Structure-Function in Antibodies to Double-Stranded DNA

Systemic lupus erythematosus (SLE) is a multifactorial autoimmune disease affecting multiple organs. Despite highly diverse clinical manifestations, patients with SLE have in common high titers of serum autoantibodies that target normal tissues or cells. The binding to self-antigens and the formation of immune complexes can subsequently trigger pronounced inflammatory responses, which lead to injury and damage in target organs. Of the SLE-related antibodies, antibodies to double-stranded DNA have received the most focused experimental attention. These antibodies are highly specific for SLE, and are believed to play an instrumental role in kidney, skin, and brain-related manifestations. Considering the pathogenicity of anti-DNA antibodies, blocking their interaction with self-antigens in target tissues should have therapeutic potential. In this chapter, we discuss key aspects of the molecular structure of anti-dsDNA antibodies, and review some important features of antigen recognition by these antibodies. We point out several recent and surprising observations regarding the contribution of the constant region to the antigenic specificity and the catalytic potential of lupus associated antibodies. Finally, recent studies on the development of novel therapeutic approaches to block anti-DNA antibody deposition in SLE are highlighted, including the identification of DNA-mimicking peptides.