Anti-DNA antibodies from autoimmune mice arise by clonal expansion and somatic mutation.

TLDR

The origin of autoantibodies in systemic autoimmune diseases is debated, with hypotheses ranging from nonspecific B‑cell activation to antigen‑driven responses. The authors examined monoclonal anti‑DNA antibodies isolated from spleen cells of autoimmune MRL/lpr mice to test whether they arise from antigen‑driven selection. The study demonstrates that anti‑DNA antibodies arise through antigen‑driven selection, with somatic mutations—particularly arginine residues—conferring dsDNA specificity, and that anti‑idiotypes are broadly reactive rather than V‑family specific.

Abstract

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.