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Biomedical subjects

M W Russell

Publications and source records attributed to M W Russell.

At least 19 recordsLinked to original sources
PubMed1992

Liposomes and conjugate vaccines for antigen delivery and induction of mucosal immune responses.

In this brief review, emphasis was placed on the effectiveness of liposomes as carriers/vehicles of soluble antigens and as adjuvants for use in oral vaccine development. Evidence was provided that oral administration of antigen in liposomes resulted in a mucosal response which was higher than that obtained when the oral vaccine consisted of antigen alone. Specific mucosal responses were enhanced by incorporating lipophilic MDP into the antigen/liposome vaccines. Antigens shown to be effective in inducing a protective mucosal response when given in an oral liposome vaccine were anti-idiotypic antibodies, purified S. mutans GTF, CHO and Ag I/II. Evidence is also provided that CTB may be an effective oral adjuvant when coupled to proteins or peptides by either chemical or genetic methods. Further studies, however, will be required to characterize the effectiveness and safety of CTB in conjugate vaccines for inducing specific mucosal responses and to develop practical means to prepare oral liposome vaccines for use in humans.

Animals↗
PubMed1992

Molecular heterogeneity of human IgA antibodies during an immune response.

Human IgA occurs in multiple molecular forms (polymeric and monomeric) and two subclasses which show differential distribution between the mucosal and circulatory compartments of the immune system. However, the molecular form and subclass of specific IgA antibodies are influenced, especially during an immune response, by the type of antigen and duration of the response as well as by the route of exposure. These considerations question previously held notions that polymeric IgA and an increased representation of the IgA2 subclass among circulating antibodies or antibody-secreting cells signify their mucosal origin. Although the functional properties of different molecular forms and subclasses of IgA antibodies are incompletely understood, it appears that there is physiological benefit in the diversity of the IgA immune system.

Animals↗
PubMed1992

Serum antibody responses to Streptococcus mutans antigens in humans systemically infected with oral streptococci.

Sera from patients with subacute bacterial endocarditis (SBE) due to Streptococcus mutans or other oral streptococci and from normal subjects were assayed by enzyme-linked immunosorbent assay for antibodies to defined S. mutans antigens. Antibodies of IgG and IgA isotypes to Ag I/II and Ag III were greatly elevated in S. mutans-SBE sera, and the IgA antibodies in 3 sera included both polymeric and monomeric forms. Elevated IgM and IgG anti-lipoteichoic acid and IgG and IgA anti-serotype c polysaccharide antibodies were also found. The sera of 4 of 6 patients infected with other oral streptococci also displayed antibodies to S. mutans Ag I/II. Sera of 3 patients infected with Streptococcus mitis or Streptococcus oralis, but none of the S. mutans-infected cases, showed elevated antibodies to human heart sarcolemma, and all SBE sera had elevated rheumatoid factor. These results suggest that the known surface protein antigens of S. mutans are immunodominant in humans, and are not likely to be heart cross-reactive.

Antibodies, Bacterial↗
PubMed1992

Inhibition of Streptococcus mutans adherence to saliva-coated hydroxyapatite by human secretory immunoglobulin A (S-IgA) antibodies to cell surface protein antigen I/II: reversal by IgA1 protease cleavage.

The effect of human secretory immunoglobulin A (S-IgA) and serum antibodies to surface protein antigen (Ag) I/II on the adherence of Ag I/II-bearing Streptococcus mutans and of free Ag I/II to saliva-coated hydroxyapatite (SHA) was investigated. The inhibition by S-IgA of binding of both S. mutans and free Ag I/II to SHA was dependent on antibody to Ag I/II. Essentially no difference was found between S-IgA1 and S-IgA2 with respect to antibody-dependent inhibition of Ag I/II binding to SHA, but S-IgA1 inhibited S. mutans adherence more effectively than did either serum immunoglobulin A1 (IgA1) or IgG antibodies. The antiadherence effect of S-IgA was abrogated after cleavage by IgA1 protease. Purified Fab alpha fragments containing Ag I/II-binding activity enhanced the binding of free Ag I/II to SHA and showed greater binding to SHA than did intact S-IgA1. Despite its relative inability to interact with precoated SHA, S-IgA1 containing antibody to Ag I/II was readily incorporated into the salivary pellicle during coating, but this did not promote Ag I/II binding. These data suggest that S-IgA antibodies can inhibit the initial adherence of S. mutans to salivary pellicle-coated tooth surfaces in an adhesin-specific fashion, but the presence in the oral cavity of bacterial IgA1 proteases would potentially interfere with this antiadherence mechanism.

