathogenesis of neuropathy is still unknown. We examined sural nerve biopsy specimens from two patients with sensorimotor and small fiber sensory neuropathy associated with high titers of IgM monoclonal antibodies to sulfatide. Electrophysiological and pathological findings were consistent with predominant demyelination in the patient with sensorimotor involvement, whereas evidence of demyelination was obtained only by teased fiber examination in the other patient. The ultrastructural study disclosed in both cases the presence of myelinated fibers with widely spaced myelin, due to a separation of leaflets of the intraperiod lines. Immunocytochemistry, performed on frozen sections, demonstrated the presence of IgM and complement product C3d bound to myelin sheaths of almost all fibers. Few fibers were immunoreactive for complement components C1q and C5. In addition, the terminal complement complex neoantigen C5b-C9, not associated with S protein, was detected on some myelinated fibers. The results suggest that, at the least in some forms of demyelinating neuropathy associated with antisulfatide antibodies, pathological changes are complement mediated. Our data further confirm previous clinical and experimental observations that complement activation initiates separation of myelin intraperiod lines.

Aged↗

PubMed1995

Complement activation in amyloid plaques in Alzheimer's disease brains does not proceed further than C3.

In Alzheimer's disease (AD) patients, the complement components Clq, C4 and C3 can be detected in different types of beta/A4 plaques, one of the hallmarks of AD. Contradictory findings on the presence of late complement components in AD brains have been reported. Nevertheless, it was suggested in recent studies that in AD brain complement activation results in complement membrane attack complex (MAC) formation and that complement activation may act as an intermediate between beta/A4 deposits and the neurotoxicity observed in AD. In the present study the presence of a number of complement components and regulatory proteins in AD temporal cortex and, for comparison, in glomerulonephritis (GN) was analysed. In GN kidneys, besides Clq, Clr, Cls and C3, the late components and the C5b-9 complex are also associated with capillary basement membrane and mesangial immune complex deposits. In AD temporal cortex Clq, C4 and C3 are co-localized with beta/A4 deposits. However, in contrast to the GN kidney, the late complement components C5, C7 and C9, as well as the C5b-9 membrane attack complex cannot be detected in beta/A4 positive plaques. The absence of the cytolytic C5b-9 complex in AD brain suggests that in AD, the complement MAC does not function as the proposed inflammatory mediator between beta/A4 deposits and the neurofibrillary changes.

Aged↗

PubMed1975

Mechanism of complement-induced cell lysis. Demonstration of a three-step mechanism of EAC1-8 cell lysis by C9 and of a non-osmotic swelling of erythrocytes.

Sheep erythrocytes were sized by an electrical method during lysis by antibody and complement. No volume changes were observed upon to the EAC1-8 cell intermediate. Three steps could be distinguished in the reaction of C9 with EAC1-8 cells: fixation of C9 to EAC1-8 cells, a process which proceeds also at 0 degrees C; temperature-dependent swelling of the EAC1-9 cells; and lysis of the cells. We could show that swelling of the erythrocytes induced by the complement reaction is independent of protein osmotic forces and is caused by an alteration of the erythrocyte membrane.

Animals↗

PubMedDate not supplied

[Levels of the individual complement components in the blood serum of volunteers on diets with a various levels of optimal protein composition].

Protein fractions of complement (C3, C4, C5 and C9) and the control protein Ct-inhibitor) were studied in blood serum of practically healthy men placed on the diet marked by protein deficiency. It was noted that C3 and C9 were particularly sensitive to protein deficiency in the diet (5 to 8.2 g/day according to nitrogen), with the titers of these fractions being low.

Complement System Proteins↗

PubMed1986

The ninth complement component in rheumatoid arthritis, Behçet's disease and other rheumatic diseases.

Using an immunoradiometric assay with two monoclonal antibodies plasma C9 levels were measured in 49 patients with rheumatoid arthritis, eight patients with Behçet's disease, six patients with ankylosing spondylitis, nine patients with psoriatic arthropathy, six patients with systemic lupus erythematosus, five patients with erosive osteoarthritis and four patients with acute gout. Plasma C9 levels were also followed sequentially in four patients with Behçet's disease to show fluctuation during disease activity. The upper limit of normal for plasma C9 was 90 mg/l, 2 standard deviations above the known mean value. Significantly raised levels were found in active rheumatoid arthritis (119.7 +/- 28.3), Behçet's disease (177.9 +/- 26.2) and ankylosing spondylitis (116.1 +/- 23.1). In Behçet's disease the raised C9 levels normalized during disease quiescence suggesting that C9 is a good monitor of disease activity. CRP and ESR values were also measured. In rheumatoid arthritis C9 was more consistently elevated in active disease than CRP or ESR. As there was no association between these measures on mathematical analysis it was concluded that plasma C9 is a better indicator of disease activity in rheumatoid arthritis.

