Induction of autoimmunity in a transgenic model of B cell receptor peripheral tolerance: Changes in coreceptors and B cell receptor-induced tyrosine-phosphoproteins

Abrogation of peripheral tolerance in transgenic mice that express a unifor m B-cell receptor may create a powerful tool to examine the molecular mecha nisms that underlie the autoimmune response in B cells. Here we report that processes that induce a systemic lupus erythematosus-like syndrome in norm al mice, namely chronic graft vs host reaction, trigger systemic autoimmuni ty in a well-established transgenic mice model of B cell receptor periphera l tolerance. The induction of graft vs host reaction in mice that carry bot h a rearranged B cell Ag receptors specific for hen egg lysozyme and expres sing chronically circulating hen egg lysozyme Ag resulted in induction of h igh and sustained levels of circulating anti-hen egg lysoyme autoantibodies and glomerulonephritis with proteinuria, This was associated with marked c hanges in expression of cell-surface proteins, such as CD23 and complement receptor 2, B cells from the graft vs host-induced mice could proliferate i n vitro in response to self-Ag, and upon stimulation with anti-IgD demonstr ated rapid phosphotyrosine phosphorylation of specific proteins, which coul d not be induced in the anergic double transgenic B cells. Conversely, loss of tolerance was not associated with a higher induction in the level of Sy k kinase phosphorylation following stimulation with anti-IgD, Taken collect ively, these data establish that 1) processes that induce a systemic lupus erythematosus-like syndrome in normal mice can abrogate peripheral toleranc e in transgenic mice expressing self-tolerized B cells, and that 2) loss of tolerance in this model is associated with marked changes in surface expre ssion of B cell coreceptors as well as with selective changes in IgD-induce d signaling by discrete tyrosine-phosphoproteins, but not Syk kinase.