Gene-Environment Collaboration in Autoimmune Disease

自身免疫性疾病中的基因-环境合作

基本信息

批准号：
10246383
负责人：
MARY H. FOSTER
金额：
$ 36.23万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-30 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10246383
关键词：
ANCA vasculitis Abbreviations Address Affect Antibodies Antibody-mediated protection Antigen-Presenting Cells Antigens Antineutrophil Cytoplasmic Antibodies Autoantibodies Autoimmune Autoimmune Diseases Autoimmune Process Autoimmunity B-Lymphocytes Biological Models Biology Bone Marrow Bone Marrow Transplantation Bronchoalveolar Lavage Caregivers Cell Communication Cell Culture Techniques Cells Collaborations Complex Data Diagnosis Disease Disease susceptibility Dissection Environment Environmental Exposure Event Exposure to Flow Cytometry Fluorescence-Activated Cell Sorting Genes Genetic Genetic Heterogeneity Genetic Predisposition to Disease Glomerulonephritis Goals HLA-DR Antigens Health Care Costs Hematopoietic stem cells Human Immune Immune system Immunity Immunization Immunoassay Immunofluorescence Immunologic Individual Infusion procedures Inhalation Injury Intervention Intravenous Kidney Kidney Failure Leukocytes Ligands Limb structure Link Lung Lupus Lymphocyte Lymphoid Tissue Major Histocompatibility Complex Measures Mediator of activation protein Microdissection Modeling Monitor Morbidity - disease rate Mus Nature Nephritis Organ Pathogenesis Patients Peroxidases Phenotype Population Proteinase 3 Public Health Regulation Relapse Reporter Role Route Silicon Dioxide Site Structure of germinal center of lymph node System Systemic Lupus Erythematosus TNFRSF10A gene Testing Therapeutic Intervention Thymus Gland Toll-like receptors Transgenes Transgenic Organisms Vasculitis autoimmune pathogenesis autoreactive B cell autoreactivity crystallinity environmental agent experimental study gene environment interaction glomerular basement membrane immunoreactivity in vivo Model insight intraperitoneal mouse model novel prevent recruit respiratory risk variant secondary lymphoid organ tertiary lymphoid organ tissue injury tool young adult

项目摘要

Inhaled silica has been compellingly linked to several human autoimmune diseases, including systemic lupus erythematosus and ANCA vasculitis that destroy kidneys, lungs, and other organs. However, little is known about the mechanism of autoimmune induction or the role of genetic susceptibility. Autoantibodies are prominent in these disorders and key mediators of tissue injury. The experiments proposed here test the overarching hypothesis that the silica-exposed lung creates a microenvironment that alters autoimmune cell regulation in genetically susceptible individuals. We further propose that this breach in B cell tolerance occurs through the intermediary of pulmonary tertiary lymphoid structures or iBALT that promote survival and activation of autoreactive lymphocytes, and that the human HLA DRB1*1501 risk allele and Toll-like receptor ligand co-exposure contribute to this breach. This hypothesis can be tested using in vivo models that permit complex and dynamic immune cell interactions at the environment/lung interface and that are amenable to mechanistic dissection. We propose three Specific Aims supported by extensive preliminary data and established cross-disciplinary collaborations. Specific Aim 1 tests the hypothesis that silica- induced iBALT is a major site for loss of B cell tolerance, and that the extent and nature of iBALT formation and defective tolerance varies according to genetic susceptibility. We will measure recruitment and activation of autoreactive B cells within iBALT and secondary lymphoid organs of silica-exposed subjects using flow cytometry, immunoassay, cell culture, and microdissection. This aim is possible using a unique and experimentally tractable murine model system developed in our lab, in which an autoantibody transgene serves as a reliable reporter to track autoreactive cells and monitor well-defined tolerance phenotypes within the context of genetically distinct B6 and autoimmune MRL, NZB, and BXSB strains that collectively mirror human lupus genetic heterogeneity. Specific Aim 2 tests the role of a potent human autoimmune risk allele, HLA class II DRB1*1501, in silica-induced iBALT induction and proteinase 3 (PR3)- ANCA vasculitis. This aim uses two novel humanized models that replace murine class II molecules with human class II DR2 (DRA1/DRB1*1501). We will measure silica exposure impact on autoreactive cell recruitment and tolerance using DR2+ B6 autoAb Tg mice, and on anti-PR3 autoreactivity and vasculitis using dual humanized Hu-HSC mice expressing DR2 both in thymus and on human immune cells and subject to PR3 immunization or PR3-ANCA infusion. Specific Aim 3 tests the capacity of silica to break tolerance to myeloperoxidase (MPO) or to modify anti-MPO immunity and MPO-ANCA vasculitis. This aim takes advantage of MPO immunoreactivity and disease-susceptibility in MRL and MPO-deficient B6 models. Ultimately, insight into mechanisms of silica-controlled autoimmunity will identify new targets and new routes for therapeutic intervention to arrest injury and prevent relapses in patients with autoimmune disease.

