Secondary heavy chain rearrangement: a mechanism for generating anti-double-stranded DNA B cells.
The chronic graft-versus-host (cGVH) reaction results in a syndrome that closely resembles systemic lupus erythematosus (SLE). It is induced in nonautoimmune mice by the transfer of alloreactive T cells. The availability of anti-DNA transgenes allows us to study the genetic origins of autoantibodies in this model. We induced cGVH in two anti-DNA H chain site-directed transgenic mouse strains. This resulted in clonal expansion and selection of specific mutations in the anti-double-stranded (ds) DNA B cell population. These data, together with a high frequency of anti-dsDNA B cell clones recovered as hybridomas, suggested that anti-dsDNAs are the product of an antigen-driven immune response. Genetic analysis associated this response with the generation of anti-dsDNA B cells through secondary rearrangements that replaced the site-directed transgene (sd-tg) with endogenous VH genes.
Sekiguchi
Debora R
DR
Division of Rheumatology, Department of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Eisenberg
Robert A
RA
Weigert
Martin
M
D000595:Amino Acid Sequence; D000818:Animals; D000974:Antibodies, Antinuclear / Q000737:chemistry / Q000235:genetics* / Q000276:immunology*; D000911:Antibodies, Monoclonal / Q000276:immunology; D000918:Antibody Specificity; D001402:B-Lymphocytes / Q000276:immunology*; D001483:Base Sequence; D004247:DNA / Q000276:immunology*; D004797:Enzyme-Linked Immunosorbent Assay; D015322:Gene Rearrangement, B-Lymphocyte / Q000235:genetics; D006086:Graft vs Host Disease / Q000276:immunology; D006825:Hybridomas / Q000276:immunology / Q000378:metabolism; D007126:Immunoglobulin Allotypes / Q000737:chemistry / Q000235:genetics / Q000276:immunology; D007074:Immunoglobulin G / Q000235:genetics / Q000276:immunology; D007143:Immunoglobulin Heavy Chains / Q000737:chemistry / Q000235:genetics* / Q000276:immunology*; D007147:Immunoglobulin Light Chains / Q000737:chemistry / Q000235:genetics; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D019076:Transgenes / Q000235:genetics
D000974:Antibodies, Antinuclear; D000911:Antibodies, Monoclonal; D007126:Immunoglobulin Allotypes; D007074:Immunoglobulin G; D007143:Immunoglobulin Heavy Chains; D007147:Immunoglobulin Light Chains; D004247:DNA