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PubMed1995

Further identification of human plasma glycoproteins interacting with the galactose-specific lectin Jacalin.

In this report we show that Jacalin binds the heme-binding protein hemopexin and the C4b-binding protein sgp120 in human plasma. The interaction of Jacalin with hemopexin confirms that a single O-linked oligosaccharide is sufficient to mediate binding of a protein to this lectin. Retention of sgp120 by immobilized Jacalin demonstrated that this protein was O-glycosylated and, therefore, clearly different from another C4b-binding protein, the complement protein C2 which is physicochemically similar but exclusively N-glycosylated. In addition, Jacalin was also shown to bind several proteolytic enzymes which remain to be identified.

Amino Acid Sequence↗
PubMed2005

Selective expression of a splice variant of decay-accelerating factor in c-erbB-2-positive mammary carcinoma cells showing increased transendothelial invasiveness.

By differential-display-PCR a subclone of the SK-BR-3 cell line with high in vitro transendothelial invasiveness was identified to express increased levels of a new alternative splice variant of decay-accelerating factor (DAF). DAF seems to play an important role in some malignant tumours since on the one hand the expression of complement inhibitors on the surface of tumour cells prevents the accumulation of complement factors and in consequence cell lysis. On the other hand, DAF has been identified as a ligand for the CD97 surface receptor which induces cell migration. Immunofluorescence procedures, Western blot analyses, and cDNA clone sequencing were employed to confirm the expression of DAF restricted to invasive tumour cells. Using a radioactive RNA-in situ hybridisation on freshly frozen tissue microarrays and RT-PCR on native tumour tissue, the expression of alternative spliced DAF mRNA was demonstrated in invasive breast cancer. Due to the fact that it could thereby not be detected in normal mammary tissues, it has to be confirmed in larger studies that the DAF splice variant might be a specific tumour marker for invasive breast cancer.

Alternative Splicing↗
PubMed2005

Design and synthesis of low molecular weight compounds with complement inhibition activity.

An attempt was made to synthesize a series of non-cytotoxic low molecular weight compounds of varying substitutions and functionalities having pharmacophore activity like carbonyl compounds, carboxylic acid and bioisosteres like tetrazole and phenyl acrylic acid. The in vitro assay of these analogues for the inhibition of complement activity revealed significant inhibitory activity for varying substituents and, particularly, for bioisosteres, that is, tetrazole and phenyl acrylic acid derivatives.

Acrylates↗
PubMed2004

A novel series of potent and selective small molecule inhibitors of the complement component C1s.

Activation of the classical pathway of complement has been implicated in disease states such as hereditary angioedema, ischemia-reperfusion injury and acute transplant rejection. The trypsin-like serine protease C1s represents a pivotal upstream point of control in the classical pathway of complement activation and is therefore likely to be a useful target in the therapeutic intervention of these disease states. A series of thiopheneamidine-based inhibitors of C1s has been optimized to give a 70 nM inhibitor that inhibits the classical pathway of complement activation in vitro.

Binding Sites↗
PubMed2005

Heparin treatment in pregnancy loss: Potential therapeutic benefits beyond anticoagulation.

Interventions with heparin therapies have increased fetal survival in patients with antiphospholipid syndrome (APS). In this review, several physiological and pharmacological effects of heparin are described. These different mechanisms of action could explain the beneficial effects of heparin in the treatment of recurrent pregnancy loss in patients with APS. In addition to direct effects of heparin on the coagulation cascade, heparin might protect pregnancies by reducing the binding of antiphospholipid antibodies, reducing inflammation, facilitating implantation and or inhibiting complement activation.

Abortion, Habitual↗
PubMed2005

A randomized, placebo-controlled trial of complement inhibition in ischemia-reperfusion injury after lung transplantation in human beings.

