HIGH-AFFINITY RHEUMATOID-FACTOR TRANSGENIC B-CELLS ARE ELIMINATED IN NORMAL MICE

Although systemic autoimmune diseases can be accompanied by multiple a utoantibodies, certain specificities are dominant. Presumably, these s pecificities and their cognate Ags have properties that make them part icularly amenable to autoimmune induction. Rheumatoid factors (RFs) ar e a dominant class of autoantibodies in rheumatoid arthritis and certa in other autoimmune syndromes. To study the regulation of RFs in norma l and autoimmune animals, we previously created a RF Ig transgenic mod el based on an RF isolated from an autoimmune MRL/lpr mouse. Using thi s model, called AM14, we were surprised to find that normal mice do no t regulate disease-related RF B cells. This raised the question of whe ther RFs in general are not susceptible to tolerance induction, perhap s due to the unique properties of serum IgG and ifs FcRs. Alternativel y, RFs can be tolerized, and the disease-related RFs are below the aff inity threshold for such tolerance. To distinguish these possibilities , we generated a second RF transgenic model with the same specificity but much higher affinity than AM14. We found that, in contrast to AM14 , high affinity RF B cells are subject to central tolerance, showing t hat there is not an absolute defect in RF B cell tolerance, but, rathe r, that RF B cell tolerance is affinity dependent even in normal anima ls. This is also the first model in which a disease-related specificit y has been shown clearly to delete in a system in which Ag-positive an d negative mice can be produced and compared.