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PubMed2000

Combined glomerular deposition of polymeric rat IgA and IgG aggravates renal inflammation.

BACKGROUND: IgA nephropathy (IgAN) is characterized by deposition in the glomerular mesangium of IgA together with C3, C5b-9, and properdin. IgG deposition as a risk factor in IgAN was recently confirmed by a long-term follow-up of patients with IgAN. We previously reported on an acute model of IgA-mediated glomerular inflammation in Wistar rats. METHODS: To investigate the effect of the combination of IgA and IgG on glomerular injury, Wistar rats were injected with a minimum dose of rat IgG in the presence or absence of a subnephritogenic dose of polymeric rat IgA. Subsequently, glomerular complement activation, influx of inflammatory cells, proteinuria, and hematuria were assessed. RESULTS: Administration of IgG to the rats resulted in maximal proteinuria of 20.3 +/- 12.1 mg/24 h on day 2 and an absence of overt glomerular inflammation. Administration of polymeric rat IgA antibodies to rats resulted in hematuria with a moderate mesangial complement deposition. In the combination group, however, glomerular deposition of C5b-9 was dramatically increased. This was accompanied by increased proteinuria as compared with rats receiving IgA or IgG antibody injections alone on day 7. Microhematuria occurred in rats receiving either polymeric rat IgA or IgG alone or the combination. While both rat IgG and polymeric IgA induced minor mesangial cell (MC) proliferation and MC lysis, the combination resulted in a pronounced, significant increased percentage of aneurysm formation on day 7 after injection. CONCLUSIONS: We conclude that in this model of IgA-induced glomerulopathy, a selective, complement-dependent glomerular inflammation is induced in Wistar rats by glomerular codeposition of rat isotypic monoclonal antibodies.

Animals↗
PubMedDate not supplied

Effects of centrifugation leukapheresis with hydroxyethyl starch on the complement system of granulocyte donors.

In granulocyte donors during centrifugation leukapheresis (CL), total hemolytic complement, Clq, C3, factor B, and properdin decreased, but only to the extent expected from hemodilution. Crossed immunoelectrophoresis showed no C3 conversion in plasma obtained from the leukapheresis appeared during CL or in donor plasma immediately after CL. When serum was incubated with hydroxyethyl starch, total hemolytic complement did not decrease and C3 conversion was not detected by crossed immunoelectrophoresis. This investigation revealed no evidence that complement activation is associated with CL.

Blood Donors↗
PubMed2001

Composition of nephritic factor-generated glomerular deposits in membranoproliferative glomerulonephritis type 2.

Two observations suggest that nephritic factors (NFs) may be nephritogenic. First, glomerulonephritis is present in unusual frequency in three conditions in which the function of factor H is blocked, a dysfunction also produced by NFS: Second, in membranoproliferative glomerulonephritis (MPGN) type 2, subepithelial deposits on the paramesangial portion of the glomerular basement membrane are found only in renal biopsy specimens obtained during hypocomplementemia when NF is presumably present. In the present study, the composition of these deposits with respect to C3 derivatives was assessed by immunohistological evaluation using anti-C3c and anti-C3d. The assessment used routinely obtained photomicrographs, as well as immunohistologic examination of freshly cut tissue using the double-antibody method. Deposits in patients with typical hypocomplementemic MPGN type 2 reacted only with anti-C3c, whereas those in two patients with rapidly progressive MPGN type 2, six patients with poststreptococcal acute glomerulonephritis, and five patients with juvenile acute nonproliferative glomerulitis reacted with anti-C3d, as well as anti-C3c. Because all products derived from the breakdown of C3 except C3c react with anti-C3d, the deposits in typical MPGN type 2 must be composed only of C3c. With complete breakdown of bound C3b, C3c is released into the fluid phase. Therefore, the C3c in the deposits cannot be a product of a glomerular complement reaction, but instead must be formed in the circulation by the reaction of NF with native C3. Supporting C3c as the only constituent of these deposits is the observation that they are devoid of properdin and C5 is present in only small amounts.

