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High affinity autoreactive IgG antibodies have been implicated in the development of lupus nephritis and other autoimmune disorders. With the discovery of activation-induced deaminase (AID), this question could be finally tested by examining the impact of AID deficiency in autoimmune-prone mice like the MLR/lpr strain. We have recently shown that AID-deficient MRL/lpr mice experienced a complete abrogation of lupus nephritis, and increased survival despite a dramatic increase in autoreactive IgM. Subsequent studies demonstrated that anti-dsDNA IgM is not pathogenic and in fact protects MRL/lpr from glomerulonephritis. AID-deficiency is also associated with decreased antibody-independent B cell-mediated autoimmunity likely through the loss of high affinity receptors through somatic hypermutation. Combined these results directly implicate AID in the development of B cell mediated autoimmunity. However, studies with hyper IgM AID-deficient patients indicate an increase in the incidence of certain autoimmunities. These results, likely the result of the immunodeficiency associated with AID deficiency, suggest caution in therapeutic approaches based in AID inhibition.