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THE long-standing hypothesis^1,2 that tolerance to self antigens is mediated by either elimination^3–8 or functional inactivation (anergy; refs 9-11) of self-reactive lymphocytes is now accepted, but little is known about the factors responsible for initiating one process rather than the other. In the B-cell lineage, tolerant self-reactive cells persist in the peripheral lymphoid organs of transgenic mice expressing lysozyme and anti-lysozyme immunoglobulin genes⁹, but are eliminated in similar transgenic mice expressing anti-major histocompatibility complex immunoglobulin genes⁸. By modifying the structure of the lysozyme transgene and the isotype of the anti-lysozyme immunoglobulin genes, we demonstrate here that induction of anergy or deletion is not due to differences in antibody affinity or isotype, but to recognition of monomeric or oligomeric soluble antigen versus highly multivalent membrane-bound antigen. Our …