Search PubMed⌕ Search

Biomedical subjects

M W Russell

Publications and source records attributed to M W Russell.

At least 73 records · Page 4Linked to original sources
PubMed1996

The molecular genetics of the congenital long QT syndromes.

During the past half decade, significant insight into the clinical electrocardiographic, and genetic features of the congenital long QT syndromes has emerged. Based on this foundation, recent linkage analysis studies have demonstrated the genetic heterogeneity of the Romano-Ward long QT syndrome and led to the discovery of two of the four (or more) responsible genes. Further functional characterization of these two genes, the HERG potassium channel and the SCN5A voltage-gated cardiac sodium channel, as well as the identification and characterization of the other long QT syndrome genes, may allow improved diagnosis and therapy for these disorders. Furthermore, the increased understanding of myocardial repolarization that is gained from characterization of these genes may lead to improved treatment for other ventricular arrhythmias, including those related to potassium-channel blockade, central nervous system insult, and, possibly, myocardial infarction.

Animals↗
PubMed1996

Persistence of serum and salivary antibody responses after oral immunization with a bacterial protein antigen genetically linked to the A2/B subunits of cholera toxin.

Primary oral immunization of mice with a bacterial protein antigen genetically coupled to the A2 and B subunits of cholera toxin induced specific secretory immunoglobulin A and serum immunoglobulin G antibodies that persisted at substantial levels for at least 11 months. A subsequent single booster immunization did not further enhance the antibody responses. Long-term antibody persistence may be especially important in infections caused by common pathogens for which continuous immunity would be advantageous.

Adhesins, Bacterial↗
PubMed1996

Salivary, nasal, genital, and systemic antibody responses in monkeys immunized intranasally with a bacterial protein antigen and the Cholera toxin B subunit.

Previous attempts to induce mucosal antibodies in rhesus monkeys by enteric immunization have resulted in only modest and short-lived responses, dominated by immunoglobulin M (IgM) antibodies in the plasma. In this study, two groups of rhesus monkeys were immunized intranasally three times at 2-week intervals with a bacterial protein antigen (AgI/II) either chemically coupled to or mixed with the B subunit of cholera toxin (CT), a known potent mucosal immunogen and carrier for other immunogens. Cells secreting antibodies, predominantly of the IgA isotype, to AgI/II and to CT were detected in the peripheral blood 1 week after each immunization, indicating the dissemination of IgA-secreting precursor cells through the mucosal immune system. IgG and, to a lesser extent, IgA antibodies to both proteins were induced in the plasma commencing after the second immunization. Plasma IgE concentrations and IgE antibody levels were not consistently raised during the immunization period. IgA antibodies were found in nasal and vaginal washes. Nasal IgG but not IgA antibodies showed a significant positive correlation with plasma IgG antibody levels, suggesting that they were largely derived by transudation from the circulation. Analysis of the molecular form of vaginal IgA indicated that both secretory and monomeric forms of IgA were present in various proportions. Furthermore, neither IgG nor IgA antibodies in vaginal washes were correlated with plasma antibody responses, suggesting the contribution of locally synthesized antibodies of both isotypes. Comparison of the responses between the two groups of animals showed only sporadic significant differences, indicating that intranasal immunization with AgI/II either coupled to or mixed with the B subunit of CT was equally effective at inducing generalized IgA antibody responses in the mucosal immune system and predominantly IgG antibodies in the plasma.

Administration, Intranasal↗
PubMed1995

Mucosal immunization with a bacterial protein antigen genetically coupled to cholera toxin A2/B subunits.

The generation of secretory IgA Abs for specific immune protection of mucosal surfaces depends on stimulation of the mucosal immune system, but this is not effectively achieved by parenteral or even oral administration of most soluble Ags. To harness the exceptional mucosal immunogenicity of cholera toxin (CT), which is largely attributed to the cell-binding property of its B subunit, for the generation of other oral vaccines, we have genetically replaced the toxic A1 subunit of CT with a 42-kDa segment of a streptococcal protein adhesin. This construct was expressed in Escherichia coli as a chimeric protein that retained the GM1 ganglioside-binding activity of CT subunit B and the antigenicity of the streptococcal adhesin, as shown by GM1-ELISA developed with Abs to the steptococcal segment. The protein composition of chromatographically purified chimeric protein was verified by SDS-PAGE and Western blotting with Abs to both antigenic components of the construct. Peroral administration of this chimeric immunogen in mice elicited high levels of mucosal IgA and serum IgG Abs to the streptococcal adhesin, which persisted for at least 6 mo. This strategy allows the development of similar constructs from other candidate Ags for oral immunization against a variety of mucosally acquired infections.

Adhesins, Bacterial↗
PubMed1995

Dual function of human IgA antibodies: inhibition of phagocytosis in circulating neutrophils and enhancement of responses in IL-8-stimulated cells.

