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Biomedical subjects

D S Dwyer

Publications and source records attributed to D S Dwyer.

12 recordsLinked to original sources
PubMed1990

Alteration of the humoral immune response against muscle acetylcholine receptor by timed administration of alpha(1----3)dextran.

Previously, we discovered a profound idiotypic connectivity among antibodies involved in the immune responses to alpha(1----3)dextran (Dex) and the acetylcholine receptor (AChR). The present studies were undertaken to assess whether these connections represent functional pathways for regulation. It was found that immunization of mice with Dex prior to challenge with AChR reduced the subsequent response to receptor. The timing of the Dex administration was crucial for this effect with a 6-day delay between Dex and AChR being optimal whereas 0- or 12-day delays proved ineffective. The suppressive effect was specific for Dex, as treatment with the closely related, but idiotypically distinct, alpha(1----6)dextran did not diminish the anti-AChR response. Consistent with functional connections in the AChR-Dex network, an inverse relationship between anti-AChR and anti-Dex antibodies was observed in these studies. Thus, high levels of anti-AChR antibodies were associated with low levels of anti-Dex antibodies and vice versa. A similar relationship was observed for serum antibodies from patients with myasthenia gravis. To investigate the mechanism for the antigen-induced cross-regulation, hybridomas were constructed from spleen cells of mice treated 6 days earlier with Dex. A variety of idiotypes (Id), anti-Id and anti-anti-Id were obtained from this fusion. In addition, sera from day-6 mice were examined for the expression of key anti-Id which might provide regulation in the anti-AChR response. The main feature of these sera was the presence of EB3-7-reactive antibodies which did not bind Dex, and hence were not identical to J558. A monoclonal antibody with similar properties was obtained from the day-6 fusion (DX6) which had additional binding specificity for anti-AChR antibodies. Antibodies induced by Dex immunization appear to participate in the cross-regulation observed here. Understanding the mechanisms involved in this phenomenon will have important implications for network theory and for prediction of immune responsiveness.

Animals↗
PubMed1990

Monoclonal antibody against alpha(1----3) dextran transfers suppression of the immune response to the acetylcholine receptor.

Previous studies have demonstrated that immunization of BALB/c mice with alpha(1----3) dextran (Dex) is accompanied by a reduction in the subsequent immune response to the acetylcholine receptor (AChR), depending on the timing of the Dex administration relative to AChR challenge. Here, we report that suppression of the anti-AChR response can be transferred by a monoclonal antibody, known as DX2, which is specific for Dex. Serum transfer experiments have also supported the notion that antibody is important for this effect. In addition, two new idiotypic markers have been defined that are expressed mainly by antibodies against Dex, including DX2. The anti-idiotypic reagents (Sh135 and EB5) are derived from the immune response to the AChR. A human monoclonal antibody which binds to Dex (SR 11) resembles the BALB/c antibodies that are involved in the suppression of the anti-AChR response. These findings emphasize the functional relevance of the AChR-Dex network not only for the BALB/c immune response to the AChR, but also for humans with the autoimmune disease, myasthenia gravis.

Animals↗
PubMed1989

Amino acid sequence homology between ligands and their receptors: potential identification of binding sites.

Mice were immunized with alpha-bungarotoxin (BGT), a nearly irreversible antagonist of the acetylcholine receptor (AChR), to produce monoclonal antibodies (Mabs). One of the Mabs (JMC2.7) bound not only to BGT, but to the AChR as well. To understand the molecular basis for this novel cross-reaction, the amino acid sequences of these proteins were searched for areas of similarity which might constitute the shared epitope. A number of short segments of sequence homology were found, one of them representing the BGT-binding site of the AChR. Because a portion of BGT resembles that part of the AChR that binds toxin, the self-binding of BGT was evaluated. As shown here, BGT binds specifically to itself to form dimers. In order to extend these observations, other ligand-receptor pairs were examined for sequence homology. The sodium channel and alpha-scorpion toxins were found to have distinct areas of similarity, as do interleukin 2 (IL-2) and the IL-2 receptor. As a general principle, we propose that peptide ligands and their receptors may often share amino acid sequence homology. In fact, the sites of interaction between two proteins may largely be determined by these regions of similarity.

Amino Acid Sequence↗
PubMed1987

Idiotypes and autoimmunity.

By the analysis of hybridomas constructed from B cells early in development we have shown that: (i) the early neonatal B cell repertoire consists of a highly autoreactive set of B cells showing extensive multispecificity and interconnectivity; (ii) many of these antibodies express anti-idiotypic activity towards autologous germline-encoded idiotypic antibodies; (iii) the anti-idiotypic activities of such B cells and/or their antibody products play a major role in establishing the clonal dominance of certain well-characterized idiotypes in the responses to phosphorylcholine (PC) and alpha 1----3 dextran; and (iv) results obtained in comparisons between antibodies to the acetylcholine receptor and alpha 1----3 dextran in humans and mice showed extensive idiotypic connectivity. Some of the anti-idiotypic specificities involved were also apparent in the neonatally derived antibodies. These results suggest that there are extensive idiotype-directed interactions between B cells early in development which appear to be essential for establishing the adult B cell repertoire and the accompanying clonal dominance of appropriate idiotypes. Similar interactions may also play a role in the development of certain autoimmune disorders.