Antibodies, Monoclonal↗
PubMed1979

Immune response of a patient with deficiency of the fourth component of complement and systemic lupus erythematosus.

The clinical details of a five-year-old boy with systemic lupus erythematosus and an inherited deficiency of the fourth component of complement (C4) have been reported elsewhere. In this study of his immune responses, immunization with bacteriophage phi X 174 demonstrated diminished antibody formation, abnormal immunologic memory and failure to switch from IgM to IgG during secondary response. We also noted persistent lymphopenia and reductions in peripheral-blood T lymphocytes, lymphocyte responses to mitogens and allogeneic cells and granulocyte chemotaxis. Kinetic studies revealed that delayed activation of the alternative pathway was corrected by purified C4 only if the classical pathway was not blocked. This finding is consistent with the concept that minute amounts of C3b provided through the classical pathway are necessary to prime the properdin system. Inability to activate the classical complement pathway, abnormal kinetics of alternative-pathway activation and depressed antibody responses to a T-cell-dependent antigen may predispose C4-deficient patients to viral infection or immune-complex formation.

Antibodies, Bacterial↗
PubMed1975

A new complement function: solubilization of antigen-antibody aggregates.

Antigen-antibody aggregates are solubilized when incubated with fresh serum at 37 degrees, yielding immune-complexes of relatively small molecular weight which contain antigen, antibody, and complement (C3)determinants. Solubilization is complement-dependent,requires free Mg++ but not Ca++, and proceeds in sera from C4- or C5-deficient animals. It is accelerated in the presence of Ca++ in normal or C4-deficient guinea pig serum, suggesting involvement of the Cl-bypass activation of the properdin system. Immune precipitates can also be solubilized by monovalent fragments (Fab) of antibodies directed against determinants of the antibody molecules included in the antigen-antibody lattice. Similarly, it is suggested that complement-mediated solubilization might be induced by the combination of a complement fragment with the antibody in the immune-aggregate.

Animals↗
PubMed1979

Regulation of the amplification C3 convertase of human complement by an inhibitory protein isolated from human erythrocyte membrane.

An activity that is inhibitory to the properdin-stabilized amplification C3 convertase (C3b,Bb,P) was solubilized from human erythrocyte (E(hu)) membranes by Nonidet P-40 and purified to homogeneity. The inhibitory membrane glycoprotein had an apparent M(r) of 1-1.2x10(6) on gel filtration in the presence of Nonidet P-40. On sodium dodecyl sulfate/polyacrylamide gel electrophoresis it presented a single stained band with an apparent M(r) of 205,000, with or without prior reduction of disulfides. The inhibitory protein of the E(hu) membrane produced a dose-related, first-order decay of C3b,Bb,P function on sheep erythrocytes (E(s)) and released (125)I-labeled Bb from these sites, indicating a mechanism of inhibition by decay-dissociation of the amplification C3 convertase. The 50% inhibitory dose of the E(hu) membrane protein was not altered by removal of sialic acid from the E(s) bearing C3b,Bb,P sites. E(hu) membrane protein also serves as a cofactor for C3b inactivator-induced cleavage of the alpha polypeptide chain of C3b. Thus, the inhibitory membrane protein can abrogate the activity of amplification convertase sites that have formed and also can prevent generation of such sites by augmenting irreversible inactivation of C3b.Discrimination between cells by the alternative complement pathway occurs after initial deposition of C3b and is related to the modulation by surface constituents of the capacity of bound C3b to function as a subunit of the amplification C3 convertase. The existence in the E(hu) membrane of a protein that can impair the functions of membrane-bound C3b and C3b,Bb,P could represent a molecular basis for preventing inappropriate self-recognition.

Binding Sites↗
PubMed1981

Enzymatic treatment transforms trypomastigotes of Trypanosoma cruzi into activators of alternative complement pathway and potentiates their uptake by macrophages.

