CONTROL OF AUTOANTIBODY AFFINITY BY SELECTION AGAINST AMINO-ACID REPLACEMENTS IN THE COMPLEMENTARITY-DETERMINING REGIONS

Rheumatoid factor (RF) autoantibodies can be produced in healthy indiv iduals after infections or immunizations and thus escape normal toleri zation mechanisms. It has not been clear whether such autoantibodies c an undergo somatic hypermutation and affinity maturation similar to an tibodies to exogenous antigens. We have investigated how these autoant ibodies are regulated in normal individuals by analyzing the sequences of monoclonal IgM RFs obtained as hybridomas from donors after immuni zation. The variable regions undergo extensive hypermutation, but in c ontrast to antibodies against exogenous antigens, there is a strong se lection against mutations that result in replacement of amino acids in the hypervariable, or complementarity-determining, regions. Furthermo re, we found no increase in affinity of these RFs with the accumulatio n of mutations. This suggests that high-affinity variants are tolerize d during the hypermutation process and there is a peripheral mechanism operating on certain autoreactive B cells that, while not deleting of anergizing all autoreactive cells, prevents the generation of high-af finity autoantibodies. Comparison of RFs by using the V(H)1 DP-10 heav y chain variable region segment from both normal individuals and rheum atoid arthritis (RA) patients suggests that RF from RA patients may no t be subject to such a controlling mechanism.