Arthritis, Rheumatoid↗

PubMed2026

Complement expression profiles in human glomerular mesangial cells, endothelial cells, podocytes and proximal tubular epithelial cells.

BACKGROUND: Local expression of complement components in the kidney has been reported sporadically in both diseased and normal kidneys. This study aimed to comprehensively characterize the expression of complement components in human glomerular mesangial cells (GMCs), glomerular endothelial cells (GECs), podocytes, and proximal tubular epithelial cells (PTECs) in non-diseased renal tissue. METHODS: Complement expression in cultured human renal intrinsic cells was initially evaluated using reverse transcription polymerase chain reaction and immunofluorescence staining. These findings were further examined using publicly available single-cell RNA-sequencing datasets and 10×Genomics single-cell RNA sequencing of non-diseased human kidney tissue. The analyses focused on complement components involved in the initiation of the classical, lectin, and alternative pathways, as well as components shared among these activation pathways, terminal pathway components, complement regulators, and complement receptors. RESULTS: Complement components unique to the initial phase for classical pathway (C1S, C1R, C2, C4), lectin pathway (MBL2, FCN1, MASP1), alternative pathway (CFB, CFD), and the C3 component shared by the three activation pathways were detected in these cells. The components shared by the terminal pathways including C5, C6, C7, C8 and C9 exhibited lower expression, while complement regulators (CFH, CFI, CD55/DAF, CD46/MCP, CD59, C4BPB, PROS1/Protein S) or receptors (CD93/C1QR1, CR1), particularly membrane-bound proteins, such as DAF, MCP and CD59, which inhibit complement activation and the formation of the membrane attack complex, showed relatively high expression. CONCLUSION: These results showed that all four types of intrinsic renal cells expressed multiple complement components associated with the classical, lectin, and alternative pathways. In non-diseased kidney tissue, complement regulatory molecules involved in the control of complement activation showed relatively higher expression, whereas components of the terminal complement pathway were expressed at relatively lower levels, suggesting that renal intrinsic cells maintain a locally poised but tightly regulated complement system.

Humans↗

PubMed1999

Association of terminal complement proteins in solution and modulation by suramin.

The association of terminal complement proteins was investigated by analytical ultracentrifugation and multi-angle laser light scattering. Native C8 and C9 formed a heterodimer in solution of physiological ionic strength with a free-energy change DeltaG degrees of -8.3 kcal/mol and a dissociation constant Kd of 0.6 microM (at 20 degrees C) that was ionic strength- and temperature-dependent. A van't Hoff plot of the change in Kd was linear between 10 and 37 degrees C and yielded values of DeltaH degrees = -12.9 kcal/mol and DeltaS degrees = -15.9 cal mol-1 deg-1, suggesting that electrostatic forces play a prominent role in the interaction of C8 with C9. Native C8 also formed a heterodimer with C5, and low concentrations of polyionic ligands such as protamine and suramin inhibited the interaction. Suramin induced high-affinity trimerization of C8 (Kd = 0.10 microM at 20 degrees C) and dimerization of C9 (Kd = 0.86 microM at 20 degrees C). Suramin-induced C8 oligomerization may be the primary reason for the drug's ability to prevent complement-mediated hemolysis. Analysis of sedimentation equilibria and also of the fluorescence enhancement of suramin when bound to protein provided evidence for two suramin-binding sites on each C9 and three on each C8 in the oligomers. Oligomerization could be reversed by high suramin concentrations, but 8-aminonaphthalene-1,3,6- trisulfonate (ANTS2- ), which mimics half a suramin molecule, could not compete with suramin binding and oligomerization suggesting that the drug also binds nonionically to the proteins.

Calorimetry, Differential Scanning↗

PubMed1986

Glomerulonephritis induced by monoclonal anti-Thy 1.1 antibodies. A sequential histological and ultrastructural study in the rat.

