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PubMed1997

Complement and glutamate neurotoxicity. Genotypic influences of C5 in a mouse model of hippocampal neurodegeneration.

Using mice genetically deficient in the complement (C)-system component C5, this study explored a potential novel role of the C-system in Ca(2+)-mediated control of glutamate AMPA receptor functions. We found that Ca2+ preincubation of frozen brain tissue sections enhances AMPA binding capacity more dynamically in C5 deficient (C5-) than congenic C5 sufficient (C5+) mice. The Ca(2+)-mediated response was mostly localized to the CA3 and CA1 subdivisions of the pyramidal layers of the hippocampal formation. In C5- mice, kainic acid (KA) excitotoxicity that models hippocampal neurodegeneration abolished the Ca(2+)-mediated induction of hippocampal AMPA binding. The changes in AMPA binding preceded temporally and overlapped anatomically the appearance of apoptotic features in the same hippocampal neuron layers. C5- mice showed greater hippocampal neurodegeneration then C5+ mice. NMDA binding controlled for specificity of glutamate-mediated changes and found no C5 genotypic influences. The study gives further credence to the role of the C-system in modifying the intensity and outcome during response to conditions leading to hippocampal neurodegeneration.

Animals↗
PubMed1988

Identification of a human C5 beta-chain epitope exposed in the native complement component but concealed in the SC5b-9 complex.

Monoclonal antibodies obtained after immunization of mice with human C5 were screened for activity against native C5 and SC5b-9. Clone 568 reacted with the C5 beta-chain in western blotting and with purified native C5 in double antibody enzyme immunoassays. The reactivity of clone 568 against serum decreased markedly when serum was activated with zymosan. The residual activity was found to be against free C5, whereas the antibody did not react at all with the SC5b-9 complex. Thus, the antibody 568 reacts with an activation-dependent C5 epitope, which is concealed when C5 is incorporated into the terminal complement complex.

Animals↗
PubMed1972

Fatal anaphylaxis-like reaction induced by yeast mannans in nonsensitized mice.

Some yeast mannans increased vascular permeability and caused anaphylaxis-like reactions, fatal in some cases, in nonsensitized CFW mice. In SWR mice deficient in the complement system component C5, anaphylactic shock did not develop after the injection of mannans but was readily induced by goat serum after the mice had been sensitized with Bordetella pertussis and goat serum. The observed biological activity of the yeast mannans appears to depend upon the alpha(1 --> 2) and alpha(1 --> 6) linkages in their main chain. Their relative inactivity in C5-deficient mice and the consumption of whole hemolytic complement after their addition to normal mouse serum suggest that yeast mannans may activate late-acting complement components to produce anaphylatoxin from complement components C5 and C3.

Anaphylaxis↗
PubMed2001

Complement-dependent immune complex-induced bronchial inflammation and hyperreactivity.

Bronchoconstriction responses in the airway are caused by multiple insults and are the hallmark symptom in asthma. In an acute lung injury model in mice, IgG immune complex deposition elicited severe airway hyperreactivity that peaked by 1 h, was maintained at 4 h, and was resolved by 24 h. The depletion of complement with cobra venom factor (CVF) markedly reduced the hyperreactive airway responses, suggesting that complement played an important role in the response. Blockade of C5a with specific antisera also significantly reduced airway hyperreactivity in this acute lung model. Complement depletion by CVF treatment significantly reduced tumor necrosis factor and histamine levels in bronchoalveolar lavage fluids, correlating with reductions in airway hyperreactivity. To further examine the role of specific complement requirement, we initiated the immune complex response in C5-sufficient and C5-deficient congenic animals. The airway hyperreactivity response was partially reduced in the C5-deficient mice. Complement depletion with CVF attenuated airway hyperreactivity in the C5-sufficient mice but had a lesser effect on the airway hyperreactive response and histamine release in bronchoalveolar lavage fluids in C5-deficient mice. These data indicate that acute lung injury in mice after deposition of IgG immune complexes induced airway hyperreactivity that is C5 and C5a dependent.

Animals↗
PubMed2002

Thioglycollate peritonitis in mice lacking C5, 5-lipoxygenase, or p47(phox): complement, leukotrienes, and reactive oxidants in acute inflammation.

