Regulation of autoreactive B cells during the formation of the pre-immune and memory B cell repertoires

To prevent the formation of autoantibody mediated autoimmune diseases, autoreactive B cells are subjected to negative selection during the formation of the pre-immune repertoire. However, not all autoreactive B cells are purged from the pre-immune repertoire. Why some B cells can evade negative selection during the formation of the pre-immune repertoire, and whether self-antigens can prevent the maturation of autoreactive B cells into memory cells is not clear. Here, I used a series of transgenic mice, which express the hemagglutinin of influenza virus A/PR/8/34 as a neo-self antigen on different sets of tissues within the body, to examine the extent to which the neo-self PR8 HA mediates the negative selection of autoreactive B cells during the formation of the primary and memory B cell repertoires. The sensitivity of autoreactive PR8 HA-specific B cells to negative selection during the formation of the pre-immune repertoire was found to exactly segregate with distinct PR8 HA-specific B cell clonotypes irrespective of the expression of the neo-self HA, indicating that the sensitivity of autoreactive B cells to negative selection from the pre-immune repertoire is an intrinsic characteristic of each individual B cell. By contrast, the sensitivity of autoreactive B cells to negative selection during memory formation was found to be sensitive to the expression of the neo-self HA, and may require the expression of the self-antigens in certain amounts and/or certain cell types. Surprisingly, I also found that the neo-self HA could direct the activation and maturation of autoreactive B cells to memory cells when provided with CD4+ T cell help, indicating that self-antigens are not pre-disposed towards the negative selection of B cell, but can also be positive mediators of B cell activation. These findings not only provide insight into the factors which can allow for the persistence of autoreactive B cells within the peripheral B cell repertoire, but also highlight a need for the establishment of CD4+ T cell tolerance in the establishing B cell tolerance to self-antigens