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PubMed1994

Peripheral nerve injury induces Schwann cells to express two macrophage phenotypes: phagocytosis and the galactose-specific lectin MAC-2.

In N mice, peripheral nerve injury is followed by the normal rapid progression of Wallerian degeneration: Schwann cells proliferate and lose their myelin, which is phagocytized and metabolized by blood-borne macrophages. The role of Schwann cells in myelin phagocytosis is debated. Additionally, the molecular mechanisms underlying myelin phagocytosis by the two cell types are not well understood. To elucidate the role of Schwann cells as phagocytes we studied, electron microscopically, in vivo and in vitro degenerating, frozen, and neuroma nerve segments. The major cell types composing these tissues differed: Schwann and macrophages in in vivo degenerating; Schwann in in vitro degenerating; macrophages in frozen; Schwann, macrophages, and fibroblasts in neuroma nerve segments. Both macrophages and Schwann cells phagocytized myelin. We further studied, by immunocytochemistry and immunoblot analysis, the expression of molecules that are characteristically displayed by inflammatory and mature murine macrophages: MAC-1 (the C3b complement receptor), MAC-2 (a galactose-specific lectin), the Fc receptor, and the F4/80 antigen. All were detected in the macrophage-rich, in vivo degenerating, frozen, and neuroma nerve segments. Surprisingly, MAC-2 was also expressed in the macrophage-scarce, Schwann-rich, in vitro degenerating nerve. Immunocytochemistry and immunoblot analysis of isolated non-neuronal cells revealed that both macrophages and Schwann cells displayed MAC-2 on their surface and in their cytoplasm. Morphometry unveiled that galactose and lactose specifically inhibited myelin phagocytosis, as predicted if MAC-2 was mediating myelin phagocytosis by lectinophagocytosis (lectin-mediated phagocytosis). The role of MAC-2 in mediating myelin phagocytosis was further supported by two observations made in W mice that display very slow progression of Wallerian degeneration. First, the failure to degenerate in vivo was associated with deficient MAC-2 production. Second, degeneration that occurred in vitro was associated with MAC-2 production. Furthermore, a strong positive correlation between levels of MAC-2 expression and the extent of myelin destruction by phagocytosis was observed over a wide range of values.

Animals↗
PubMed1993

The temporal relationship between urinary C5b-9 and C3dg and clinical parameters in human membranous nephropathy.

We have previously reported that urinary excretion of the complement activation products C3dg and C5b-9 in human membranous nephropathy (MN) correlated with clinical outcome in a cross-sectional analysis. We report here the results of a retrospective longitudinal study of the temporal relationship between urinary C3dg and C5b-9 excretion and clinical parameters. A group of 23 adult patients with biopsy-proven MN were studied over a mean time period per patient of 3.5 years. Freshly voided urine samples were collected regularly; C3dg and C5b-9 were measured by ELISA (mean number of samples per patient = 13). During the period of the study, nine patients with declining renal function (group A) were treated with a standard steroid regimen. Serum creatinine had improved or stabilized in seven of these patients at the end of treatment. All nine patients were excreting C3dg and C5b-9 before treatment. Six other patients with declining renal function (group B) were not treated with steroids because of clinical contraindications. Serum creatinine continued to increase during the study in four of these six patients. C3dg and C5b-9 were present in the urine samples of these six patients on the majority of dates tested. Eight patients maintained stable renal function during the study (group C), either normal (6 patients) or impaired (2 patients). Of these patients, six were consistently negative for urinary C3dg and C5b-9 despite persistent proteinuria, and one patient who was initially positive became negative within 15 months, and remained negative for the rest of the study period. One patient was positive on one of 12 occasions tested. These results suggest that urinary complement activation products indicate ongoing active glomerular damage and may prove to be important determinants for the introduction and monitoring of therapy.

Complement Activation↗
PubMed1996

Ultrafiltration after cardiopulmonary bypass in children: effects on hemodynamics, cytokines and complement.

