Activating systemic autoimmunity: B's, T's, and tolls

A recent advance in the treatment and understanding of autoimmune disease has been the efficacy of B-cell-targeted therapy. Such therapies are effective for several such diseases, with systemic autoimmunity being a prototypical example. The mechanism of action is not fully defined, but blocking B cell Ag presentation to T cells is likely to be important. T-B interactions probably engender a positive feedback loop that amplifies and sustains autoimmunity. But how is self-tolerance first broken to initiate this loop? I propose, based on recent data, a model in which autoreactive B cells are activated first, independent of T cells, but dependent upon BCR and TLR signals. These activated B cells then break T cell tolerance, resulting in full-blown autoimmunity.