Leukotriene B(4) (LTB(4)) is an easily diffusible proinflammatory chemotactic factor that has been posited to prime the initial inflammatory response for the action of other mediators, including C5a. 5-Lipoxygenase-deficient (5LX(-/-)) and C5-deficient mice only generated about 50% as much peritoneal leukocytosis as wild-type mice following intraperitoneal (IP) challenge with the sterile irritant, thioglycollate (P<0.005). Pretreatment of C5- mice with the specific 5-lipoxygenase inhibitor, zileuton, reduced peritoneal leukocytosis to almost unstimulated levels, suggesting that LTB(4) can act independently of C5a. Previously, LTB(4) and C5a have been shown in vitro to be inactivated by metabolites of superoxide. In the current study, we examined the fate of LTB(4) in the p47(phox-/-) mouse model of chronic granulomatous disease (CGD) in which the phagocyte NADPH oxidase is unable to produce superoxide. p47(phox-/-) mice generated more thioglycollate-elicited peritoneal leukocytosis than wild-type mice. Pretreatment with zileuton caused a 76% reduction in peritoneal leukocytosis in p47(phox-/-) mice (P<0.005) and a 54% reduction in wild-type mice (P<0.05), whereas pretreatment with dexamethasone or toradol (a cyclooxygenase inhibitor) had no effect. Following IP LTB(4) (1 microg/mouse), total recovered peritoneal LTB(4) was similar between p47(phox-/-) and wild-type mice at 10 and 30 min, but was approximately fivefold greater in p47(phox-/-) mice at 180 min. These data suggest that LTB(4) and C5a have separate but overlapping roles in thioglycollate-elicited peritonitis, and at least the leukotriene component is, in turn, regulated by reactive oxidants.

Animals↗
PubMed1979

Digestion of the fifth component of complement by leukocyte enzymes. Sequential generation of chemotactic activities for leukocytes and for tumor cells.

Leukocytes contain within their lysosomal granules enzymatic activity that will generate from C5 chemotactic activity for leukocytes (neutrophils) and tumor (Walker carcinosarcoma) cells. Similar activity has been found in phagocytic supernatant fluids from neutrophils and in purified preparations of the leukocyte neutral proteases elastase and cathepsin G. White leukotactic activities can be generated from either the third (C3) or the fifth (C5) components of complement, only C5 serves as a source for generation of the chemotactic activity for tumor cells. As has been previously shown with trypsin, the C5-related chemotactic activities generated by leukocyte proteases are time-dependent: leukotactic activity appears early, then disappears, and is replaced by chemotactic activity for tumor cells. The generation of these chemotactic activities from C5 is blocked by prior treatment of leukocyte preparations with the neutral protease inhibitor Trasylol. The demonstration that enzyme activities from leukocytes have the ability to generate tumor cell chemotactic factors from C5 suggests a possible mechanism by which the development of metastatic lesions may be promoted at sites of tissue injury or inflammation.

Animals↗
PubMed1999

[Clinico-pathogenetic features of viral hepatitis A course].

AIM: To study mechanisms enhancing realization of autoimmune disorders in acute viral hepatitis A at initial stages. MATERIALS AND METHODS: 32 patients with moderate and 4 patients with severe VHA (17 females and 19 males, age from 15 to 38 years) verified by finding serum anti-HAV IgM at enzyme immunoassay (EIA) have undergone examination which included: measurement of beta 2-microglobulin, C5-components of complement, circulating immune complexes (CIC), zero lymphocytes; test for antinuclear antibodies (ANA) and smooth muscle antibodies (SMA). RESULTS: All the patients exhibited high levels of beta 2-microglobulin, zero lymphocytes, CIC, low concentration of C5-components of complement. SMA were detected at the height of intoxication in 27 patients, in early convalescence--in 31 patients. ANA were discovered only in one patient. CONCLUSION: The findings suggest development of autoimmune reactions in acute VHA patients. These reactions may trigger onset of autoimmune hepatitis.

Adolescent↗
PubMed1985

Enhanced complement-mediated lysis of type III paroxysmal nocturnal hemoglobinuria erythrocytes involves increased C9 binding and polymerization.

The interaction of terminal complement proteins (C5-C9) with normal erythrocytes and type III paroxysmal nocturnal hemoglobinuria erythrocytes (PNH-E) has been compared in terms of binding of the C5-9 complex, C9 polymerization, and C9 insertion into membranes. Complement components C5, C7, and C8 bind equally well to both types of erythrocytes, whereas the binding of C9 to PNH-E is 5-6 times greater than that to normal erythrocytes. The kinetics of C9 binding was compared with the kinetics of lysis for both types of cells under conditions leading to 100% lysis. There was a noticeable lag time between C9 binding and lysis of normal erythrocytes, but the lysis of PNH-E proceeded without a lag and the kinetics of lysis more closely paralleled C9 binding. The efficiency of C9 insertion was similar for both types of cells, but C9 polymerization was significantly enhanced on PNH-E. These data indicate that the enhanced susceptibility of type III PNH-E toward lysis by C5-9 can be correlated with abnormally high C9 binding and increased formation of poly(C9).

