EDITING DISEASE-ASSOCIATED AUTOANTIBODIES

We have generated site-directed transgenic mice whose transgenes code for anti-DNA antibodies. These antibodies are representative of the lu pus-associated anti-DNAs seen in mouse models of autoimmunity and huma n SLE, and have the usual characteristics of pathogenic autoantibodies . As conventional transgenics in nonautoimmune mice, anti-DNA B cells have been shown to be deleted or inactivated. Autoreactive B cells can also escape negative regulation by a process called receptor editing. Here we describe two combined immunoglobulin H and L chain site-direc ted transgenic mouse models and characterize their editing phenotypes. One model, 3H9R/V kappa 4R, has a deletion-prone phenotype and underg oes editing, primarily by inactivation of the light chain by leap-frog ging events. In the other model, 3H9R/V kappa 8R, B cells are suscepti ble to anergy and maintain most of their HR and LR chains. These studi es clarify the relationship between editing and other mechanisms of to lerance.