It should be noted that TLOs were induced not only in the stomach but also in other organs of AID2/2 mice . Therefore, these organs are also considered to be potential targets for an autoimmune response. Indeed, autoimmune diseases have been found to develop in multiple organs in humans with AID mutation . The precise mechanism by which AID deficiency promotes the generation of self-reactive B cells is an open question at this moment. A previous Axitinib report revealed that the BCR diversity is increased in AID2/2 mice . Consequently, gastric Ag-specific B cells might emerge from the expanded B-cell repertoire. Under physiological conditions, B-cell autoimmunity is counteracted by several tolerance mechanisms including receptor editing, anergy, and clonal deletion. Particularly, as many as 50% of newly produced B cells are reported to show an anergic phenotype , suggesting the primary importance of anergy in peripheral tolerance . Although anergic B cells have a shorter lifespan relative to wild-type mature B cells , anergy is a reversible process: anergic B cells have been shown to revert to naIve B cells upon hapten stimulation . This observation raises the possibility that escape from anergy could result in autoimmunity. Mice and humans lacking functional AID display B-cell hyperplasia and a hyperactivated immune system . Based on these observations, we speculate that the aberrant activation stress may drive B-cell clones, which are normally retained in an anergic state, toward an autoimmune response. Intercrossing of AID 2/2 mice with transgenic mice expressing a BCR prone to anergy should help clarify this speculation. Several mechanisms have been proposed to explain why AID deficiency leads to dysregulated proliferation of B cells. One possibility is that AID2/2 B cells are devoid of inhibitory signals though FccRIIB due to the lack of IgG Ab MK-0683 production. FccRIIB is the only FccR that contains a cytoplasmic ITIM motif. Crosslinking of the BCR and FccRIIB by IgG antibody-antigen complexes leads to negative feedback regulation for B cell activation via the phosphorylation of ITIM tyrosines and subsequent recruitment of the inositol phosphatase SHIP to the plasma membrane. Therefore, FccRIIB2/2 mice display elevated Ig levels and enhanced immune complex-mediated tissue injury in response to Ag challenge . Furthermore, involvement of this inhibitory receptor in peripheral tolerance has been supported by the fact that FccRIIB2/2 mice on a C57BL/6 background spontaneously develop autoantibody-mediated lupus glomerulonephritis . Although significantly different types of autoimmue diseases, namely systemic versus organ-specific, are induced in FccRIIB2/2 and in AID2/2 mice, respectively, this phenotypic difference is most likely due to the inability of AID2/2 mice to produce high-affinity autoimmune IgG Abs. AID-/- mice produce abnormally large amounts of IgM, whereas IgG is absent. IgM, like IgG, can promote complement activation, which in turn could support B-cell activation, because opsonization of Ags by complement components remarkably enhances both B cell activation as well as Ag uptake by B cells .