In the absence of bound antibody, trypomastigote bloodstream forms of Trypanosoma cruzi fail to activate the alternative complement pathway. We now demonstrate that treatment with trypsin and, to a lesser extent, with sialidase converts these protozoa into activators of the pathway, as judged by their lysis in normal sera or sera genetically deficient in fourth or second component of complement (C4 or C2) and their Mg2+-dependent consumption of C3 as measured by crossed immunoelectrophoresis. In addition, after pretreatment with enzyme and incubation in C5-deficient serum, trypomastigotes were shown to possess both C3 and properdin factor B (B) on their surface as judged by immunofluorescence. Requirement for the late components C5-C9 was suggested by the failure of C5-deficient sera to lyse trypsin-treated parasites. The inability to activate the alternative complement pathway was regained by these organisms after incubation in vitro. This restoration of insusceptibility was inhibited when puromycin was included in the culture medium. Treatment of the trypomastigotes with trypsin also potentiated their uptake by mouse peritoneal macrophages without apparent interference with their capacity to differentiate and multiply inside the cell. These findings suggest that untreated trypomastigotes normally escape recognition by the alternative pathway in vivo because of the presence on their surface of trypsin- and sialidase-sensitive regulatory molecules, the expression of which is dependent on protein synthesis.

Animals↗
PubMed1989

Conservation of structural and functional domains in complement component C3 of Xenopus and mammals.

The cDNA sequence and the deduced amino acid sequence of the Mr 34,000 C-terminal fragment of Xenopus laevis complement component C3 are presented. The sequence of Xenopus C3 has 57% nucleotide identity to the corresponding sequence of human C3 and approximately 49% amino acid identity to C3 from human, mouse, and rabbit. The Xenopus C3 sequence shows clusters of high and of low similarity to the mammalian C3 sequences. One of these regions of high similarity represents the domain of mammalian C3b involved in the binding of properdin, a regulator of the alternative pathway of complement activation. It is not clear whether the other highly conserved regions are involved in binding to other C3 ligands. The Xenopus C3 sequence completely lacks the Arg-Gly-Asp sequence, which has been suggested to be the recognition site of the human complement receptor type 3 on the iC3b fragment of human C3. The Xenopus C3 gene is shown not to be linked to the Xenopus major histocompatibility complex, as is also the case in mammals. Since the gene of the related molecule C4 is MHC-linked in both mammals and Xenopus, the C3 and C4 genes may have separated before Xenopus and mammals speciated.

Amino Acid Sequence↗
PubMed1997

cDNA cloning and expression of bovine procollagen I N-proteinase: a new member of the superfamily of zinc-metalloproteinases with binding sites for cells and other matrix components.

Procollagen N-proteinase (EC 3.4.24.14) cleaves the amino-propeptides in the processing of type I and type II procollagens to collagens. Deficiencies of the enzyme cause dermatosparaxis in cattle and sheep, and they cause type VIIC Ehlers-Danlos syndrome in humans, heritable disorders characterized by accumulation of pNcollagen and severe skin fragility. Amino acid sequences for the N-proteinase were used to obtain cDNAs from bovine skin. Three overlapping cDNAs had an ORF coding for a protein of 1205 residues. Mammalian cells stably transfected with a complete cDNA secreted an active recombinant enzyme that specifically cleaved type I procollagen. The protein contained zinc-binding sequences of the clan MB of metallopeptidases that includes procollagen C-proteinase/BMP-1. The protein also contained four repeats that are homologous to domains found in thrombospondins and in properdin and that can participate in complex intermolecular interactions such as activation of latent forms of transforming growth factor beta or the binding to sulfatides. Therefore, the enzyme may play a role in development that is independent of its role in collagen biosynthesis. This hypothesis was supported by the observation that in some tissues the levels of mRNA for the enzyme are disproportionately high relative to the apparent rate of collagen biosynthesis.

