Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Complement C5”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 1,459 records · Page 81Linked to original sources
PubMed1989

The C5-sufficient A/J congenic mouse strain. Inflammatory response and resistance to Listeria monocytogenes.

A/J mouse strain poorly responds to an inflammatory stimulus and is highly susceptible to Listeria monocytogenes (Lm) infection. This defect in the phagocyte inflammatory response caused by the C5 component of C deficiency was shown, by linkage analysis, to be the major reason for the extreme susceptibility of A/J mice to Lm infection. The importance of this genetic defect in C5 in relation to the poor macrophage inflammatory response and to the susceptibility to Lm infection was evaluated by developing a C5-sufficient congenic A/J mouse strain. This A/J.C5 mouse strain was studied for its inflammatory response and for its susceptibility to Lm infection. C5-sufficient congenic A/J.C5 mice showed a slight improvement (2X) in their level of macrophage inflammatory response; however, they did not mount an as strong response as the Listeria-resistant C57BL/6J mice which donated the C5 allele. When infected with Lm, A/J.C5 mice were found to be as resistant as C57BL/6J mice. These results suggest that the presence of C5 on an A/J background partially improves the deficient macrophage inflammatory response of that strain. This increase is sufficient to render the A/J.C5 mouse strain highly resistant to Listeria infection. A/J.C5 mouse strain represents a new tool for the study of the importance of C5 in resistance to infection and in the regulation of the macrophage inflammatory response.

Animals↗
PubMed1988

Expression of C5a anaphylatoxin receptor in monoblastic cells involves facilitation of an adenosine 3',5'-monophosphate-dependent process.

We have previously reported a synergistic effect of 1,25-dihydroxyvitamin D [1,25-(OH)2D] and agents that elevate intracellular cAMP to induce the expression of the C5a complement receptor in U937 cells. In this report we examine the mechanism of this synergy, considering the hypothesis that the steroid hormone works by facilitating what is ultimately a cAMP-dependent process. We show that U937 cells cultured with 1,25-(OH)2D alone before culture with prostaglandin (PGE2) alone will express C5a receptor (an average of 55 +/- 4% of the receptors expressed with continuous exposure of cells to both agents; P less than 0.05). The reverse, PGE2 followed by 1,25-(OH)2D, causes very little receptor induction. This demonstrates the ability of 1,25-(OH)2D to induce changes in the state of the cell, such that activation of cAMP-dependent protein kinase has effects that are otherwise not seen, in other words 1,25-(OH)2D can prime the cell for the subsequent action of the cAMP messenger system. Furthermore, we are able to substitute, during the priming period, the protein synthesis inhibitor cycloheximide (CHX) for 1,25-(OH)2D. Cells cultured for 24 h with CHX will express C5a receptor when cultured for a second 2-day period with PGE2 at about 77 +/- 7% of the amount obtained with simultaneous exposure to 1,25-(OH)2D and PGE2. The CHX effect is time dependent and visible after 2 h. CHX is not synergistic with 1,25-(OH)2D. Other agents that can also substitute for 1,25-(OH)2D, but not for cAMP, in facilitating C5a receptor expression include retinoic acid and ionomycin, but with less potency. The 1,25-(OH)2D and PGE2 synergy is sensitive to the presence of isobutylmethylxanthine, implicating its dependence on the maintained elevation of intracellular cAMP levels. The synergy does not appear to be sensitive to changes in extracellular or intracellular calcium. We conclude from these results that 1,25-(OH)2D may promote the expression of C5a receptor in these cells in a fashion similar to that by which CHX potentiates other genes, i.e. that 1,25-(OH)2D increases levels of the mRNA encoding the C5a receptor. The mechanism of cAMP's subsequent and necessary action in the induction of C5a receptor expression is not yet clear.

1-Methyl-3-isobutylxanthine↗
PubMed1984

'Inactivated' third component of complement (C3b-like C3; C3i) acquires C5 binding capacity and supports C5 activation upon covalent fixation to a solid surface.