Antibodies, Bacterial↗
PubMed1992

Genetic control of immune responses in mice to synthetic peptides of a Streptococcus mutans surface protein antigen.

The immune responses to a cell surface protein antigen (PAc) of Streptococcus mutans and a peptide corresponding to residues 301 to 319 of the protein antigen [PAc(301-319)] in various strains of mice were studied, with attention being given to the haplotype of major histocompatibility complex (MHC) class II genes. Subcutaneous immunization of mice carrying the MHC class II I-Ad gene [BALB/c, B10.D2, B10.GD, and (B10.D2 x B10.G)F1 mice] with the peptide induced strong serum immunoglobulin G (IgG) responses to recombinant PAc (rPAc) and the peptide. Subcutaneous immunization of mice carrying the haplotype k or b of the H-2 I-A gene (C3H/HeN, C57BL/6, B10.BR, B10.A, or B10 mice) with the peptide induced intermediate serum IgG responses to rPAc and the peptide, and subcutaneous immunization of mice carrying the haplotype s or q of the H-2 I-A gene (DBA/1, B10.S, or B10.G mice) induced weak serum IgG responses to rPAc and the peptide compared with the responses of mice carrying the I-Ad gene. PAc(301-319) strongly induced PAc(301-319)-specific T-cell proliferation in B10.D2 mice but not in B10.G mice. The T-cell proliferation in B10.D2 mice was inhibited by treatment of antigen-presenting cells with anti-I-Ad monoclonal antibody but not with anti-I-Ab monoclonal antibody. These results indicate that the immune responses to the peptide in mice are genetically restricted or dominated by the MHC class II gene (I-Ad). To map antigenic epitopes in PAc(301-319) and PAc in mice bearing different H-2 haplotypes, 10 overlapping decapeptides covering PAc(301-319) and 153 decapeptides covering the entire mature PAc were synthesized. Of 10 decapeptides covering PAc(301-319), 6, 7, 1, and 1 decapeptides showed strong reactions with anti-PAc(301-319) sera from B10.D2 (H-2d), B10.GD (H-2g2), B10.BR (H-2k), and B10.A (H-2a) mice, respectively. None of these overlapping decapeptides reacted with anti-PAc(301-319) sera from B10.S (H-2s) and B10.G (H-2q) mice. Epitope-scanning analyses of the mature PAc molecule showed that antigenic epitopes scattered throughout the molecule and that antigenic epitope patterns differed in mice with different H-2 haplotypes. In addition, there was little overlap of immunogenic peptides among the mice with different haplotypes.

Amino Acid Sequence↗
PubMed1992

Immunization against dental caries.

The development of a vaccine against dental caries involves identification of appropriate antigens of mutans streptococci against which protective immune responses can be mounted, and the selection of a method of immunization that will generate sustained levels of salivary antibodies. Antigens receiving most attention include streptococcal surface proteins that are involved in attachment to tooth surfaces and glucosyltransferases that synthesize adhesive glucans from sucrose. Recent advances in mucosal immunology and the introduction of novel strategies for inducing mucosal immune responses now raise the possibility of constructing an effective and safe vaccine. Passive immunization by the oral application of performed antibodies against selected antigens of mutans streptococci has also shown promise and may facilitate understanding of the mechanisms of protective immunity against caries.

Animals↗
PubMed1992

Antibody-secreting cell responses in the mouse liver.

To elucidate the origins of biliary IgA antibodies, we investigated the isotype and specificity of antibody-secreting cells (ASC) in the liver in comparison with the spleen and intestinal lamina propria of mice immunized by peroral or parenteral routes. The profile of specific IgM, IgG1, IgG2a, and IgA ASC in the liver resembled that of the spleen rather than the lamina propria, regardless of the route of immunization. Peroral immunization increased the proportion of specific IgA ASC in all three organs. However, liver mononuclear cells (MNC) contained a higher proportion of total IgA-secreting cells than spleen cells. After immunization, the number and proportion of B220+ B cells were increased in the liver but not in the spleen. Although the predominant isotype of Ig and specific antibody in bile in response to immunization by either route was IgA, IgM and IgG were clearly detectable. However, specific activities of biliary antibodies relative to total Ig isotype were generally higher than in serum. The predominance of IgA-secreting cells in the liver and the large amount of IgA secreted in the bile resemble the situation at other secretory sites of the mucosal immune system. However, specific antibody-secreting cells appear to accumulate in the liver promptly after immunization, regardless of isotype, and contribute locally produced antibodies to the bile.

