Endosomal TLR transport in B cell signaling and autoimmunity

项目摘要 核酸敏感（NA）-TLR，特别是TLR 7和TLR 9，是狼疮发病机制的核心参与者， 因此，靶向NA-TLR信号传导已显示出具有治疗功效，但临床相关的 特异性抑制NA-TLR的策略仍然难以捉摸。因此，存在对更好地 了解它们的基本生物学。NA-TLR从内质网转运到内质网， 内溶酶体区室，在那里它们接合配体并提供信号以激活细胞， 其次是免疫系统。该项目建议定义关键的内体区室 与NA-TLR信号传导、B细胞活化、自身抗体产生和终末器官疾病相关。这是基于 前提是NA-TLR的内体转运类似于用于NA-TLR的胞内转运系统。 溶酶体相关细胞器的生物发生和功能，NA-TLR是NA-TLR中LRO的部分形式。 TLR表达细胞。LRO形成复合物的缺乏与一种罕见的隐性疾病有关， 称为Hermansky-Pudlak综合征（HPS），由几个独立的遗传和功能组成， 这些缺陷具有共同的途径和几乎相同的表型。本项目将利用HPS中的缺陷 基因以鉴定NA-TLR信号传导和自身免疫所需的LRO生物发生的阶段， 特别是AP-3和BLOC-1至-3复合物中的缺陷。这将通过确定以下方面的作用来实现： 这些基因在狼疮的发展中（aim 1），定义了AP-3在B细胞中TLR信号传导中的作用（aim 2）， 并确定这四个基因在B细胞TLR转运和信号传导中的功能（目的3）。这个项目应该 产生新的见解NA-TLR信号转导的生物学内溶酶体区室和 这些区室与NA-TLR介导的B细胞活化、自身抗体产生和系统性免疫应答的相关性 自身免疫性疾病。

PROJECT SUMMARY Nucleic acid-sensing (NA)-TLRs, notably TLR7 and TLR9, are central players in the pathogenesis of lupus and consequently targeting NA-TLR signaling has been shown to have therapeutic efficacy, but a clinically relevant strategy for specifically inhibiting NA-TLRs has remained elusive. Thus, there is substantial interest in better understanding their basic biology. NA-TLRs are transported from the endoplasmic reticulum to the endolysosomal compartment where they engage ligands and provide signals to activate cells and subsequently the immune system. This project proposes to define the critical endosomal compartments relevant to NA-TLR signaling, B cell activation, autoAb production, and end organ disease. This is based on the premise that endosomal transport of NA-TLRs is similar to the intracellular trafficking system utilized for the biogenesis and function of lysosome-related organelles and that NA-TLRs are a partial form of LROs in NA- TLR-expressing cells. Deficiency of LRO-forming complexes is associated with a rare recessive disorder, called the Hermansky-Pudlak syndrome (HPS) composed of several independent genetic and functional defects that share a common pathway and nearly identical phenotype. This project will use deficiencies in HPS genes as to identify the stages of LRO biogenesis required for NA-TLR signaling and autoimmunity using specifically defects in the AP-3 and BLOC-1 to-3 complexes. This will be accomplished by defining the role of these gene in the development of lupus (aim1), defining the role of AP-3 in TLR signaling in B cells (aim 2), and defining how these four genes function in B cell TLR transport and signaling (aim 3). This project should yield new insights into the biology of NA-TLR signaling within the endolysosomal compartments and the relevance of these compartments to NA-TLR-mediated B cell activation, autoAb production, and systemic autoimmune disease.