This proposal represents the initial attempt of the principal investigator to secure support to enable him to continue research begun as a Fellow at the NIH. The purpose of this proposal is to investigate the mechanism(s) responsible for B cell hyperactivity which is observed in spontaneous autoimmune states. Previous work has documented that some, but not all, strains of spontaneously autoimmune mice are resistant to the normally suppressive effect of passively administered antibody. This observation will be pursued with additional in vivo studies. We also propose to evaluate the ability of purified, monoclonal anti-hapten to regulate the anti-hapten response of isolated B cells both in vitro and in the splenic focus assay. This study will evaluate the role of non-B cells (T cells or accessory cells) in the observed resistance or susceptibility of B cells to antibody mediated regulation, as well as the role of antibody class or domain in feedback regulation of B cells. These studies will also assess the immunogenicity or suppressive capacity of passively administered immune complexes formed with the monoclonal reagents. Since preliminary in vivo data suggest that resistance to feedback suppression is a heritable trait, the studies should be extended to investigate any genetic basis for defective feedback regulation. The long range goal of this project is to provide a better understanding of the elements responsible for the B cell hyperactivity which underlies autoimmunity. With this information, it may be possible to devise specific therapeutic intervention aimed at the faulty autoregulation of the B cell compartment.