We have sought to elucidate the responses of human peripheral blood neutrophils to antigenic surfaces complexed with human specific IgA antibodies obtained either as myeloma proteins that recognize staphylococcal alpha-toxin, or from the serum of patients with subacute bacterial endocarditis due to Streptococcus mutans, or from colostrum. In contrast to IgG, IgA antibodies bound to antigen-coated fluorescent microspheres, and subsequently exposed to complement (or not), did not promote phagocytosis, as measured by flow cytometric enumeration of cell-associated microspheres. Instead, IgA antibodies interfered with complement-dependent phagocytosis mediated by IgG antibodies. These properties were shown by different forms of IgA antibodies, including serum and secretory IgA, as well as by monoclonal or polyclonal antibodies. Neutrophils did not respond to the production of superoxide to IgA antibodies complexed with antigen-coated microspheres or with antigen deposited on a solid surface and IgA antibodies suppressed IgG antibody- and complement-mediated superoxide release. However, neutrophils pretreated with interleukin-8 ingested IgA-opsonized microspheres and released superoxide when exposed to IgA antibody-antigen complexes. IgG antibody-antigen complexes did not stimulate increased superoxide release in interleukin-8-treated neutrophils. These findings were consistent with a selective increase in the surface expression of Fc alpha R by interleukin-8-treated neutrophils. We conclude that IgA antibodies interfere with the phagocytic activities of normal circulating human neutrophils and may promote these activities in inflammatory neutrophils activated by interleukin-8 in which Fc alpha R is up-regulated.

Complement System Proteins↗
PubMed1995

Catheter interruption of atrioventricular conduction using radiofrequency energy in a patient with transposition of the great arteries.

Percutaneous catheter mapping and radiofrequency ablation of the AV node-His bundle system (with subsequent transvenous endocardial ventricular pacing) were performed on an 18-year-old woman with transposition of the great arteries and intact ventricular septum and chronic arrhythmias 15 years following a Mustard operation. Exclusion of the AV conduction tissue from the systemic venous circulation by the complex anatomy and the Mustard repair was circumvented by a retrograde approach across the aortic valve to the morphological right ventricle yielding access to the AV node-His bundle system.

Adolescent↗
PubMed1995

Identity of Streptococcus mutans surface protein antigen III and wall-associated protein antigen A.

Preparations of Streptococcus mutans surface proteins AgIII and antigen A from different laboratories were compared with regard to amino acid composition, N-terminal amino acid sequence, electrophoretic mobility, and antigenic similarity. Despite previous observations of differences in physical properties, data indicate that these two preparations represent the same protein.

Amino Acid Sequence↗
PubMed1994

Comparison of systemic and mucosal priming for mucosal immune responses to a bacterial protein antigen given with or coupled to cholera toxin (CT) B subunit, and effects of pre-existing anti-CT immunity.

Intraperitoneal immunization with a bacterial protein antigen conjugated to cholera toxin B subunit (CTB) was generally less effective than intragastric or intranasal immunization in generating mucosal IgA antibodies, and in priming the mucosal immune system to respond to intragastric or intranasal boosting. Previous intragastric or intranasal immunization which generated high levels of mucosal and circulating antibodies to CTB did not suppress mucosal IgA responses induced by intragastric or intranasal immunization with bacterial antigen conjugated to or mixed with CTB, but serum antibody responses were inhibited depending on the route of immunization and whether CTB was conjugated to or mixed with the antigen.

Administration, Intranasal↗
PubMed1994

All forms of human IgA antibodies bound to antigen interfere with complement (C3) fixation induced by IgG or by antigen alone.

Polyclonal human secretory IgA1 and IgA2 antibodies to a bacterial protein antigen Streptococcus mutans AgI/II, and polyclonal human serum IgA1 and IgA2 antibodies to staphylococcal alpha-toxin, were found to interfere with antigen-mediated C3b fixation. In fluid phase, immune complexes of antigen and IgA failed to fix C3b, whereas antigen-IgG complexes did fix C3b. Partial removal of glycan chains with Streptococcus mitis SK96 glycosidases diminished the capacity of IgA antibodies to interfere with antigen-mediated C3b fixation by the alternative complement pathway. The authors conclude that native serum or secretory IgA antibodies suppress C3b fixation, and that the glycan chains play a significant role in maintaining this property.

Antibodies, Anti-Idiotypic↗
PubMed1994

Secretory IgA response in oral immunotherapy. Investigation in birch pollinosis.

A rationale for oral immunotherapy (OIT) might be founded on two potential mechanisms: induction of a mucosal secretory IgA response, or induction of systemic hyporesponsiveness (oral tolerance). Previous studies have shown clinically that there is a beneficial effect of OIT in birch pollinosis, in both children and adults. During OIT, birch pollen antigens in enterocoated capsules were given to 20 adults (participating in a double-blind, placebo-controlled trial) and 10 children, all suffering from birch pollinosis. Saliva and tears (only adults) samples were collected before, during, and after OIT. Each sample was assayed for both IgA antibodies against birch pollen antigens and total IgA by enzyme-linked immunosorbent assay. IgA antibody levels were also expressed in relation to total IgA concentrations, to correct for variations in secretion and flow rate between subjects and at different times. Changes in birch-specific secretory IgA antibodies in saliva and tears could not explain the beneficial effect of OIT in birch pollinosis. Further studies in this field are warranted.

