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PubMed1978

The relation of rheumatoid arthritis to hypogammaglobulinemia.

The following hypothesis is proposed. Hypogammaglobulinemia is produced by an excess of normal 7S complement-fixing anti-immunoglobulin which is specific for "altered" Fc portions of immunoglobulin. This is present lesser amount in normal blood, is not reactive with the native immunoglobulins of blood, and plays a part in controlling the normal level of antibody production. When it is present in excess, some patients respond by producing also an excess of normal non-complement-fixing 7S anti-immunoglobulin of the same specificity as well as classical 19S IgM rheumatoid factor. These latter agents successfully prevent the hypogammaglobulinemia but they produce "side effects". These "side effects" constitute classical rheumatoid arthritis.

Agammaglobulinemia↗
PubMed1967

Stability of rubella complement-fixing antigens.

Various types of rubella complement-fixing (CF) antigen preparations derived from infected BHK-21 cell cultures were examined for stability to certain chemical and physical agents. Antigens studied included: infected culture fluids concentrated 100-fold, ether-treated fluid concentrates, alkaline buffer extracts of infected cells, and large- and small-particle CF antigens separated by Sephadex gel filtration. All preparations were stable at -20 C for months, and were unaffected by three cycles of freezing and thawing. Ether treatment rendered antigens highly susceptible to thermal inactivation at 56 C; untreated antigens were inactivated slowly and showed a persistent fraction of activity even after 2 hr. Large-particle antigen was found to be slightly more susceptible than small-particle antigen to thermal inactivation and ether treatment. CF activity in alkaline buffer extracts was more labile than that in untreated or ether-treated fluid concentrates upon dialysis, Sephadex gel filtration, and sucrose density gradient centrifugation.

Antigens↗
PubMed1990

Pharmacological studies on 6-amidino-2-naphthyl[4-(4,5-dihydro-1H-imidazol-2-yl)amino] benzoate dimethane sulfonate (FUT-187). I: Inhibitory activities on various kinds of enzymes in vitro and anticomplement activity in vivo.

FUT-187, a newly synthesized compound, was studied on its inhibitory activities mainly on proteolytic enzymes, in comparison with those of FUT-175 and FOY-305, known serine protease inhibitors. FUT-187, as well as FUT-175 and FOY-305, had selective inhibitory activities on serine proteases including Clr, Cls, kallikrein, trypsin, plasmin and thrombin; its activities on these enzymes except Clr and pancreatic kallikrein were relatively lower than those of FUT-175 and FOY-305. Further studies were conducted focusing on complement-mediated reactions. In spite of its lower activities against Clr and Cls, inhibitions by FUT-187 on the complement-mediated hemolysis in vitro and in vivo were only a little weaker than or equivalent to that of FUT-175. FOY-305 was ineffective in these tests. Forssman shock in guinea pigs is known to be initiated by the activation of the complement system. The protective effect of intravenous or oral FUT-187 against this shock was definitely superior to that of FUT-175. Furthermore, FUT-187 inhibited changes accompanied with Forssman shock, such as increase in lung weight, the decrease in platelet counts and CH50, and histopathological changes. These results suggested that FUT-187 should be a more potent oral therapeutic agent than FUT-175 for various inflammatory diseases attributed to the excessive activation of the complement system followed by platelet aggregation.

Amylases↗
PubMed1988

Synergism between inflammatory mediators in vivo. Induction of airway hyperresponsiveness to C3a in the guinea pig.

