ANTIGEN-INDUCED APOPTOTIC DEATH OF LY-1 B-CELLS RESPONSIBLE FOR AUTOIMMUNE-DISEASE IN TRANSGENIC MICE

STUDIES on transgenic mice expressing immunoglobulins against self-antigens 1-6 have shown that self-tolerance is maintained by active elimination (clonal deletion) 1-3,7, functional inactivation (clonal anergy) 4,5,8 of self-reactive B cells, or a combination of both 6. We have established and characterized a transgenic mouse line expressing an anti-erythrocyte autoantibody 6. In contrast to other autoantibody transgenic lies, about 50% of the animals of this transgenic line suffer from autoimmune disease, indicating a loss of self-tolerance. Here we show that peritoneal Ly-1 B cells (also known as B-1 cells 9) are responsible for this autoimmune disease in our transgenic mice. A few self-reactive Ly-1 B cells that have somehow escaped the deletion mechanism expand in the peritoneum because of the absence of self-antigen. These Ly-1 B cells are eliminated in vivo by apoptosis once exposed to self-antigen. On the basis of these results we propose a novel autoantibody production mechanism whereby self-reactive B cells sequestered in compartments free of self-antigens may survive, proliferate and be activated for generation of pathogenic autoantibodies in autoimmune diseases.