The present report describes the natural history of an experimental acute glomerulonephritis with massive proteinuria induced by a single intravenous injection of a (mouse) monoclonal anti-rat Thy 1.1 antibody into the rat. The disease is characterized by direct although transient binding of this monoclonal antibody to glomerular basement membrane and mesangium after injection as demonstrated by immunofluorescence microscopy. Immediate activation of complement occurs as shown by glomerular deposition of C3 and C9. Concomitant activation of the coagulation cascade is reflected by the presence of fibrinogen deposits in the affected glomeruli. One hour after injection mesangial alterations are prominent including condensation of mesangial cell chromatin, and lysis of mesangial cells as shown by light- and electron- microscopy, leading to the formation of aneurysms in the capillary tuft. Commencing on day 4 mesangial cell proliferation can be observed, accompanied by glomerular crescent formation at day 14, which decreases gradually 3 weeks after antibody administration, whereas mesangial hypercellularity can be observed up week 10 after intravenous injection of the antibody. The disease is clinically characterized by a massive transient proteinuria starting immediately after antibody injection, reaching mean values of 300 mg/24 hours at days 2 to 4, gradually decreasing to normal levels after 3 weeks. It is concluded that in this unique model of glomerulonephritis induced by a monoclonal antibody, recognition of Thy 1.1 epitopes as well as activation of complement including the C5-C9 membrane attack complex may play a major role in the pathogenesis of this experimental disease.

Animals↗

PubMed1989

Deposits of terminal complement complex (TCC) in muscularis mucosae and submucosal vessels in ulcerative colitis and Crohn's disease of the colon.

Extensively washed, ethanol fixed and paraffin embedded colonic specimens from 15 patients with ulcerative colitis (UC) and nine patients with Crohn's disease (CD) of the colon, ileal specimens from six patients with CD of the ileum, and histologically normal control specimens obtained from 10 patients operated for colonic carcinoma, were examined by immunohistochemistry with a monoclonal antibody specific for a neoepitope in the C9 part of the terminal complement complex (TCC). The submucosal blood vessels in inflammatory bowel disease (IBD) showed significantly more TCC positivity than the controls, and vascular TCC deposition was statistically related (p less than 0.001) to degree of inflammation. Five of the six ileal CD specimens contained likewise vascular TCC deposits. In addition, five UC specimens and one colonic CD specimen contained TCC-positive fibrils in the muscularis mucosae or submucosa. There was no significant difference in vascular TCC deposits between UC and CD. The results suggested that terminal complement activation takes place in the intestinal lesions of IBD.

Adolescent↗

PubMed1984

Effect of erythrocyte membrane modulation by lysolecithin on complement-mediated lysis.

Alterations of the physiochemical properties of membranes, such as acyl chain length of phospholipids, cholesterol content, and disturbance of the bilayer packing, affect the efficiency of membrane attack by C5b-9. In the present study, we explored the effect of lysolecithin (LL), a naturally occurring derivative of membrane phospholipids, on membrane damage by C5b-9. Sublytic doses of the L isomer of palmitoyl-lysolecithin were incorporated into the erythrocyte membranes of guinea pig (gpE) or sheep (shE) and the cells were then lysed with C5b6-C9. Marked enhancement of complement-mediated lysis was observed with LL-treated gpE after 2 hr of incubation, whereas the lytic enhancement was either nil or only marginal in shE. Studies on the kinetics of LL incorporation and metabolism in gpE membranes with 14C-LL showed that LL was rapidly incorporated and catabolized to generate free fatty acid (FA). Maximal accumulation of labeled FA in the membrane and loss of membrane-incorporated LL, resulting in approximately equimolar amounts of LL and FA, occurred at 2 hr, concomitant with enhancement of complement-mediated lysis. In shE such a breakdown of LL occurred only minimally. This quantitative difference in LL breakdown between gpE and shE was in accord with lysophospholipase activity that was two and one-half to seven times more active in gpE than shE membranes. When an ether-linked analog of LL (1-O-hexadecyl-sn-phosphorylcholine), which is resistant to lysophospholipase, was incorporated in gpE, the lytic enhancement was not observed. The results of our experiments indicate that the membrane modulating effect of LL on lysis by C5b-9 requires the enzymatic breakdown of LL.

Animals↗

PubMed2003

Complement activation contributes to hypoxic-ischemic brain injury in neonatal rats.

Conflicting data have emerged regarding the role of complement activation in the pathophysiology of cerebral ischemia. On the basis of considerable evidence implicating inflammatory mediators in the progression of neonatal brain injury, we evaluated the contribution of complement activation to cerebral hypoxic-ischemic (HI) injury in the neonatal rat. To elicit unilateral forebrain HI injury, 7-d-old rats underwent right carotid ligation followed by 1.5-2 hr of exposure to 8% oxygen. Using immunoprecipitation and Western blot assays, we determined that HI induces local complement cascade activation as early as 8 hr post-HI; there was an eightfold increase in the activation fragment inactivated C3b at 16 hr. With immunofluorescence assays and confocal microscopy, both C3 and C9 were localized to injured neurons 16 and 24 hr post-HI. To investigate the contribution of systemic complement to brain injury, we administered the complement-depleting agent cobra venom factor (CVF) 24 hr before HI lesioning and evaluated both acute HI-induced complement deposition and the extent of resulting tissue injury 5 d after lesioning. CVF depleted both systemic and brain C3 by the time of surgery and reduced infarct size. Analysis of lesioned, CVF-treated animals demonstrated minimal neuronal C3 deposition but no reduction in C9 deposition. C3-immunoreactive microglia were identified in injured areas. These results indicate that complement activation contributes to HI injury in neonatal rat brain, systemic administration of CVF does not eliminate complement deposition within injured brain, and microglia may represent an important local source of C3 after acute brain injury.

