VARIABLE REGION SEQUENCES OF AUTOANTIBODIES FROM MICE WITH EXPERIMENTAL SYSTEMIC LUPUS-ERYTHEMATOSUS

We have sequenced nine monoclonal antibodies (mAb) derived from C3H.SW mice in which experimental systemic lupus erythematosus (SLE) was ind uced. The hybridomas were selected for binding to DNA or to HeLa nucle ar extract (NE). Three mAb were found to bind DNA, and are shown to ex hibit sequence characteristics of pathogenic anti-DNA antibodies. One, mAb 2C4C2, is shown to use a heavy chain V region gene (V(H)) identic al to the V(H) of anti-DNA mAb isolated from other lupus-prone mice, n amely (NZB x NZW)F1. The light chain V region gene (V(L)) of mAb 2C4C2 is 98 % homologous to the V(L) of another anti-DNA mAb, also isolated from (NZB x NZW)F1 mice. The other two anti-DNA mAb, 5G12-4 and 5G12- 6, share 93 % of their V(H) sequences with that of mAb 2C4C2. Six mAb bound proteins of HeLa NE. Four of these six antibodies were found to use the VH124 V(H) and V-L7 V(L). The nine mAb use a total of five V(H ) and four V(L) germ-line genes, demonstrating that the autoantibodies induced in mice with experimental SLE do not originate from one B cel l clone. Three of these nine V(H) and V(L) were identical in sequence to germ-line genes, while at least three others had somatic mutations. The latter suggests that the above autoantibodies arise in mice by bo th usage of existing (pre-immune) B cells, and through an antigen-driv en process. Furthermore, it appears that autoantibodies found in mice with experimental SLE use genetic elements similar to those used by mA b that were isolated from mouse strains which develop lupus spontaneou sly.