Early Pathogenic Steps in Xenobiotic-Induced Autoimmunity

自身免疫被认为是遗传学、环境诱因和随机事件共同作用的结果。 系统性自身免疫性疾病的一个特征，如系统性红斑狼疮(SLE)，是自身抗体 抗核抗原(ANA)，然而，启动这种自身抗体反应的事件仍然很少 明白了。这在很大程度上是由于对人类自身免疫何时开始以及如何开始的不完全理解。 以及自发自身免疫的动物模型。然而，某些环境/外来生物暴露有 在人类中与自身免疫有关，并在实验动物模型中复制，从而提供了模型 已知启动事件及其暴露地点的系统。这些诱导的自身免疫模型 提供了一个独特的机会来剖析已知的激动剂和 明显更容易识别自身免疫所必需的早期事件，这些事件很难 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的 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 与人类的病理结果有关，包括炎症标志物、自身抗体和肾脏 病理学。这些观察结果在实验动物模型中得到了忠实的重现。重要的是 小鼠汞诱导自身免疫(MHgIA)诱导MHC限制性自身抗体反应 核仁蛋白原纤维蛋白，也存在于系统性红斑狼疮和硬皮病患者中。我们认为，澄清 汞诱导的抗纤维蛋白反应将提供对早期事件的洞察，这是产生 以及自身反应性B细胞的扩张，这是自身免疫反应的一个基本特征。我们提出了三个目标 这将定义次级淋巴器官中不同但相关的事件，导致耐受性丧失和 汞暴露后产生自身抗体。目标1将定义早期免疫学步骤 异种生物诱导的自身免疫及其引流淋巴结的免疫病理变化 单次和多次皮下接触汞后，皮肤、脾和骨髓中的汞含量增加。在《目标2》中，我们 将确定哪些因素对活化的CD4T细胞、自身免疫GC的发展至关重要，以及 自身抗体在mHgIA的早期阶段。拟议的实验将确定几个关键的缺陷 SLE或mHgIA(Unc93b1、TLR7、IL6和IFNG)中T依赖免疫反应所需的基因影响 早期和自身免疫次级淋巴器官对HgCl2的反应。最后，目标3研究将确定 HG诱导的自身反应性B细胞谱--表征B细胞抗原受体进化谱 汞暴露于次级淋巴器官所致。当这些研究完成后，将导致更大的 了解导致自身抗体产生的早期分子和细胞事件。

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.