Animals↗
PubMed1987

Overlap myasthenic syndrome: combined myasthenia gravis and Eaton-Lambert syndrome.

A patient with a known history of pernicious anemia had the combined features of autoimmune myasthenia gravis (MG) and the Eaton-Lambert syndrome (ELS). Initially, this patient had all the features typical of MG, and after thymectomy developed all the typical features of ELS. In view of the coexistence of two autoimmune neuromuscular transmission disorders in one patient, we termed this disorder "overlap myasthenic syndrome."

Action Potentials↗
PubMed1986

Idiotypic network connectivity and a possible cause of myasthenia gravis.

Extensive idiotypic connectivity has been discovered between the antibodies composing the immune responses against the acetylcholine receptor (AChR) and alpha-1,3-dextran. The idiotypic connections form an elaborate network linking these disparate antigen systems, and there is an hierarchical organization of the antibodies in this network. The key anti-Ids that interconnect these two responses are more crossreactive, lower-affinity antibodies. Interestingly, 15% of patients with MG, which is caused by autoantibodies against the AChR, have serum antibodies against DEX. Control sera are negative for anti-DEX antibodies. Certain anti-DEX antibodies also bind to anti-AChR antibodies via idiotypic interactions. These findings suggest a model for the initiation of autoimmunity in MG. Antibodies made in response to DEX epitopes on the surface of certain bacteria would elicit the production of anti-Ids. However, some of these anti-Ids would also be autoantibodies against the AChR. Thus, is some circumstances, autoimmunity may develop as a consequence of the normal operation of regulatory idiotypic networks.

Animals↗
PubMed1985

Enhanced activation of a T cell line specific for acetylcholine receptor (AChR) by using anti-AChR monoclonal antibodies plus receptors.

Immune complex-mediated regulation of the immune response has been studied by using T cell lines and monoclonal antibodies (MAb), both specific for the acetylcholine receptor (AChR). Rat T lymphocytes bearing the W3/25 phenotype and specific for AChR from Torpedo californica have been propagated in vitro for nearly 1 yr. These T cells proliferate in response to optimal concentrations of AChR presented by irradiated syngeneic thymus cells. At suboptimal concentrations of antigen there is little activation of the T cell line. We report here that the addition of small amounts of anti-AChR MAb produces dramatic stimulation of the T cell lines at suboptimal doses of AChR. Enhanced activation depends on the isotype and not the fine specificity of the MAb that are used. The observed phenomenon is antigen specific, and in fact, the immune complexes may actually suppress the proliferative response of irrelevant T cells to some extent. The MAb plus antigen are rapidly bound to the surface of the antigen-presenting cell, which we have shown is the dendritic cell.

Adjuvants, Immunologic↗
PubMed1979

Regulation of the immune response by polyamines.

Regulation of the immune system is accomplished, in part, by numerous soluble factors and small molecules. One such class of regulatory substances may be the polyamines which are present in a variety of tissues. Stimulation of the immune response often occurs by crosslinking of lymphocyte surface proteins, followed by the production of some transmembrane signal. The activation pathway may be interrupted if certain necessary steps are blocked. It is proposed that polyamines exert regulatory influences by modulating crosslink formation; a step catalyzed by the enzyme transglutaminase. A model is outlined which describes the events initiating lymphocyte activation and the role of polyamines in this process. Certain drugs which might mimic the actions of polyamines are also discussed. During evolution of the control of growth processes in cells, relatively simple molecules (the polyamines) may have assumed a pivotal role in initiating and terminating the proliferative response. This idea has been applied to regulation of the immune system.

Animals↗
PubMed1979

A modified assay for antibody against the nicotinic acetylcholine receptor in myasthenia gravis.

Myasthenia gravis is an autoimmune disease which may be detected by the presence of serum antibodies against the nicotinic acetylcholine receptor at the neuromuscular junction. Immunoprecipitation assays have been developed to measure these immunoglobulins and calculate titres. These assays require the labelling of the receptor with 125I-alpha-bungarotoxin which binds irreversibly. However, the standard immunoprecipitation assay may significantly underestimate the titres of some myasthenic patients. We have discovered patients with antibodies specific for the alpha-bungarotoxin binding site of purified rat muscle receptor. If labelled toxin is already present on the receptor, these antibodies are unable to bind to the protein. This phenomenon may lead to underestimates of the actual antibody titre. To circumvent this problem, we have designed a modified immunoprecipitation assay to evaluate titres.

Acetylcholine↗