Editing disease-associated autoantibodies.
We have generated site-directed transgenic mice whose transgenes code for anti-DNA antibodies. These antibodies are representative of the lupus-associated anti-DNAs seen in mouse models of autoimmunity and human SLE, and have the usual characteristics of pathogenic autoantibodies. As conventional transgenics in nonautoimmune mice, anti-DNA B cells have been shown to be deleted or inactivated. Autoreactive B cells can also escape negative regulation by a process called receptor editing. Here we describe two combined immunoglobulin H and L chain site-directed transgenic mouse models and characterize their editing phenotypes. One model, 3H9R/Vkappa4R, has a deletion-prone phenotype and undergoes editing, primarily by inactivation of the light chain by leap-frogging events. In the other model, 3H9R/Vkappa8R, B cells are susceptible to anergy and maintain most of their HR and LR chains. These studies clarify the relationship between editing and other mechanisms of tolerance.
Chen
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Department of Molecular Biology, Princeton University, New Jersey 08544, USA.
Prak
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Weigert
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D000483:Alleles; D000818:Animals; D000974:Antibodies, Antinuclear / Q000235:genetics*; D000915:Antibody Affinity; D001327:Autoimmune Diseases / Q000276:immunology*; D015322:Gene Rearrangement, B-Lymphocyte; D005803:Genes, Immunoglobulin; D006825:Hybridomas; D007108:Immune Tolerance; D007143:Immunoglobulin Heavy Chains / Q000235:genetics; D007135:Immunoglobulin Variable Region / Q000235:genetics*; D007145:Immunoglobulin kappa-Chains / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D017384:Sequence Deletion
D000974:Antibodies, Antinuclear; D007143:Immunoglobulin Heavy Chains; D007135:Immunoglobulin Variable Region; D007145:Immunoglobulin kappa-Chains