Amino Acid Sequence↗
PubMed1973

Quantitative studies of phagocytosis. Kinetic effects of cations and heat-labile opsonin.

Kinetic analysis of the initial ingestion rate of albumin-coated paraffin oil particles by human granulocytes and rabbit alveolar macrophages was undertaken to study the mechanism of action of cations and of heat-labile opsonin on engulfment. The rate of uptake of the particles was stimulated by Ca(++), Mg(++), Mn(++), or Co(++). At high concentrations (> 20 mM) Ca(++) and Mg(++) inhibited the rate of ingestion. Treatment of the particles with fresh serum (heat-labile opsonin) also stimulated the rate of ingestion. (125)I-labeled C3 was bound to the particles during opsonization. C3-deficient human serum lacked opsonic activity, which was restored by addition of purified C3. Normal, C2-deficient, and hereditary angioneurotic edema sera had equivalent opsonic activity. The serum opsonic activity thus involved C3 fixation to the particles by means of the properdin system. Although Mg(++) and heat-labile opsonin both accelerated the maximal rates of ingestion of the particles, neither altered the particle concentrations associated with one-half maximal ingestion rates. Opsonization of the particles markedly diminished the concentrations of divalent cations causing both stimulatory and inhibitory effects on ingestion rates and altered the shapes of the cation activation curves. (45)Ca was not bound to the particles during opsonization. The results are consistent with a mechanism whereby divalent cations and heat-labile opsonin activate ingestion by stimulating the work of engulfment rather than by merely enhancing cell-particle affinity, and whereby heat-labile opsonin acts by potentiating the effects of divalent cations.

Angioedema↗
PubMed1956

Phagocytin: a bactericidal substance from polymorphonuclear leucocytes.

A technique has been developed for collecting large numbers of polymorphonuclear leucocytes from peritoneal exudates in rabbits. These cells are obtained essentially free from other cell types and from debris. When microphages so procured are disrupted by physical methods and extracted with aqueous salt solutions, the soluble fraction manifests striking bactericidal activity, especially on Gram-negative enteric bacilli. The susceptible microorganisms are not lysed. This bactericidal substance, which has been called phagocytin, appears to be limited in distribution mainly to the polymorphonuclear leucocyte. No phagocytin is present in extracts of rabbit heart, kidney, or skeletal muscle, and rabbit liver and spleen contain much less than do packed leucocytes. Extracts of human and of guinea pig microphages show less bactericidal activity than rabbit cell preparations. Similar extracts of rat and mouse polymorphonuclear leucocytes contain no demonstrable phagocytin. As indicated by its behavior on dialysis, on exposure to proteolytic enzymes, and on salt fractionation, phagocytin appears to be a protein with general properties characteristic of a globulin. It is clearly different from lysozyme and from properdin. Although phagocytin is reasonably stable at temperatures of 65 degrees C. and lower for several hours, solutions of it gradually lose bactericidal activity on standing for prolonged periods at 4 degrees C. This instability, and also the ease with which phagocytin is inactivated, presumably by adsorption, on exposure to a variety of materials, have thus far rendered fruitless efforts to isolate it.

Animals↗
PubMed1958

Inactivation of endotoxin by a humoral component. II. Interaction of endotoxin with serum and plasma.

A humoral substance which inactivates endotoxin in vitro has been shown to be clearly distinguishable from complement, properdin, and specific antibody. For the present, it is designated "endotoxin-detoxifying component" or EDC. Animal species could be grouped in three categories with regard to the EDC activity of their sera; rat serum was highly potent; chimpanzee, dog, horse, and guinea pig sera were much less active; mouse, rabbit, and sheep sera exhibited no activity. The EDC potency of human sera varied widely, ranging from high to barely discernible activity. In contrast to the variations of EDC potency in serum, citrated plasma from all species manifested high potency of about the same magnitude. The influence of time, temperature, pH, and concentration of reactants on the inactivation of endotoxin by EDC was examined. EDC activity in plasma and serum was found to be labile to beating at 56 degrees C. for 1 hour. Bacterial endotoxins, derived by different isolation procedures from smooth and rough Gram-negative species, varied considerably in susceptibility to EDC action.

