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PubMed1995

Complement component C7 is a plasminogen-binding protein.

Ab deposition, whether by reaction with the specific Ag or by preformed immune complexes, is followed by activation and deposition of complement components. Tissue destruction is observed in the Ab- and complement-induced lesions. The proteolytic enzyme plasmin is thought to participate in the Ab- and complement-mediated organ pathology. Plasmin is generated from plasma-derived plasminogen by cell-derived plasminogen activators (PAs). Two types of PAs are known, urokinase-type PA (uPA) and tissue-type PA (tPA). We investigated whether the PA system and the complement system can interact to promote local plasmin generation. Among the terminal complement components C5b6, C7, C8, and C9, the nonenzymatic component C7 is a plasminogen-binding protein. Radioligand binding studies revealed that the isolated component, as well as C7 after its incorporation into the terminal complement complex C5b-9, can bind plasminogen. Binding was inhibited by the lysine analogues 6-aminohexanoic acid and tranexamic acid, implicating the lysine binding sites of plasminogen into the binding interaction. tPA-mediated plasminogen activation was enhanced in the presence of C7. Based on these findings, an interaction is proposed between the complement system and the plasminogen activator system; a mechanism that may focus plasmin activity to structures that have been tagged by Ab and complement deposition.

Autoradiography↗
PubMed1975

Platelet aggregation induced by anaphylatoxin and its inhibition.

Anaphylatoxin (AT), a splitting product of the fifth component of the complement system can be prepared by incubation of rat plasma with low-molecular weight dextran (MW 2000) at 37 degrees C, or by treatment with cobra venom factor. Using the turbidimetric method of Born the effect of AT was studied on platelets from man, dog, rabbit, cat, guinea pig, and rat. AT was found to induce aggregation only in platelet rich plasma from cat and guinea pig. This aggregation could be reduced by several known inhibitors of aggregation and platelet function, such as phentolamine, tosylarginine-methylester (TAMe), p-chloromercuribenzoate (PCMB), and ethylenediamine-tetraacetic acid (EDTA) whereas adenosine, methysergide-bimaleinate, and mepyramine-maleate proved to be ineffective. Experiments with PCMB and TAMe suggest a release reaction induced by AT. Further more, there is evidence that with platelets from guinea pigs AT produces some tachyphylactic state.

Adenosine↗
PubMed1976

Potentiation of C56-initiated lysis by leucocyte cationic proteins, myelin basic proteins and lysine-rich histones.

Synthetic polycations such as poly-L-lysine (PLL) have recently been shown to enhance C56-initiated lysis by neutralization of serum-derived inhibitors of the C567 complex, collectively designated C567-INH. In the present report we have examined the effect of several naturally occurring polycations on C56-initiated lysis. Lysosomal granule extracts from rabbit peritoneal exudate cells were found to potentiate C56-initiated lysis via counteraction of C567-INH in the fluid phase; this was dependent upon the amount of C567-INH present and independent of cell concentration. The basic proteins of guinea-pig, bovine, and monkey myelin as well as lysine-rich histones also potentiated EC567 formation, but this effect seemed to occur predominantly at the cell surface. The presence of biologically derived cationic proteins at sites of complement activation during inflammation thus might lead to enhanced tissue damage by favouring the formation of cell-C567 intermediates by either or both of these mechanisms.

Animals↗
PubMed1993

Use of C6-deficient rats to evaluate the mechanism of hyperacute rejection of discordant cardiac xenografts.

