Activation of B Cells by Host Toll-Like Receptor Ligands

宿主 Toll 样受体配体激活 B 细胞

• 批准号: 8378438
• 负责人: Ann Marshak-Rothstein
• 金额: $ 0.79万
• 依托单位: UNIV OF MASSACHUSETTS MED SCH WORCESTER
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-01 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8378438
• 关键词: Address; Adverse effects; Affinity; Antigen-Antibody Complex; Autoantibodies; Autoantigens; Autoimmune Diseases; Autoimmune Process; B-Cell Activation; B-Lymphocytes; Binding; Binding Proteins; Biotin; Bone Marrow Stem Cell; Cell Line; Cell membrane; Cell physiology; Cells; Chromatin; Chronic; Complement Factor B; Complex; CpG Islands; DNA; DNA Sequence; Data; Dendritic Cells; Dendritic cell activation; Detection; Development; Disease; Disease Outcome; Disease Progression; Fluorescence Resonance Energy Transfer; Goals; Homo; IFNAR1 gene; IFNAR2 gene; Immune; Immune system; In Vitro; Individual; Instruction; Interferons; Label; Life; Ligands; Locales; Mediating; Modeling; Mus; Nature; Onset of illness; Pathogenesis; Pathway interactions; Phenotype; Play; Proliferating; Property; RNA; RNA Sequences; Receptors, Antigen, B-Cell; Reporter; Rheumatoid Factor; Role; Severity of illness; Signal Transduction; Source; System; Systemic Lupus Erythematosus; Systemic disease; TLR7 gene; TLR9 gene; Therapeutic; Toll-like receptors; Transgenic Model; United States; autoreactive B cell; base; cell type; drug development; functional outcomes; in vivo; inhibitor/antagonist; insight; macrophage; novel; rRNA Genes; rRNA Precursor; receptor; response; spatiotemporal; standard care; systemic autoimmune disease; tool; trafficking

B cells isolated from the B cell receptor (BCR) transgenic model AM 14 recognize a prototypic autoantigen, lgG2a, with relatively low affinity, and are relatively unresponsive to most lgG2a-containing immune complexes (IC). However, these rheumatoid factor producing B cells proliferate vigorously in response to IC consisting of lgG2a bound to DNA- or RNA-associated autoantigens via a mechanism that involves sequential engagement of the BCR located on the plasma membrane and Toll-like receptor 9 (TLR9) or TLR7, located in a cytoplasmic compartment. This experimental system has clearly implicated TLR7 and TLR9 in the activation of autoreactive B cells and shown that these receptors are specific for CG-rich dsDNA - potent endogenous DNA ligands include CpG islands. Importantly, we have shown that the functions elicited by physiologically relevant ICs cannot be reproduced with artificial ligands. However the exact role played by TLR7 and TLR9 in disease onset and progression is still unclear, and very little is known about the distinct functions elicited by TLR9 compared to TLR7 triggered pathways. The overall goal of the current application is to gain a better understanding of exactly how TLR9 and TLR7-expressing cell types contribute to SLE pathogenesis. Specific questions that will be addressed in this project include: (1) what are the natural sources of endogenous TLR ligands and when do they become available to the immune system; (2) what structural features of RNA determine TLR7 reactivity; (3) can TLR7 and TLR9 form functional heterodimers that detect DNA/RNA autoantigens; (4) which cellular compartments are involved in the detection of TLR7 and TLR9 ligands and how does the specific compartment regulate function; (5) how do type 1 interferons modulate the autoantibody repertoire and autoreactive B cell function; and (6) what functional outcomes distinguish BCR/TLR9 from BCR/TLR7 activation. The results of the studies will provide important information regarding the development of novel therapies for the treatment of systemic diseases such as SLE. RELEVANCE (See instructions): SLE is a chronic life threatening autoimmune disorder that afflicts up to 2 million individuals within the United States. Current therapeutic options can moderate disease severity but often have deleterious side effects that limit their extended use. Insights gained from this proposal should facilitate the development of drugs that specifically target the relevant immune effector mechanisms without the debilitating side effects of now associated with standard treatments

从B细胞受体（BCR）转基因模型AM 14分离的B细胞识别原型自身抗原， IgG 2a，具有相对低的亲和力，并且对大多数含IgG 2a的免疫应答相对不敏感。 络合物（IC）。然而，这些产生类风湿因子的B细胞对IC的反应是剧烈增殖的 由IgG 2a通过涉及以下的机制与DNA或RNA相关的自身抗原结合组成 位于质膜上的BCR和Toll样受体9（TLR 9）的顺序接合，或 TLR 7，位于细胞质区室中。这个实验系统已经清楚地暗示了TLR 7， TLR 9在自身反应性B细胞活化中的作用，并显示这些受体对富含CG的dsDNA具有特异性 - 有效的内源性DNA配体包括CpG岛。重要的是，我们已经表明，功能 由生理相关的IC引起的不能用人工配体再现。然而，确切的作用 TLR 7和TLR 9在疾病发生和发展中的作用尚不清楚，关于TLR 7和TLR 9在疾病发生和发展中的作用也知之甚少。 与TLR 7触发的途径相比，TLR 9引发的不同功能。当前的总体目标 应用是为了更好地了解TLR 9和TLR 7表达细胞类型如何发挥作用 SLE的发病机制。本项目将解决的具体问题包括：（1） 内源性TLR配体的天然来源以及它们何时可用于免疫系统;（2） RNA的哪些结构特征决定了TLR 7的反应性;（3）TLR 7和TLR 9能否形成功能性的 检测DNA/RNA自身抗原的异源二聚体;（4）哪些细胞区室参与了DNA/RNA自身抗原的检测。 TLR 7和TLR 9配体的检测以及特定区室如何调节功能;（5）如何 1型干扰素调节自身抗体库和自身反应性B细胞功能;（6）什么 功能结果将BCR/TLR 9活化与BCR/TLR 7活化区分开。研究结果将提供 关于治疗全身性疾病的新疗法开发的重要信息 例如SLE。 相关性（参见说明）： SLE是一种慢性危及生命的自身免疫性疾病，在美国有多达200万人受到其折磨。 States.目前的治疗选择可以减轻疾病的严重程度，但往往有有害的副作用 这限制了它们的广泛使用。从这一建议中获得的见解应有助于药物的开发 专门针对相关的免疫效应机制，而没有现在的衰弱副作用。 与标准治疗相关