Profound idiotypic network connectivity exists between the immune responses to the acetylcholine receptor (AChR) and Alpha 1,3 dextran (DEX). The DEX epitope is present on certain members of the Enterobacteriaceae family suggesting that the immune responses to the AChR and certain bacteria are also connected. Because the AChR is the target of an autoimmune response in myasthenia gravis (MG), the idiotypic connection between AChR and DEX may provide the basis for the initiation of autoimmunity. The major objectives of this research are to investigate: i) the functional organization of idiotype(id) networks which bridge disparate antigen systems, ii) the molecular basis for shared idiotypy between antibodies from different antigen systems, and iii) the initiation of autoimmunity via the normal operation of id networks. To pursue these objectives, a combination of in vivo and in vitro approaches will be employed. Idiotypic connectivity among monoclonal antibodies (Mabs) from the AChR and DEX antigen systems will be assessed by ELISA techniques. To evaluate the functional connectivity between these two antigens, crossover regulation by anti-ids will be examined. For these studies, mice will be pretreated with anti-ids from one antigen system (e.g., AChR) to measure their effect on the subsequent immune response to the other antigen (e.g., DEX). Furthermore, mice will be immunized with AChR and DEX simultaneously or slightly staggered to analyze functional connectivity from the standpoint of antigen. It is possible that mice cannot mount an effective response to both antigens administered simultaneously if the antibodies against these antigens are idiotypically connected. In related studies, mice will be suppressed from birth for ids of the AChR and DEX systems and will then be challenged with these antigens as adults to find how alterations in the developing immune repertoire influence the adult response to idiotypically connected antigens. To determine the molecular basis for shared idiotypy in the AChR-DEX network, Mabs will be analyzed which express shared ids. Membership in a defined V/H region family will be assessed in dot blotting experiments. More detailed analysis of the primary structure will be accomplished by sequencing the V/H and V/L genes of key organizing antibodies. Finally, the human immune response to AChR and DEX in patients with MG will be further analyzed to determine the relationship between the antibodies against these antigens.