Initiation of systemic autoimmunity and sequence specific anti-DNA autoantibodies

Antibodies to double-stranded DNA (dsDNA) are a defining feature of Systemi c Lupus Erythematosus (SLE). The molecular characterization of anti-dsDNA a utoantibodies reveals that they are actively selected for binding to antige n. Evidence for antigen selection includes the use of suitable rearrangemen t products, the switching of IgM isotype to IgG, and the acquisition of som atic mutations that raise the affinity for dsDNA. Through a process of spec ificity maturation, anti-dsDNA antibodies can arise from anti-single strand ed DNA (ssDNA) antibodies that also occur in nonautoimmune individuals. To clarify circumstances leading to the initiation of systemic autoimmunity, w e compare features of immune responses to nucleic acids that operate before and after disease develops. Evidence indicating that anti-dsDNA antibodies bind with DNA sequence preference is highlighted to propose that sequence- specific anti-dsDNA antibodies may be induced by an infectious agent and in turn may extend the response to endogenous nuclear antigens. Thus, sequenc e-specific anti-dsDNA B cells may provide an important stimulus to break th e tolerance to self.