C plays a critical role in the hyperacute rejection (HAR) of discordant xenografts (Xg), but the relative contribution of early vs late C components is unknown. In this study, genetic differences in C6 activity were correlated with HAR of guinea pig cardiac Xg by the rat. Seven rat strains were tested for C activity. Six strains (PVG.R1 (R1), PVG.1A (1A), DA, W/F, F344, LEW) had readily detectable C activity in the total and alternative pathways. Some PVG rats also had adequate C activity [PVG (C+)] but others [PVG (C-)] had a profound C6 deficiency. All rats with adequate C activity (n = 35) rejected cardiac Xg between 15 and 80 min. PVG (C+) (n = 6) rats also rejected cardiac Xg hyperacutely (26 +/- 12 min), whereas PVG (C-) (n = 16) rats, which had high preformed IgM natural antibody titers, rejected cardiac Xg in 1 to 2 days (2678 +/- 542 min). Transfer of serum from R1 rats to PVG (C-) recipients with vigorously beating Xg caused HAR of cardiac Xg within 116 +/- 75 min. Transfer of fresh PVG (C-) serum or heat-inactivated R1 serum did not induce HAR. HAR was characterized by intravascular platelet aggregation and interstitial hemorrhage, whereas Xg transplanted to PVG (C-) recipients had patent vessels at 30 min but were heavily infiltrated by granulocytes and monocytes at 2 days. These findings indicate that a deficiency in C6 prevents HAR but allows an accelerated acute rejection that may be mediated by the generation of vasoactive and chemotactic C3a and C5a.

Animals↗
PubMed1993

Low-antigen-content diet in the treatment of patients with IgA nephropathy.

Since dietary macromolecular antigens can be involved in the pathogenesis of IgA nephropathy (IgAN), the effect of a low-antigen-content diet was evaluated in 21 patients (10 women, 11 men, mean age 27.7 +/- 10 years) with immunohistochemical findings of active IgAN. The diet was followed for a 14-24-week period (mean 18.8 +/- 6); in all cases the effects of the treatment were evaluated by clinical and serological parameters, and in 11 patients also by repeat renal biopsy. After dietetic therapy a significant reduction of urinary proteins was recorded (P < 0.001); in particular, heavy proteinuria (> 1 g/day), present in 12 cases during the 6 months preceding the treatment, was markedly reduced or disappeared in 11. At post-treatment control biopsy mesangial and parietal deposits of immunoglobulins, complement C5 fraction and fibrinogen were significantly reduced. The improvement of the objective parameters such as heavy proteinuria, a strong predictor of a poor prognosis, and of immunohistochemical alterations indicate that a low-antigen diet can positively affect patients with IgAN. These results could be ascribed to a reduction of nephritogenic food antigen input and to a putative functional restoration of the mononuclear phagocytic system.

Adolescent↗
PubMed1977

Histamine-induced inhibition of normal human basophil chemotaxis to C5a.

Histamine in concentrations as low as 10(-8) M inhibited the chemotactic response of normal human basophils to C5a. Histamine had no effect on basophil chemotaxis to lymphocyte-derived chemotactic factor. Histamine inhibition of basophil chemotaxis to C5a was prevented by metiamide, a drug which blocks H2 receptors for histamine. Since the accumulation of basophils in delayed cutaneous basophilic hypersensitivity (CBH) reactions may occur in part because of chemotaxis to C5a, and since C5a can induce histamine release, histamine inhibition of chemotaxis may limit basophil infiltration in CBH lesions.

Basophils↗
PubMed1993

Differences in expression of lupus nephritis in New Zealand mixed H-2z homozygous inbred strains of mice derived from New Zealand black and New Zealand white mice. Origins and initial characterization.

BACKGROUND: F1 hybrids of New Zealand Black (NZB) and New Zealand White (NZW) mice develop autoimmune glomerulonephritis resembling human lupus nephritis. Susceptibility to this complex autoimmune syndrome in humans and mice has been linked to genes mapping in or near the major histocompatibility complex that govern immune responses and levels of certain complement components. Previous studies showed that both parental strains contribute major histocompatibility complex-linked genes that are important for disease of the F1 hybrid. EXPERIMENTAL DESIGN: New inbred strains of New Zealand Mixed (NZM) mice were derived by selective inbreeding of progeny of a cross between NZB and NZW mice. Twelve of the 27 new NZM strains were selected for analysis. Mice were observed for up to 10 months of age to document the occurrence of nephritis and strain-specific differences in disease expression. H-2, Hc, and coat color loci were determined for each strain to establish homozygosity of NZB and NZW polymorphic markers. Strains were screened for the presence of anti-dsDNA autoantibodies. RESULTS: In some NZM strains early onset of lupus nephritis in females resembled the (NZB x NZW)F1 model, whereas in other strains early disease also occurred in males. Age at death and severity of nephritis vary among the lines; a few strains remain relatively free of glomerular lesions. Histocompatibility (H-2) typing showed that all strains are homozygous for the NZW haplotype (Ku, Au, Sz, Dz). Coat color analysis for four loci on chromosomes 2, 4, and 7 was consistent with specific reassortments and recombinations to explain the grey, tan, and white mice with red/pink eyes and the presence or absence of the fifth component of serum complement (C5) (Hc, chromosome 2). Anti-dsDNA autoantibodies were found in all but one of the NZM strains reported here. CONCLUSIONS: The NZM strains of mice are a unique set of inbred strains that have inherited various genomic segments of the two parental strains that lead to phenotypic differences in disease expression. These results indicate that the previously proposed strict requirement for H-2 heterozygosity for the development of nephritis in the (NZB x NZW)F1 hybrid mice may not be valid. It is assumed that both the Lpn-1 locus of NZB and the Lpn-2 locus of NZW and a sufficient number of other disease-associated genes of both ancestral strains have been recombined in these new strains to produce the various patterns of renal disease.