Animals↗
PubMed1961

Studies on primary atypical pneumonia. III. A factor in normal serum which enhances the reaction between PAP virus and convalescent serum.

A factor present in fresh normal human or guinea pig serum enhances the primary atypical pneumonia (PAP) antibody titers in serological reaction with its homologous virus as tested by indirect fluorescent antibody staining. This factor is not properdin. It has many properties similar to complement but may not be identical with complement. The addition of this enhancement factor to human sera convalescent from primary atypical pneumonia has made the serological test more sensitive without affecting its specificity.

Complement System Proteins↗
PubMed1962

The biological, immunological, and physicochemical characterization of a transmissible agent capable of inducing DNA and thymine degradation in cultured human cells.

EXPERIMENTS DESIGNED TO CHARACTERIZE AN UNIDENTIFIED TRANSMISSIBLE AGENT BROUGHT FORTH THE FOLLOWING FINDINGS: The cytopathology consisted of the formation of intranuclear globules, collapse of the involved nuclei, and the extrusion of nuclear materials. The relatively dormant primary human amnion cells were less susceptible than the rapidly growing cell lines. Similarly, the slowly multiplying ribose variants were less susceptible than their corresponding parent cell lines. Interferon-like activity was released from infected cells. Infectivity was readily demonstrated following storage at 0-4 degrees C for at least 8 months or at 37 degrees C for at least 2 weeks. Freeze-thawing, however, markedly reduced or completely destroyed its infectivity. Infectivity was destroyed completely by ether and chloroform; partially by desoxycholate, and not affected by trypsin, papain, RNAse, DNAse, hyaluronidase, lysozyme, lecithinase, or pancreatic lipase. The rate of inactivation by 0.025 per cent formalin was much slower than that of vaccinia and herpes viruses. Its synthesis was suppressed by 5-fluorodeoxyuridine. This suppression was not reversed by thymidine and/or uracil. Heat-stable neutralizing antibody could not be demonstrated in 379 human and animal serums, in human gamma globulins, or in serums from animals "immunized" with this agent. Heat-labile inhibitors (lipoprotein-like) capable of inhibiting the infectivity of this agent were demonstrated in 154 of the 157 serums tested. Experimental evidence indicated the non-identity of this ubiquitous inhibitor and the properdin system. The non-infectious complex between this agent and the ubiquitous serum inhibitor may be dissociated (hence, become infectious) by simple dilution. Repeated attempts to reisolate a similar agent have not been successful. We have hypothesized that this agent is a virus consisting of DNA wrapped in a surface coat rich in lipid, and suggest that this virus be referred to tentatively as a lipovirus.

Animals↗
PubMed1972

Genetic polymorphism in human glycine-rich beta-glycoprotein.

Extensive polymorphism of glycine-rich beta-glycoprotein (GBG) was found in human sera. In all instances, GBG consisted of at least five components on electrophoresis. Patterns were such that they provided evidence for four alleles (at a locus designated Gb) which were expressed as autosomal codominant traits. Gb(S) and Gb(F) were found in all populations but with different frequencies, Gb(F1) was found in Negroes, and Gb(S1) was found in Caucasians. From electrophoretic studies of GBG, evidence was obtained that suggested that the GBG molecule was a tetramer consisting of A and B subunits in a proportion of about 1.6:1. The genetically controlled differences in GBG embodied in the Gb system indicated the presence of a third moiety of the molecule (C), possibly a polypeptide subunit. Electrophoretic studies of fragments from defined types of GBG suggested that GBG cleavage induced by complement or properdin activation in serum occurred through this C moiety, since two variants were detectable in one fragment and two were found in the other fragment. On comparison of fetal-maternal Gb types, approximately one-half the pairs showed differences. This indicated that GBG did not cross the placental barrier.

