Production of high affinity autoantibodies in autoimmune New Zealand Black, New Zealand White F-1 mice targeted with an anti-DNA heavy chain

Lupus-prone, anti-DNA, heavy (H) chain ''knock-in" mice Here obtained by ba ckcrossing C57BL/6 mice. targeted with a rearranged H chain from a V(H)11(S 107)-encoded anti-DNA hybridoma (D42), onto the autoimmune genetic backgrou nd of New Zealand Black/New Zealand White (NZB/NZW) F-1 mice, The targeted female mire de, doped typical lupus scrologic manifestations, with the appe arance of transgenic IgM anti-DNA autoantibodies at a young age (2-3 mo) an d high affinity somatically mutated IgM and IgG anti-DNA Abs at a later age (6-7 mo). However, they did not develop clinical, lupus-associated glomeru lonephritis and survived to at least 18 mo of age, L chain analysis of tran sgenic anti-DNA Abs derived from diseased NZB/NZW mouse hybridomas showed a very restricted repertoire of V kappa utilization, different from that of nonautoimmune (C57BL/6 x BALB/c)F-1 transgenic anti-DNA Abs. Strikingly, a single L chain was repetitively selected by most anti-DNA, transgenic NZB/N ZW B cells to pair with the targeted H chain. This L chain had the same V k appa-J kappa rearrangement as that expressed by the original anti-DNA D42 h ybridoma. These findings indicate that the kinetics of the autoimmune serol ogic manifestations are similar in wild-type and transgenic lupug-prone NZB /NZW F-1 mice and suggest that the breakdown of immunologic tolerance in th ese mice is associated with the preferential expansion and activation of B cell clones expressing high affinity anti-DNA H/L receptor combinations.