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PubMed1989

Phosphorylcholine acts as a Ca2+-dependent receptor molecule for lymphocyte perforin.

Large granular lymphocytes and cytolytic T-lymphocytes (CTL) contain numerous cytoplasmic granules thought to be responsible, at least in part, for the cytolytic activity of these effector cells. Isolated granules are lytic for a variety of target cells and the granule proteins are specifically released upon target-cell interaction. Major proteins in mouse CTL granules are a family of seven serine proteases designated granzymes A to G, and a pore-forming protein called perforin (cytolysin). Purified perforin is cytolytic in the presence of Ca2+ and shows ultrastructural, immunological and amino-acid sequence similarities to complement component C9. Despite these similarities, perforin and C9 are clearly distinct in their mode of target-cell recognition. Whereas C9 insertion is absolutely dependent on a receptor moiety assembled from the complement proteins C5b, C6, C7, and C8 on the target-cell membrane, no requirement for a receptor molecule has been reported for perforin. Here, we demonstrate that phosphorylcholine acts as a specific, Ca2+-dependent receptor molecule for perforin.

Animals↗
PubMed1984

Detection and quantification of the terminal C5b-9 complex of human complement by a sensitive enzyme-linked immunosorbent assay.

An enzyme-linked immunosorbent assay for detection and quantification of the terminal complexes (SC5b-9 and membrane attack complex) of human complement is described. We separate the complex from the native complement components, to use antibodies against the native components in a 'double-antibody sandwich' technique. It is thereby possible to detect the terminal complement complex in solution without the requirement of specific antibodies against the neoantigens. The results show that the assay is both sensitive and specific. Evidence is presented that a terminal complement complex occurs in a normal plasma pool. The terminal complement complex may be valuable for evaluating both the physiology and pathophysiology of the complement system in vivo.

Antibody Specificity↗
PubMed1985

Mechanism of membrane damage by streptolysin-O.

Streptolysin-O (SLO) is a thiol-activated, membrane-damaging protein toxin of Mr 69,000 that is produced by most strains of beta-hemolytic group A streptococci. Native, primarily water-soluble toxin molecules bind to cholesterol-containing target membranes to assemble into supramolecular curved rod structures (25 to 100 nm long by ca. 7.5 nm wide), forming rings and arcs that penetrate into the apolar domain of the bilayer. Electron microscopic analyses of toxin polymers in their native and reconstituted membrane-bound form indicate that the convex surface of the rod structures is a hydrophobic, lipid-binding domain, whereas the concave surfaces appear to be hydrophilic. The embedment of the rings and arcs generates large transmembrane slits or pores of up to 30-nm diameter that can be directly visualized by negative staining and freeze-fracture electron microscopy. SLO oligomers were isolated in extensively delipidated form in detergent solution, and cholesterol was found not to detectably contribute to the observed rod structures. The rods are stable structures that resist prolonged exposure to trypsin and chymotrypsin. They can be reincorporated into cholesterol-free phosphatidylcholine liposomes to generate lesions identical to those observed on erythrocytes lysed by native SLO. Thus, although cholesterol plays a key role in the initial binding of SLO to the membrane, it does not directly participate in the formation of the membrane-penetrating toxin channels. Membrane damage by SLO is basically analogous to that mediated by previously studied channel formers, namely, the C5b-9 complement complex and staphylococcal alpha-toxin.

Animals↗
PubMed1991

Immunopathology of subcutaneous rheumatoid nodules.

Nodules obtained from five patients with classical seropositive rheumatoid arthritis were studied by an immunofluorescence technique using polyclonal antibodies to IgG, IgA, IgM, C3c, and fibrin, and monoclonal antibodies to the terminal (C5b-9) complement complex (reaction with a neoantigen in C9 revealed during activation), DR antigens, T cells, macrophages, and interdigitating cells. In all instances the central necrotic areas stained strongly for fibrin and more weakly for IgG, IgA, IgM, C3, and terminal complement complex. The surrounding palisading cells reacted with antibodies to DR and macrophages. In the peripheral granulomatous tissue most of the lymphocytes reacted with the antibodies to T cells, whereas various amounts of the larger mononuclear cells were stained by antibodies to DR antigens, macrophages, and interdigitating cells. In all instances the walls of some of the smaller vessels in the granulomatous tissue stained for fibrin, C3, and terminal complement complex. Plasma cells were not seen except for scattered IgM cells in one nodule. These results support the view that the palisading cells are derived from macrophages, and indicate that there is vasculitis with activation of C3 and the terminal complement pathway in the granulomatous tissue.

