The role of clonal selection and somatic mutation in autoimmunity

Abstract

Polyclonal activation has been proposed as the reason that autoantibodies are produced during autoimmune disease. This model denies a role for specific antigen selection of B cells and predicts instead a multiclonal population of unmutated or randomly mutated autoantibodies. We have found that the genetic features and clonal composition of spontaneously derived immunoglobulin G (IgG) antiself-IgG (rheumatoid factor (RF] autoantibodies derived from the autoimmune MRL/lpr mouse strain are inconsistent with both the predictions of this model and the actual outcome of experimental polyclonal activation. Instead we have found that MRL/lpr RFs are oligoclonal or even monoclonal in origin. They harbour numerous somatic mutations which are distributed in a way that suggests immunoglobulin-receptor-dependent selection of these mutations. In this sense, the MRL/lpr RFs resemble antibodies elicited by exogenous antigens after secondary immunization. The parallels suggest that, like secondary immune responses, antigen stimulation is important in the generation of MRL/lpr RFs.

Analysis of Vκ genes in rheumatoid arthritis (RA) synovial B lymphocytes provides evidence for both polyclonal activation and antigen-driven selection

“…A3B6, however, had no detectable autoreactivity, but the IgG produced by the B4D8 hybridoma was a RF. The expressed V gene in B4D8 had 25 nucleotide changes compared with the Humkv325 gene, of which 13 out of 15 changes in the CDR1 and 2, and 3 were replacement changes consistent with antigen-induced nucleotide mutations [39,40].…”

Idiotypic and subgroup analysis of human monoclonal rheumatoid factors. Implications for structural and genetic basis of autoantibodies in humans.

“…The (26)(27)(28)(29)(30). These autoantibodies are produced by 3-20% of murine hybridomas derived from LPS-stimulated splenic B cells (31,32). To explain this large representation of RF-secreting B cells within the normal immune system, Schlomchik et al determined the sequences of RFs that arise in LPS-stimulated mice.…”

Naturally Occurring Human Phosphorylcholine Antibodies Are Predominantly Products of Affinity-Matured B Cells in the Adult

“…Agdriven selection processes are characterized by the accumulation of replacement mutations. By consensus, a skewed replacement to silent mutation ratio (R/S) of .2.9 in the CDR regions is considered indicative of Ag-driven affinity maturation (23). In our study, the Abs generated from memory PC + B cells typically had CDR regions with R/S ratios of .5 (Fig.…”