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

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.

Categorical selection of the antibody repertoire in splenic B cells

“…Although without direct analysis of the binding characteristics of these marginal zone Ig these data must be viewed as circumstantial, there is evidence in the literature of an association between short, N regiondepleted CDR-H3 and self-and poly-reactivity, and between enrichment for charged CDR-H3 amino acids and pathogenic self-reactivity. For example, short, N-less CDR-H3 are a marker of the neonatal CDR-H3 repertoire in both mouse and human, which is itself enriched for self-and poly-reactivity [30,31] An excess of charged amino acids in CDR-H3 has been associated with pathogenic self-reactivity, especially to DNA [16,[32][33][34]. In this light, it should be noted that B cells expressing anti-dsDNA reactivity have been shown to be excluded from the follicles [35].…”

Instability of Natural Antibody Repertoires in Systemic Lupus Erythematosus Patients, Revealed by Multiparametric Analysis of Serum Antibody Reactivities

“…17 for review], but only by their characteristic high affinity for some target antigens (e.g. DNA), resulting from somatic mutation and antigen-driven affinity maturation [18,19].…”

Inducible resistance to Fas-mediated apoptosis in B cells

“…Inasmuch as these B cells appear to be eliminated in a Fas-dependent fashion [15], [117][118][119][120][121], the induction of Fas-resistance (as a result of interaction with ever present self antigen) could lead to deleterious consequences, because of the possibility that normal processes of autoreactive B cell deletion might be thwarted. It would seem necessary for the rules governing the regulation of Fas-mediated apoptosis to be different for autoreactive B cells in comparison to normal (foreign antigen-specific) B cells.…”