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PubMed1990

[Three cases of oligomeganephronia].

Three cases of bilateral renal hypoplasia with oligomeganephronia are reported. In all three patients urine abnormalities were pointed out by annual urine screening for school-children and they showed mild or moderate deterioration of renal function. One patient had repeated episodes of urinary tract infection, and bilateral vesico-ureteral reflux (grade III) was found by the voiding cystourethrography. Light microscopic findings of renal biopsy specimens were similar in three cases; significant hypertrophy of the glomerulus and tubulus; mild mesangial expansion, and interstitial changes. Further histological examination which was done in one case showed widespread foot process fusion, mesangial interposition and membrane-like structures by electron microscopy, and mesangial IgA deposition by immunofluorescence. Three was no alteration in immuno-staining pattern for basement membrane components, including type VI and V collagens, laminin and fibronectin, in the glomeruli.

Adolescent↗

PubMed1989

[Toxic organic damage].

Pathohistological findings are playing an important role in the advice of toxic organ damages. After presentation of some details about the frequency of toxic organ damages, the pathways of toxic agents in the organism are discussed. In cells toxic damage may induce cell necrosis, functional disturbance, inhibition of cell proliferation or malignant transformation; in extracellular structures it may lead to degradation phenomena in the connective tissue matrix. As demonstrated in example of calciphylaxis, a combination of different noxes may not only add but even potentiate the effects of the single noxes. In intracellular reparation processes the lysosomal system is involved. In case of necrosis regeneration is possible in most kinds of tissues, if connective tissue rails are preserved. Otherwise an irreversible reparative fibrotic alteration of organ structure is induced which develops according to particular general and schematic rules. As mostly character and course of the tissue reaction is unspecific, pathohistological findings do not enable conclusions on the type of inducing toxic agent. The following presentation of some examples of toxic damages with pathognomonic histological appearance deals with asbestosis, silicosis, chloroquine-induced cardiomyopathy, aluminum-induced osteopathy and a recently described liver cirrhosis in early childhood induced by copper-containing drinking water. Some limits of traditional pathohistological evaluation of toxic organ damages have been overcome by application of new morphological techniques. Own investigations revealed that the immunocytochemical demonstration of the C5b-9-complement complex enables a better and earlier detection of irreversibly damaged cells. Discrimination of toxic and virus-induced tissue damage is facilitated by the technique of in-situ-hybridization. Sometimes a specific recognition and localization of toxic agents is achieved by X-ray microanalysis, electron-spectroscopic imaging (= ESI) resp. laser microprobe mass spectrometry (= LAMMA); comparing these techniques X-Ray microanalysis and ESI, both, enable specific identification of chemical elements, while LAMMA, in addition, offers some information about the involved molecules and isotopes.

Cells↗

PubMedDate not supplied

Myasthenia gravis: demonstration of membrane attack complex in muscle end-plates.

The membrane attack complex (MAC) assembles from C5b-9 complement components and has neoantigenic properties. Antihuman-MAC rabbit immunserum was applied in order to localize the MAC in myasthenic muscles. Using the indirect immunoperoxidase method MAC was demonstrated at the motor end-plates in eleven myasthenic patients who underwent thymectomy. This result provides direct evidence of antibody-dependent complement-mediated injury of acetylcholine receptors in myasthenia gravis.

Adolescent↗

PubMed1995

Tumor necrosis factor in renal injury.

Inflammatory diseases of the renal glomerulus and tubulointerstitium are characterized by destructive and restorative processes. These alterations are mediated by soluble molecules, including cytokines that instruct target cells to alter their proliferation, differentiation phenotype, secretion and migration. One of these cytokines is tumor necrosis factor-alpha (TNF alpha). Its expression within the glomerulus has been observed in both resident cells and infiltrating monocytes/macrophages in response to cell stimulation with chemicals, immune complexes, bacterial lipopolysaccharides, and advanced glycosylation end products. Its release can be amplified by deposits of terminal complement proteins (C5b-9) or formation of platelet-activating factor and reactive oxygen species, and, on the contrary, blunted by that of prostaglandins or anti-inflammatory interleukin (IL)-6 and IL-10. The roles of TNF alpha in the pathogenesis of glomerular diseases include reduction of blood flow and filtration rate, alteration of the barrier function of capillary wall, formation of capillary thrombi and infiltration of the structure by blood-borne cells. Expression of TNF alpha has been observed in tubulointerstitium as well, mainly in proximal tubular epithelial cells. In vitro, this expression can be amplified by IL-1 and, inversely, suppressed by immunosuppressive drugs. Roles of TNF alpha in tubulointerstitium remain largely undefined, but may include infiltration of the interstitium by inflammatory cells and alteration in tubular transport of fluid and electrolytes. Extensive study will be necessary to further elucidate intracellular signals induced by TNF alpha binding to target cells within the kidney and thus to establish possibilities of therapeutic intervention.

