Initiation of systemic autoimmunity and sequence specific anti-DNA autoantibodies

Antibodies to double-stranded DNA (dsDNA) are a defining feature of Systemic Lupus Erythematosus (SLE). The molecular characterization of anti-dsDNA autoantibodies reveals that they are actively selected for binding to antigen. Evidence for antigen selection includes the use of suitable rearrangement products, the switching of IgM isotype to IgG, and the acquisition of somatic mutations that raise the affinity for dsDNA. Through a process of specificity maturation, anti-dsDNA antibodies can arise from anti-single stranded DNA (ssDNA) antibodies that also occur in nonautoimmune individuals. To clarify circumstances leading to the initiation of systemic autoimmunity, we 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, sequence-specific anti-dsDNA B cells may provide an important stimulus to break the tolerance to self.