Autoantibody production and immunodysregulation are two principal manifestations of SLE, which is characterized by lymphopenia, T cell subset disproportions, and hypergammaglobulinemia during phases of active disease. A large body of phenomenological data suggest that anti- lymphocyte autoantibodies contribute to such immunological abnormalities in this disorder, at least in part. The pathogenetic significance of anti- lymphocyte antibodies in this regard will be explored in this proposal. A novel aspect of the planned research will be the use of in vitro B cell culture systems producing both IgM and IgG autoantibodies to circumvent the problem of in vivo absorption of perhaps the most interesting and important anti-lymphocyte autoantibodies, especially those of the IgG class, which are poorly understood at this time. Thus far, this problem has frustrated a full characterization of autoantibody specificities in- this system in studies that have used patient serum alone.
Four specific aims are proposed: 1) to establish a CD40 system, independent of T cells to obtain B cells which produce IgM and IgG antibodies that can be used to generate heterohybridomas secreting monoclonal human antibodies specific for lymphocytes in normal subjects; 2) using the CD40 system, to derive IgM and IgG producing B cell lines and clones from patients with SLE to ascertain the spectrum of anti-lymphocyte autoantibodies demonstrable in culture supernatants; 3) to identify and biochemically characterize the target antigens of anti-lymphocyte autoantibodies produced by SLE B cells in culture; and 4) to explore the idiotype/V-gene usage relationship between the autoantibodies to lymphocyte surface antigens and certain autoantibodies to intracellular antigens, both with respect to different autoantibody specificities in a given patient and to autoantibodies with similar specificities in different patients. A consortium is being established between the University of Virginia and the University of North Carolina at Chapel Hill to facilitate the conduct of the proposed studies. This consortium will combine the complementary investigative skills of the two groups and will assure the recruitment of a sufficient number of newly diagnosed SLE patients. It is anticipated that fundamentally new insights into the role of anti-lymphocyte autoantibodies in the immunodysregulation of SLE will be forthcoming from the proposed research.
