The antigenic origin of anti-dsDNA antibodies in SLE

PROJECT SUMMARY/ABSTRACT Anti-dsDNA antibodies are serological hallmarks of systemic lupus erythematosus (SLE), and key markers for diagnosis and disease activity. The close association of anti-dsDNA antibodies with SLE has suggested that understanding the origin of these antibodies would reveal key mechanisms in SLE pathogenesis. Nonetheless, while anti-dsDNA antibodies are likely the best-characterized autoantibodies at the genetic and molecular level, their antigenic origin and mechanisms of pathogenicity remain unclear. To date, the conclusion from previous studies is that anti-dsDNA antibodies in SLE originate from non-reactive precursors, which undergone affinity maturation against dsDNA as the primary antigen. Different to this paradigm, our preliminary studies suggest an alternative hypothesis in which anti-dsDNA antibodies are cross-reactive antibodies that originate from germline precursors targeting a protein self-antigen, and that cross-reactivity to dsDNA results from somatic hypermutation. Because gaining reactivity to dsDNA has little or no effect on reactivity to the original protein antigen, this process creates cross-reactive autoantibodies with the functional capacity to target the protein and bind dsDNA with high affinity. As a model, this new paradigm offers a rational explanation for the high heterogeneity of anti-dsDNA antibodies in terms of origin, physicochemical and pathogenic properties. To address this novel hypothesis, we will define the extended antigen specificity of a large set of mutated and germline reverted SLE-derived monoclonal anti-dsDNA antibodies using a human proteome microarray platform. The goal is to uncover both the primary specificities that preceded the origin of anti-dsDNA antibodies, and the protein targets that may determine their pathogenic effect in SLE. The final goal of this work is to gain new insights into disease mechanisms, thus laying the foundation to explore novel therapies.