Animals↗

PubMed1993

Cells lacking glycan phosphatidylinositol-linked proteins have impaired ability to vesiculate.

Erythrocytes shed membrane vesicles in response to many stimuli. It has been previously demonstrated that glycan phosphatidylinositol-linked (GPI-linked) proteins such as decay accelerating factor and acetylcholinesterase are concentrated in these vesicles relative to the erythrocyte membrane. We have examined the requirement for GPI-linked proteins for the process of vesiculation. Erythrocytes that do not express GPI-linked proteins, obtained from patients with paroxysmal nocturnal hemoglobinuria (PNH), release between 10% and 50% of the quantity of vesicles as normal cells in response to the Ca2+ ionophore A23187. Platelets from the same patients produced 10% to 20% of the amount of vesicles as normal platelets. In addition, a mutant B-lymphoblastoid cell line that lacks GPI-linked molecules produces about half of the number of vesicles as compared with the wild-type cell line in response to the Ca2+ ionophore. Prior findings indicate that vesiculation is one of the mechanisms that the cell uses to remodel the plasma membrane, as well as protect itself from membrane-damaging agents such as the terminal complement components C5b-9. On the basis of the present results, we conclude that GPI-linked proteins play an important role in membrane vesiculation.

Acetylcholinesterase↗

PubMed1994

Eosinophilia myalgia syndrome: absence of immunoglobulin reactivity suggests a cellular rather than humoral mechanism.

The idiopathic disorder Eosinophilia Myalgia Syndrome (EMS), characterized by peripheral eosinophilia, myalgia and frequently fasciitis, can be triggered by ingestion of some commercial preparations of L-Tryptophan. Activated T-lymphocytes and macrophages are involved in the pathogenesis of EMS. We investigated immunohistochemically the potential role of immunoglobulins and of the terminal C5b-9 complement factor (membrane attack complex) in EMS. We found no evidence for direct involvement of immunoglobulins. However, membrane attack complex immunoreactivity was present in vessel walls in EMS, but completely absent in controls. These observations suggest that the fasciitis in EMS involves a cellular rather than a humoral reaction and that complement activation could be of importance.

Adult↗

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↗

PubMed1997

Preneoplasia-associated expression of calcyclin and of binding sites for synthetic blood group A/H trisaccharide--exposing neoglycoconjugates in human lung.

Development of preneoplastic lesions in human lung is supposed to be accompanied with alterations of distinct biochemical features which might functionally be crucial for this alteration. To contribute to the definition of such determinants in peripheral lung parenchyma, the files of the Department of Pathology, Thoraxklinik, (a total of 2890 cases) were screened for respective tissue specimens. Seventy one cases with complete clinical documentation were found and an age-, sex-, and disease-matched control group was formed. When compared to control group patients, especially the tumor free cases with preneoplastic aberrations revealed a history of exposure to external noxes. Several probes with assumed relevance were tested with the panel of specimens for both groups, focussing on comparative analysis of alveolar lining cells. In addition to labelled neoglycoconjugates which include tissue lectin-seeking probes that expose mono-, di- and blood group-related trisaccharides, presence of calcium- and annexin-binding calcyclin, of complement component C5b, of the lymphokine macrophage migration inhibitory factor, and of ligands of the serum amyloid P component was evaluated. Compared to normal cells at the alveolar surface in controls, the preneoplastic cells displayed an apparent down-regulation of expression of A/H-trisaccharide-specific binding sites and an upregulation of expression of calcyclin. These three characteristics correlated with the phenotypic alterations and encourage further studies to elucidate the functional significance of reduced expression of the glycoligand-specific sites and the presence of this member of the S100-family of Ca(2+)-binding proteins.

Adult↗

PubMed1997

Anatomic, physiologic, bacteriologic and immunologic aspects of peritonitis.