OBJECTIVES: The purpose of the study was to evaluate the clinical and hemodynamic effect of intraoperative extracorporeal ultrafiltration (UF) and its potential in reducing the plasma concentration of circulating cytokines and complement activation products following open heart surgery in children. METHODS: Eighteen children with congenital heart disease were prospectively randomized into a control group (n = 9) and a group who underwent UF (n = 9). Serial plasma samples for measurements of circulating cytokines (interleukin 6 (IL-6), tumor necrosis factor alpha (TNF), and its soluble receptor (sTNF receptor)), and complement factors (C3 activation products (C3a and C3bc) and terminal complement complex (TCC)) were obtained before, during and up to 48 h after cardiopulmonary bypass (CPB). A pulmonary artery thermodilution catheter was introduced preoperatively for hemodynamic monitoring. RESULTS: Postoperative hemodynamics were similar in both groups. Plasma levels of IL-6, sTNF receptors, C3a, C3bc and TCC increased significantly perioperatively (P < 0.01) in both groups. TNF was detected transiently in 16 patients perioperatively and in 4 of the 9 ultrafiltrate samples in concentrations similar to the plasma levels. Complement activating products were not detected in the ultrafiltration samples except for small amounts of C3a in two cases. Compared to the control group the plasma levels of C3a, C3bc and TCC were unaffected by the ultrafiltration procedure. The level of IL-6 and sTNF receptors increased significantly after 15 min of UF but there was no significant difference between the two groups postoperatively. CONCLUSIONS: In this study no clinical or hemodynamic effect was registered after UF. TNF and C3a were occasionally detected in the ultrafiltrate but we were unable to demonstrate reduction of these or any of the other markers tested in the group subjected to ultrafiltration.

Cardiopulmonary Bypass↗
PubMed1995

Mechanism of antigenic variation in Shigella flexneri bacilli. III. Complement sensitivity of S. flexneri 1b strains and their 3b variants selected either as Lac+ recombinants or phage F2 resistant mutants.

Several S. flexneri 1b serotype strains of clinical isolation were compared with their 3b serotype variants isolated either as Lac+ recombinants from crosses of S. flexneri x E. coli Hfr C, or F2-resistant mutants. The studied variants 3b were deprived of type I antigen but acquired type III antigen. They appeared to be less sensitive to killing action of complement present in normal bovine serum although kinetics of killing and its effectiveness differed between the strains.

Animals↗
PubMed1996

Tissue homeostatic role of naturally occurring anti-band 3 antibodies.

Self antigens exposed to the immune system constitutively or in the process of tissue homeostasis may stimulate a TH2 type immunity giving rise to low titer, low affinity naturally occurring antibodies which are involved in actively maintaining peripheral tolerance to self and in tissue homeostatic clearance processes. In reviewing the tissue homeostatic aspect of naturally occurring antibodies to band 3 protein of the human erythrocyte membrane, we address crucial issues of how these and other types of naturally occurring antibodies (NAb) (eg. anti-spectrin NAb) gain functionality and how this can induce opsonization by complement C3b under physiological conditions. Exoplasmic, chemical cross-linking of band 3 protein is sufficient to increase specific anti-band 3 binding under physiological conditions. Formation of oligomers following this non-oxidative cross-linking protocol disfavors a recognition mechanism involving exposure of a neoantigen. New data on NAb binding to erythrocytes further demonstrates that specific binding of any low affinity NAb can only be determined in the presence of whole human IgG and physiological ionic strength, where competition of the predominantly positively charged NAb for binding to the negatively charged cell surface is high. Hence, specific and physiologically relevant binding of low affinity NAb is gained by bivalent binding and suppression of exclusive charge-charge interactions by other NAb sharing the range of pl values. Therefore, many investigations on NAb/cell interactions which have been carried out in the absence of whole IgG have yielded controversial data.

Anion Exchange Protein 1, Erythrocyte↗
PubMed1997

Paraneoplastic syndrome simulating encephalitis in the course of testicular seminoma.

