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Systemic lupus erythematosus (SLE) is a prototypic autoimmune disease characterized by antibodies to DNA. These antibodies serve as markers of diagnosis and prognosis as well as serological markers of disease pathogenesis. While designated as autoantibodies, SLE anti-DNA target sites that are widely conserved among DNA of both self and foreign origin. This crossreactivity, a feature that appears common among SLE antinuclear antibodies, raises the possibility that immune responses to DNA may arise from stimulation by foreign DNA. This possibility has gained credence from observations that DNA from bacteria has potent immunological properties. These properties include polyclonal B cell activation and induction of cytokines such as IL-12. Furthermore, sera of normal human subjects contain anti-DNA antibodies which selectively bind to DNA from certain bacterial species. Immunization experiments in mice fully support the possibility that bacterial DNA can initiate or sustain SLE anti-DNA production. Recently, studies in mice have demonstrated that self DNA has immunological activity and is not inert as has been widely assumed. As shown in in vitro experiments, DNA from mammalian species including human and bovine, can inhibit cytokine production induced by bacterial DNA and, in certain, systems, the cytokine response to LPS. As such, self DNA may play a regulatory role in immunity, inhibiting response in settings of tissue inflammation or destruction where self antigens are released from cells. These considerations suggest that anti-DNA responses in SLE could result from a crossreactive response to foreign DNA or an aberrant response to self DNA in which the inhibitory signals of mammalian DNA are insufficient or overcome. In either instances, models of SLE must take into account that DNA plays an active role in immune responses and, depending upon species and base composition, may be stimulatory or inhibitory.