Epitopes↗
PubMed1973

Activation of the alternate complement pathway by autologous red cell stroma.

The present study demonstrates the ability of human autologous RBC stroma to activate the alternate complement pathway (C3-Activator system, properdin system), as evidenced by the generation of C3-Activator (C3A) from C3-Proactivator (C3PA) when RBC ghosts and sonicated ghosts are incubated with autologous serum. Intact RBC's, hemoglobin, and concentrated platelet stroma, on the other hand, are inactive in this regard. We postulate that this in vitro activity of RBC stroma may occur intravascularly when erythrocytes are damaged by immune or nonimmune mechanisms. The ensuing interaction of activated complement components with platelets leading to release of platelet factor three (PF-3) may constitute a mechanism for activation of the coagulation system during acute hemolytic episodes.

Blood Coagulation↗
PubMed1975

The mechanism of action of the C3b inactivator (conglutinogen-activating factor) on its naturally occurring substrate, the major fragment of the third component of complement (C3b).

The fixation of the third component of complement (C3) results in many important biological phenomenon, among which are (a) immune adherence (1), (b) enhancement of phagocytosis (2,3), (c) the release of an anaphylatoxin which is a potent releaser of histamine (4), and (d) the feedback activation of the alternative pathway (5,6). The physiological mechanisms involving C3 fixation require the generation of a C3 convertase which may occur by two separate pathways. C3 convertase can be generated, in the form of C42, by the so-called classical pathway of activation or in the form C3b,B by the alternative or properdin pathway (7). In both cases, C3 is converted to C3b by cleavage of a small peptide, C3a. Normal human serum contains an inactivator of activated C3b. This C2b inactivator or conglutinogen-activating factor (KAF) has been shown to inhibit both immune hemolysis and the immune adherence properties of C3b and to cause cleavage of C3b in the fixed and fluid- phase stages (8-11). Although it is known that the C3b inactivator is not depleted during its reaction with C3b and that C3b treated with the C3b inactivator becomes extremely sensitive to proteolytic digestion by trypsin and "trypsin-like" enzymes (9), the exact molecular nature of the action of the C3b inactivator on C3b has not been studied. In an effort to delineate the products of this interaction, purified C3b and C3b inactivator were allowed to react for various specific lengths of time and the products of these reactions were then analyzed.

Animals↗
PubMed1975

The opsonic fragment of the third component of human complement (C3).

Human peripheral blood phagocytes ingest Escherichia coli 026:B6 lipopolysaccharide (LPS)-coated paraffin oil droplets containing Oil red O only if fresh serum deposits C3 on the surfaces of the particles (opsonizes them), by reactions involving the properdin system. The rate of binding of purified [125-I]C3 in serum to LPS-coated particles correlated precisely with the rate of acquisition of ingestibility assayed spectrophotometrically. Once opsonized, LPS-coated particles remained fully ingestible and retained fixed [125-I]C3 radioactivity even after exposure to extremes of temperature, pH, ionic strength, phospholipases, urea or guanidine, some nonionic and ionic detergents, and organic solvents. Trypsin, human conglutinogen-activating factor, another heat-stable activity found in human serum, and sodium dodecyl sulfate removed radioactivity and diminished ingestibility of the opsonized particles. Alkylation, reduction plus alkylation and F(ab')2 from anti-C3 blocked ingestibility but did not alter particle-bound radioactivitymelectrophoretic and tryptic peptide autoradiographic analysis of dodecyl sulfate eluates of opsonized particles, cleansed of many contaminating proteins by boiling with 2 M NaCl (yet still opsonized), revealed that the polypeptide with C3-derived radioactivity had a mol wt of approximately 140,000 and was composed of 70,000 mol wt subunits linked by disulfide bonds. Immunochemical analysis and comparison of the peptide structure of the eluate with that of C3 indicated that the opsonic fragment is not the fragment defined as C3b but a smaller derivative of C3.

Chemical Phenomena↗