The haemolytic activity of human C3 was destroyed by freezing and thawing or by treatment with methylamine. This partially denatured C3 (C3i) was coupled to activated Thiol-Sepharose via its single SH group. The fixed C3i was capable of reversibly binding C5 and of supporting C5 cleavage in the presence of factors B and D. Soluble C3i lacked these properties. C3i was also fixed to sheep red cells which had been supplied with activated thiol groups by treatment with N-succinimidyl-3-(2-pyridyldithio)-propionate. The E-C3i thus obtained were lysed by factors B, D and late complement components C5-C9. The experiments demonstrate that upon fixation, C3i becomes C3b-like in functional activity directed to C5 utilization.

Binding Sites↗
PubMed1995

Complement inhibition with an anti-C5 monoclonal antibody prevents acute cardiac tissue injury in an ex vivo model of pig-to-human xenotransplantation.

Prevention of hyperacute xenograft rejection in the pig-to-primate combination has been accomplished by removal of natural antibodies, complement depletion with cobra venom factor, or prevention of C3 activation with the soluble complement inhibitor sCR1. Although these strategies effectively prevent hyperacute rejection, they do not address the relative contribution of early (C3a, C3b) versus late (C5a, C5b-9) activated complement components to xenogeneic organ damage. To better understand the role of the terminal complement components (C5a, C5b-9) in hyperacute rejection, an anti-human C5 mAb was developed and tested in an ex vivo model of cardiac xenograft rejection. In vitro studies demonstrated that the anti-C5 mAb effectively blocked C5 cleavage in a dose-dependent manner that resulted in complete inhibition of both C5a and C5b-9 generation. Addition of anti-C5 mAb to human blood used to perfuse a porcine heart prolonged normal sinus cardiac rhythm from a mean time of 25.2 min in hearts perfused with unmodified blood to 79,296, or > 360 min when anti-C5 mAb was added to the blood at 50 micrograms/ml, 100 micrograms/ml, or 200 micrograms/ml, respectively. In these experiments, activation of the classical complement pathway was completely inhibited. Hearts perfused with blood containing the highest concentration of anti-C5 mAb had no histologic evidence of hyperacute rejection and no deposition of C5b-9. These experiments suggest that the activated terminal complement components C5a and C5b-9, but not C3a or C3b, play a major role in tissue damage in this porcine-to-human model of hyperacute rejection. They also suggest that targeted inhibition of terminal complement activation by anti-C5 mAbs may be useful in clinical xenotransplantation.

Acute Disease↗
PubMed1988

Chronic meningococcal meningitis. An association with C5 deficiency.

A 44-year-old man with a history of presumed meningococcal meningitis 32 years before, presented with a three-month illness, characterized by fever, 13.5-kg (30-lb) weight loss, occipital headache, shoulder pain, and muscle weakness, which had been diagnosed as "polymyositis" and treated accordingly. Evaluation revealed meningococcal meningitis due to serogroup W135 and a C5 deficiency. Evidence for the occurrence of chronic meningococcal meningitis is described.

Adult↗
PubMed1992

C5 deficiency in A/J mice is not associated with resistance to the development of secondary amyloidosis.

The aim of the study was to determine whether C5 deficiency in the mouse is associated with resistance to the development of secondary amyloidosis. Chronic inflammation was induced in the F2 progeny, derived from matings between amyloid-susceptible and amyloid-resistance mice, by daily injections of azocasein for thirty days. Using a restriction fragment length polymorphism generated by digestion of genomic DNA with the restriction enzyme HindIII, C5 sufficient and deficient DNA can be clearly differentiated. Eight mice were found to be C5 sufficient, 32 were heterozygotes and 14 were found to be C5 deficient. Grading of the splenic amyloid load from negative to 4+ was performed after staining tissue squashes with Congo red and viewing them under a polarizing microscope. Seventeen mice were noted to have negative to trace, 18 had moderate (1+ - 2+) and 19 had heavy (3+ - 4+) amyloid deposition. There was no correlation between splenic amyloid load and C5 deficiency. Based on these results it is clear that C5 deficiency and resistance to secondary amyloidosis are not associated.