OBJECTIVE: Complement activation has been shown to play a significant role in ischemia-reperfusion injury after lung transplantation. TP-10 (soluble complement receptor 1 inhibitor) inhibits the activation of complement by inactivating C3a and C5a convertases. This was a clinical trial of TP-10 to reduce ischemia-reperfusion injury in lung transplantation. METHODS: In a randomized, double-blinded, multicenter, placebo-controlled trial, 59 patients from four lung transplant programs received TP-10 (10 mg/kg, n = 28) or placebo (n = 31) before reperfusion. This dose achieved 90% complement inhibition for 24 hours, and activity had returned toward normal by 72 hours. RESULTS: At 24 hours, 14 of 28 patients in the TP-10 group (50%) were extubated, whereas only 6 of 31 patients in the placebo group (19%) were (P = .01). The total times on the ventilator and in the intensive care unit both tended to be shorter in the TP-10 group, but these differences did not achieve statistical significance. Among patients requiring cardiopulmonary bypass (n = 5 in placebo group and n = 7 in TP-10 group), the mean duration of mechanical ventilation was reduced by 11 days in the TP-10 group (10.6 +/- 5.0 days vs 21.5 +/- 5.9 days in placebo group, P = .2). Operative deaths, incidences of infection and rejection, and length of hospital stay were not significantly different between the two groups. CONCLUSIONS: Short-term complement inhibition with TP-10 led to early extubation in a significantly higher proportion of lung transplant recipients. The effect of TP-10 was greater among patients undergoing cardiopulmonary bypass, with a large reduction in ventilator days. Complement inhibition thus significantly decreases the duration of mechanical ventilation and could be useful in improving the outcome of lung transplant recipients.

Adolescent↗
PubMed2005

Complement-opsonized HIV: the free rider on its way to infection.

The complement system (C) is one of the main humoral components of innate immunity. Three major tasks of C against invading pathogens are: (i) lysis of pathogens by the formation of the membrane attack complex (MAC); (ii) opsonization of pathogens with complement fragments to favor phagocytosis; and (iii) attraction of inflammatory cells by chemotaxis. Like other particles, HIV activates C and becomes opsonized. To escape complement-mediated lysis, HIV has adopted various properties, which include the acquisition of HIV-associated molecules (HAMs) belonging to the family of complement regulators, such as CD46, CD55, CD59, and the interaction with humoral regulatory factors like factor H (fH). Opsonized virus may bind to complement receptor positive cells to infect them more efficiently or to remain bound on the surface of such cells. In the latter case HIV can be transmitted to cells susceptible for infection. This review discusses several aspects of C-HIV interactions and provides a model for the dynamics of this process.

Complement Inactivator Proteins↗
PubMed2005

Oxiagin from the Naja oxiana cobra venom is the first reprolysin inhibiting the classical pathway of complement.

A basic glycoprotein oxiagin with molecular mass of 49.8 kDa was isolated from the venom of Central Asian cobra Naja oxiana. Partial amino acid sequence determination has shown that oxiagin belongs to reprolysins, a subfamily of animal metalloproteinases possessing a characteristic multidomain structure. Oxiagin was found to inhibit the classical pathway of the complement system. A study of the oxiagin influence on the different stages of the classical pathway showed that it inhibited the formation of C3-convertase. To achieve it, oxiagin binds to IgG on the surface of sheep erythrocytes sensitized with rabbit antibodies, thus, preventing the interaction of component C2 (without its inactivation) with immobilized C4b. IC50 for the inhibiton of classical pathway of complement system by oxiagin is 80 nM, while it does not affect the alternative pathway at concentrations up to 1.2 microM. Oxiagin possessed hemagglutinating activity towards sheep and rabbit erythrocytes, and this activity as well as the complement inhibition by oxiagin were suppressed by D-galactose. Oxiagin is the first representative of snake venom reprolysins that inhibits the complement system, utilizing non-proteolytic inhibiting strategy.

Amino Acid Sequence↗
PubMed2004

Host-pathogen interactions in Streptococcus pyogenes infections, with special reference to puerperal fever and a comment on vaccine development.

Streptococcus pyogenes (group A streptococcus) causes a variety of diseases, including acute pharyngitis, impetigo, rheumatic fever and the streptococcal toxic shock syndrome. Moreover, S. pyogenes was responsible for the classical example of a nosocomial infection, the epidemics of puerperal fever (childbed fever) that caused the death of numerous women in earlier centuries. The most extensively studied virulence factor of S. pyogenes is the surface M protein, which inhibits phagocytosis and shows antigenic variation. Recent data indicate that many M proteins confer phagocytosis resistance because the variable N-terminal region has non-overlapping sites that specifically bind two components of the human immune system, the complement inhibitor C4b-binding protein (C4BP) and IgA-Fc. Concerning puerperal fever, molecular and epidemiological analysis suggests that the S. pyogenes surface protein R28 may have played a pathogenetic role in these epidemics. This article summarizes the properties of M protein and the R28 protein and considers a potential problem encountered in connection with the use of animal models for vaccine development.