The anatomic aspect of peritonitis describes the division of the abdominal cavity into the supracolic, infracolic and paracolic spaces, moreover the lesser sac and the cul-de-sac of the pelvis. Physiologically the peritoneum plays an important role in the passive exchange of fluid and absorption of particles. Endotoxin, which is elaborated by bacteria activates the classical as well as the alternative complement pathway. It activates also the arachidonic acid metabolism, leading to the release of prostaglandins (PG) and leukotriens (LTC). The local host defense against a bacterial invasion includes the activation of cellular and humeral immunologic defense mechanism, in which the final product of the complement pathway (C5b-9), as well as chemoattractants C3a, C5a and C567 play a key role.

Abdomen↗

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↗

PubMed1994

Protection of thyroid cancer cells by complement-regulatory factors.

BACKGROUND: Clinical and experimental studies have suggested that complement activation may play a role in tumor cytotoxicity. Little information is available concerning the presence of complement activation and the localization of complement-regulatory factors in cells or tissues of malignant tumors. The aim of the present study was to examine, using immunohistochemistry and immunoelectron microscopy, whether the complement system is activated in tissues of thyroid carcinoma and whether thyroid carcinoma cells are protected from cell lysis by in situ complement activation. METHODS: Fresh tissues were obtained by thyroidectomy from 15 patients with papillary carcinomas, 7 with follicular carcinomas, and 5 with follicular adenomas. In addition, five specimens of histologically normal thyroid tissue and five specimens of chronically inflamed tissue adjacent to thyroid neoplasms were studied. Immunohistochemical and immunoelectron microscopic localization of complement components, C3d and C5b-9, and the complement-regulatory factors, such as s-protein, decay-accelerating factor (CD55), membrane cofactor protein (CD46), complement receptor types 1 (CD35) and 2 (CD21), and protectin (CD59), were examined in these tissues. RESULTS: The staining patterns of C3d, C5b-9, and s-protein were positive and homogeneous in the nonneoplastic and most neoplastic thyroid tissues. Immunoelectron microscopy showed these antigens were localized mainly on the subepithelial and vascular basement membranes and attached to the cell surface of thyroid follicular cells. Decay-accelerating factor (CD55) was present homogeneously on the basement membranes, on the basal cell border of the thyroid follicular cells, and often on the luminal surface of carcinoma cells. Both membrane cofactor protein (CD46) and protectin (CD59) were expressed strongly on the cell surface of almost all benign and malignant thyroid follicular cells. Membrane cofactor protein was expressed on both the basal and lateral membrane, showing cell-to-cell interaction, but rarely on the luminal surface, whereas protectin was expressed strongly on the luminal surface and often on the basal cell border but rarely on the lateral membrane. Neither complement receptor type 1 (CD35) nor complement receptor type 2 (CD21) was expressed on any thyroid follicular cells. CONCLUSIONS: The present study confirmed the presence of complement activation with subsequent deposition of C3d and C5b-9 complexes in thyroid carcinomas. It also indicated that thyroid carcinoma cells are protected from cell lysis because of complement activation in multiple phases by complete coverage of the entire cell membrane surface with complement-regulatory factors. These findings were similar to those found in nonneoplastic thyroid follicular cells.

Adenoma↗

PubMed1985

Quantitation of activation of the human terminal complement pathway by ELISA.

We have devised an enzyme-linked immunosorbent assay (ELISA) to quantitate fluid phase terminal complement pathway activation. Upon activation to form C5b-9, terminal complement components express neoantigens not present in the unassembled individual components. Expression of one of these neoantigens occurs at the step of C9 activation. C9 neoantigen is present in fluid phase SC5b-9 complexes, membrane-bound MC5b-9 complexes, and in in vitro polymerized C9. Under physiologic conditions, the presence of C9 neoantigen indicates that the terminal complement pathway is activated through the terminal component C9. In our assay for C9 neoantigen, we used rabbit antiserum to polymerized C9 rendered specific for C9 neoantigenic determinants by serial absorption with human serum, human C9, and other terminal complement components bound to Sepharose. Using the IgG from this antiserum, we devised a sandwich ELISA to bind SC5b-9 from solution onto polystyrene plates. The ELISA plates were developed with the use of goat antiserum to native C9 epitopes followed by a swine anti-goat IgG-alkaline phosphatase conjugate. Quantitation of SC5b-9 in solution was performed by comparing sample OD to a standard curve generated with human SC5b-9 that was purified from zymosan-activated serum. The assay was sensitive to as little as 100 ng of SC5b-9/ml and should be useful for screening plasma, serum, cerebrospinal fluid, or other biological fluids for the presence of terminal complement pathway activation.