A case of paraneoplastic syndrome diagnosed post mortem in a 68-year-old man with a single submandibular lymphatic metastasis of testicular seminoma is presented. The syndrome developed 3 years after orchidectomy and clinically combined the features of limbic and bulbar encephalitis together with signs of cerebellar degeneration. Histological examination revealed marked loss of cerebellar Purkinje and granular cells and to a lesser extent of cerebral cortical neurons. Additionally axonal injury (spheroids) and multifocal demyelination with sparse lymphocytic infiltrations was observed. Immunohistochemically, strong reaction with monoclonal anti-human IgG in some neurons of cerebellum was detected whereas the reaction with anti-complement (C3b) receptor in corresponding sections was negative. It is suggested that the presented case may represent a "burn out" stage of paraneoplastic syndrome associated with anti-neuronal antibodies, however the isolation of specific antibodies was not performed.

Aged↗
PubMed1998

Membrane cofactor protein: importance of N- and O-glycosylation for complement regulatory function.

Membrane cofactor protein (MCP; CD46) is a type 1 membrane glycoprotein that inhibits complement activation on host cells. It also is a measles virus (MV) receptor, an adherence factor for group A Streptococcus pyogenes, and a cellular pilus receptor for pathogenic Neisseria. The amino terminus of MCP consists of four complement control protein (CCP) repeats, three of which (CCP-1, -2, and -4) possess N-glycans. Immediately following the CCP modules is an alternatively spliced region for extensive O-glycosylation (termed the STP domain). Previous studies established that the N-glycan of CCP-2 is essential for MV binding and infection and that the splicing variants of the STP domain not only affect MV binding and fusion, but also differentially protect against complement-mediated cytolysis. In this report, we dissect the role of these carbohydrates on complement regulatory function. We constructed, expressed, and characterized proteins deleting these carbohydrates. For MCP-mediated protection against cytolysis, the N-glycans of CCP-2 and -4 were necessary, the STP segment influenced but was not essential, and the N-glycan of CCP-1 was not required. In addition, the rate and magnitude of cell surface cleavage of C4b to C4c and C4d by MCP and factor I correlated with cytoprotection. These studies expand the structure-function understanding of the active sites of MCP and elucidate an important role for carbohydrates in its function, a finding consistent with their conservation in the MCP of other species.

Animals↗
PubMed1999

Genetic polymorphism of human complement factor I (C3b inactivator) in the Chinese Han population.

The human complement factor I (IF) polymorphism has been analysed by polyacrylamide gel isoelectric focusing electrophoresis of neuraminidase-treated EDTA plasma samples followed by immunoblotting and enzymatic detection. In a population study among 121 random individuals from Chengdu, PR China, three different common phenotypes were observed. The results show that IF is polymorphic in the Chinese population. The allele frequencies were as follows: FI*A = 0.153, FI*B = 0.847. The distribution of observed phenotypes was in accordance with the Hardy-Weinberg equilibrium. In comparison to other Asian population studies, the frequency of the IF*A allele was the highest in the Chinese population studied here.

Alleles↗
PubMed1996

Identification of three physically and functionally distinct binding sites for C3b in human complement factor H by deletion mutagenesis.

Human complement factor H controls spontaneous activation of complement in plasma and appears to play a role in distinguishing host cells from activators of the alternative pathway of complement. In both mice and humans, the protein is composed of 20 homologous short consensus repeat (SCR) domains. The size of the protein suggests that portions of the structure outside the known C3b binding site (SCR 1-4) possess a significant biological role. We have expressed the full-length cDNA of factor H in the baculovirus system and have shown the recombinant protein to be fully active. Mutants of this full-length protein have now been prepared, purified, and examined for cofactor activity and binding to C3b and heparin. The results demonstrate (i) that factor H has at least three sites that bind C3b, (ii) that one of these sites is located in SCR domains 1-4, as has been shown by others, (iii) that a second site exists in the domain 6-10 region, (iv) that a third site resides in the SCR 16-20 region, and (v) that two heparin binding sites exist in factor H, one near SCR 13 and another in the SCR 6-10 region. Functional assays demonstrated that only the first C3b site located in SCR 1-4 expresses factor I cofactor activity. Mutant proteins lacking any one of the three C3b binding sites exhibited 6- to 8-fold reductions in affinity for C3b on sheep erythrocytes, indicating that all three sites contribute to the control of complement activation on erythrocytes. The identification of multiple functionally distinct sites on factor H clarifies many of the heretofore unexplainable behaviors of this protein, including the heterogeneous binding of factor H to surface-bound C3b, the effects of trypsin cleavage, and the differential control of complement activation on activators and nonactivators of the alternative pathway of complement.

