Role of TLRs in plasma cell differentiation and survival

点击翻译按钮获取中文摘要

DESCRIPTION (provided by applicant): The enduring nature of protective humoral immunity is largely dependent on the longevity of the plasmacell (PC). Conversely, it is this long-lived capacity that is a significant hindrance in antibody-mediated autoimmune diseases, like systemic lupus erythematosus. Thus, understanding the factors that determine PC development and survival takes on considerable importance in terms of both biology and therapeutics. In this regard, several elements of PC development, maturation and maintenance have been recently elucidated. We have identified a rapidly growing, self-renewing, post-germinal center B cell that is a proximal precursor of PCs (PCpre). Residing in the bone marrow (BM), these cells are self-replenishing and also terminally differentiate to long-lived PCs. To date, the factors that control the differentiation and survival of PCpre and PCs remain uncertain. BCR engagement, Toll-like receptor(TLR) stimulation and bystander T cell help have all been implicated as critical elements for PC survival, yet still contested. Until recently, the generation of long-lived BM PCs was considered an exclusive property of the acquired immune system. However, we now know that the magnitude and quality of the innate immune response exerts a profound impact on the ensuing adaptive immune response. We show that depending on the nature of TLR signaling, one can control the emergence of long-lived PCs. Furthermore, expression of membrane Ig on PCpre and the fact that antigen can enhance the affinity of the resulting PCs, suggests that the combined signals through BCR and TLRs may play a role in PCpre selection in the BM as a means to achieve enhanced antibody affinity. Finally, the chronic nature of antibody-mediated autoimmunity and humoral immune longevity are inextricably linked. Because long-lived BM PCs likely contribute to disease pathology and progression, we hypothesize that TLR signaling is altered in lupus, leading to the inappropriate establishment of long-lived autoantibody-producing PCs. This hypothesis will be tested in two specific aims. First, we will investigate the contribution of TLR activation to PCpre differentiation and survival. Second, we will determine whether the TLR signature of autoimmune B cells controls their differentiation fate and homeostasis.