Administration, Oral↗
PubMed1994

Affinity and specificity of the interactions between Streptococcus mutans antigen I/II and salivary components.

Adherence to salivary pellicle-coated tooth surfaces and aggregation by salivary components of Streptococcus mutans involves a major cell surface protein termed antigen (Ag) I/II. The objectives of this study were to evaluate the affinity and specificity of the interactions between AgI/II and human saliva in assays of 125I-AgI/II binding to saliva-coated hydroxyapatite (SHA) and of S. mutans aggregation by salivary agglutinin (SAG), monitored turbidimetrically. 125I-AgI/II binding to SHA followed saturation kinetics, and Scatchard plot analysis indicated two binding sites with dissociation constants of the order of 10(-10) mol/L and 10(-9) mol/L. The binding to SHA of the C-terminal one-third of AgI/II which corresponds to AgII was less than one-fifth that of the whole molecule and did not show evidence of saturation. The binding of 125I-AgI/II was inhibited by native or recombinant fragments that mapped in the N-terminal part of the molecule and that contained the alanine-rich repeat region, whereas fragments mapping at the central or C-terminal one-third had no effect. As with binding to SHA, the regions of AgI/II which inhibited aggregation mapped at the N-terminal part of the molecule, but, in addition, a recombinant segment mapping at the central part and containing the proline-rich repeat region was also inhibitory. The S. mutans-aggregating activity of SAG or whole saliva was inhibited by amino compounds, and most strongly by L-lysine and analogues possessing omega-primary amine groups. These data support the role of AgI/II as an adhesin with high-affinity binding for SHA receptors, mediated by the N-terminal part of the molecule. This region is also involved in SAG-induced S. mutans aggregation, which is sensitive to amino compounds.

Adhesins, Bacterial↗
PubMed1994

The role of the carbohydrate chains in complement (C3) fixation by solid-phase-bound human IgA.

In contrast to antigen-antibody complexes containing native human IgA, solid-phase-deposited IgA activates the alternative complement pathway and binds C3b. To investigate the role of carbohydrate chains in this, various human IgA preparations were treated with neuraminidase alone or together with N-glycanase or O-glycanase, or with mixed glycosidases from the oral bacterium, Streptococcus mitis. Depletion of oligosaccharides was determined by carbohydrate analysis. Removal of sialic acid and N-linked glycan chains greatly increased the C3b-fixing properties of normal serum IgA1 and IgA2. Myeloma IgA1 and IgA2 proteins and secretory IgA had higher C3b-binding activity than normal serum IgA, and this was further increased by removal of sialic acid and N-linked glycans. Fc alpha and Fc alpha-SC fragments of myeloma and secretory IgA1, respectively, but not Fab alpha fragments, obtained by cleavage with bacterial IgA1 proteases and also free secretory component, fixed C3b by the alternative pathway.

Complement C3b↗
PubMed1993

Induction of mucosal immunity by intranasal application of a streptococcal surface protein antigen with the cholera toxin B subunit.

The level and distribution of isotype-specific antibodies in various secretions and of antibody-secreting cells in corresponding lymphoid organs and tissues were compared in mice immunized with Streptococcus mutans surface protein antigen I/II (AgI/II) conjugated to the cholera toxin B subunit (CTB), given intranasally (i.n.) or intragastrically (i.g.), with or without free cholera toxin (CT) as an adjuvant. Immunization i.n. induced stronger initial antibody responses to AgI/II in both serum and saliva than immunization i.g., but salivary immunoglobulin A (IgA)-specific antibody responses to immunization about 3 months later were not increased relative to total salivary IgA concentrations. Specific antibodies induced by i.n. immunization were as widely distributed in serum, saliva, tracheal wash, gut wash, and vaginal wash as those induced by i.g. immunization. Likewise, specific antibody-secreting cells were generated in the spleen, salivary glands, intestinal lamina propria, and mesenteric and cervical lymph nodes by either route of immunization. The strongest salivary IgA antibody response was induced by AgI/II-CTB conjugate given i.n., but the addition of CT did not further enhance it. However, free CTB could effectively replace CT as an adjuvant in i.n. immunization with unconjugated AgI/II. Booster i.n. immunization with AgI/II plus either free CT or CTB induced stronger recall serum antibody responses than conjugated AgI/II-CTB with or without CT as an adjuvant. Therefore, i.n. immunization with a protein antigen and free or coupled CTB is an effective means of generating IgA antibody responses expressed at several mucosal sites where protective immunity may be beneficial.

Adjuvants, Immunologic↗