Intrinsic mechanisms of regulation of anti-Sm B cell anergy

One of the fundamental properties of the immune system is its capacity to avoid autoimmune diseases. The mechanisms regulating this process, known as self-tolerance, are many and varied. Self-reactive B cells that are not deleted in the bone marrow are regulated by anergy in the periphery. This mechanism renders self-reactive B cells unresponsive to activating signals. The use of immunoglobulin transgenic mouse models specific for self or neo-self antigens have indicated that anergy encompasses a broad spectrum of complex and multi-factorial states of cell unresponsiveness. The work presented here addresses the regulatory complexity of anergy in anti-Sm B cells. In this study using a high affinity anti-Sm mouse model, I have identified several mechanisms for anti-Sm B cell anergy. In addition, I have shown that the mechanisms of anergy differ depending on affinity of the B cell receptor (BCR) for Sm and subset identity. High affinity anti-Sm B cells, unlike low affinity anti-Sm B cells, are unable to survive in the presence of competitor B cells. This defect correlates with a BAFF non-responsiveness and increased cell death. Both high and low affinity anti-Sm follicular B cells express signaling competent BCRs, although BCR ligation induces rapid cell death, which correlates with an imbalance of pro and anti-apoptotic protein expression. In contrast, the BCRs expressed by marginal zone B cells from the high affinity mouse model are defective in signaling suggesting an uncoupling of the signalsome from the BCR on these cells. Activation by toll-like receptors (TLRs) is also defective in anergic B cells. I find that TLR-induced activation of anergic anti-Sm B cells is regulated by two mechanisms; activation induced cell death and a block in Plasma cell (PC) differentiation. The block in PC differentiation occurs prior to the expression of PC-specific genes. The importance of each mechanism to the regulation of B cells of different subset varies, with the block in PC differentiation not occurring efficiently until after B cells reach maturity. Together, the data presented provide evidence of the complexity and variety of anti-Sm B cells regulation and provide insight to the mechanisms of B cell anergy