Amyloid↗
PubMed2001

Hepatocyte nuclear factor 1alpha controls the expression of terminal complement genes.

The terminal components of the complement system contribute to host defense by forming the multiprotein membrane attack complex (MAC) which is responsible for cell lysis and several noncytotoxic effects. Most of the complement proteins are synthesized in the liver, but the mechanisms controlling their tissue-specific expression have not been elucidated. In this study we show that mice lacking the hepatic transcription factor hepatocyte nuclear factor 1alpha (HNF1alpha) fail to transcribe C5 and C8A complement genes. In addition, mRNAs encoding for several other terminal complement components or subunits are expressed at lower levels, including C8beta, C8gamma, and C9. We next used a reconstitution assay involving human sera with selective complement deficiencies to assess mouse complement activity. Sera from HNF1alpha-deficient mice showed negligible hemolytic activity of both C5 and C8alpha-gamma subunits. The activity of C8beta was severely affected despite only a 50% reduction in C8beta mRNA levels in the liver. This is reminiscent of C8alpha-gamma-deficient patients who accumulate extremely low levels of the C8beta subunit. Our results demonstrate that HNF1alpha plays a key role in the expression of C5 and C8A genes, two terminal complement component genes that are essential for the assembly of MAC as a result of complement activation.

Animals↗
PubMed1989

In-vitro lysis of sensitized Trypanosoma cruzi by platelets: role of C3b receptors.

Incubation of Trypanosoma cruzi bloodstream trypomastigotes (Btrys) with C5-deficient blood in the presence of anti-T. cruzi immune mouse serum (IMS) or its IgG fraction resulted in an immediate formation of small clumps in which one could easily see platelets adhered to the parasites. After 4 h of incubation most of the clumps had disappeared and the number of the parasites was considerably reduced. Twenty-four hours later there were only a few remaining parasites. This same sequence of events was also observed when the parasites were incubated with isolated platelets in presence of IMS or its IgG fraction. When the parasites were incubated with plasma in the presence of IMS or its IgG fraction but in the absence of platelets there was strong agglutination of the parasites but no reduction in their number. Incubation of the parasites with platelets and IMS or its IgG fraction in C3-depleted plasma prevented adherence of the platelets to the parasites and their subsequent lysis. It is concluded that platelets are able to induce in-vitro lysis of the Btrys and that this phenomenon is dependent on the platelet' receptor for C3b.

Agglutination↗
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↗
PubMed1989

Identification of receptor-binding residues in the inflammatory complement protein C5a by site-directed mutagenesis.

C5a is an inflammatory mediator potentially involved in a number of diseases. To help define which of its 74 residues are important for receptor binding and response triggering, changes in the amino acid sequence of C5a were introduced by site-directed mutagenesis. Synthetic C5a-encoding genes incorporating point mutations were expressed in Escherichia coli, and the mutant proteins were purified to homogeneity. Modifications of the C5a molecule causing parallel reductions in binding to polymorphonuclear leukocyte membranes and in stimulation of polymorphonuclear leukocyte locomotion (chemokinesis) suggest that carboxyl-terminal residues Lys-68, Leu-72, and Arg-74 interact with the receptor. Substitutions in the disulfide-linked core of C5a revealed involvement of Arg-40 or nearby residues, because potency losses were associated with only localized conformational changes as detected by NMR. Surprisingly, a substitution at core residue Ala-26, which did not alter C5a core structure, appeared from NMR results to reduce potency by causing a long-distance conformational change centered on residue His-15. Thus, at least three discontinuous regions of the C5a molecule appear to act in concert to achieve full potency.

Amino Acid Sequence↗
PubMed1976

Complement-mediated acinar cell necroses in pancreatitis induced by basement membrane antibodies.