Administration, Oral↗
PubMed1991

Immunogenicity and protective effect against oral colonization by Streptococcus mutans of synthetic peptides of a streptococcal surface protein antigen.

Streptococcus mutans is known to be a major causative organism of human dental caries. A surface protein Ag with a molecular mass of 190 kDa of S. mutans (PAc) is receiving attention as an anticaries vaccine. We have recently determined the complete nucleotide sequence of the gene for PAc. In this study, four peptides were synthesized on the basis of amino acid sequence of PAc. Among these peptides, PAc(301-319) corresponding to the alanine-rich repeating amino acid region was the most strongly bound by polyclonal murine anti-rPAc antibodies. The peptide partially inhibited the binding of polyclonal anti-rPAc antibodies to rPAc. The peptide induced the proliferation of T cells from BALB/c mice immunized with rPAc. Subcutaneous immunization with PAc(301-319) or rPAc emulsified in CFA/IFA induced high serum IgG responses to rPAc and PAc(301-319). In addition, serum IgG responses to a surface protein Ag with a molecular mass of 210 kDa of Streptococcus sobrinus were elicited in mice immunized by s.c. injection with PAc(301-319) or rPAc. Intranasal immunization with PAc(301-319) coupled to cholera toxin B subunit (CTB) or with rPAc and free CTB induced high serum IgG responses to rPAc. The immunization with PAc(301-319) coupled to CTB or rPAc and free CTB suppressed the colonization of murine teeth by S. mutans. These results suggest that intranasal immunization with the peptide or rPAc may be effective for the prevention of dental caries.

Animals↗
PubMed1991

Distribution, persistence, and recall of serum and salivary antibody responses to peroral immunization with protein antigen I/II of Streptococcus mutans coupled to the cholera toxin B subunit.

After peroral immunization of mice with surface protein antigen (Ag) I/II of Streptococcus mutans conjugated to the cholera toxin B (CTB) subunit, cells actively secreting immunoglobulin A (IgA) antibodies specific for Ag I/II, but not for CT, were induced in the salivary glands; salivary IgA anti-Ag I/II antibodies and total salivary IgA were also elevated. The development of large numbers of IgA and IgG antibody-secreting cells in the mesenteric lymph nodes and spleen and high levels of serum IgA and IgG antibodies to Ag I/II and CT demonstrated that a response to both antigens occurred. At least two to three intragastric doses of 15 micrograms or more of Ag I/II-CTB conjugate, plus free CT as an adjuvant, were needed to induce the salivary IgA anti-Ag I/II response, which peaked at about 35 days and persisted at lower levels for 5 to 6 months. A single booster intragastric immunization did not induce enhanced salivary IgA anti-Ag I/II antibodies relative to the primary response, but serum IgA and IgG antibodies to both Ag I/II and CT showed evidence of marked anamnestic responses. The results indicated that relatively long-term mucosal IgA antibody responses could be induced by peroral immunization with small quantities of a CTB-conjugated protein. However, additional factors governed the distribution of cells secreting antibodies of different specificities, or capable of mounting anamnestic responses, between different compartments of the mucosal and circulatory immune systems.

Adjuvants, Immunologic↗
PubMed1991

Selective transport of IgA. Cellular and molecular aspects.

The principal characteristic immunoglobulin of mucosal surfaces, secretory immunoglobulin A (S-IgA), is the product of two different types of cell present in mucosal and glandular tissues. Submucosal plasma cells, which are generated largely within the common mucosal immune system, synthesize predominantly polymeric, J chain-containing IgA, which is selectively bound by polymeric immunoglobulin receptor or secretory component (SC) on the basolateral surfaces of mucosal and glandular epithelial cells. The molecular and cellular events involved in SC expression, its intravesicular transport together with its polymeric IgA ligand to the apical surface of the epithelial cell, during which IgA becomes covalently linked to SC, and the proteolytic cleavage of SC from the apical membrane to release S-IgA into the lumen have been elucidated. Additional receptors and mechanisms for the uptake, catabolism, and transport of IgA exist, especially in the liver. The biologic significance of IgA transport lies in the secretion of large quantities of S-IgA antibodies for the protection of huge areas of mucosal surfaces and for the provision of passive immunity to suckling infants, and in the immune elimination of antigenic materials by hepatobiliary transport.

