Mechanisms of DNA-Specific Autoimmunity in Systemic Lupus Erythematosus

系统性红斑狼疮 DNA 特异性自身免疫机制

• 批准号: 10374852
• 负责人: Jill P Buyon
• 金额: $ 49.38万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-06-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10374852
• 关键词: Adaptor Signaling Protein; Affinity; Anti-DNA Antibodies; Antibodies; Antibody Formation; Antibody Response; Antigen Receptors; Antigen-Antibody Complex; Antigens; Apoptotic; Autoantibodies; Autoantigens; Autoimmunity; B-Lymphocytes; Benign; Cells; Chromatin; Clinical; DNA; Deoxyribonucleases; Disease; Flare; Genomic DNA; Glomerulonephritis; Human; Immune response; Immune signaling; Immunoglobulin G; Immunology; Inflammation; Longitudinal Studies; Membrane; Modeling; Mus; Mutate; Mutation; MyD88 protein; Nature; Nuclear Antigens; Nucleosomes; Pathogenicity; Pathology; Pathway interactions; Patients; Phenotype; Regulation; Ribonucleoproteins; Role; Severities; Signal Pathway; Signal Transduction; Specificity; Specimen; Surface; Systemic Lupus Erythematosus; Testing; Therapeutic; Tissues; Translating; Work; autoreactivity; biobank; cell type; circulating DNA; ds-DNA; early onset; experience; extracellular; immune activation; innate immune mechanisms; insight; novel; novel strategies; response; sensor; serological marker; tool

ABSTRACT The hallmark of systemic lupus erythematosus (SLE) is the production of antibodies to nuclear antigens such as ribonucleoproteins and DNA, with the resulting immune complexes causing systemic immune activation and tissue inflammation. High-affinity IgG antibodies to double-stranded DNA (dsDNA) are particularly pathogenic and associate with the severity of tissue damage. The mechanisms of tolerance to self-DNA and of its breakdown in SLE are poorly understood. We have studied these mechanisms by focusing on DNASE1L3, a secreted DNase that is mutated in several cases of early-onset familial SLE. We found that DNASE1L3-deficient mice develop a massive anti- dsDNA antibody response, whereas the response to other antigens was absent or delayed. This response and the ensuing immune activation and tissue damage required innate immune signaling through the adaptor protein MyD88. DNASE1L3-deficient mice and human patients showed the accumulation of genomic DNA within circulating apoptotic microparticles, and this DNA was recognized by autoantibodies in a DNASE1L3-sensitive manner. Thus, DNASE1L3 maintains tolerance to self-DNA by digesting potentially antigenic cell-extrinsic DNA in apoptotic microparticles. The proposed work will apply the newly developed conceptual framework and experimental tools to analyze the fundamental mechanisms of anti-DNA immune responses and their relevance to human SLE. In Aim 1, we will use DNASE1L3-deficient mice as a model of primary anti-dsDNA reactivity to characterize the nature and regulation of DNA-reactive B cells. In Aim 2, we will characterize innate immune mechanisms of anti-DNA antibody response, particularly the identity of MyD88-dependent sensing pathways. In Aim 3, we will translate our findings to human SLE patients, studying the antibody response to DNASE1L3-sensitive chromatin on microparticles. Collectively, these studies would provide insights into the origin and mechanisms of the pathogenic anti-DNA responses in SLE, and facilitate targeted approaches towards their therapeutic blockade.

抽象的 系统性红斑狼疮 (SLE) 的标志是产生抗核抗体 核糖核蛋白和 DNA 等抗原，产生的免疫复合物引起全身性感染 免疫激活和组织炎症。双链 DNA 高亲和力 IgG 抗体 (dsDNA) 具有特别致病性，并且与组织损伤的严重程度相关。这 SLE 患者对自身 DNA 的耐受及其分解的机制尚不清楚。我们有 通过关注 DNASE1L3 研究了这些机制，DNASE1L3 是一种在多种细胞中发生突变的分泌性 DNase。 早发家族性 SLE 病例。我们发现DNASE1L3缺陷的小鼠会产生大量的抗- 双链 DNA 抗体反应，而对其他抗原的反应缺失或延迟。这 反应以及随后的免疫激活和组织损伤需要先天免疫信号传导 通过接头蛋白 MyD88。 DNASE1L3 缺陷小鼠和人类患者表现出 循环凋亡微粒内基因组 DNA 的积累，该 DNA 被自身抗体以 DNASE1L3 敏感的方式识别。因此，DNASE1L3 维持 通过消化凋亡微粒中的潜在抗原细胞外源 DNA 来耐受自身 DNA。 拟议的工作将应用新开发的概念框架和实验工具 分析抗 DNA 免疫反应的基本机制及其与人类的相关性 系统性红斑狼疮。在目标 1 中，我们将使用 DNASE1L3 缺陷小鼠作为初级抗 dsDNA 反应性模型 描述 DNA 反应性 B 细胞的性质和调节。在目标 2 中，我们将描述先天的特征 抗 DNA 抗体反应的免疫机制，特别是 MyD88 依赖性的身份 传感通路。在目标 3 中，我们将把我们的发现转化为人类 SLE 患者，研究 对微粒上 DNASE1L3 敏感染色质的抗体反应。总的来说，这些研究 将提供对 SLE 致病性抗 DNA 反应的起源和机制的见解， 并促进有针对性的治疗封锁方法。