To study the role of the serum complement system in the early necrosis of acinar cells an acute pancreatitis was produced by injection of basement membrane antibodies into the pancreatic duct of mice and rats. In all animals deposition of complement (C3) and antibasement membrane IgG could be observed in an identical position within areas of acinar cell necrosis. The extent of parenchymal damage and the intensity of complement deposits corresponded to the injected dose of antibodies. The importance of cytolytically active complement components (C5-9) was demonstrated in congenitally C5-defective old line mice which did not show typical centrolobular necroses 1 hr after intraductal injection of antibodies. However, the normocomplementemic mice developed extensive necroses of acinar cells. The results support the hypothesis of a complement-induced acinar cell necrosis in acute pancreatitis.

Acute Disease↗
PubMed1982

A comparative evaluation of receptor reactivities for C3b, iC3b, and C3d on Raji lymphoblastoid cells.

Raji cells were described to carry receptors for iC3b, C3d, C3b-beta 1 H and beta 1 H. Controversial opinions, however, exist whether or not these cells carry also receptors for C3b. Using highly purified C3, definitely devoid of beta 1 H and C5, for preparation of C3b intermediates, it could be shown that Raji cells bound to C3b cells. Furthermore, Raji cells reacted with monoclonal antibodies that interfered with binding of C3b to human erythrocytes, lymphocytes and renal cells. The receptor for C3b on Raji cell, however, exhibited some special properties and, therefore, required some distinct experimental conditions for its detection: (1) The origin of the erythrocytes used for preparation of the C3b intermediates seemed to be important; this was not the case when iC3b and C3d receptor reactivity was assessed. (2) Rosettes already formed between Raji cells and EAC1423b showed the tendency to disintegrate within the first 30 min after the rosette formation assay. Again, this effect could not be observed with iC3b- and C3d-dependent rosette formation. (3) Incubation of the Raji cells at 37 degrees C as well as 4 degrees C before rosette formation resulted in a rhythmic loss and reappearance of C3b receptor reactivity. At room temperature (19-22 degrees C) this effect was much less expressed. There was no influence of preincubation at 4 and 37 degrees C, respectively, on the iC3b and C3d receptor reactivity of Raji cells. (4) Diisopropylfluorophosphate (DFP) present during rosette formation enhanced, within a certain range of concentration, the percentage of C3b-dependent rosette formation. iC3b and C3d receptor reactivity was not influenced. A similar reaction pattern was observed with pokeweed mitogen (PWM)-stimulated tonsil lymphocytes. In the concentrations tested, DFP showed no effect on the rosette formation between C3b, iC3b, and C3d cells, respectively, and unstimulated tonsil lymphocytes. The data presented suggest that C3b receptors on Raji cells undergo some special metabolism, possibly controlled by fluid phase or cell-bound proteases. This might be a common property of C3b receptors on blast-like and transformed cells, differing from that of unstimulated small lymphocytes.

Binding Sites, Antibody↗
PubMed1975

Role of complement components in the susceptibility to Plasmodium berghei infection among inbred strains of mice.

Inbred strains of mice, sensitive and resistant to Plasmodium berghei infections, including a complement deficient strain were infected with P. berghei. Daily levels of parasitaemia were determined and serum levels of complement components (C3 and C5) measured by standard haemolytic assay. Serum levels of C3 and C5 were depressed in all strains of mice infected with P. berghei. There was no difference in the infectivity and course of P. berghei infection in the co-isogenic C5 deficient and non-deficient strains. The significance of these observations is discussed.

Agglutination Tests↗
PubMed1980

Leukopenia, hypoxia, and complement function with different hemodialysis membranes.

