Early Pathogenic Steps in Xenobiotic-Induced Autoimmunity

外源性自身免疫的早期致病步骤

基本信息

批准号：
10579269
负责人：
Kenneth Michael Pollard
金额：
$ 52.36万
依托单位：
SCRIPPS RESEARCH INSTITUTE, THE
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-02-24 至 2026-11-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10579269
关键词：
Affect Animal Model Antibody Formation Antigen Receptors Appearance Autoantibodies Autoantigens Autoimmune Autoimmune Diseases Autoimmune Responses Autoimmunity B cell repertoire B-Cell Antigen Receptor B-Lymphocytes Biological Models Blood Bone Marrow CD4 Positive T Lymphocytes Characteristics Chronic DBA/2 Mouse Development Diagnosis Disease Early identification Epitopes Event Excision Experimental Animal Model Exposure to Genes Genetic Human Hypertrophy Immune Tolerance Immune response Immunologics Inflammation Inflammatory Response Interferon Type II Interleukin-6 Kidney Knowledge Link Lymphoid Mercuric chloride Mercury Modeling Molecular Mus Natural Immunity Nuclear Antigens Nucleic Acids Nucleolar Proteins Outcome Pathogenicity Pathologic Pathology Patients Pattern Peptide Initiation Factors Production RNA Resistance Scleroderma Serology Severity of illness Silicon Dioxide Site Spleen Sterility Structure of germinal center of lymph node Study models Systemic Lupus Erythematosus T-Lymphocyte Tissues Xenobiotics adaptive immunity autoreactive B cell clinical diagnosis draining lymph node experimental study fibrillarin genetic element human disease human model inflammatory marker insight response secondary lymphoid organ subcutaneous systemic autoimmune disease urinary

项目摘要

Autoimmunity is thought to result from a combination of genetics, environmental triggers, and stochastic events. A characteristic of systemic autoimmune diseases, like systemic lupus erythematosus (SLE), are autoantibodies against nuclear antigens (ANA), however the events that initiate such autoantibody responses remain poorly understood. This is due largely to an incomplete understanding of when and how autoimmunity begins in humans and animals models of spontaneous autoimmunity. However, certain environmental/xenobiotic exposures have been linked to autoimmunity in humans and reproduced in experimental animal models, thus providing model systems where the initiating event and its exposure site are known. These induced models of autoimmunity provide a unique opportunity for dissecting the immunological response specific to known inciting agents and are significantly more amenable to identifying the early events necessary for autoimmunity that are difficult to study in spontaneous autoimmune diseases. We propose to exploit this feature in order to study the early molecular and cellular events leading to loss of B cell tolerance and autoantibody production. Mercury exposure in humans is linked with pathological outcomes including inflammatory markers, autoantibodies and renal pathology. These observation have been faithfully reproduced in experimental animal models. Importantly, murine mercury-induced autoimmunity (mHgIA) induces an MHC-restricted autoantibody response against the nucleolar protein fibrillarin which is also found in patients with SLE and Scleroderma. We believe that elucidation of the mercury-induced anti-fibrillarin response will provide insight into the early events necessary for the creation and expansion of autoreactive B cells, a cardinal feature of the autoimmune response. We propose three aims that will define different, but related, events in the secondary lymphoid organs that result in loss of tolerance and autoantibody production following mercury exposure. Aim 1 will define the early immunological steps in xenobiotic-induced autoimmunity, and characterize the immunopathologic changes in the draining lymph nodes (LNs), spleen and bone marrow following single and multiple subcutaneous exposures to mercury. In Aim 2 we will determine what factors are critical for the development of activated CD4 T cells, autoimmune GCs, and autoAbs in the early stages of mHgIA. Proposed experiments will determine how the deficiencies of several key genes required for T-dependent immune responses in SLE or mHgIA (Unc93b1, Tlr7, Il6, and Ifng) affect the early and autoimmune secondary lymphoid organ responses to HgCl2. Finally, Aim 3 studies will determine the Hg-induced autoreactive B cell repertoire by characterizing the evolving B cell antigen receptor repertoire induced by mercury exposure in secondary lymphoid organs. When completed these studies will lead to a greater understanding of the early molecular and cellular events leading to development of autoantibody production.

自身免疫被认为是遗传、环境触发因素和随机事件共同作用的结果。系统性自身免疫性疾病（如系统性红斑狼疮 (SLE)）的一个特征是自身抗体抗核抗原（ANA），然而引发此类自身抗体反应的事件仍然很差明白了。这主要是由于对人类自身免疫何时以及如何开始的不完全了解和自发性自身免疫动物模型。然而，某些环境/外源性物质暴露已与人类自身免疫有关，并在实验动物模型中复制，从而提供了模型起始事件及其暴露位置已知的系统。这些诱导的自身免疫模型提供了一个独特的机会来剖析特定于已知刺激剂的免疫反应，并且明显更容易识别自身免疫所需的早期事件，而这些事件很难识别自发性自身免疫性疾病的研究。我们建议利用这一特征来研究早期导致 B 细胞耐受性丧失和自身抗体产生的分子和细胞事件。汞暴露在人类中与病理结果相关，包括炎症标志物、自身抗体和肾病病理。这些观察结果已在实验动物模型中忠实再现。重要的是，小鼠汞诱导的自身免疫 (mHgIA) 会诱导 MHC 限制性自身抗体反应核仁蛋白纤维蛋白，也存在于系统性红斑狼疮和硬皮病患者中。我们相信澄清汞诱导的抗纤维蛋白反应的研究将提供对创造所需的早期事件的深入了解自身反应性 B 细胞的扩增，这是自身免疫反应的一个主要特征。我们提出三个目标这将定义次级淋巴器官中不同但相关的事件，这些事件导致耐受性丧失和接触汞后会产生自身抗体。目标 1 将定义早期免疫学步骤异生素诱导的自身免疫，并表征引流淋巴结的免疫病理学变化单次和多次皮下接触汞后的淋巴结（LN）、脾脏和骨髓。在目标 2 中，我们将确定哪些因素对于活化 CD4 T 细胞、自身免疫 GC 和 mHgIA 早期阶段的自身抗体。拟议的实验将确定如何解决几个关键的缺陷 SLE 或 mHgIA 中 T 依赖性免疫反应所需的基因（Unc93b1、Tlr7、Il6 和 Ifng）影响早期和自身免疫性次级淋巴器官对 HgCl2 的反应。最后，目标 3 研究将确定通过表征不断进化的 B 细胞抗原受体库来研究汞诱导的自身反应性 B 细胞库由次级淋巴器官中的汞暴露引起。这些研究完成后将带来更大的成果了解导致自身抗体生产发展的早期分子和细胞事件。