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Production of High Affinity Autoantibodies in Autoimmune New Zealand Black/New Zealand White F₁ Mice Targeted with an Anti-DNA Heavy Chain¹

Dinorah Friedmann^*, Nurit Yachimovich^*, Gustavo Mostoslavsky^*, Yael Pewzner-Jung^*, Arie Ben-Yehuda^*, Klaus Rajewsky and Dan Eilat^2,*

^* Division of Medicine, Hadassah University Hospital, Faculty of Medicine, Hebrew University, Jerusalem, Israel; and Institute for Genetics, University of Köln, Köln, Germany

Lupus-prone, anti-DNA, heavy (H) chain "knock-in" mice were obtained by backcrossing C57BL/6 mice, targeted with a rearranged H chain from a V_H11(S107)-encoded anti-DNA hybridoma (D42), onto the autoimmune genetic background of New Zealand Black/New Zealand White (NZB/NZW) F₁ mice. The targeted female mice developed typical lupus serologic manifestations, with the appearance of transgenic IgM anti-DNA autoantibodies at a young age (2–3 mo) and 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 glomerulonephritis and survived to at least 18 mo of age. L chain analysis of transgenic anti-DNA Abs derived from diseased NZB/NZW mouse hybridomas showed a very restricted repertoire of V utilization, different from that of nonautoimmune (C57BL/6 x BALB/c)F₁ transgenic anti-DNA Abs. Strikingly, a single L chain was repetitively selected by most anti-DNA, transgenic NZB/NZW B cells to pair with the targeted H chain. This L chain had the same V-J rearrangement as that expressed by the original anti-DNA D42 hybridoma. These findings indicate that the kinetics of the autoimmune serologic manifestations are similar in wild-type and transgenic lupus-prone NZB/NZW F₁ mice and suggest that the breakdown of immunologic tolerance in these mice is associated with the preferential expansion and activation of B cell clones expressing high affinity anti-DNA H/L receptor combinations.

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