Anti-DNA B cells in MRL/lpr mice show altered differentiation and editing pattern.
We have studied the regulation of anti-DNA B cells in transgenic mice with a heavy chain transgene (3H9H/56R). This transgene codes for a heavy chain that forms anti-double-stranded DNA (dsDNA) antibody when paired with most members of the endogenous Vkappa repertoire, but certain L chains, referred to as Vkappa editors, do not sustain dsDNA binding in combination with 3H9H/56R. In the nonautoimmune 3H9H/56R BALB/c, most B cells generated do not bind DNA because the transgene itself is edited or is associated with a Vkappa editor. A minor population of B cells (30%) bind dsDNA and express the lambda1 light chain (known to sustain 3H9H/56R DNA binding). These 3H9/56R/lambda1 B cells coexpress a kappa editor, and we propose that the down-regulation of the anti-DNA BCR caused by the dual L chain expression may prevent activation of this kappa/lambda population. These kappa/lambda B cells are sequestered in the marginal zone. Here, we studied the influence of autoimmunity on expression and regulation of 3H9H/56R. In 3H9H/56R MRL/lpr mice, the expression of anti-dsDNA is vastly accelerated. Anti-dsDNA B cells use noneditor kappas but, in addition, most anti-dsDNA B cells have edited the heavy chain transgene. lambda1 B cells (without the coexpression of a kappa editor) are found and the kappa/lambda1 MZ population is absent. Our results suggest that improper editing and failure to sequester autoreactive B cells may contribute to the breakdown of tolerance in MRL/lpr mice.
Li
Yijin
Y
Department of Molecular Biology, Princeton University, Princeton, NJ 08544, USA.
Li
Hui
H
Ni
Dongyao
D
Weigert
Martin
M
D000595:Amino Acid Sequence; D000818:Animals; D000974:Antibodies, Antinuclear / Q000276:immunology* / Q000378:metabolism; D015703:Antigens, CD / Q000378:metabolism; D015551:Autoimmunity; D001402:B-Lymphocytes / Q000276:immunology*; D001483:Base Sequence; D002454:Cell Differentiation / Q000502:physiology*; D004247:DNA / Q000276:immunology / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000276:immunology / Q000378:metabolism; D005434:Flow Cytometry; D007143:Immunoglobulin Heavy Chains / Q000737:chemistry / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D007145:Immunoglobulin kappa-Chains / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008815:Mice, Inbred Strains; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D016415:Sequence Alignment; D013154:Spleen / Q000166:cytology; D019076:Transgenes
D000974:Antibodies, Antinuclear; D015703:Antigens, CD; D004268:DNA-Binding Proteins; D007143:Immunoglobulin Heavy Chains; D007145:Immunoglobulin kappa-Chains; D004247:DNA