B cell tolerance to SLE-associated specificities

Although the production of autoantibodies in systemic lupus erythematosus (SLE) is thought to be the consequence of a dysfunctional immune system, direct evidence of the regulation of B cells with SLE-associated specificities and the breakdown of this regulation in individuals with SLE is limited. It is possible that SLE-prone individuals have a genetic makeup distinct from nonautoimmune-prone individuals that allows the generation of autoreactive B cells and provides the autoantigen. In this case nonautoimmune individuals are not tolerant: failure to generate either the autoantigen(s) and/or the autoreactive B cells means the immune system would not be confronted with this problem of autoreactivity. In order to determine whether autoantibody production in SLE is the consequence of a breakdown in a B cell tolerance that is present in nonautoimmune individuals, we have examined the fate of B cells with several types of SLE-associated specificities in nonautoimmune and SLE-prone mice bearing a transgene that increases the frequency of B cells with SLE-associated anti-DNA specificities. We have found that nonautoimmune transgenic mice prevent the serum expression of different types of anti-DNA autoantibodies through a differential regulation of the B cells bearing these specificities: B cells specific for ssDNA persist in nonautoimmune mice but these cells are blocked in their ability to secrete antibody, while some anti-dsDNA B cells are present but destined to die rapidly, and yet another set of B cells which have an anti-DNA specificity unique to SLE cannot be recovered from nonautoimmune individuals even when the ability to generate these B cells has been assured through the introduction of a transgene. In contrast, SLE-prone transgenic (and non-transgenic) mice fail to regulate these autoreactive anti-DNA B cells as evidenced by the expression of autoreactive antibody in the serum. We conclude from these observations that there is indeed B cell tolerance to SLE-associated specificities in nonautoimmune mice, and that this tolerance breakdowns in individuals with SLE