From B-Cell Tolerance to Autoimmunity

Despite numerous mechanisms that exist to purge the B-cell repertoire of potentially dangerous autoreactive cells, it is now clear that numerous cells with the capability of binding self determinants survive negative selection and persist peripherally as anergic or ignorant cells. Exactly how these B cells are normally constrained, and then aberrantly activated in the context of autoimmunity, are two major questions in B-cell biology. A better understanding of the mechanisms involved in these processes could provide important insights to the regulation of alloreactivity. One clue to our understanding of autoimmunity comes from the nature of the autoantigens commonly targeted in systemic autoimmune diseases. Autoantigens often consist of macromolecular complexes that incorporate self-nucleic acids, and numerous in vitro studies have now shown that many of these canonical autoantigens are essentially potent endogenous autoadjuvants. Mice expressing a low affinity BCR specific for autologous IgG2a can be potently activated by DNA or RNA-associated immune complexes through a mechanism dependent on both the BCR and either TLR9 or TLR7, and serve as a useful prototype for autoreactive B cells in general. A number of groups have now tested this BCR/TLR paradigm in vivo. As expected, Tlr9^-/- autoimmune-prone mice fail to produce autoantibodies directed against chromatin, while Tlr7^-/- mice fail to produce autoantibodies directed against numerous RNA-associated proteins. However, the Tlr9^-/- mice develop accelerated clinical disease, while the Tlr7^-/- mice exhibit remarkably prolonged survival. We have now shown that BCR/TLR9 and BCR/TLR7 induce inherently different functional outcomes in B cells. Quite remarkably, both in vitro and in vivo, BCR/TLR7-dependent activation of autoreactive B cells leads to a more prolonged response and increased numbers of antibody producing cells. This response can be defined by a unique gene-expression profile and associated with proteins known to promote plasmablast differentiation. By contrast, BCR/TLR9 activation appears to initially limit autoreactive B-cell expansion; although in the context of systemic autoimmunity TLR9 is required for the production of DNA-reactive autoantibodies. Together these data indicate that the outcome BCR/TLR9 engagement of autoreactive B cells is highly dependent on environmental cues, and suggest that BCR/TLR7 B-cell activation is a key factor in the initiation of systemic lupus erythematosus and other systemic disorders.