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

• 批准号: 9980282
• 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
• 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/9980282
• 关键词: Affect; Affinity; Antibiotic Therapy; Antibodies; Antigens; Antinuclear Antibodies; Autoantibodies; Autoantigens; Autoimmune Process; 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

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.

摘要 系统性红斑狼疮（SLE）是系统性自身免疫性疾病的原型，主要影响 年轻的女性它造成严重的发病率和死亡率。有效治疗，无明显副作用 用于诱导缓解和预防复发的方法是缺乏的。我们的新假设认为HLA-D SLE发病机制的一个重要方面是，自身抗体（自身抗体）和自身反应性T细胞是由 活化T细胞与自身抗原（自身抗原）和环境（如细菌）抗原交叉反应， HLA-DR限制性方式。在一段时间内，自身反应性T细胞的积累导致产生 复杂的自身抗体，导致临床疾病在适当的主机。缓解发生在减少自动- 反应性T细胞和自身抗体特异性。复发发生与重复刺激的分子模拟， 主持人最初的临床表现和复发取决于刺激的性质， 分子模拟物我们已经广泛地绘制了T细胞表位在狼疮相关的Ag，SmD。这辆汽车 交叉反应性分子内和分子间T细胞表位。分子内交叉反应性T细胞的存在 表位是它们在SLE中被靶向的原因。存在多个交叉反应性T细胞表位 snRNP多肽之间的相互作用为我们了解B细胞表位在淋巴细胞中的扩散机制提供了新的思路。 SLE。在SmD中已经鉴定出多个T细胞抗原区域。每一个区域似乎都诱导了独特的 自身抗体特异性模式。多个T细胞受体（TCR）被用于应答用以下免疫接种： englishitalianofrançaisdeutsch中文几个来自命令植物群的微生物模拟物被鉴定出具有诱导多样性的能力 auto-Ab以与亲本肽类似的方式。模拟物之间存在交叉反应的B细胞表位 和亲本SmD肽。破伤风类毒素（TT）T细胞表位与SmD表位的交叉反应性 已经被记录在案。这些结果和其他初步数据为目前的建议提供了基础， 我们更好地了解环境银诱导SLE相关的自身抗体的作用。三个具体目标 具体目标1：将我们在DR 3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Ab诱导与微生物群和破伤风类毒素相关;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， 在（NZM 2328 xNOD）F1、NZM 2328和（NZM 2328 xNOD）F2中， 具体目标3：从NZM 2328和NZM2328.DR3衍生无菌小鼠，以显示 狼疮肾炎和狼疮相关自身抗体在无菌或无菌环境中不会发生， 支持微生物群在SLE相关自身抗体的发展中起关键作用的论点。上 在基本水平上，预期结果将为SLE中自身抗体的起源提供见解，并将提供证据， T和B细胞在SLE中均起重要作用。他们还将支持靶向微生物群作为一种新方法 治疗和预防SLE的发展。