Influence of BLyS on Peripheral B Lymphocyte Tolerance
How self-reactive B cells are regulated during naïve and antigen-driven B cell development remains poorly understood. The peripheral B cell pro-survival cytokine B lymphocyte stimulator (BLyS) has been proposed to participate in the regulation of immunological tolerance. This thesis focused on the role BLyS plays in the selection processes governing formation of the naïve B cell repertoire, and during antigen-driven B cell differentiation. To address these questions I employed targeted immunoglobulin heavy chain transgenic mouse lines designated as heavy chain knock-in (HKI). HKI mice produce large numbers of naïve follicular B cells that are either weakly (HKI65) or strongly (HKIR) self-reactive with nuclear autoantigens. Past work in related but distinct systems suggested that BLyS availability plays a central role in the selection of self-reactive cells. By contrast, I found that counter-selection of nuclear antigen-reactive HKI B cells was not influenced by changes in BLyS availability. Mature, naive, autoreactive HKIR and HKI65 B cells were equally outcompeted for representation in the periphery by a polyclonal B cell population. However, the failure of HKIR and HKI65 B cells to thrive was not due to a higher dependency of HKI B cells on BLyS for survival. As such, my data indicate the existence of peripheral tolerance mechanisms that regulate the frequency of autoreactive follicular B cells independent of the BLyS pathway. For the second part of my thesis, I tested the role of BLyS in the selection of autoreactive HKI B cells during antigen-driven B cell differentiation as these cells enter germinal centers (GCs). Experiments were performed to determine whether BLyS expression or presentation by follicular helper T cells (TFH) influences the counter-selection of self-reactive HKI B cells in the GCs. The resulting data indicate that GCs were established and maintained in the absence of BLyS production in TFHs. However, the effect of BLyS on germinal center negative selection was difficult to interpret, owing in part to modest differences observed between the participation of HKIR and HKI65 clones in the GCs. One potential conclusion is that local BLyS activity is dispensable for germinal center B cell survival.
Nikbakht, Neda, "Influence of BLyS on Peripheral B Lymphocyte Tolerance" (2013). ETD Collection for Thomas Jefferson University. AAI3557586.