Antibody Specificity↗

PubMed1995

Monoclonal antibodies directed against human C5 and C8 block complement-mediated damage of xenogeneic cells and organs.

The hyperacute rejection (HAR) of xenotransplanted organs is initiated by the deposition of natural antibodies on donor endothelium followed by the activation of the recipient complement system, which rapidly destroys the graft. Studies of the role of activated complement in HAR have suggested that natural antibody as well as early (C3a, C3b) and late (C5a, C5b-9) activated complement components may contribute to cell activation and damage. Attenuation of HAR has been achieved by blockade of C3 activation with soluble CR1 or consumptive depletion of complement with cobra venom factor; however, similar studies using specific inhibitors of terminal complement components have not been described. To address the contribution of C5a and the membrane attack complex (C5b-9, MAC) to complement-mediated xenogeneic cell and organ damage, we utilized functionally blocking monoclonal antibodies directed against the human terminal complement components C5 and C8. Our data show that both anti-C5 and anti-C8 mAbs protect porcine aortic endothelial cells from membrane damage mediated by human C5b-9. Additionally, both the anti-C5 and anti-C8 mAbs blocked complement-mediated generation of membrane prothrombinase activity on porcine aortic endothelial cells challenged with human serum. To test the ability of these antibodies to attenuate antibody and complement-mediated damage of xenogeneic organs, an ex vivo model was developed wherein isolated rat hearts were perfused with human serum in the presence or absence of the anti-C5 and anti-C8 mAbs. Our data demonstrate that mAbs directed against human C5 and C8 prevented organ damage by human serum complement and suggest that these molecules may serve as potent inhibitors of HAR.

Animals↗

PubMed2005

Mechanisms of immune-deposit formation and the mediation of immune renal injury.

The passive trapping of preformed immune complexes is responsible for some forms of glomerulonephritis that are associated with mesangial or subendothelial deposits. The biochemical characteristics of circulating antigens play important roles in determining the biologic activity of immune complexes in these cases. Examples of circulating immune complex diseases include the classic acute and chronic serum sickness models in rabbits, and human lupus nephritis. Immune deposits also form "in situ". In situ immune deposit formation may occur at subepithelial, subendothelial, and mesangial sites. In situ immune-complex formation has been most frequently studied in the Heymann nephritis models of membranous nephropathy with subepithelial immune deposits. While the autoantigenic target in Heymann nephritis has been identified as megalin, the pathogenic antigenic target in human membranous nephropathy had been unknown until the recent identification of neutral endopeptidase as one target. It is likely that there is no universal antigen in human membranous nephropathy. Immune complexes can damage glomerular structures by attracting circulating inflammatory cells or activating resident glomerular cells to release vasoactive substances, cytokines, and activators of coagulation. However, the principal mediator of immune complex-mediated glomerular injury is the complement system, especially C5b-9 membrane attack complex formation. C5b-9 inserts in sublytic quantities into the membranes of glomerular cells, where it produces cell activation, converting normal cells into resident inflammatory effector cells that cause injury. Excessive activation of the complement system is normally prevented by a series of circulating and cell-bound complement regulatory proteins. Genetic deficiencies or mutations of these proteins can lead to the spontaneous development of glomerular disease. The identification of specific antigens in human disease may lead to the development of fundamental therapies. Particularly promising future therapeutic approaches include selective immunosuppression and interference in complement activation and C5b-9-mediated cell injury.

Animals↗

PubMed2004

Two new actions of sea nettle (Chrysaora quinquecirrha) nematocyst venom: studies on the mechanism of actions on complement activation and on the central nervous system.

Chrysaora quinquecirrha (sea nettle) nematocyst venom is lethal to rainbow killifish (Adina xenica) when injected intraperitoneally or topically applied to the exposed brain or denuded epithelium. The lethal activity is thermostable requiring 100 degrees C heat for inactivation. This paper reports here for the first time that the venom also activates the complement system with the subsequent formation of the C5b-9 terminal complement complex. The events are associated with both a strong chemoattractant release and the tissue damage. These are also, at least in part, responsible for the pathogenesis of some clinical signs and symptoms associated to the jellyfish stings.

Administration, Cutaneous↗

PubMed1994

Alternative pathway activation of complement by cultured human proximal tubular epithelial cells.