Animals↗

PubMed1981

Immunologic abnormalities in myelofibrosis with activation of the complement system.

Eighteen patients with agnogenic myeloid metaplasia with myelofibrosis were studied for clinical and laboratory evidence of immunologic dysfunction. Clinical findings included the presence of arthritis, vasculitis, and erythema nodosum. Laboratory abnormalities included the presence of circulating immune complexes, antinuclear antibodies, positive direct Coombs tests, elevated latex fixations, and a circulating lupus type anticoagulant. Total hemolytic complement was markedly depressed in four patients. Analysis of complement (C) components C1-C9 and factor B demonstrated significant reduction of only C3 and factor B. By crossed-immunoelectrophoresis, both C3 and factor B, but not C4, were cleaved, indicating that C activation was occurring predominantly via the alternative pathway. The control proteins beta 1H and C3b inactivator were decreased in three of four patients with hypocomplementemia. These data suggest that immunologic mechanisms associated with activation of the complement system play an important role in the disease process of some patients with agnogenic myeloid metaplasia with myelofibrosis.

Aged↗

PubMed1988

A sensitive method to detect synthesis of the functional classical, alternative and terminal pathway of complement by cells cultured in vitro.

A new method used to study in vitro synthesis by human monocytes and alveolar macrophages of the essential complement components for the functional classical, alternative and terminal pathway is presented. The method is based on accumulation of major complements components on activators of the alternative (agarose beads) and classical (lgM-sensitized sheep erythrocytes; ElgM) pathway during co-culture with the phagocytes. There was a time-dependent increase in binding of labelled protein to the co-cultured activators, demonstrating de novo protein synthesis by the phagocytes. Moreover, there was a significant binding to the co-cultured agarose beads and ElgM of monoclonal anti-C3c, anti-C3g, polyclonal anti-C5-C9 and of two monoclonal antibodies (poly C9-MA and MCaEll) to a neoantigen of polymerized C9 present in the terminal complement complex (TCC). In addition, we found a significant binding of polyclonal anti-C4 antibodies to co-cultured ElgM. Incubation of the activators in human serum, subsequently revealed the same pattern of antibody binding. There was no binding of anti-S protein antibodies to the activators after incubation with serum or with the phagocytes. We thus conclude that mononuclear phagocyte-produced complement in the form of C3b, iC3b, and the TCC (C5b-9) was deposited on both activators, whereas C4b was detected on the ElgM. It is our hope that this method can be applied when studying complement biosynthesis by cells other than mononuclear phagocytes.

Animals↗

PubMed1999

No evidence for association of multiple sclerosis with the complement factors C6 and C7.

Four genome screens in multiple sclerosis have been completed and each has identified evidence for linkage in the pericentromeric region of chromosome 5. This region encodes a number of candidate genes including those for the complement components C6, C7 and C9. We have used a multiplexed oligoligation assay (OLA) to test single nucleotide polymorphisms (SNPs) from the C6 and C7 genes for evidence of association with multiple sclerosis in our sibling pair families. There was no statistically significant difference in the allele frequencies of these polymorphisms in the index cases from our families when compared with locally derived controls. No evidence for transmission distortion was seen with any of the polymorphisms, or with the haplotype built from the three SNPs from the C7 gene. Despite offering themselves as potential candidates these complement genes appear not to confer susceptibility to multiple sclerosis.

Autoimmune Diseases↗

PubMed2005

Cutting edge: murine CD59a modulates antiviral CD4+ T cell activity in a complement-independent manner.

CD59 blocks formation of the membrane attack complex of complement by inhibiting binding of C9 to the C5b-8 complex. To investigate a role for CD59 in promoting T cell responses, we compared T cell activation in CD59a-deficient (Cd59a-/-) and wild-type (WT) mice after in vitro stimulation and after infection with rVV. Virus-specific CD4+ T cell responses were significantly enhanced in Cd59a-/- mice compared with WT mice. Similarly, Cd59a-/- T cells responded more vigorously to in vitro stimulation with CD3-specific Abs compared with WT mice. This effect of CD59a on T cell proliferation was found to be complement-independent. Collectively, these results demonstrate that CD59a down-modulates CD4+ T cell activity in vitro and in vivo, thereby revealing another link between complement regulators and T cell activation.

Animals↗