A DISEASE-RELATED RHEUMATOID-FACTOR AUTOANTIBODY IS NOT TOLERIZED IN A NORMAL MOUSE - IMPLICATIONS FOR THE ORIGINS OF AUTOANTIBODIES IN AUTOIMMUNE-DISEASE

We have analyzed B cell tolerance in a rheumatoid factor (RF) transgen ic mouse model. The model is based on AM14, a hybridoma originally iso lated from an autoimmune MRL/lpr mouse that has an affinity and specif icity typical of disease-related RFs from this strain, AM14 binds to i mmunoglobulin (Ig)G2a of the ''a'' allotype (IgG2a(a)) and not to IgG2 a(b). Thus, by crossing the transgenes onto an IgH(a) (BALB/c) backgro und or to a congenic IgH(b) (CB.17) background, we could study the RF- expressing B cells when they were self-specific-(IgH(a)) or when they were not self-specific (IgH(b)). These features make the AM14 model un ique in focusing on a true autoantibody specificity while at the same time allowing comparison of autoreactive and nonautoreactive transgeni c B cells, as was possible in model autoantibody systems such as anti- hen egg lysozyme. Studies showed that AM14 RF B cells can make primary immune responses and do not downregulate sIgM, indicating that the pr esence of self-antigen does not induce anergy of these cells. In fact, IgH(a) AM14 transgenic mice have higher serum levels of transgene-enc oded RF than their IgH(b) counterparts, suggesting that self-antigen-s pecific activation occurs even in the normal mouse background. Since A M14 B cells made primary responses, we had the opportunity to test for potential blocks to self-reactive cells entering the memory compartme nt. We did not find evidence of this, as AM14 B cells made secondary i mmune responses as well. These data demonstrate that a precursor of a disease-specific autoantibody can be present in the preimmune repertoi re and functional even to the point of memory cell development of norm al mice. Therefore, immunoregulatory mechanisms that normally prevent autoantibody production must exert their effects later in B cell devel opment or through T cell tolerance. Conversely, the data suggest that it is not necessary to break central tolerance, even in an autoimmune mouse, to generate pathologic, disease-associated autoantibodies.