Animals↗
PubMed1990

Degradation of IgA proteins by Pseudomonas aeruginosa elastase.

Human colostral IgA and myeloma proteins of both IgA1 and IgA2 subclasses were susceptible to cleavage by Pseudomonas aeruginosa elastase. Detailed analysis of the cleavage products of IgA myeloma proteins revealed complete degradation of Fab with no evidence of intact Fab fragments as intermediate cleavage products. In contrast, both IgA1 and IgA2 proteins were resistant to cleavage by alkaline protease from P. aeruginosa. The susceptibility of human IgA proteins to elastase suggests a mechanism by which P. aeruginosa might evade the potentially protective function of IgA by producing this enzyme.

Bacterial Toxins↗
PubMed1990

Immunological cross-reactivity between Streptococcus mutans and human heart tissue examined by cross-immunization experiments.

Hyperimmunization of rabbits with Streptococcus mutans or other related cariogenic streptococci sometimes induces serum antibodies that react with human heart muscle. To determine whether antigen I/II (AgI/II), a major surface protein antigen present in most human isolates of these organisms, was responsible for inducing cross-reactive antibodies, we tested it for antigenic similarity to heart components, exploiting the ability of immune systems to mount anamnestic responses to antigens previously encountered. Mice immunized with a strain of Streptococcus pyogenes type M6, known to be heart cross-reactive, or with intact S. mutans cells developed antibodies that could be detected on a human heart sarcolemmal preparation. However, mice immunized with AgI/II and boosted with sarcolemma were unable to develop significant antisarcolemmal antibodies attributable to prior sensitization by AgI/II. Similarly, AgI/II was unable to recall antisarcolemmal responses in mice previously immunized with sarcolemma. Nevertheless, strong immunoglobulin G antibody responses to AgI/II were detected at the single-cell level in spleens and as circulating antibodies in all mice immunized with AgI/II or AgI/II-bearing S. mutans. We conclude that the ability of S. mutans to induce heart-reactive antibodies is not due to antigenic similarity between AgI/II and components of human heart but may be caused by other cross-reactive antigens in the bacterial cells or by nonspecific stimulation of the immune system.

Animals↗
PubMed1990

Streptococcus mutans and the problem of heart cross-reactivity.

Investigations of immune responses to Streptococcus mutans have fostered consideration of vaccination as a possible preventive measure against dental caries. However, the finding that hyperimmune rabbit antisera to S. mutans sometimes give immunofluorescent reactions on human heart raised concerns over safety, especially as most individuals display circulating antibodies to this common oral organism. Recent progress in elucidating the molecular mechanisms of the well-established immunological cross-reactivity between group A streptococci and human heart tissue and the structure of S. mutans antigens permits a re-evaluation of this problem. This review examines the evidence for heart cross-reactivity induced by S. mutans in relation to studies on group A streptococci and current understanding of autoimmunity. Although the mechanisms involved in this phenomenon need further clarification, it now appears that it cannot be ascribed to antigenic similarity between heart tissue and a high-molecular-weight surface protein antigen of S. mutans.

Antibody Formation↗
PubMed1990

Benzodiazepine tranquilizers and the risk of accidental injury.

To determine whether benzodiazepine tranquilizers increase the risk of accidental injury requiring medical attention, we used pharmacy claims submitted to a large third-party payer to identify 4,554 persons who had been prescribed these agents and a matched control group of 13,662 persons who had been prescribed drugs other than benzodiazepines. We then used diagnoses recorded on claims submitted by medical care providers to identify all accident-related care received by these persons during three months before their first-observed prescription for a benzodiazepine or nonbenzodiazepine agent, respectively, and six months subsequently. We found accident-related care was more likely among persons who had been prescribed benzodiazepines; among these persons, the probability of an accident-related medical encounter was higher during months in which a prescription for a benzodiazepine had recently been filled compared to other months; and persons who had filled three or more prescriptions for these agents in the six months following initiation of therapy had a significantly higher risk of an accident-related medical event than those who had filled only one such prescription. Approximately two-fold risks of accident-related care were found, after controlling for age, sex, and prior utilization.