Animals↗
PubMed1984

C3b covalently bound to IgG demonstrates a reduced rate of inactivation by factors H and I.

We have prepared C3b covalently linked to IgG via a hydroxylamine-sensitive bond between the C3b alpha' chain and sites predominantly, but not exclusively, located in the IgG heavy chain. This C3b species displays relative resistance to inactivation by factors H and I when compared with free C3b. This resistance appears to be due entirely to reduced affinity of C3b-IgG for factor H. Resistance to inactivation is not conferred on C3b by binding to another serum glycoprotein of similar size, ceruloplasmin, and may be a special property of IgG. C3b-IgG demonstrates an enhanced capacity to consume serum C3 relative to C3b. These alterations of the behavior of C3b when bound to IgG may in part explain the augmentation of alternative pathway activity by IgG. In addition, IgG-induced protection of C3b might influence both complement-mediated killing and phagocytosis of bacteria, as well as modify the in vivo handling of IgG-containing soluble immune complexes.

Ceruloplasmin↗
PubMed1983

Induction of granulocyte histaminase release by particle-bound complement C3 cleavage products (C3b, C3bi) and IgG.

The interaction of opsonized particles with human granulocytes promotes a number of important biologic functions, including phagocytosis, superoxide generation, and release of a variety of enzymes, including histaminase. We have previously determined that histaminase release occurs via a C3-dependent process. Although fluid-phase C3b dimers can mediate release, the relative effects of particle-bound C3b and C3bi and of IgG have not been examined. In this report we demonstrate that particle-bound C3 deposited on activators of the alternative C pathway effected histaminase release in the absence of IgG. Particle-bound C3bi and C3b were both effective as mediators of histaminase release. The extent of release varied as a function of the activating surface on which C3 was deposited (zymosan C3b was considerably more potent than C3b bound to rabbit erythrocytes, which was slightly more potent than C3b bound to neuraminidase-treated sheep erythrocytes). In contrast, C3b or C3bi deposited on nonactivating surfaces (such as sheep erythrocytes) at inputs of up to 2,000,000 molecules per granulocyte failed to induce histaminase release unless IgG was also present. The ability of C3b bound to particles that serve as activators of the alternative pathway to induce histaminase release is apparently not the result of decreased susceptibility of C3b to proteolysis or to an increased binding affinity to the C3b receptor, but may relate to the interaction of other surface structures on activating particles with the PMN membrane.

Amine Oxidase (Copper-Containing)↗
PubMed1975

Restoration by purified C3b inactivator of complement-mediated function in vivo in a patient with C3b inactivator deficiency.

In a patient with lifelong increased susceptibility to infection and multiple abnormalities in complement-mediated functions, the infusion of normal plasma had been seen to produce a prolonged partial correction of serum abnormalities. It was subsequently shown that the patient was genetically deficient in the C3b inactivator and that immunochemical depletion of C3b inactivator from normal serum resulted in abnormalities similar to those found in the patient's serum, including alternative pathway C3 activation. Highly purified C3b inactivator was obtained from the euglobulin fraction of normal human serum, sterilized by filtration, and infused intravenously. Partial or complete correction of almost all the known serum abnormalities was obtained. C3b almost disappeared from the serum within 4-5 h, as did Factor C activity. Native C3, C5, and serum hemolytic activity rose to normal or near-normal levels over 4 days and were sustained for another week. Factor B, properdin, opsonic activity, and bactericidal activity reached a level at least two-five times that found before the infusion within 24 h and fell over the next 5 days. These observations prove the primary role of C3b inactivator deficiency in the patient's disease and demonstrate clearly the curcial role in vivo of C3b inactivator in modulating alternative pathway activity.

