Systemic lupus erythematosus (SLE) is a chronic multisystem disease characterized by a variety of immunological abnormalities, and has become a prototype for study of autoimmunity and immune complex-mediated tissue injury. Considerable evidence suggests that different types of autoantibodies to lymphocytes may be of fundamental importance with respect to immune system dysfunction in this disorder. Investigation during the past four years has increased our understanding of resting and activated T cell target antigen specificities in this system, and has delineated several interesting mechanisms by which anti-lymphocyte autoantibodies influence cell surface antigen expression, T cell populations in the circulation, and T cell activation. While broader in scope than the original application, the overall objective of the present proposal continues to be the definition of the nature and significance of anti-lymphocyte autoantibodies in SLE. Emphasis in Aim I is placed on the identification and biochemical characterization of autoantibody target molecules on different cell types. Special effort will be made to determine whether anti-lymphocyte antibody-reactive antigens are carbohydrate in nature become phosphorylated during T cell activation, and are attached to the cytoskeleton. Experiments in Aim II will study anti-lymphocyte antibodies as activation ligands, and will clarify the mechanism(s) by which they inhibit T cell activation.
Aim III concerns the relationship of anti-lymphocyte autoantibodies with clinical disease expression and the natural history of SLE. Lymphocytes and serum obtained from patients at different points in their illness, or with clinically distinct manifestations, will be analyzed in comparative immunofluorescence/cytotoxicity and Western blotting experiments. Also of interest in this aim are experiments to determine whether in vivo T cell subset depletion and endogenous T cell activation contribute to hypoproliferation in vitro. Autoantibodies and monoclonal antibodies which cross- react with cellular constituents from nuclear, cytoplasmic and plasma membrane compartments will be used in Aim IV to search for homologous epitopes shared by membrane surface targets of anti-lymphocyte autoantibodies. Cross-reactive idiotypes and light chain restriction of anti-lymphocyte antibody Ig will be sought as well. Anti-lymphocyte antibodies in patients with virus infections and non-SLE auto-immune diseases will be studied in Aim V to provide clues, vis a vis molecular mimicry (epitope homology), regarding putative microbial triggers of SLE and related disorders.
Showing the most recent 10 out of 17 publications