Animal Husbandry↗
PubMed1996

Signaling by hemolytically inactive C5b67, an agonist of polymorphonuclear leukocytes.

The hemolytically inactive complement component complex C5b67, designated iC5b67, can signal human polymorphonuclear leukocytes (PMN) both as a pertussis toxin-inhibitable agonist for chemotaxis and as an antagonist for C5a- and FMLP-stimulated chemotaxis and superoxide production. The signaling pathways utilized by iC5b67 have been further investigated. In contrast to mastoparan, iC5b67 failed to directly activate G proteins to stimulate inositol phosphate formation in COS cells that had been transfected with G alpha 16. In COS cells co-transfected with both G alpha 16 and the C5a receptor, iC5b67 could neither activate phospholipase C nor inhibit C5a receptor-mediated activation of phospholipase C. iC5b67 stimulated GTPase activity in a membrane-enriched fraction from PMN. These data support the hypothesis that iC5b67 signals through a unique receptor, likely G protein linked, but distinct from the C5a receptor. iC5b67 was able to mobilize intracellular stores to elicit increases in intracellular Ca2+. Based on the effects of herbimycin A, wortmannin, and chelerythrine on iC5b67-induced PMN chemotaxis, iC5b67 signaling involved activation of tyrosine and phosphatidylinositol 3-kinases, but not protein kinase C. Relevant to the capacity of iC5b67 to antagonize PMN superoxide production, iC5b67 induced rapid and sustained increases in intracellular cAMP, which others have shown can inhibit superoxide formation. Although iC5b67 antagonizes C5a and FMLP receptor-mediated superoxide generation, iC5b67 had no effect on PMA-induced superoxide formation. The distinct agonist and antagonist signaling pathways activated by iC5b67 in the PMN diverge soon after initial iC5b67 receptor-mediated transduction steps.

Alkaloids↗
PubMed1977

Complement system in human colostrum: presence of nine complement components and factors of alternative pathway in human colostrum.

Evidence has been obtained for the presence in human colostrum of all nine components of complement (C), C1 through C9, and factors of the alternative pathway. Samples of colostrums collected from five women at 1-4 days after normal parturition were assayed for the haemolytic activities of individual components. As compared with normal human sera, the activities of each component ranged from 0.03 to 7% of those in sera. The activities of C4, C7 and C9 were relatively high, while that of C1 was extremely low. In most of the cases, the activities of individual components gradually increased following delivery, when expressed as the activity per unit weight (g) of protein in the colostrum. When the colostrums were treated with cobra venom factor, most of the colostrums showed 10-20% reduction in the C3 activity. This finding indicates the presence of factors such as B and D which are involved in the activation of C through the alternative pathway. The role as a defense factor of the C system in human colostrum and milk is discussed in connection with the ability of secretory IgA to react with C.

Colostrum↗
PubMed1996

Mechanisms and kinetics of the synthesis and release of platelet-activating factor (PAF) by polyacrylonitrile membranes.

