Role of TLRs in plasma cell differentiation and survival

描述（由申请人提供）： 保护性体液免疫的持久性在很大程度上取决于浆细胞（PC）的寿命。相反，正是这种长期存在的能力是抗体介导的自身免疫性疾病（如系统性红斑狼疮）的重要障碍。因此，了解决定PC发展和生存的因素在生物学和治疗学方面都具有相当重要的意义。在这方面，最近已经阐明了PC的发展，成熟和维护的几个要素。我们已经确定了一个快速增长，自我更新，后生殖中心B细胞，是近端前体的PC（PCpre）。这些细胞存在于骨髓（BM）中，可以自我补充，并最终分化为长寿的PC。迄今为止，控制PCpre和PC的分化和存活的因素仍然不确定。BCR参与，Toll样受体（TLR）刺激和旁观者T细胞帮助都被认为是PC生存的关键因素，但仍有争议。直到最近，长寿命的BM PC的产生被认为是获得性免疫系统的独有特性。然而，我们现在知道，先天免疫反应的大小和质量对随后的适应性免疫反应产生深远的影响。我们表明，根据TLR信号的性质，可以控制长寿PC的出现。此外，PCpre上膜IG的表达和抗原可以增强所得PC的亲和力的事实表明，通过BCR和TLR的组合信号可能在BM中的PCpre选择中起作用，作为实现增强的抗体亲和力的手段。最后，抗体介导的自身免疫的慢性性质和体液免疫寿命是密不可分的。因为长寿命的BM PC可能有助于疾病的病理和进展，我们假设TLR信号在狼疮中改变，导致长寿命的自身抗体产生PC的不适当建立。这一假设将在两个具体目标中得到检验。首先，我们将研究TLR激活对PC前分化和存活的贡献。其次，我们将确定自身免疫B细胞的TLR特征是否控制其分化命运和稳态。

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.