Complement activation during exposure of plasma to cuprophan has been postulated to cause leukopenia and hypoxia in hemodialysis patients. To determine if hypoxia is related to leukopenia and if complement activation leads to a depletion of functional complement components, we dialyzed four patients three times sequentially against each of four types of membranes: cuprophan, regenerated cellulose, cellulose acetate, and polyacrilonitrile. Within 20 min there was a marked leukopenia with cuprophan from 5541 +/- 376 to 1216 +/- 94 (P less than 0.001) and with regenerated cellulose from 5541 +/- 411 to 1533 +/- 203 (P less than 0.001). With cellulose acetate, the change from 5558 +/- 400 to 3783 +/- 341 (P less than 0.001) was less dramatic, and with polyacrilonitrile the fall from 5591 +/- 381 to 464 +/- 401 (P less than 0.02) was minimal. After 2 and 4 hours of dialysis, a rebound leukocytosis was seen with cuprophan, regenerated cellulose, and cellulose acetate, but not with polyacrilonitrile. Transient thrombocytopenia occurred with cuprophan and regenerated cellulose. In spite of the variable degree of leukopenia, all membranes induced a similar and significant hypoxia, which was progressive throughout dialysis, even during the rebound leukocytosis. After 4 hours, the mean PO2 ranged from 91 to 93 mm Hg with all membranes. Functional hemolytic titers of whole complement, C3, C5, and C4 were normal prior to hemodialysis and failed to decrease after 4 hours with any membrane. It is concluded that hemodialysis leukopenia is membrane-dependent and is not the cause of hypoxia. In addition, hemodialysis complement activation does not lead to functional complement depletion and is of no clinical significance.

Adult↗
PubMed1988

Complement C5a receptor antagonism by protamine and poly-L-Arg on human leukocytes.

It is shown that protamine selectively and dose-dependently inhibits complement C5a-induced leukocyte responses such as histamine release from basophils, chemiluminescence and beta-glucuronidase release from neutrophils. Protamine produces parallel rightward displacements of the C5a dose-response curves. The inhibitory capacity of the polypeptide is reversible and disappears following repeated washing of exposed cells. In neutrophils poly-L-Arg similarly and specifically antagonizes C5a-induced chemiluminescence and enzyme release. This polymer alone, however, degranulates basophils and neutrophils, leading to histamine and enzyme release, respectively. It is concluded that on human neutrophils the arginine-rich polycations protamine and poly-L-Arg exhibit a competitive C5a receptor antagonism. In addition, protamine inhibits the C5a receptors on basophils. It is hypothesized that molecular conformations of the arginine-rich polycations might bind reversibly to, and block negatively charged groups at the C5a-receptor sites.

Basophils↗
PubMed1995

Anti-C5 monoclonal antibody therapy prevents collagen-induced arthritis and ameliorates established disease.

Activated components of the complement system are potent mediators of inflammation that may play an important role in numerous disease states. For example, they have been implicated in the pathogenesis of inflammatory joint diseases including rheumatoid arthritis (RA). To target complement activation in immune-mediated joint inflammation, we have utilized monoclonal antibodies (mAbs) that inhibit the complement cascade at C5, blocking the generation of the major chemotactic and proinflammatory factors C5a and C5b-9. In this study, we demonstrate the efficacy of a mAb specific for murine C5 in the treatment of collagen-induced arthritis, an animal model for RA. We show that systemic administration of the anti-C5 mAb effectively inhibits terminal complement activation in vivo and prevents the onset of arthritis in immunized animals. Most important, anti-C5 mAb treatment is also highly effective in ameliorating established disease. These results demonstrate a critical role for activated terminal complement components not only in the induction but also in the progression of collagen-induced arthritis and suggest that C5 may be an attractive therapeutic target in RA.

Animals↗
PubMed1990

Pulmonary clearance and phagocytic cell response in a murine model of Branhamella catarrhalis infection.

C5-sufficient Swiss-Webster mice (C5+) and C5-deficient DBA/2J mice (C5-) when challenged endotracheally with 2 x 10(7) cfu of Branhamella catarrhalis rapidly clear the lungs of viable bacteria in 48 h. This rapid clearance correlates with a striking influx of polymorphonuclear neutrophils that is of equal magnitude in both C5+ and C5- animals. Supernatant from Todd-Hewitt broth culture of B. catarrhalis exhibits in vivo chemotactic activity in the murine lung and in vitro chemotactic activity in Boyden chambers. The ability of B. catarrhalis to recruit granulocytes, independent of complement, may suggest a role for this organism in promoting protease-mediated lung destruction.

Animals↗