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 中分离出的 B 细胞可识别原型自身抗原， IgG2a，亲和力相对较低，对大多数含 IgG2a 的免疫反应相对无反应 复合物（IC）。然而，这些产生类风湿因子的 B 细胞响应 IC 的作用而剧烈增殖。 由 IgG2a 与 DNA 或 RNA 相关自身抗原结合组成，其机制包括 位于质膜上的 BCR 和 Toll 样受体 9 (TLR9​​) 的顺序接合或 TLR7，位于细胞质区室中。该实验系统清楚地暗示了 TLR7 和 TLR9 参与自身反应性 B 细胞的激活，并表明这些受体对富含 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，我们已经证明了函数 由生理学相关的 IC 引发的效应不能用人工配体重现。不过具体作用 TLR7和TLR9在疾病发生和进展中的作用仍不清楚，并且对TLR7和TLR9在疾病发生和进展中的作用知之甚少。 与 TLR7 触发途径相比，TLR9 引发的功能不同。当前的总体目标 应用程序是为了更好地了解 TLR9 和 TLR7 表达细胞类型如何发挥作用 SLE发病机制。本项目要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供免疫系统使用； (2) RNA 的哪些结构特征决定了 TLR7 的反应性； (3) TLR7和TLR9能否形成功能性的 检测 DNA/RNA 自身抗原的异二聚体； (4) 哪些细胞区室参与 TLR7和TLR9配体的检测以及特定区室如何调节功能； (5)怎么办 1 型干扰素调节自身抗体库和自身反应性 B 细胞功能；以及（6）什么 功能结果将 BCR/TLR9 与 BCR/TLR7 激活区分开来。研究结果将提供 有关开发治疗全身性疾病的新疗法的重要信息 如系统性红斑狼疮。 相关性（参见说明）： SLE 是一种危及生命的慢性自身免疫性疾病，美国境内有多达 200 万人受到影响 国家。目前的治疗选择可以减轻疾病的严重程度，但通常会产生有害的副作用 这限制了它们的扩展使用。从该提案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，而不会产生现在令人衰弱的副作用 与标准治疗相关