Antigens, Bacterial↗
PubMed2004

Inflammation, complement, ischemia and amoebic survival in acute experimental amoebic liver abscesses in hamsters.

We have examined the role of inflammatory cells, ischemia and serum complement on the development of acute experimental amoebic liver abscess in hamsters (AEALAH). In hamsters made leukopenic by whole body radiation (800 rad) and daily intraperitoneal glycogen injections, the absence of inflammatory cells and liver tissue damage surrounding the parasites resulted in their rapid (24 h) disappearance from the liver, which showed no lesions. Focal liver ischemia, always present in control AEALAH with inflammation and tissue destruction, was reproduced in radiated hamsters by injection of amoebae mixed with Superdex microspheres, but again in the absence of inflammation, amoebae caused no liver damage and disappeared in 24 h. In hamsters made hypocomplementemic by injection of purified cobra venom factor (CVF), amoebae caused AEALA indistinguishable from controls, but in leukopenic + hypocomplementemic hamsters, amoebae were unable to produce lesions and disappeared from the liver in 48 h. We conclude that inflammation and tissue damage are required for the survival of amoebae in AEALAH and for the progression of the experimental disease.

Acute Disease↗
PubMed2000

Spontaneous classical pathway activation and deficiency of membrane regulators render human neurons susceptible to complement lysis.

This study investigated the capacity of neurons and astrocytes to spontaneously activate the complement system and control activation by expressing complement regulators. Human fetal neurons spontaneously activated complement through the classical pathway in normal and immunoglobulin-deficient serum and C1q binding was noted on neurons but not on astrocytes. A strong staining for C4, C3b, iC3b neoepitope and C9 neoepitope was also found on neurons. More than 40% of human fetal neurons were lysed when exposed to normal human serum in the presence of a CD59-blocking antibody, whereas astrocytes were unaffected. Significant reduction in neuronal cell lysis was observed after the addition of soluble complement receptor 1 at 10 microg/ml. Fetal neurons were stained for CD59 and CD46 and were negative for CD55 and CD35. In contrast, fetal astrocytes were strongly stained for CD59, CD46, CD55, and were negative for CD35. This study demonstrates that human fetal neurons activate spontaneously the classical pathway of complement in an antibody-independent manner to assemble the cytolytic membrane attack complex on their membranes, whereas astrocytes are unaffected. One reason for the susceptibility of neurons to complement-mediated damage in vivo may reside in their poor capacity to control complement activation.

Antibodies, Blocking↗
PubMed2003

A novel cytomedical vehicle capable of protecting cells against complement.

We have developed "Cytomedicine," which consists of functional cells entrapped in semipermeable polymer, and previously reported that APA microcapsules could protect the entrapped cells from injury by cellular immune system. However, microencapsulated cells were not protected from humoral immune system. Here, we developed a novel APA microcapsule, in which APA microbeads (APA(Ba) microbeads) were modified to contain a barium alginate hydrogel within their centers in an attempt to make it more difficult for antibody and complement to permeate the microcapsules. The permeability of APA(Ba) microbeads was clearly less than that of APA microcapsules, presumably due to the presence of barium alginate hydrogel. Cells encapsulated within APA(Ba) microbeads were protected against treatment with xenogeneic anti-serum. Furthermore, murine pancreatic beta-cells encapsulated in APA(Ba) microbeads remained viable and continued to secrete insulin in response to glucose. Therefore, APA(Ba) microbeads may be a useful carrier for developing anti-complement device for cytomedical therapy.

Alginates↗
PubMed2002

In vivo anti-complement effect of bilirubin-IXalpha.

The effect of the IXalpha isomer of unconjugated bilirubin (UB) on complement-mediated intravascular hemolysis was evaluated in rats carrying naturally occurring heteroantibodies against sheep erythrocytes. Several doses of UB were administered i.v. to these animals in order to induce different levels of hyperbilirubinemia. Intravascular hemolysis was promoted by transfusion with a sheep red cell suspension. Hemoglobin in urine was assessed as a marker of intravascular hemolysis. The urinary excretion of hemoglobin was attenuated by UB in a dose-dependent manner. To establish whether complement was involved in the hemolytic reaction, we evaluated the hemolytic activity of complement in these same animals, before and after sheep erythrocyte transfusion. The significant consumption of complement, which was partially prevented by UB, corroborated its participation in the intravascular hemolytic reaction in the current experimental conditions. The data suggest an inhibitory action of UB on complement-mediated hemolysis in vivo.

Animals↗