The complement anaphylatoxin C3a causes acute bronchoconstriction after intravenous infusion in guinea pigs. At doses of 6 to 600 micrograms/kg, the peptide causes significant and dose-dependent increases in resistance (RL) and decreases in dynamic compliance (Cdyn). Inhibition of serum carboxypeptidase N, the enzyme thought to be responsible for control of C3a activity in blood, by pretreating animals with DL-2-mercaptomethyl-3-guanidinoethylthiopropanoic acid (MGPA), resulted in a 4-fold potentiation of the response to 200 micrograms/kg C3a. Responses to lower C3a doses were not significantly affected. Pretreating animals intravenously with histamine prior to administration of C3a resulted in potentiation of C3a-induced bronchoconstriction at all doses tested, decreasing the amount of C3a required to double RL by 15-fold, from 110 to 7 micrograms/kg. The effect appears to be relatively specific for C3a since histamine pretreatment did not alter airway responsiveness to methacholine. Similarly, pretreatment with methacholine at a dose that caused an increase in RL comparable to histamine did not alter subsequent responses to C3a. Administration of capsaicin, under conditions that elicit acute release of endogenous substance P, also resulted in potentiation of C3a responses, to an extent similar to that observed for histamine. These data are consistent with an increase in pulmonary vascular permeability facilitating accessibility of C3a for its receptor to cause bronchoconstriction before it is inactivated by serum carboxypeptidase N. Further, when C3a is generated in the presence of histamine-and/or substance-P-releasing agents, it may be responsible for a greater fraction of altered pulmonary mechanics than has previously been appreciated.

Airway Resistance↗
PubMed1994

A role for reactive oxygen species in zymosan and beta-glucan induced protein tyrosine phosphorylation and phospholipase A2 activation in murine macrophages.

Previously we have shown that reactive oxygen species (ROS) formation induced by phorbol ester in association with vanadate is essential for protein tyrosine phosphorylation and phospholipase A2 (PLA2) activation. Here we show that the interaction of beta-glucan particles (glucanp) or zymosan with complement receptor type 3 (CR3) leads, when associated with vanadate, to a cascade of reactions culminating in PLA2 activation. Vanadate + zymosan (or glucanp) markedly enhance protein tyrosine phosphorylation in bone marrow derived macrophages (BMMs), whereas neither of the agents alone has any effect. The enhancement was due to both sustained activation of protein tyrosine kinase (PTK) and inactivation of protein tyrosine phosphatase (PTP) as assessed in lysates of treated cells. Zymosan elevates membranal PKC, an effect that is potentiated by vanadate. Activation of both PTK and PKC leads to the activation of NADPH oxidase and to ROS formation. The formed ROS together with vanadate are potent inactivators of PTP leading to amplification of tyrosine phosphorylation and myelin basic protein kinase (MBP-K) activation. The activation of the cascade of protein kinases eventually leads to activation of PLA2. All the activation steps, i.e., activation of PTK, NADPH oxidase, MBP-K,PLA2 and the inactivation of PTP are sensitive to the NADPH oxidase inhibitor diphenyleneiodonium (DPI), to antioxidants and to PKC inhibitors. Thus, ROS formation (in the presence of vanadate) is critical for protein phosphorylation processes constituting the regulatory pathway of PLA2 activation by ligand-CR3 interaction.

Animals↗
PubMed1994

[Angioneurotic edema and anesthesia: preparation and perioperative monitoring].

Hereditary angioneurotic oedema is an autosomal dominant disease associated with serum deficiency of functional C1-inhibitor. It is characterized by periodic swelling of subcutaneous tissues, abdominal viscera and upper airways. Lethal acute episodes of oedema can occur during anaesthesia and surgery. It is essential to prepare such patients before surgery. This article describes three cases (kidney transplantation, caesarean section, normal delivery) and the various preventive measures used to avoid acute episodes during anaesthesia and surgery. Antibrinolytic agents, androgens, fresh frozen plasma, C1-inhibitor concentrate can be administered. Their various indications are discussed.

Adult↗
PubMed1991

Complement-mediated inactivation of interferon-gamma in ELISA systems.

