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PubMed2006

In vitro evaluation of biospecific and pseudobiospecific ligands aimed at extracorporeal treatment for immunoglobulin E removal.

This work investigated the potential use of an alternative adsorbent to anti-immunoglobulin E (IgE)-agarose for IgE selective adsorption therapy. A screening of several commercially available adsorbents (Concanavalin A, Lens culinaris[Lc], d-tryptophan, poly-l-lysine, and aminohexyl immobilized on agarose) was done through batch system assays, considering some criteria, such as adsorption capacity, selectivity, and biocompatibility. In the Lc-agarose adsorbent, total IgE, and specific IgE--for the airborne allergens Dermatophagoides pteronyssinus and Blomia tropicalis--were significantly better removed (63, 58, and 59%, respectively) than immunoglobulin G (19%), immunoglobulin A (33%), immunoglobulin M (9%), and albumin (18%). This adsorbent was packed into a column and the effect of superficial velocity, ratio of plasma volume to bed volume, number of perfusions, and temperature on IgE adsorption were evaluated. In vitro simulation of therapeutic adsorption (single perfusion) indicated that about 50% of total IgE could be eliminated.

Adsorption↗
PubMed1998

Molecular genetics of the complement C3 convertases in lower vertebrates.

Evolution of the two gene families of the complement system involved in the formation of the C3 convertases, B/C2 and C3/C4/C5, was studied at the cDNA level in lower vertebrates. Cyclostomes, the most primitive extant vertebrates, seem to possess only one member each of these families, indicating that gene duplication between B and C2 or among C3, C4 and C5 occurred in the lineage of jawed vertebrates. Typical C3 and C4 cDNAs were identified in both amphibian (Xenopus) and teleost (medaka fish), locating the C3/C4 gene duplication before the divergence of ray-finned fish and lobe-finned fish. On the other hand, typical B cDNA was identified in Xenopus, whereas teleost counterparts from three species all showed intermediate character between B and C2, suggesting the possibility that the B/C2 gene duplication occurred in the tetrapod lineage. Genetic linkage between these two family genes within the MHC was observed in Xenopus but not in medaka fish.

Animals↗
PubMed2006

The innate immune modulators staphylococcal complement inhibitor and chemotaxis inhibitory protein of Staphylococcus aureus are located on beta-hemolysin-converting bacteriophages.

Two newly discovered immune modulators, chemotaxis inhibitory protein of Staphylococcus aureus (CHIPS) and staphylococcal complement inhibitor (SCIN), cluster on the conserved 3' end of beta-hemolysin (hlb)-converting bacteriophages (betaC-phis). Since these betaC-phis also carry the genes for the immune evasion molecules staphylokinase (sak) and enterotoxin A (sea), this 8-kb region at the 3' end of betaC-phi represents an innate immune evasion cluster (IEC). By PCR and Southern analyses of 85 clinical Staphylococcus aureus strains and 5 classical laboratory strains, we show that 90% of S. aureus strains carry a betaC-phi with an IEC. Seven IEC variants were discovered, carrying different combinations of chp, sak, or sea (or sep), always in the same 5'-to-3' orientation and on the 3' end of a betaC-phi. From most IEC variants we could isolate active bacteriophages by mitomycin C treatment, of which lysogens were generated in S. aureus R5 (broad phage host). All IEC-carrying bacteriophages integrated into hlb, as was measured by Southern blotting of R5 lysogens. Large quantities of the different bacteriophages were obtained by mitomycin C treatment of the lysogens, and bacteriophages were collected and used to reinfect all lysogenic R5 strains. In total, five lytic families were found. Furthermore, phage DNA was isolated and digested with EcoR1, revealing that one IEC variant can be found on different betaI-phis. In conclusion, the four human-specific innate immune modulators SCIN, CHIPS, SAK, and SEA form an IEC that is easily transferred among S. aureus strains by a diverse group of beta-hemolysin-converting bacteriophages.

3' Flanking Region↗
PubMed1982

Mycoplasma pneumoniae pneumonia associated with IgA nephropathy.

An 18-yr-old male developed Mycoplasma pneumoniae pneumonia associated with IgA nephropathy. In the biopsied renal tissue, immunofluorescence showed striking deposits of IgA, C3 and C3 activator in the mesangium, and electron microscopic examination showed electron-dense deposits in the mesangial region. When the patient's serum was preincubated with rabbit antiserum to human IgA, the passive hemagglutination titer for M. pneumoniae was much decreased. We suggest that in some cases, IgA nephropathy may follow infection by an organism which stimulates in IgA antibody response, leading to the formation of IgA antigen antibody immune complex deposits in the glomerular mesangium.

Adolescent↗
PubMed1979

[Description of an unusual enzymic activity cleaving the third component of complement].