吸入二氧化硅与多种人类自身免疫性疾病密切相关，包括全身性疾病红斑狼疮和 ANCA 血管炎会破坏肾脏、肺和其他器官。然而，很少的是了解自身免疫诱导机制或遗传易感性的作用。自身抗体在这些疾病中很突出，也是组织损伤的关键介质。这里提出的实验测试了总体假设是，暴露于二氧化硅的肺部创造了一个改变自身免疫细胞的微环境遗传易感个体的调节。我们进一步提出 B 细胞耐受性的这种破坏通过促进生存的肺三级淋巴结构或 iBALT 的中介发生和自身反应性淋巴细胞的激活，以及人类 HLA DRB1*1501 风险等位基因和 Toll 样受体配体共同暴露导致了这种破坏。该假设可以使用体内模型进行测试允许环境/肺界面上复杂且动态的免疫细胞相互作用，并且适合机械解剖。我们提出了三个具体目标，并得到广泛的初步支持数据并建立跨学科合作。具体目标 1 检验二氧化硅的假设诱导的 iBALT 是 B 细胞耐受性丧失的主要位点，iBALT 形成的程度和性质耐受缺陷根据遗传易感性而变化。我们将衡量招聘和二氧化硅暴露受试者 iBALT 和次级淋巴器官内自身反应性 B 细胞的激活使用流式细胞术、免疫测定、细胞培养和显微切割。使用独特的方法可以实现这一目标以及我们实验室开发的实验上易于处理的小鼠模型系统，其中自身抗体转基因作为一个可靠的报告者来追踪自身反应细胞并监测明确的耐受性遗传上不同的 B6 和自身免疫 MRL、NZB 和 BXSB 菌株的表型共同反映了人类狼疮遗传异质性。具体目标 2 测试强大人类的角色自身免疫风险等位基因，HLA II 类 DRB1*1501，在二氧化硅诱导的 iBALT 诱导和蛋白酶 3 (PR3) 中- ANCA 血管炎。该目标使用两种新颖的人源化模型，用两种替代小鼠 II 类分子人类 II 类 DR2 (DRA1/DRB1*1501)。我们将测量二氧化硅暴露对自身反应细胞的影响使用 DR2+ B6 autoAb Tg 小鼠的招募和耐受性，以及抗 PR3 自身反应性和血管炎使用在胸腺和人类免疫细胞上表达 DR2 的双人源化 Hu-HSC 小鼠，接受 PR3 免疫或 PR3-ANCA 输注。具体目标 3 测试二氧化硅的破碎能力对髓过氧化物酶 (MPO) 的耐受性或改变抗 MPO 免疫和 MPO-ANCA 血管炎。这个目标利用 MPO 免疫反应性和 MRL 和 MPO 缺陷 B6 模型中的疾病易感性。最终，深入了解二氧化硅控制的自身免疫机制将确定新的目标和新的方法治疗干预的途径以阻止自身免疫性疾病患者的损伤并预防复发。

项目成果

期刊论文数量（2）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Déjà Vu But New: Using T Cells to Deplete B Cells to Treat Lupus.

似曾相识但新鲜：使用 T 细胞消耗 B 细胞来治疗狼疮。

DOI：
10.1053/j.ajkd.2019.04.009
发表时间：
2019
期刊：
American journal of kidney diseases : the official journal of the National Kidney Foundation
影响因子：
0
作者：
Sadun,RebeccaE;Foster,MaryH
通讯作者：
Foster,MaryH