Multiple mechanisms contribute to the pathogenesis of spontaneous SLE. However, despite the presence of polyclonal T and B cell hyperactivity, autoimmunity in lupus is not global, it is directed mainly against nuclear antigens and other products of apoptosis. Autoantibodies that bind DNA play a major role in the development of lupus nephritis, yet, B cells of normal subjects produce natural anti-DNA autoantibodies. Moreover, DNA is only a target antigen and not the primary immunogen, because deliberate immuniza-tion with DNA does not lead to SLE. Extensive studies with the NZB x SWR model, as well as human SLE have simplified some of these complex-ities and paradoxes of lupus and are helping to define the primary immunogen (s) that drives the pathogenic autoimmune response. The New Zealand Black (NZB) mice are prone to autoimmune hemolytic anemia, but they rarely develop glomerulonephritis. However, when NZB mice are crossed with the NZW or the SWR strain, the F1 progeny, called BWF1 and SNF1 respectively, develop severe lupus nephritis that is very similar to human lupus. And, analogous to humans, the BWF1 or SNF1 mice develop lupus without superimposition of any of the genes that secondarily accelerate the disease in the MRL-lpr or BXSB models of SLE. However, the NZW mice (parents of BWF1) are not normal; they themselves develop mild lupus and they produce high levels of retroviruses, just like the NZB strain. The SWR mice, on the other hand, are non-autoimmune and virus-free. Hence, the normal SWR mice have served as valuable genetic tools for dissecting the roles of various NZB traits in the etiology of autoimmune disease. For instance, retro-viruses were considered to be the etiologic agents of lupus for several decades. Genetic studies with NZB x SWR crosses revealed the NZB genes re-sponsible for the high level expression of retroviruses and gp70, but those genes could be segregated from the development of SLE. We showed that the retroviruses in NZB were endogenous, thus being another target autoantigen, but they were not the cause of autoimmunity. Expression of MCF-like retroviral genes that was recently proclaimed to be another causal factor, can also be dissociated from lupus, because they are expressed by normal non-autoim-mune mice as well. Thus the genetic test with the NZB x SWR crosses changed the emphasis in lupus research, from the pursuit of a viral etiology to elucidating basic defects in the immune system that deviates the response to common antigens towards autoimmunity. Remarkably, when the NZB mice are crossed with other normal strains, such as, C57BL/6 or AKR, lupus is suppressed in their F1 1 progeny. Therefore, the NZB x SWR cross has also been useful in identifying the genetic factors contributed by a’normal’nonautoimmune strain in the develop-ment of autoimmune disease. The above studies led us to ask why the SNF1 1 progeny but not the NZB parents, uniformly develop lupus nephritis? We found that the SNF1 1 mice produce a select population of pathogenic anti-DNA autoantibodies that are qualitatively different: they are of the complement-fixing IgG class and predominantly cationic in charge. Moreover, their antigen combining sites share a recurrent idiotype and similar antigenic fine-specificity patterns. These clonally restricted, cationic autoantibodies are found in the