A large enzymatic complex cleaving C3 (C3'ase) in the absence of magnesium (EDTA) has been partially characterized in two patients. On gel filtration EDTA-C3'ase was found in an 800 000 fraction containing antigenic C4, IgA and IgG in addition to alpha-2-macroglobulin and IgM normally present. EDTA-C3'ase was specifically neutralized by antibodies to IgG, IgA and C4. The characteristics of this unusual enzymatic complex are compatible with that of a C4b2a complex stabilized by its specific binding to an auto-antibody of the IgG and/or IgA class.

Chromatography, Gel↗
PubMed1992

Requirements for the production of high-titre C3 nephritic factor (NEF) antibody in vitro.

C3 nephritic factor (NEF) is an IgG autoantibody directed against neoantigenic determinants of the alternative C3 convertase (C3b.Bb). Structural and functional studies require important amounts of this antibody, which are difficult to obtain from patients' sera. We have developed a method for increasing NEF production in vitro. Epstein-Barr virus is a herpes virus which transforms B lymphocytes. Some authors were able to induce the production of NEF in vitro after infection with Epstein-Barr virus (EBV). These works were preformed without any previous cellular selection of B cells. We have performed a method of preselecting antigen-binding cells prior to EBV transformation. Non-preselected cells yielded 0.16 U/million cells in culture (U/M) of NEF antibody, whereas enriched cells for NEF antibody in eliminated 8 U/M (sheep erythrocytes coated with anti-IgG, A, M). Specific NEF synthesis can be increased, in peripheral blood mononuclear cells (PBMC) from patients by in vitro stimulation with the antigens recognized by NEF [C3b.Bb, 21,000 MW protein from patients' E membranes and 26,000 MW protein from sheep E membranes (ShE)]. The highest stimulation is induced by the C3b.Bb and by 26,000 MW protein, 21,000 MW protein had lowest stimulatory effect. In this work also we have shown that patients having NEF antibody in sera have an increase of the CD5-CD19 subset, when compared with the controls.

Antigens, CD↗
PubMed1992

Autoantibody to the alternative pathway C3/C5 convertase and its anti-idiotypic response. A study in affinity.

In an effort to understand the development and control of autoantibody production, we studied the affinity of autoantibody to the alternative pathway C3/C5 convertase (C3 nephritic factor (C3NeF)) and its autoanti-idiotypic antibodies, Ab2 alpha and Ab2 beta. These were isolated and purified from newborns, normal adults, and patients with membranoproliferative glomerulonephritis. In all cases, both IgG and IgM C3NeF were available for study. The affinity of IgG and IgM C3NeF for their natural Ag (10(8) liters/mol) as well as for the internal image of that Ag displayed on Ab2 beta was high (10(10) liters/mol). Furthermore, the affinity of IgG C3NeF was nearly 100-fold higher in patients than in newborns, whereas there were no significant changes with IgM C3NeF. By contrast, there were not differences in the affinity of IgG Ab2 alpha (which does not display any likeness to the native Ag) from normal adults and patients to any C3NeF isolate. There was, however, a progressive increase in affinity between both Ab2 alpha preparations and IgG C3NeF from newborns, adult normal subjects, and patients, implying an alteration in C3NeF to account for the changes in affinity. These data suggest that Ag-driven affinity maturation occurs with autoantibody but may not occur within the idiotypic network. These data also indicate that as autoantibody affinity matures, it appears to modify its idiotype, perhaps in an effort towards autoregulation.

Adult↗
PubMed1985

[Effect of Expafusion (HES 40/0.5) on the corpuscular elements of blood and inhibitors of blood coagulation].

The present study reports on an investigation of 32 normal subjects who were given intravenously 500 ml of hydroxyethyl starch (HES) over 30 min. In 16 normal subjects, 500 ml of blood had been previously withdrawn over 20 min. Tolerance proved to be good. Side effects such as hyperergic reactions, influence on circulatory or cardiac function were not observed. Changes in corpuscular elements of blood did not exceed the dilution effect and mostly returned to the initial value 60 min after termination of HES infusion. The change in thrombocyte function, immunoglobulins and the inhibitors alpha 1-antitrypsin, alpha 2-macroglobulin, as well as C1-inactivator and C3-activator only slightly, but not more pronounced than it could have been expected by the dilution effect. A favorable effect could be recorded in erythrocyte filtration according to Schmidt-Schoenbein. Here, we found an improved flow property which exceeded the hemodilution effect and lasted over the 4-hour test period. In addition, thrombocyte aggregation during ADP administration in the Born chamber did not show any change which suggests that a clinically relevant effect on thrombocyte function and thus the danger of hemorrhage during HES administration can be excluded.

Adolescent↗
PubMed1987

Characterization of three monoclonal antibodies against C3 with selective specificities.

