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

基本信息

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
项目类别：
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

项目摘要

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）的标志是生产核的抗体抗原，例如核糖核蛋白和DNA，产生的免疫复合物引起了全身性免疫激活和组织炎症。对双链DNA的高亲和力IgG抗体（DSDNA）特别致病，并与组织损伤的严重程度相关。这对SLE的耐受性及其分解的耐受性的理解很少。我们有研究了这些机制，通过专注于DNase1L3，这是一种分泌的DNase，在几种中被突变早发性家族性SLE病例。我们发现DNase1l3缺陷型小鼠会形成大量的抗抗 dsDNA抗体反应，而对其他抗原的反应是不存在或延迟的。这反应以及随之而来的免疫激活和组织损伤需要先天免疫信号通过适配器蛋白MyD88。 DNASE1L3缺乏小鼠和人类患者显示基因组DNA在循环凋亡微粒中的积累，该DNA为由自身抗体以DNase1L3敏感的方式识别。因此，dnase1l3保持通过在凋亡微粒中消化潜在的抗原细胞 - 超支DNA，对自动-DNA的耐受性。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的相关性 sle。在AIM 1中，我们将使用DNASE1L3缺陷型小鼠作为对原代抗DSDNA反应性的模型表征DNA反应性B细胞的性质和调节。在AIM 2中，我们将以先天性来表征抗DNA抗体反应的免疫机制，尤其是MyD88依赖性的身份感知途径。在AIM 3中，我们将我们的发现转化为人类SLE患者，研究对微粒上对DNase1L3敏感染色质的抗体反应。总的来说，这些研究将提供有关SLE中致病性抗DNA反应的起源和机制的见解，并促进针对其治疗性封锁的靶向方法。