Carrier Proteins↗
PubMed1990

[Components of human complement system. Testing and isolation of C3 and C5].

Modified reagents for testing the hemolytic activity of human complement components, C3 and C5, have been obtained. These reagents were obtained by treatment of human blood serum pools with a saturated solution of KBr (reagent R3) or 2 M KSCN and denaturated yeasts (reagent R5). These reagents were found to be rich in the serum factor obtained through the use of DEAE-cellulose DE-52 and containing the active component of the complement (C4). To test the sensitivity and specificity of the above reagents, components C3 and C5 were purified. After this procedure these components emerged as hemolytically active, electrophoretically and immunophoretically homogeneous components, C3 and C5. DEAE-cellulose DE-52, DEAE-Sephacel, Hydroxylapatite and Ultra-gel AcA-34 were used consecutively as purification agents. The activity yields of components C3 and C5 with regard to the initial serum levels were 31% and 18%, respectively.

Chromatography, Gel↗
PubMed2001

Complement and myoblast transfer therapy: donor myoblast survival is enhanced following depletion of host complement C3 using cobra venom factor, but not in the absence of C5.

Myoblast transfer therapy (MTT) is a potential cell therapy for myopathies such as Duchenne Muscular Dystrophy and involves the injection of cultured muscle precursor cells ('myoblasts') isolated from normal donor skeletal muscles into dystrophic host muscle. The failure of donor myoblast survival following MTT is widely accepted as being due to the immune response of the host. The role of complement as one possible mechanism for the initial, very rapid death of myoblasts following MTT was investigated. Donor male myoblasts were injected into the tibialis anterior (TA) muscles of female host mice that were: (i) untreated; (ii) depleted of C3 complement (24 h prior to MTT) using cobra venom factor (CVF); and/or (iii) deficient in C5 complement. Quantification of surviving male donor myoblast DNA was performed using the Y-chromosome specific (Y1) probe on slot blots for samples taken at 0 h, 1 h, 24 h, 1 week and 3 weeks after MTT. Peripheral depletion of C3 was confirmed using double immunodiffusion, and local depletion of C3 in host TA muscles was confirmed by immunostaining of muscle samples. Cobra venom factor treatment significantly increased the initial survival of donor myoblasts, but there was a marked decline in myoblast numbers after 1 h and little long-term benefit by 3 weeks. Strain specific variation in the immediate survival of donor male myoblasts following MTT in untreated C57BL/10Sn, DBA-1 and DBA-2 (C5-deficient) female hosts was observed. Cobra venom factor depletion of C3 increased initial donor male myoblast survival (approximately twofold at 0 h) in C57BL/10Sn and DBA-1 host mice and approximately threefold in DBA-2 hosts at 0 h and 1 h after MTT. The rapid and extensive number (approximately 90%) of donor male myoblasts in untreated DBA-2 mice (that lack C5) indicates that activation of the membrane attack complex (MAC) plays no role in this massive initial cell death. The observation that myoblast survival was increased in all mice treated with CVF suggests that CVF may indirectly enhance donor myoblast survival by a mechanism possibly involving activated C3 fragments.

Animals↗
PubMed1980

Analysis of the different types of leukocyte membrane complement receptors and their interaction with the complement system.

The specificity, distribution, and structure of 8 different types of leukocytes membrane complement (C) receptors (CR1, CR2, CR3, and receptors for C1q, beta 1H, C3e, C3a, and C5a) are discussed. Recent data are reviewed on the synthesis of C components by macrophages and B lymphocytes, and how these components may function in the activation of these two cell type by the C system. Commonly used C receptor assay procedures are evaluated in terms of both specificity and sensitivity. Specific assay procedures are recommended for measuring CR1 (C4b-C3b receptor), CR2 (C3d receptor), CR3 (C3bi receptor), and the beta 1H receptor. Assays include both rosette and fluorescence procedures for detection of C receptors on either mouse or human leukocytes. Primary systems have been selected for optimal sensitivity and specificity, and where possible, acceptable alternative systems that are less sensitive or specific are suggested for laboratories lacking facilities for C purification.

Animals↗