The recovery of a predetermined amount of interferon-gamma (IFN-gamma) added to normal serum was studied in two independent sandwich ELISA systems specific for rat and human IFN-gamma. In both assays the ELISA activity was rapidly lost in fresh but not in heat-inactivated (30', 56 degrees C) serum. Ninety percent of the initial activity had disappeared within 30 minutes upon incubation at 37 degrees C. Serum-mediated inhibition was not species-specific as the ELISA activity of rat IFN-gamma diminished equally well in rat and human sera. Inhibition was critically dependent on the isotype of the solid-phase monoclonal antibody (mAb) used in the ELISA systems. IgG1 and IgG2a mAbs efficiently inhibited the ELISA activity of IFN-gamma, whereas an IgA mAb was ineffective. The inhibition was not influenced by a wide variety of anti-proteolytic agents but was effectively blocked by anti-complementary substances or treatments directed to the first (C1) and third (C3) component of complement. Our results indicate that activation of the classical pathway of complement (CPC) and the concomitant covalent binding of C3 to the IFN-gamma molecule play a major role in the inhibitory process. It is concluded that reduction of the ELISA activity is attributable to diminished accessibility of the detector antibody for the IFN-gamma protein as a consequence of C3 binding.

Binding Sites↗
PubMed1983

Autoantibodies cytotoxic to gastric parietal cells in serum of patients with pernicious anemia.

We measured the complement-dependent cytotoxic activity of serum in 60 patients with pernicious anemia. Canine gastric mucosal cells served as the indicator of cytotoxicity, which was expressed as a percentage of the maximal effect produced by a cytolytic agent (Triton X-100). Serum from patients with pernicious anemia showed a higher average activity (11.8 +/- 10.3 per cent, P less than 0.001) than serum from 29 patients with systemic lupus erythematosus (1.0 +/- 1.8 per cent), 10 with scleroderma (0.1 +/- 0.1 per cent), 10 with rheumatoid arthritis (0.6 +/- 0.6 per cent), 22 with multiple sclerosis (0.4 +/- 1.2 per cent), and 23 with chronic persistent hepatitis (0.03 +/- 0.1 per cent), and serum from 64 healthy persons (0.4 +/- 1.0 per cent). Serum from patients with pernicious anemia was not toxic to canine liver or kidney cells. Absorption with gastric mucosal cells and heat inactivation of complement abolished the cytotoxic reaction. The cytotoxic factor resided in the IgG fraction of immunoglobulin, and the amount of cytotoxicity was proportional to the IgG concentration. Cytotoxic activity correlated with the presence of parietal-cell-surface--reactive autoantibody demonstrated by immunofluorescence. We conclude that cytotoxic autoantibodies to parietal cells may contribute to the loss of such cells from the gastric mucosa of patients with pernicious anemia.

Adult↗
PubMed1994

Activation of the contact system and fibrinolysis in autoimmune acquired angioedema: a rationale for prophylactic use of tranexamic acid.

C1-inhibitor deficiency results in bouts of mucocutaneous edema and may be inherited (hereditary angioedema) or acquired (acquired angioedema [AAE]). The two forms have the same clinical picture but differ in the response to treatment. Prophylaxis with antifibrinolytic agents produces better results in the acquired form than in the inherited form, in which androgen derivatives are more effective. It is hypothesized that activation of the contact and fibrinolytic systems is involved in the pathogenesis of attacks. We evaluated these two systems in plasma from eight patients with AAE and anti-C1-inhibitor autoantibodies (autoimmune AAE) by measuring the cleavage of high molecular weight kininogen and the complexes formed by plasmin and its inhibitor alpha 2-antiplasmin. We also measured complement parameters, autoantibody titer, and cleaved C1-inhibitor (relative molecular mass = 96,000), because autoantibodies to C1-inhibitor are known to facilitate its cleavage by proteases. Plasma was obtained from patients in remission, during prophylactic treatment with the antifibrinolytic agent tranexamic acid (2 to 4.5 gm/day) and also from two patients during acute attacks of edema. Levels of cleaved high molecular weight kininogen and antiplasmin-plasmin complexes in patients with AAE were both higher in basal conditions, during treatment, and during acute attacks than those in normal subjects (p < 0.001). The cleaved inactive form of C1-inhibitor was also present in all patients in all three conditions. Therapy with antifibrinolytic agents reduced the frequency and intensity of symptoms without significantly changing any of the biochemical parameters.(ABSTRACT TRUNCATED AT 250 WORDS)

Acute Disease↗
PubMed1993

Process-scale purification of immunoglobulin M concentrate.

