For each putative tolerance mechanism, there have been numerous descriptions of its breakdown that could lead to autoimmunity. Genetic alterations in intra-cellular signaling pathways are prime candidates because enhanced signaling through the antigen receptor, reduced signaling through inhibitory receptors, or abnormalities in intracellular negative regulators of lymphocyte activation could readily contribute to autoreactivity (reviewed in ). Also, extracellular factors that could influence tolerance and contribute to autoimmunity have been invoked, such as viral- or bacterial-derived antigens that cross-react with the BCR or TCR (reviewed in ), coincidental signaling through Toll-like receptors to enhance APC function by pathogens (reviewed in ), or even self-materials  or increased self-antigen load due to a deficiency in antigen clearance machinery . However, of primary importance in the productive activation of B cells is the availability of T-cell help, because somatic mutation to produce the high-affinity antibodies that characterize protective immunity and of autoanti-bodies that can arise spontaneously in autoimmune disease generally requires the action of CD4+ T-helper cells (see Chapter 5).
Even in autoimmune mouse strains where B-cell defects have been described, T cells are necessary for full expression of autoimmune disease (reviewed in ). Of all the B-cell tolerance mechanisms, only deletion, the ultimate form of tolerance, can resist strong T-cell drive. However, there is no shortage of newly emerging autoreactive B cells that escape negative selection and receptor editing; in a recent study 4% of the normal, mature B-cell repertoire had autoreactivity to native DNA , the prototypic target of autoantibodies in systemic lupus erythematosus (see Chapter 11). Furthermore, somatic mutation driven by Th and self-antigen could readily convert weakly autoreactive B cells to produce high-affinity autoantibodies . Taken together, it is difficult to escape the conclusion that the onus for control of immune tolerance is the predominate purview of the T-cell repertoire.
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