Anti-DNA antibodies from autoimmune mice arise by clonal expansion and somatic mutation.
The proximate cause of autoantibodies characteristic of systemic autoimmune diseases has been controversial. One hypothesis is that autoantibodies are the result of polyclonal nonspecific B cell activation. Alternatively, autoantibodies could be the result of antigen-driven B cell activation, as observed in secondary immune responses. We have approached this question by studying monoclonal anti-DNA autoantibodies derived from unmanipulated spleen cells of the autoimmune MRL/lpr mouse strain. This analysis shows that anti-DNAs, like rheumatoid factors (19), are the result of specific antigen-driven stimulation. In addition, correlation of sequences with fine specificity shows that: (a) somatic mutations can cause specificity for dsDNA and that such mutations are selected for; (b) arginine residues play an important role in determining specificity; and (c) anti-idiotypes that recognize the majority of anti-DNA are probably not specific for any one family of V regions.
Shlomchik
M
M
Institute for Cancer Research, Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111.
Mascelli
M
M
Shan
H
H
Radic
M Z
MZ
Pisetsky
D
D
Marshak-Rothstein
A
A
Weigert
M
M
D000595:Amino Acid Sequence; D000818:Animals; D000911:Antibodies, Monoclonal; D000918:Antibody Specificity; D001323:Autoantibodies / Q000235:genetics*; D001327:Autoimmune Diseases / Q000235:genetics* / Q000276:immunology; D001483:Base Sequence; D002999:Clone Cells; D004247:DNA / Q000276:immunology*; D004277:DNA, Single-Stranded / Q000276:immunology; D004797:Enzyme-Linked Immunosorbent Assay; D005803:Genes, Immunoglobulin; D007143:Immunoglobulin Heavy Chains / Q000235:genetics; D007133:Immunoglobulin Joining Region / Q000235:genetics; D007135:Immunoglobulin Variable Region / Q000235:genetics; D007145:Immunoglobulin kappa-Chains / Q000235:genetics; D051379:Mice; D008815:Mice, Inbred Strains; D008817:Mice, Mutant Strains; D008969:Molecular Sequence Data; D009154:Mutation; D015345:Oligonucleotide Probes; D012333:RNA, Messenger / Q000235:genetics; D013045:Species Specificity
D000911:Antibodies, Monoclonal; D001323:Autoantibodies; D004277:DNA, Single-Stranded; D007143:Immunoglobulin Heavy Chains; D007133:Immunoglobulin Joining Region; D007135:Immunoglobulin Variable Region; D007145:Immunoglobulin kappa-Chains; D015345:Oligonucleotide Probes; D012333:RNA, Messenger; D004247:DNA