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.

摘要 系统性红斑狼疮(SLE)的特征是产生抗核抗体 抗原，如核糖核蛋白和DNA，以及由此产生的免疫复合体引起系统性 免疫激活和组织炎症。抗双链DNA的高亲和力抗体 (DsDNA)具有特别的致病性，与组织损伤的严重程度有关。这个 对自身DNA的耐受机制及其在SLE中的破坏机制尚不清楚。我们有 通过重点研究DNase 1L3来研究这些机制，DNase 1L3是一种分泌的DNA酶，它在几个 早发性家族性系统性红斑狼疮5例。我们发现DNASE1L3缺陷小鼠产生了大量的抗- DsDNA抗体反应，而对其他抗原无反应或延迟反应。这 反应和随之而来的免疫激活和组织损伤需要先天免疫信号 通过接头蛋白MyD88。DNASE1L3缺陷小鼠和人类患者显示 基因组DNA在循环中的凋亡微粒中积聚，这种DNA是 以DNASE1L3敏感的方式被自身抗体识别。因此，DNASE1L3保持 通过消化凋亡微粒中潜在的抗原性细胞外源DNA来耐受自身DNA。 拟议的工作将把新开发的概念框架和实验工具应用于 分析抗DNA免疫反应的基本机制及其与人类的关系 SLE。在目标1中，我们将使用DNASE1L3缺陷小鼠作为主要抗dsDNA反应的模型，以 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抗体应答的免疫机制，特别是MyD88依赖的身份 感知路径。在目标3中，我们将把我们的发现转化为人类SLE患者，研究 微粒上对DNASE1L3敏感染色质的抗体反应。总的来说，这些研究 将为系统性红斑狼疮致病性抗DNA反应的起源和机制提供深入的见解， 并促进对其治疗封锁的有针对性的方法。