An IgM concentrate was purified from Cohn fraction III. Efficiency of euglobin precipitation was shown to be controlled by pH and ionic strength. Prekallikrein activator activity in the product was insignificant. Overall yield from the octanoic acid supernate and purity of the concentrate were 66 +/- 8 (n = 16) and 50 +/- 5% (n = 16), respectively. Solvent-detergent treatment to inactivate lipid-enveloped viruses was demonstrated and implemented into the process. Process studies to control residual virucidal agents and C4a generating activity are presented.

Chemical Fractionation↗
PubMed1990

Recognition by the DNA repair system of DNA structural alterations induced by reversible drug-DNA interactions.

Ditercalinium (NSC 335153) was synthesized as a bifunctional DNA intercalator. It is made of two 7-H pyridocarbazole rings joined by a rigid bis-ethyl bispiperidine chain. It binds to DNA with high affinity and elicits anti-tumor activity on a variety of animal tumors. 1H n.m.r. studies of ditercalinium bis-intercalated into d(CpGpCpG)2 have shown that the intercalation process occurs from the large groove of the DNA helix while the two intercalated rings are separated by two base pairs. Because of the linking chain rigidity of ditercalinium, DNA conformation has to be altered to permit the intercalation of the two rings. DNA must be bent toward the minor groove. In E. coli, ditercalinium elicits a specific toxicity on polA strains which is suppressed by an additional uvrA mutation. In vitro, the purified UvrA and UvrB proteins bind to the DNA-ditercalinium complex in an ATP dependent manner. The UvrABC complex induces single-strand nicks, but only when ditercalinium is bound to negatively supercoiled DNA. The life-time of the UvrAB-DNA-ditercalinium complex is greater than 50 min when free ditercalinium concentration is maintained constant in the incubation medium. The cytotoxicity of ditercalinium in E. coli results from the induction of a futile and abortive DNA repair. The reversible ditercalinium-DNA complex mimics a bulky DNA lesion, yet the UvrABC endonuclease is unable to cope with a reversible lesion since it cannot eliminate the causative agent. The interaction of UvrA and UvrB proteins has also been studied with DNA and other DNA-binding drugs forming high-affinity complexes such as distamycin. The Uvr protein recognition process appears to be associated with specific DNA structural alterations. In eukaryotic cells, ditercalinium is concentrated in mitochondria. Mitochondrial DNA is rapidly and totally degraded. Mitochondrial DNA coded proteins being no longer synthesized, the respiratory chain is progressively inactivated. The stimulation of the glycolytic pathway allows the cells to continue growth for several generations. Dihydro-orotate dehydrogenase is located in the inner membrane of mitochondria and its activity is dependent on mitochondria energization. It becomes inactive after ditercalinium treatment. A drop of the pyrimidine pool is then observed. Complementation of treated cells with uridine decreases 10-fold the ditercalinium toxicity. The cellular delayed toxicity of ditercalinium results from the slow induction of a pyrimidineless state associated with the progressive inactivation of mitochondria. The results show that DNA structural alterations induced by reversible drug-DNA complexes can be recognized by DNA repair enzymes.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1980

Release of endogenous C3b inactivator from lymphocytes in response to triggering membrane receptors for beta 1H globulin.