We raised 15 mouse monoclonal antibodies against human C3 from two separate fusions. Mouse plasmacytoma cells were fused with spleen cells from mice immunized either with a mixture of C3, C3b and C3c, or with a mixture of C3dg and C3d. Three of the 15 monoclonals were characterized in detail. N-7A reacted with native C3 as well as C3b and C3c. Two other monoclonals, C-5G and G-3E, recognized neoantigenic determinants on C3c and C3dg, respectively. In ELISA, C-5G reacted with C3b and C3c but not with native C3 nor with C3dg; and on the other hand G-3E reacted only with C3dg. The selective specificities of these monoclonals were further confirmed in a binding assay to C3 fragments formed on cellular intermediates. C-5G bound exclusively to EC3b, and G-3E bound to EiC3b, EC3dg and EC3d. N-7A bound only very poorly to EC3b. C-5G inhibited both the haemolytic activity of C5 convertase and also the CR1-mediated rosette formation of B-enriched peripheral mononuclear cells with EC3b. G-3E inhibited the CR2-mediated EC3dg-rosette formation of Raji cells. These monoclonals, with selective specificities, can distinguish the state of activation and degradation of the C3 molecule.

Antibodies, Monoclonal↗
PubMed1988

Purification and characterization of decay-accelerating factor (DAF) from Raji cells.

Decay-accelerating factor (DAF), a membrane protein that regulates the complement system, was purified to homogeneity from lymphoblastoid (Raji) cells (DAF-R). It exhibited almost the same molecular weight as DAF from stroma of erythrocytes (DAF-S). Purified DAF-R, which could be reincorporated into cell membranes, accelerated the decay of the C3 convertases, in both the classical (C4b2a) and the alternative (C3bBb) pathways. This activity was completely inhibited by a monoclonal anti-DAF antibody, 1C6. From these results, DAF-R and DAF-S can not be distinguished; however, the decay-accelerating activity of DAF-R was much higher than that of DAF-S. 1C6 enhanced the binding of C3 to Raji cells by incubating with six purified components of the alternative pathway, whereas it did not induce the killing of Raji cells after a short incubation period. When antibodies against Raji cells were added to the above system, the blocking of DAF activity by 1C6 resulted in efficient killing of Raji cells by autologous complement. From these results, it is clear that DAF on nucleated cells plays an important role in protecting these cells from the damage caused by autologous complement.

Burkitt Lymphoma↗
PubMed1995

[Does temperature in extracorporeal circulation affect neutrophil-endothelium interactions?].

The increasing interest in "warm" aerobic cardioplegia requires a critical reevaluation of the systemic effects of the associated normothermic cardiopulmonary bypass (CPB). As activated neutrophils seem to be essential mediators of the inflammatory response to CPB via the cytotoxicity of the products that are released during their adhesion to endothelial cells, the authors undertook a study of the influence of temperature on the interaction between the neutrophils and the endothelium in 95 patients undergoing warm (31-33.5 degrees C, n = 49) and cold (26-27 degrees C, n = 46) CPB surgery. Blood sampling was performed before, during and after CPB. The following markers of neutrophil-endocardium interaction were analysed: complement activation (C3a), cytokine production (tumor necrosis factor alpha, interleukines 1, 6 and 8, and interleukin-1 receptor antagonist); endothelial expression of cytokine-dependent [intercellular adhesion molecule (ICAM)] and cytokine-independent (P-selectin) adhesion molecules (P-selectin); expression of cytokine molecules on the surface of polynuclear neutrophils (CD11a, CD11b, CD11c); and finally, endothelial adhesion and transendothelial migration of neutrophils (interleukin 8 and elastase). The results showed that, irrespective of temperature, CPB was associated with changes strongly suggestive of phenomena of transendothelial adhesion and migration. Moreover, normothermia increased the intensity of the inflammatory response as shown by increased cytokine production, earlier expression of neutrophil adhesion molecules and increased elastase production.

Aged↗
PubMed1998

Active sites in complement component C3 mapped by mutations at indels.

Engineered mutants of human complement component C3 were used to test the idea that sites of length polymorphisms in protein families (indels) can guide a search for protein:protein interaction sites. Sequence changes were introduced at each of the 27 indels in the C3/4/5 protein family, and mutants at 26 indels were expressed by transiently transfected COS cells. Expressed proteins were assayed 1) for concentration, by ELISA and by autoradiography of radiolabeled protein; 2) for classical pathway hemolytic activity; 3) for susceptibility to proteolytic activation by the alternative pathway and cobra venom factor C3 convertases; and 4) for susceptibility to complement factor I in the presence of factor H. Most of the mutations did not appreciably alter expression or activity relative to wild-type C3, consistent with the idea that most indels occur at the protein surface. Mutations at four indels severely damaged C3 functional activity, but did not affect the stability or structure of the protein, as assessed by their effects on expression by COS cells and on susceptibility to cleavage by C3 convertases and factor I. These indels are therefore near functionally important amino acid residues; they represent good candidates for sites of protein:protein interactions. Mutation of the sequence at a fifth indel altered the equilibrium between the latent and reacted C3 conformations, and mutations at 4 other indels substantially decreased both protein activity and expression. The mutants provided an overview of the structural and functional roles played by different parts of C3.

Amino Acid Sequence↗