Production of high affinity autoantibodies in autoimmune New Zealand Black/New Zealand White F1 mice targeted with an anti-DNA heavy chain

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

Research output: Contribution to journalArticlepeer-review

Abstract

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(H)11(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 Vκ 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 Vκ- Jκ 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.

Original languageEnglish
Pages (from-to)4406-4416
Number of pages11
JournalJournal of Immunology
Volume162
Issue number8
StatePublished - 15 Apr 1999
Externally publishedYes

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