Human bone marrow-derived lymphocytes and cells from B lymphoblastoid lines were shown to have specific membrane receptors for beta 1H globin. Lymphocytes responded to the presence of beta 1H by releasing endogenously-synthesized C3b-inactivator. Very little spontaneous release of C3b-inactivator occurred in the absence of beta 1H. beta 1H-treated lymphocytes that either lacked complement receptor type one (CR1, the C4b-C3b receptor) or had their CR1 blocked with Fab'-anti-CR1 formed rosettes with C3b-coated sheep erythrocytes (EC3b) by adherence to complement receptor type two (CR2, the C3d-C3bi receptor). The mechanism of the beta 1H-induced EC3b rosette formation was shown to involve the release of lymphocyte C3b-inactivator that cleaved bound C3b into C3bi forming EC3bi. This lymphocytes-generated EC3bi then bound to CR2, forming rosettes. beta 1H-induced EC3b rosettes were completely inhibited by the presence of either anti-C3b-inactivator, F(ab')2-anti-CR2, Fab-anti-C3c, or Fab-anti-C3d, but were unaffected by the presence of fluid-phase concentrations of beta 1H up to 5.5 mg/ml or Fab'-anti-CR1. Analysis by sodium dodecyl sulfate polyacrylamide gel electrophoresis and fluorography demonstrated that cell-free supernates of beta 1H-treated lymphocytes cleaved 3H-labeled C3b on EC3b into C3bi. Inhibition studies with chelating agents and sodium azide suggested that the release of C3b inactivator might involve a calcium and energy-dependent transport of this enzyme across the membranes of beta 1H-triggered cells. Because plasma beta 1H and C3b-inactivator are known to have important functions in the distinction of alternative pathway-activating substances from normal tissue, it is possible that this beta 1H receptor-C3b-inactivatory releasing system in lymphocytes may have an analogous function.

B-Lymphocytes↗
PubMed1978

Trypanosoma (Schizotrypanum) dionisii: effect of various agents on attachment and entry to macrophages in vitro and on morphogenesis.

The attachment and entry of Trypanosoma dionisii to mouse peritoneal macrophages in vitro were studied. Both occurred to a similar extent whether parasites were alive or heat-killed, and whether macrophages were obtained from normal or immunized mice. Attachment occurred equally at 4 and 37 degrees C, but entry only occurred at the higher temperature. Neither was affected by pretreatment of parasites with active or inactivated complement. Entry, but not attachment, was inhibited by cytochalasin B; both were inhibited by trypsin. Immune mouse plasma (if inactivated) stimulated attachment but not entry (within 24 h). It also stimulated intracellular replication of T. dionisii by multiple fission and subsequent differentiation (probably within macrophages) to small extracellular trypomastigotes. No extracellular parasite and only scanty intracellular forms survived 120 h in cultures containing non-inactivated immune mouse plasma. It was concluded that attachment (in the absence of antibody) occurred to non-specific receptors in the macrophage membrane and was followed by phagocytosis of the parasites rather than their active penetration of the cell.

Animals↗
PubMed1975

Circular dichroism of C3a anaphylatoxin. Effects of pH, heat, guanidinium chloride, and mercaptoethanol on conformation and function.

Circular dichroism spectra for C3a anaphylatoxins (protein fragments generated enzymatically in serum during activation of the third component of complement (C3)) from human and porcine sources were compared in the region of 190 to 250 nm. The spectra were indistinguishable in this region, although an estimated difference of approximately 20% exists between the primary structures of human and porcine C3a. Calculations indicated a total of 40 to 45% alpha helical content based on either the 208 or 222 nm extremum of the CD spectra. Addition of either mercaptoethanol or 6 M guanidinium chloride to human C3a produced a marked decrease in the mean residue ellipticity centered at 222 nm without irreversibly affecting the biological activity. Simultaneous addition of mercaptoethanol and guanidinium chloride virtually eliminated the CD contribution at 222 nm and resulted in more than 90% inactivation of the anaphylatoxin. Removal of the denaturant and reducing agent restored both the biological activity and the CD spectrum of C3a. Heat treatment or reduction and alkylation of human C3a produced biologically inactive and conformationally modified anaphylatoxin. In contrast, C3a inactivated by enzymatic removal of the COOH-terminal arginyl residue was structurally unchanged as judged by CD measurements. Consequently, it is proposed that in addition to the essential COOH-terminal arginyl residue, a highly ordered conformation is required for biological functionality of the C3a molecule.

