Production of high affinity autoantibodies in autoimmune New Zealand Black/New Zealand white F1 mice targeted with an anti-DNA heavy chain.
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 VH11(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 Vkappa 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 Vkappa-Jkappa 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.
Friedmann
D
D
Division of Medicine, Hadassah University Hospital, Faculty of Medicine, Hebrew University, Jerusalem, Israel.
Yachimovich
N
N
Mostoslavsky
G
G
Pewzner-Jung
Y
Y
Ben-Yehuda
A
A
Rajewsky
K
K
Eilat
D
D
D000595:Amino Acid Sequence; D000818:Animals; D000974:Antibodies, Antinuclear / Q000096:biosynthesis* / Q000097:blood / Q000737:chemistry / Q000235:genetics; D000911:Antibodies, Monoclonal / Q000737:chemistry / Q000235:genetics; D000915:Antibody Affinity / Q000235:genetics*; D001483:Base Sequence; D003433:Crosses, Genetic; D004247:DNA / Q000276:immunology*; D005260:Female; D018390:Gene Targeting; D007143:Immunoglobulin Heavy Chains / Q000008:administration & dosage* / Q000235:genetics; D007135:Immunoglobulin Variable Region / Q000008:administration & dosage / Q000235:genetics; D008177:Lupus Vulgaris / Q000235:genetics / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008814:Mice, Inbred NZB; D008822:Mice, Transgenic; D008969:Molecular Sequence Data
D000974:Antibodies, Antinuclear; D000911:Antibodies, Monoclonal; D007143:Immunoglobulin Heavy Chains; D007135:Immunoglobulin Variable Region; D004247:DNA