Blood Proteins↗
PubMed1983

Endocytosis of the C3b receptor of complement within coated pits in human polymorphonuclear leukocytes and monocytes.

The distribution and endocytosis of the C3b receptor by human polymorphonuclear leukocytes and monocytes were visualized by both fluorescent and electron microscopic examination of cells that had been labeled with monospecific F(ab')2 anti-C3b receptor and anti-F(ab')2 conjugated with rhodamine or ferritin. When prefixed or unfixed cells that were labeled at 0 to 4 degrees C were examined, the receptor was distributed within clusters on the plasma membrane. After the cells had been warmed to room temperature or to 37 degrees C for 5 minutes, the fluorescently labeled receptors appeared to enter the cells, and the ferritin-tagged receptors often occurred within coated endocytic pits and coated vesicles within the cytoplasm. After incubation at 37 degrees C for 20 minutes, the C3b receptor-antibody complexes were largely cleared from the cell surface, and much of the label was found within lysosomes. These results indicate that C3b receptors may directly mediate endocytosis within coated pits, thus utilizing a mechanism shared by a variety of other receptors for the rapid, efficient, and selective internalization of extracellular ligands.

Cell Membrane↗
PubMed1978

Complement receptor subtypes C3b and C3d in lymphatic tissue and follicular lymphoma.

To substantiate the origin of follicular (nodular) lymphoma cells from germinal-centre cells, the lymphoma cells from 7 patients with follicular lymphoma and from 9 tonsils and 2 lymph nodes were studied for the presence and distribution of complement-receptor subtypes (i.e., the receptors for C3b and C3d). It was found that erythrocytes coated with antibodies and C3d (EAC3d) adhered exclusively to germinal centres, whereas erythrocytes coated with antibodies and C3b (EAC3b) adhered to germinal centres and in many instances to the regions between them. These findings indicate that germinal-centre cells bear both complement-receptor subtypes and that the B cells of the interfollicular area, which belong at least in part to the precursors of plasma cells, bear only a receptor for C3b. In frozen sections of follicular lymphomas, a similar distribution of complement-receptor subtypes was observed; EAC3d was bound exclusively to the neoplastic nodules, and EAC3b adhered to the neoplastic nodules and adjacent paranodular tissue. Receptor studies on suspended cells of both normal tonsils and follicular lymphomas revealed a slight predominance of EAC3d(+) cells or equal numbers of EAC3b(+) and EAC3d(+) cells. The complete congruence in the expression and distribution of complement-receptor subtypes between tissues from follicular lymphomas and those from normal and hyperplastic tonsils or lymph nodes suggests that follicular lymphoma represents the neoplastic counterpart of the reactive germinal centre.

Binding Sites↗
PubMed1982

On the lysis of paroxysmal nocturnal hemoglobinuria erythrocytes by complement: dual role of C3b.

The efficiency of cytolysis by the terminal complement proteins C5b-9 can be markedly enhanced by C3b molecules bound on the target cell membrane (Hammer et al. 1976). This enhancement was shown to be proportional to the number of C3b molecules on the cell membrane. The present experiments have shown that the hemolytic efficiency of the complement membrane attack system is two to five times greater on paroxysmal nocturnal hemoglobulinuria erythrocytes (PNHE) than on normal human E. This difference is attribute to a derivative of C3, probably C3b, on PNHE since it was abolished by anti-C3 but not by anti-C2. The efficiency of C5b-9 to lyse PNHE was only partially decreased by C3b inactivator and beta 1 H, indicating that the C3b on PNHE is not readily inactivated by its regulatory proteins. Furthermore, cells from a single severely affected patient consumed 3-fold more C5b6 than normal human E yet concommitantly measured membrane fluidity was normal. From these observations we conclude that cell-bound C3b on PNHE serves two functions: (a) it increases the hemolytic efficiency of membrane attack components of the complement system; and (b) it provides sites for assembly of the alternative pathway convertases.

Complement C3b↗