The RF-specific AM14 tg BCR has been used as a model to dissect the mechanisms of B cell tolerance to ICs containing nucleic acids. We have shown previously that AM14 RF B cells break tolerance in the TC mouse model of lupus through the dual engagement of the AM14 BCR and TLR9. In this study, we showed that neither the expression of Sle1 or Sle2 susceptibility loci alone was sufficient to activate AM14 RF B cells, suggesting that the production of antichromatin IgG2a(a) autoAg mediated by Sle1 and an intrinsically higher B cell activation mediated by Sle2 were required. We also showed that the B6 genetic background enhanced the selection of AM14 RF B cells to the MZB cell compartment regardless of the expression of the Sle loci and therefore, of their activation into AFCs. Furthermore, some AM14 RF B cells were selected into the B-1a compartment, where they did not differentiate into AFCs. Therefore, it is unlikely that the selection of AM14 RF B cells to the MZB or B-1a cell compartments in TC.AM14(a) mice is responsible for their breach of tolerance. Finally, we showed that the presence of expression of Sle1 in non-tg cells, most likely T cells, is necessary for the activation of AM14 RF B cells into AFCs. Overall, these results suggest a threshold model of activation of AM14 RF B cells on the B6 background with additive genetic and cellular contribution of multiple sources.
Keywords: B cell tolerance; BCR transgenic mice; autoantibody; autoimmunity.
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