Early Pathogenic Steps in Xenobiotic-Induced Autoimmunity

自身免疫性被认为是遗传、环境触发和随机事件的综合结果。 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 针对核抗原（ANA），然而，启动这种自身抗体反应的事件仍然很差， 明白这在很大程度上是由于对自身免疫何时以及如何在人类中开始的不完全理解 和自发性自身免疫的动物模型。然而，某些环境/外源性暴露 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 已知起始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，解剖特异性免疫反应，以已知的煽动剂和 更容易识别自身免疫所必需的早期事件， 自发性自身免疫性疾病的研究我们建议利用这一特点，以研究早期 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有关，包括炎症标志物、自身抗体和肾功能 病理这些观察结果在实验动物模型中得到了忠实的再现。重要的是， 小鼠汞诱导的自身免疫（mHgIA）诱导针对 核仁蛋白原纤维蛋白，也见于SLE和硬皮病患者。我们认为， 汞诱导的抗原纤蛋白反应的研究将提供对创建所需的早期事件的深入了解。 以及自身反应性B细胞的扩增，这是自身免疫反应的主要特征。我们提出三个目标 这将定义导致耐受丧失的次级淋巴器官中不同但相关的事件， 汞暴露后自身抗体的产生。目标1将定义早期免疫步骤， 外源性诱导的自身免疫，并表征引流淋巴结中的免疫病理学变化 (LNs)单次和多次皮下接触汞后的脾脏和骨髓。在目标2中， 将确定哪些因素对活化的CD 4 T细胞，自身免疫性GC的发展至关重要， mHgIA早期阶段的autoAb。建议实验将确定如何几个关键的不足之处 SLE或mHgIA中T依赖性免疫应答所需的基因（Unc 93 b1、Tlr 7、Il 6和Ifng）影响免疫应答。 早期和自身免疫性次级淋巴器官对HgCl 2的反应。最后，目标3研究将确定 通过表征进化的B细胞抗原受体库来鉴定汞诱导的自身反应性B细胞库 次级淋巴器官中汞暴露引起的。当这些研究完成后， 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.