Accidents↗
PubMed1989

Anti-inflammatory activity of human IgA antibodies and their Fab alpha fragments: inhibition of IgG-mediated complement activation.

The interaction of human IgA antibodies with the classical pathway of complement activation was investigated in a homologous human system, by means of two IgA1 and three IgG1 myeloma proteins having antibody activity against a defined antigen, staphylococcal alpha-toxin. In a solid-phase antigen-dependent C3b-binding ELISA system, the monoclonal IgG antibodies were previously shown to activate the classical complement pathway synergistically, resembling polyclonal IgG antibodies, whereas IgA antibodies were unable to activate complement by either pathway. In the present study, IgA antibodies were found to inhibit significantly the activation of complement initiated by antigen-bound polyclonal or mixed monoclonal IgG antibodies, in relation to the amount of IgA antibodies applied and bound to antigen. IgA1 myeloma proteins devoid of antigen-binding activity were without effect. Inhibition was independent of the ability of the IgA antibodies to compete against the IgG antibodies in binding to antigen, and was demonstrable with physiological concentrations of antibodies. Similar results were obtained with polyclonal serum IgA having antigen-binding activity. However, the binding of C1q to antigen-complexed IgG was inhibited only by a monoclonal IgA antibody that could compete against one of the three monoclonal IgG antibodies that bound C1q synergistically. This observation implied that at least two mechanisms were involved in the inhibition of C3b fixation. Fab alpha fragments of monoclonal IgA antibodies, obtained by cleavage with IgA1 protease from Haemophilus influenzae type b, were found to have a similar inhibitory effect on C3b fixation to the intact IgA1 antibodies. This observation supports the hypothesis that IgA1 proteases contribute to the invasive pathogenicity of certain mucosal bacteria, by cleaving secretory IgA1 antibodies to antigen-binding Fab alpha fragments, which are not only defective in mucosal defense properties, but which also protect the organisms from other immune effector systems, such as complement activation.

Antibodies, Monoclonal↗
PubMed1989

Complement-fixing properties of human IgA antibodies. Alternative pathway complement activation by plastic-bound, but not specific antigen-bound, IgA.

The complement-fixing properties of human IgA antibodies bound to specific antigen, or coated directly on plastic surfaces, were examined in comparison with those of IgG antibodies. Use was made of antigen-binding (anti-staphylococcal alpha-toxin) IgA and IgG monoclonal antibodies and normal polyclonal IgA and IgG, purified greater than 99.9% by avoidance of denaturing processes. Complement-fixation ELISA was used, with a high density of biotin-conjugated staphylococcal alpha-toxin bound to avidin-coated plates for the efficient capture of antibodies, and conditions were adjusted for the assessment of classical and alternative pathways of complement activation. Although IgA coated directly on plastic surfaces activated the alternative complement pathway in a dose-dependent manner, IgA antibodies bound to antigen failed to fix complement by either classical or alternative pathways. In contrast, IgG antibodies, either bound to antigen or coated directly on plastic, activated complement mainly by the classical pathway. It was concluded that the complexation of IgA antibodies with antigen is insufficient to elicit complement activation: rather a degree of denaturation seems to play a part in the expression of alternative complement pathway-activating properties by IgA.

Complement Activation↗
PubMed1989

Interaction between surface protein antigens of Streptococcus mutans and human salivary components.

The potential involvement of surface antigens (Ags) I/II and III of Streptococcus mutans in its adherence to salivary pellicle-coated tooth surfaces was investigated. The binding of radiolabelled Ag I/II to hydroxyapatite was increased by pretreating the mineral with human parotid saliva, and binding was maintained in the continuous presence of saliva. Binding of Ag III to hydroxyapatite was inhibited by pretreatment with, or in the presence of, saliva. Various aminohexoses, and also tris, inhibited the binding of Ag I/II. When Ags I/II and III were tested for their ability to bind to salivary components separated by SDS gel electrophoresis, several proteins capable of binding Ag I/II were identified, notably 2 proteins of apparent relative molecular mass 28,000 and 38,000. Analysis of these proteins, isolated by micro-preparative electrophoresis, indicated high proportions of proline, glycine, and glutamic acid, and overall compositions similar to basic proline-rich salivary proteins.

Antigens, Bacterial↗