PATHOGENIC AUTOANTIBODIES ARE ROUTINELY GENERATED DURING THE RESPONSETO FOREIGN ANTIGEN - A PARADIGM FOR AUTOIMMUNE-DISEASE

The immune System's ability to distinguish self and nonself is essenti al for both host defense against foreign agents and protection of self -antigens from autoimmune destruction, Such discrimination Is complica ted by extensive structural homology shared between foreign and self a ntigens, One hypothesis to explain the development of an autoimmune re sponse is that some B cells activated by foreign antigen acquire, thro ugh somatic mutation, specificity for both the eliciting foreign antig en and self antigen, If such clones arise frequently, there must be a mechanism for their elimination, We have analyzed the extent of autore activity arising in a nonautoimmune host during the response to a fore ign antigen, To overcome the process of apoptosis in primary B cells t hat might routinely eliminate autoreactive clones, we generated B-cell hybridomas from spleen cells of immunized mice by using a fusion part ner constitutively expressing bcl-2, Multiple lines were obtained that recognize simultaneously the hapten phosphorylcholine and the self an tigen double-stranded DNA, This dual specificity was not present early but was detected by day 10 after immunization, Some of these cross-re active antibodies deposit in kidneys in a pattern similar to what is s een in autoimmune disease, These results demonstrate that autoantibodi es arise at a high frequency as part of a response to foreign antigen, It has previously been shown that autoreactivity is regulated by cent ral deletion; these data demonstrate a need for negative selection in peripheral lymphoid organs also, to regulate autoantibodies acquiring their self-specificity by somatic mutation.