A tenet of modern immunology is that the adaptive immune system has evolved so as to prevent, or at least diminish responses targeting self-antigens (1). Self-reactive B cells that arise due to incomplete negative selection in the bone marrow have been shown to be removed or inactivated in the periphery, with the most strongly self-reactive cells subject to clonal deletion. Less self-reactive cells either undergo receptor editing or are rendered anergic (2, 3). Receptor editing entails the reactivation of recombinase activating genes (RAGs) and enables immunoglobulin genes to be rearranged to create new antigen specificities. Anergy is a poorly understood state whereby cells retain the ability to bind to self-antigens but are otherwise rendered insensitive to antigenic stimulation (4). However, anergy is not a perfect solution to control self-reactivity. Many multifactorial autoimmune disorders involve the disruption of B cell anergy as a potential mechanism (5). One of the best known examples is systemic lupus erythematosus (SLE), where the inappropriate activation of anergic B cells and their differentiation into plasma cells that secrete autoreactive antibodies are an important contributing pathogenic mechanism. In particular, a large number of the autoantibodies in SLE is of the 9G4 idiotype (6). It has been shown that 9G4 idiotypic B cells are present and anergic in normal individuals, but actively expand into the plasma and memory cell compartments in SLE patients (7).

Much effort has been devoted to delineating the molecular differences in the signaling pathways between anergic and normal B cells, in order to understand their difference in the ability to respond to antigenic stimulation. Multiple mechanisms are likely involved. For instance, anergic B cells differ from normal B cells in the functioning of several signaling elements down-stream of the B cell receptor, such as the tyrosine kinase Lyn and the tyrosine phosphatase SHIP-1 (4). It has also been shown that a population of human peripheral blood naive B cells expressing autoreactive IgD receptor but no IgM receptor is anergic (8), and the responsiveness of B cells to low valence antigens was decreased by the flexible hinge region of IgD (9), suggesting that switching the B cell receptor usage from IgM to IgD resulting in higher IgD/IgM ratios may be a means to achieve anergy.