Structure-Function Relationships in Anti-DNA and Anti-Phospholipid Antibodies and their Relevance to the Pathogenesis of Disease

Autoantibodies are pathogenic in systemic lupus erythematosus (SLE) and the antiphospholipid syndrome (APS). These pathogenic autoantibodies are generally characterized by IgG isotype and high affinity binding to particular antigens. In SLE, antibodies to double-stranded DNA (dsDNA), nucleosomes and alpha-actinin are particularly important. In APS, pathogenic antibodies that cause thrombosis or fetal loss are particularly characterized by binding to anionic phospholipids (PL) and beta-2-glycoprotein I. Sequence analysis of human and murine monoclonal anti-dsDNA and aPL antibodies shows that high affinity for these antigens is associated with the presence of the residues arginine (Arg), asparagine (Asn) and lysine (Lys) in the complementarity determining regions (CDRs) of their heavy and light chains. In vitro expression systems have been used to create variants of the antibodies in which these amino acids have been altered. In general, removal of arginine residues reduces affinity for dsDNA, nucleosomes and anionic PL. Arginines at different positions in the sequence have different effects on binding affinity and effects on binding are not always mirrored by effects on pathogenicity. These studies, together with molecular models of antigen/antibody complexes, help us to understand exactly how pathogenic antibodies interact with antigens. Ultimately, this understanding may aid the design of therapeutic agents to block the pathogenic effects of these antibodies.