B-CELLS ARE ANERGIC IN TRANSGENIC MICE THAT EXPRESS IGM ANTI-DNA ANTIBODIES

B lymphocytes in individuals with systemic lupus erythematosus (SLE) s ecrete pathogenic autoantibodies to DNA which cause clinical nephritis . (NZB x NZW) F1 (BW) female mice also secrete pathogenic anti-DNA aut oantibodies, and therefore are considered to be an animal model of SLE . The rearranged immunoglobulin (Ig) genes that encode an anti-DNA ant ibody from a diseased BW mouse have been cloned, and transgenic (Tg) m ice have been created by microinjection of these constructs into ferti lized eggs from normal mice. As we reported previously, when the const ruct contains the Cgamma2a heavy chain constant (C(H)) region, the mic e spontaneously secrete anti-DNA IgG and they develop mild nephritis. This demonstrated that the Ig encoded by the transgene is pathogenic. In contrast, here we report that when the construct contains the same anti-DNA Ig variable (V) regions used previously, along with the Cmu r egion, the autoreactive B cells are rendered tolerant. Most B cells in the Tg mice express the mu transgene product on their surface, and re arrangement of endogenous light chain genes is partially suppressed. F urthermore, most hybridomas made from Tg B cells secrete IgM anti-DNA. Despite this, the Tg mice have reduced levels of total serum Ig and t hey do not secrete anti-DNA IgM either spontaneously or following immu nization with DNA. We conclude that most B cells in the Tg mice have b een rendered anergic. Anergy is however reversible in vitro; lipopolys accharide stimulation of Tg B cells leads to the production of a signi ficant amount of IgM anti-DNA antibody. The studies demonstrate that i n this line of Tg mice on a normal mouse genetic background potentiall y pathogenic B cells that express a high-affinity Ig specific for a na tural autoantigen are subject to tolerance by induction of anergy.