Arthritis, Rheumatoid↗
PubMed1988

SP-40,40, a newly identified normal human serum protein found in the SC5b-9 complex of complement and in the immune deposits in glomerulonephritis.

We report herein the isolation and initial characterization of a novel protein, termed SP-40,40, which is present at moderate levels (35-105 micrograms/ml) in normal human serum. SP-40,40 is deposited in the renal glomeruli of patients with glomerulonephritis but is not found in normal glomeruli. The protein is a heterodimeric structure of relative molecular mass 80 kD, both chains of which are of a similar size (40 kD). The amino-terminal sequences of both chains are unrelated to one another and possess no significant homology to any known protein sequence. The tissue distribution of SP-40,40 closely resembles that of the terminal complement components and its physicochemical properties are similar to, but distinct from, those of the S protein of complement. We have identified SP-40,40 in the SC5b-9 complex of complement and have demonstrated incorporation of labeled SP-40,40 into this complex. These data suggest that SP-40,40 is an additional component of SC5b-9.

Amino Acid Sequence↗
PubMed1995

Heparin-binding vitronectin up-regulates latent TGF-beta production by bovine aortic endothelial cells.

Vitronectin, a serum and extracellular matrix protein, is present in vivo in two different conformations: a native form, which does not bind heparin, and a heparin-binding conformer, which results from interactions of native vitronectin with either the thrombin-antithrombin III complex or the terminal complement complex, C5b-9. We found that vitronectin stimulates the activity of the growth regulatory peptide, TGF-beta, in the conditioned media of bovine aortic endothelial cells as a result of increased production of latent TGF-beta. This effect is specific for the denatured, heparin-binding, form of vitronectin, since native vitronectin has no effect on the production of latent TGF-beta by those cells. Stimulation is time and concentration-dependent, but is independent of protease activity. Stimulation is dependent on the presence of cells, since there was no increase in TGF-beta activity observed when vitronectin was added to the conditioned media after removal from cells. Furthermore, incubation of recombinant latent TGF-beta with vitronectin in a cell-free system does not result in increased TGF-beta activity. Assays of total TGF-beta levels in heat-treated conditioned media showed that vitronectin treatment elevates the levels of total TGF-beta in the conditioned media. These results were further confirmed by western blot analysis of the conditioned media with antibodies specific for latent TGF-beta. These data suggest that vitronectin regulates expression and/or secretion of TGF-beta by bovine aortic endothelial cells. This cellular response to the heparin-binding form of vitronectin seems to be mediated by alpha v beta 3 integrins.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

Platelet-derived microparticles express high affinity receptors for factor VIII.

Factor VIII is a cofactor in the tenase enzyme complex which assembles on the membrane of activated platelets. A critical step in tenase assembly is membrane binding of factor VIII. Platelet membrane factor VIII-binding sites were characterized by flow cytometry using either fluorescein maleimide-labeled recombinant factor VIII or a fluorescein-labeled monoclonal antibody against factor VIII. Following activation by thrombin, most platelets bound factor VIII within 90 s. In addition, over the course of several minutes, membranous vesicles (microparticles) were shed from the platelet plasma membrane and each microparticle bound as much factor VIII as a stimulated platelet. Over 30 min, stimulated platelets (but not microparticles) lost the capacity to bind factor VIII. Factor VIII bound saturably to microparticles from platelets stimulated with thrombin, thrombin plus collagen, or the complement proteins C5b-9. The binding of factor VIII was compared to factor V, a structurally homologous coagulation cofactor. Analysis of microparticle binding kinetics yielded similar on and off rates for factor VIII and factor Va and KD values of 2-10 nM. In the presence of 20 nM factor Va, the binding of factor VIII to microparticles was increased, and there was a comparable increase in platelet tenase activity. At higher factor Va concentrations, factor VIII binding and tenase activity were inhibited. Conversely, factor VIII had a similar dose-dependent effect on factor Va binding and platelet prothrombinase activity. Synthetic phospholipid vesicles containing phosphatidylserine competed with microparticles for binding of factor VIII and factor Va. These studies indicate that activated platelets express a transient increase in high affinity receptors for factor VIII, whereas platelet-derived microparticles express a sustained increase in receptors. The binding characteristics of platelet membrane receptors for factor VIII are similar to those for factor Va.

Animals↗
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↗