Animals↗
PubMed1988

A yeast DNA repair gene partially complements defective excision repair in mammalian cells.

The RAD10 gene of Saccharomyces cerevisiae is required for nucleotide excision repair of DNA. Expression of RAD10 mRNA and Rad10 protein was demonstrated in Chinese hamster ovary (CHO) cells containing amplified copies of the gene, and RAD10 mRNA was also detected in stable transfectants without gene amplification. Following transfection with the RAD10 gene, three independently isolated excision repair-defective CHO cell lines from the same genetic complementation group (complementation group 2) showed partial complementation of sensitivity to killing by UV radiation and to the DNA cross-linking agent mitomycin C. These results were not observed when RAD10 was introduced into excision repair-defective CHO cell lines from other genetic complementation groups, nor when the yeast RAD3 gene was expressed in cells from genetic complementation group 2. Enhanced UV resistance in cells carrying the RAD10 gene was accompanied by partial reactivation of the plasmid-borne chloramphenicol acetyltransferase (cat) gene following its inactivation by UV radiation. The phenotype of CHO cells from genetic complementation group 2 is also specifically complemented by the human ERCC1 gene, and the ERCC1 and RAD10 genes have similar amino acid sequences. The present experiments therefore indicate that the structural homology between the yeast Rad10 and human Ercc1 polypeptides is reflected at a functional level, and suggest that nucleotide excision repair proteins are conserved in eukaryotes.

Animals↗
PubMed1975

Quantitative studies on cell-mediated immunity in the pleural cavity of guinea-pigs.

Intrapleural injection of PPD into CFA-sensitised guinea-pigs produced a reaction having many of the characteristics of classical delayed hypersensitivity. Quantitative investigations of the time course of this reaction showed that it was typified by an initial delay in the onset of increased vascular permeability, which reached its peak between 12 and 18 hr. The cellular response in the pleural cavity followed a similar pattern, attaining maximum levels between 18 and 24 hr. Mononuclear cells dominated the reaction from 12 to 48 hr. The histological appearance of the lung tissue was also studied. Treatment with Cobra venom factor, a complement-depleting agent, failed to modify this reaction. Cyclic AMP levels were assayed for both the cellular and cell-free exudates.

Animals↗
PubMed1981

Studies on the inhibition of ellagic acid-activated Hageman factor (factor XII) and Hageman factor fragments.

Hageman factor (HF, factor XII) that has been exposed to Sephadex-ellagic acid gels is a single-chain species (HFea) with amidolytic properties for the synthetic substrate H-D-phenylalanyl-L-pipecolyl-L-arginine p-nitroanilide. Earlier we reported that amidolysis was suppressed by incubation of HFea with specific antiserum. The present study provides additional evidence that the amidolytic properties of preparations of HFea are ascribable to this substance through an examination of a number of protease inhibitors. HFea's amidolytic properties were inhibited by alpha 2-plasmin inhibitor, antithrombin III in the presence of heparin, and Cl esterase inhibitor (Cl-INH). Additionally, it was inhibited by popcorn inhibitor, leupeptin, hexadimethrine bromide, protamine sulfate, dansyl-arginine N-(3-ethyl-1,5-pentanediyl) amide (DAPA), diisopropylphosphofluoridate (DFP), aprotinin, and at excessively high concentrations, soybean and lima bean trypsin inhibitors. The spectrum of action of agents that did or did not inhibit HFea supports the view that amidolysis by preparations of HFea is attributable to this enzyme. In general, the enzymatically active carboxy-terminal fragment of HF (HFf) was inhibited by the same agents that inhibited HFea, but aprotinin, protamine sulfate and hexadimethrine bromide were more effective against HFf than HFea, while the reverse was true of lima bean trypsin inhibitor.

Albumins↗