Platelet-activating factor is a recognized mediator of anaphylaxis and bioincompatibility. Here, the mechanisms and the kinetics of the production of platelet-activating factor were studied in vivo during high-flux hemodialysis and in vitro in a recirculation model with polyacrylonitrile membranes, the AN-69 and the more recent SPAN, where the Na-metallilsulfonate group is partially substituted with the less polar methacrylate group. In in vivo studies, eleven patients were studied in cross over. Patients were randomly allocated to the AN-69 (5 patients) and to the SPAN membrane (6 patients) for two weeks. Measurements were made in the second week of use. After completion of the second week, the patients were switched to the other membrane for a further two weeks. Samples for leukocyte and platelet counts, PAF in whole blood or bound to platelets, the C3a des Arg and the C5b-C9 membrane attack complex as well as samples for clearances of urea, creatinine and phosphates were taken at different time intervals during treatment. PAF was detected by biological assay after methanol extraction of whole blood or of platelet pellets obtained by sequential centrifugation. C3a des Arg and the C5b-C9 fraction were detected by commercially available immunoassays. Results were analyzed by Minitab statistical package. PAF was detectable only during treatment with AN-69 but not with SPAN 1 min after start of the extracorporeal circulation in both whole blood (4.5 +/- 2.7 ng/ml) and on platelet surface (4.1 +/- 1.2 ng/ml). No statistical significant differences were observed between AN-69 and SPAN with regard to leukocyte and platelet counts, plasma C3a des Arg and C5b-C9 levels. The structure modification did not alter functional performances as indicated by the lack of statistically significant differences in clearance values between the two membranes. In in vitro experiments performed with normal washed and whole blood recirculated in a closed circuit demonstrated the presence of a plasma-dependent, complement-independent mechanisms responsible for the triggering of PAF synthesis and release with AN-69 but not SPAN membrane. PAF was extractable from the inner and outer side of both polyacrylonitrile membranes (AN-69: inner, 4.9 +/- 0.5 ng/ml; outer, 0.1 +/- 0.05 ng/ml; SPAN: inner, 5.5 +/- 0.6 ng/ml, outer: 3.3 +/- 0.7 ng/ml, SPAN vs. p < 0.001), suggesting that absorption may be relevant with both membranes.

Acrylic Resins↗
PubMed1977

Properties of a factor increasing monocytopoiesis (FIM) occurring in serum during the early phase of an inflammatory reaction.

A factor increasing monocytopoiesis (FIM) has been demonstrated during the onset of an acute inflammatory reaction caused by an intraperitoneal injection of polystyrene latex particles. It is protein in nature, does not contain a carbohydrate moiety essential for its function, and is very probably not a glycoprotein. The molecular weight of FIM lies between 18,000 and 24,000 daltons (determined with both ultrafiltration membranes and gel filtration on Sephadex G100). The monocytosis induced by FIM is dose dependent. FIM is thermolabile, having a half-time of about 20 min at 37 degrees C in serum; temperature inactivation can be delayed by the addition of epsilon-aminocaproic acid, the half-time at 37 degrees C then being about 45 min. In vitro treatment of normal murine blood with the inducers of the inflammatory reaction does not result in FIM activity in the serum. FIM dose not have chemotactic activity toward macrophages, is not a clotting factor, is not a biologically active fragment of the complement system, and has no colony-stimulating or-enhancing activity in the vitro bone marrow colony assay. On the basis of these results, a mechanism is postulated for the humoral regulation of monocytopoiesis.

Aminocaproic Acid↗
PubMed1996

[Molecular analysis of experimental membranous glomerulonephritis (Heymann nephritis)].

Heymann nephritis is an extensively studied experimental model of human membranous nephropathy, a currently barely treatable glomerular immune disease. Several basic concepts were discovered by the study of this experiment disease, such as in situ formation of immune deposits, and the roles of the complement system and of oxygen radicals in the development of proteinuria. The major goal of our studies is to develop specific therapies for the experimental and eventually also for the human disease, based on the detailed knowledge of the molecular pathogenic mechanisms. The target of immune deposit forming antibodies was identified as a large membrane glycoprotein with structural similarities with the LDL-receptor. This protein serves as polyspecific receptor, and its intriguing properties in different organs have developed into a separate area of research. Sofar the precise amino acid sequences of several epitopes for the nephritogenic antibodies were identified, thus offering the unique possibility to develop precisely targeted specific therapeutic strategies. Here we link the mechanisms of immune deposit formation with the development of proteinuria.

Animals↗