Natural autoreactive B cells in transgenic mice reproduce an apparent paradox to the clonal tolerance theory

Naturally occurring autoreactive B cells are thought to be physically elimi nated or rendered functionally silent through different mechanisms of toler ance. However, multireactive low affinity natural autoantibody-producing B cells seem to escape these mechanisms in normal adults and could constitute the B cell pool from which pathological autoantibodies can emerge. To anal yze this apparent paradox to the clonal tolerance theory, we have made two transgenic mouse lines (muk, mu partial derivativek) producing a natural lo w affinity multireactive human autoantibody. These models enable us to test both the central tolerance mechanisms (reactivity with single-stranded DNA ) and the peripheral tolerance mechanisms after Ag administration. Not only are the multireactive B cells not deleted in the bone marrow, they circula te and remain in the periphery even after the prolonged administration of A g, the presence of membrane IgD increasing the number of mature autoreactiv e B cells. Self-reactive B cells are shown to be autoantigen ignorant both in vivo and in vitro, but they are not anergic because they can be easily a ctivated through both B cell receptor-dependent and -independent pathways. Thus, these mouse lines reproduce an apparent paradox to the clonal toleran ce theory meriting further investigation of the biological significance of this phenomenon.