Infections, Microbiome and HLA-DR in the Induction of Lupus Related Auto-antibodies

感染、微生物组和 HLA-DR 在狼疮相关自身抗体诱导中的作用

基本信息

批准号：
10212946
负责人：
Shu Man Fu
金额：
$ 54.5万
依托单位：
UNIVERSITY OF VIRGINIA
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：
2018-08-10 至 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10212946
关键词：
Affect Affinity Antibiotic Therapy Antibodies Antigens Antinuclear Antibodies Autoantibodies Autoantigens Autoimmune Autoimmunity B-Lymphocyte Epitopes B-Lymphocytes Cells Clinical Complex Data Development Diagnosis Disease Disease remission Economics Environment Epitope spreading Epitopes Event Exposure to Female Flare Generations Genes Genetic Germ-Free Gnotobiotic HLA-D Antigens HLA-DR Antigens HLA-DR3 Antigen Immune response Immunization Individual Infection Knowledge Lead Leukocytes Link Lupus Lupus Nephritis Maps Molecular Morbidity - disease rate Mus Nature Organ Paper Pathogenesis Patients Pattern Peptides Play Predisposition Process Production Proteins Publishing Quality of life Relapse Remission Induction Role Small Nuclear Ribonucleoproteins Specificity Stochastic Processes Susceptibility Gene Systemic Lupus Erythematosus T-Cell Activation T-Cell Receptor T-Lymphocyte T-Lymphocyte Epitopes Tetanus Toxoid Therapeutic Time Tissues Toxoids Transgenic Mice Transgenic Model Translating Viral Work autoreactive T cell autoreactivity cross reactivity disease diagnosis disorder later incidence prevention effective therapy effector T cell experimental study gut microbiota insight interest microbial microbiome microbiota mortality novel novel strategies pathogen polypeptide prevent prototype response side effect skin microbiota systemic autoimmune disease

项目摘要

ABSTRACT Systemic lupus erythematosus (SLE) is a prototype of systemic autoimmune disorder that affects mostly young females. It causes significant morbidity and mortality. Effective therapies without significant side effects for induction of remission and prevention of relapses are wanting. Our novel hypothesis that links the HLA-D region to the pathogenesis of SLE is that autoantibodies (auto-Ab) and auto-reactive T cells are generated by the activation of T cells cross-reactive with autoantigens (auto-Ag) and enviromental (such as bacterial) Ag in the HLA-DR restricted manner. Over a period of time accumulation of auto-reactive T cells leads to the production of complex auto-Ab, resulting in clinical disease in suitable hosts. Remission occurs with reduction of auto- reactive T cells and of auto-Ab specificities. Relapses occur with repeated stimulation by molecular mimics in the host. The initial clinical presentation and the relapses depend on the nature of the stimulation by the molecular mimics. We have extensively mapped the T cell epitopes in a lupus-related Ag, SmD. This auto-Ag has cross reactive intra- and inter-molecular T cell epitopes. The presence of intra-molecular cross-reactive T cell epitopes is the reason why they are targeted in SLE. The presence of multiple cross-reactive T cell epitopes among polypeptides of snRNP provides us the understanding of the mechanism of B cell epitope spreading in SLE. Multiple T cell antigenic regions have been identified in SmD. Each region appears to induce unique patterns of auto-Ab specificity. Multiple T cell receptors (TCR) are utilized in responses to immunization with SmD. Several microbial mimics from commansal flora were identified with the capability of inducing diverse auto-Ab in a similar manner as the parental peptide. There are cross reactive B cell epitopes between the mimics and the parental SmD peptides. Cross reactivity between tetenus toxoid (TT) T cell epitopes and those of SmD have been documented. These results and other preliminary data provide the basis for the current proposal for us to understand better the role of environmental Ag in the induction of SLE-related auto-Ab. Three specific aims are proposed: Specific Aim 1: To translate our observations in our DR3 transgenic model to normal individuals and SLE patients and to relate SLE-related Ab induction to microbiota and tetanus toxoid; Specific Aim 2: To demonstrate that antibiotic treatments that deplete or modulate the gut microbiota will modulate autoantibody production and/or disease course with prolonged survival in (NZM2328xNOD)F1, NZM2328 and NZM2328.DR3; and Specific Aim 3: To derive germ-free mice from NZM2328 and NZM2328.DR3 to show that lupus nephritis and lupus related auto-Ab will not develop in a germ-free or gnotobiotic environment, supporting the thesis that microbiota play a crucial role in the development of SLE-related auto-Abs. On the basic level, the expected results will provide insight to the origin of auto-Ab in SLE and will provide evidence that both T and B cells play important roles in SLE. They will also support targeting microbiota as a novel approach to treating and preventing the development of SLE.

抽象的系统性红斑狼疮 (SLE) 是系统性自身免疫性疾病的一种原型，主要影响年轻女性。它导致显着的发病率和死亡率。有效治疗且无明显副作用尚缺乏诱导缓解和预防复发的方法。我们的新假设将 HLA-D 联系起来 SLE发病机制的关键在于自身抗体（auto-Ab）和自身反应性T细胞的产生激活 T 细胞，与自身抗原 (auto-Ag) 和环境（如细菌）Ag 发生交叉反应 HLA-DR限制方式。经过一段时间的积累，自身反应性 T 细胞会产生复杂的自身抗体，导致合适宿主的临床疾病。缓解随着自动减少而发生反应性 T 细胞和自身抗体特异性。分子模拟物的反复刺激会导致复发主人。最初的临床表现和复发取决于刺激的性质分子模拟物。我们广泛绘制了狼疮相关 Ag、SmD 中的 T 细胞表位图谱。该自动抗原具有分子内和分子间 T 细胞表位的交叉反应。分子内交叉反应性 T 细胞的存在表位是它们成为 SLE 靶向的原因。存在多个交叉反应性 T 细胞表位 snRNP 多肽之间的关系使我们了解 B 细胞表位在系统性红斑狼疮。 SmD 中已鉴定出多个 T 细胞抗原区域。每个地区似乎都会产生独特的自身抗体特异性的模式。多种 T 细胞受体 (TCR) 用于响应免疫接种 SMD。共生菌群中的几种微生物模拟物被鉴定出具有诱导多种微生物的能力自身抗体以与亲本肽相似的方式。模拟物之间存在交叉反应性 B 细胞表位和亲本 SmD 肽。破伤风类毒素 (TT) T 细胞表位与 SmD 之间的交叉反应已被记录。这些结果和其他初步数据为当前提案提供了基础我们可以更好地了解环境Ag在诱导SLE相关自身抗体中的作用。三个具体目标提出：具体目标 1：将我们在 DR3 转基因模型中的观察结果转化为正常个体和 SLE 患者，并将 SLE 相关抗体诱导与微生物群和破伤风类毒素联系起来；具体目标 2：证明消耗或调节肠道微生物群的抗生素治疗将调节自身抗体 (NZM2328xNOD)F1、NZM2328 和 NZM2328 中的生产和/或疾病过程具有延长的生存期 NZM2328.DR3；具体目标 3：从 NZM2328 和 NZM2328.DR3 获得无菌小鼠以显示狼疮性肾炎和狼疮相关自身抗体不会在无菌或无菌环境中发生，支持以下论点：微生物群在 SLE 相关自身抗体的发展中发挥着至关重要的作用。上基本水平上，预期结果将深入了解 SLE 中自身抗体的起源，并提供证据： T 细胞和 B 细胞在 SLE 中都发挥着重要作用。他们还将支持将微生物群作为一种新方法治疗和预防 SLE 的发展。