Human proximal tubular epithelial cells (PTEC) incubated with normal human serum (NHS) were found to fix on their surface C3, properdin, terminal complement components and C5b-9 MAC neoantigen, but not C1q and C4, by immunofluorescence. Complement fixation was abrogated if PTEC were incubated with EDTA-treated NHS or C3-deficient human serum, but not with Mg EGTA-treated NHS or C1q-deficient human serum, showing the prevalent activation of the alternative pathway of complement. This event was followed by marked cytoskeleton alterations with disruption of the actin cortical network, redistribution of actin throughout the cytoplasm and formation of blebs, and by cell cytolysis. In addition, superoxide anion and hydrogen peroxide production and chemiluminescence response were detected in consequence of MAC insertion on PTEC plasma membrane. The dependency on MAC of the observed biological effects of complement fixation on PTEC surface was shown by using sera selectively deficient of terminal components of complement (C6 or C8), and therefore unable to form the C5b-9 MAC, and by restoring the ability to form MAC after addition of purified C6 or C8. The possible pathogenetic relevance of these observations in tubulointerstitial injury occurring in patients with complementuria due to non-selective proteinuria, is discussed.

Blood↗

PubMed1999

Selective blockade of membrane attack complex formation during simulated extracorporeal circulation inhibits platelet but not leukocyte activation.

OBJECTIVE: Complement activation is induced by cardiopulmonary bypass, and previous work found that late complement components (C5a, C5b-9) contribute to neutrophil and platelet activation during bypass. In the present study, we blocked C5b-9 formation during extracorporeal recirculation of whole blood to assess whether the membrane attack complex was responsible for both platelet and leukocyte activation. METHODS: In a simulated extracorporeal model that activates complement (C3a and sC5b-9), platelets (CD62P expression, leukocyte-platelet conjugate formation), and leukocytes (increased CD11b expression and neutrophil elastase), we examined an anti-human C8 monoclonal antibody that inhibits C5b-9 generation for its effects on cellular activation. RESULTS: Anti-C8 significantly inhibited sC5b-9 formation but did not block C3a generation. Anti-C8 also significantly inhibited the increase in platelet CD62P and monocyte-platelet conjugate formation seen with control circulation. Moreover, compared with control circulation, in which the number of circulating platelets fell by 45%, addition of anti-C8 completely preserved platelet counts. In contrast to blockade of both C5a and sC5b-9 during simulated extracorporeal circulation, neutrophil activation was not inhibited by anti-C8. However, circulating neutrophil and monocyte counts were preserved by addition of anti-C8 to the extracorporeal circuit. CONCLUSIONS: The membrane attack complex, C5b-9, is the major complement determinant of platelet activation during extracorporeal circulation, whereas C5b-9 blockade has little effect on neutrophil activation. These data also suggest a role for platelet activation or C5b-9 (or both) in the loss of monocytes and neutrophils to the extracorporeal circuit.

Antibodies, Monoclonal↗

PubMed2000

Identification and functional characterization of a new gene encoding the mouse terminal complement inhibitor CD59.

CD59 is a 18- to 20-kDa, GPI-anchored membrane protein that functions as a key regulator of the terminal step of the complement activation cascade. It restricts binding of C9 to the C5b-8 complex, thereby preventing the formation of the membrane attack complex (C5b-9 of complement). A single human CD59 gene has been identified, and corresponding genetic homologues from rat, mouse, and pig have been characterized in previous studies. In this study, we report the discovery and functional characterization of a separate cd59 gene in the mouse (referred to as cd59b, the previously characterized mouse cd59 gene as cd59a). Mouse cd59b is 85% and 63% identical to cd59a at the nucleotide and amino acid level, respectively. In cDNA transfection experiments with Chinese hamster ovary cells, peptide-tagged cd59b was detected on the cell surface by flow cytometry and was shown to be susceptible to phosphatidylinositol-specific phospholipase C cleavage. Chinese hamster ovary cells expressing cd59b were significantly more resistant than control cells to human and mouse complement-mediated lysis. These results suggest that cd59b encodes a GPI-anchored protein that is functionally active as a membrane attack complex inhibitor. Northern blot analysis revealed that cd59b is expressed selectively in the mouse testis. In contrast, the major transcript of cd59a was shown to be expressed at high levels in the heart, kidney, liver, and lung, but only minimally in the testis. These results revealed the existence of two distinct cd59 genes in the mouse that are differentially regulated and that may have nonoverlapping physiological functions in vivo.

Amino Acid Sequence↗