A Multiomic Search for Antigens in Autoimmune Hepatitis

摘要/项目摘要 自身免疫性肝炎（AIH）传统上被认为是罕见的，病因不明。70多年来， 首先，皮质类固醇的非特异性免疫抑制仍然是治疗的基础。像 其他自身免疫性疾病，最近的数据表明，AIH的发病率和患病率可能正在上升。我们 一个小组已经表明，AIH不仅不成比例地影响妇女，而且影响有色人种，无论是在圣 弗朗西斯科的服务不足的人口和全国范围内的住院治疗AIH。为了解 针对这些差异，我们开展了合作研究AIH的生物学机制。与 在美国肝病研究协会的资助下，我们进行了转录组学分析， 来自印第安纳州大学的AIH患者和对照的全血样本。AIH患者的血液 值得注意的是干扰素信号传导的激活和几个样品中pegivirus的存在。分子 拟态被认为是AIH发病机制之一，例如暴露于病毒抗原可导致 肝脏中结构相似抗原的异常免疫识别。而罕见的自体抗原 2型自身免疫性肝炎已被确定，没有自身抗原已确定在更常见的1型 啊。我们的合作者已经开发出一种用于识别人类和病毒抗原的系统，称为噬菌体 免疫沉淀测序（PhIP-Seq）。在一项正在进行的研究中， 了解肝病（POSULD），我们一直在收集AIH的临床数据和生物标本 患者和对照组。通过PhIP-Seq对少量POSULD样本进行初步分析 鉴定了六种AIH的潜在自身抗原。这些数据表明，分析更多的样本，从种族， 不同种族的AIH患者和对照组可能导致自身抗原的鉴定， 自身抗原，并阐明这种神秘疾病的发病机制。根据这些发现，我们假设 在1型AIH中存在一种迄今尚未确定的肝自身抗原，其结构可能类似于 病毒抗原这一假设将在以下具体目标中得到解决：（1）确定人类 1型自身免疫性肝炎患者自身抗原的研究;（2）研究1型自身免疫性肝炎患者的病毒抗原， 如果发现任何抗原，评估其与目标1中发现的任何人自身抗原的相似性。这种探索性的 这项研究提高了我们对AIH发病机制的理解，这些发现可能会为健康提供见解。 我们和其他人观察到的差异。此外，旨在治疗或预防病毒性肝炎的疗法也是有效的。 感染或改变对所述抗原的免疫应答可以为AIH的治疗开辟新的途径。

Abstract/Project Summary Autoimmune hepatitis (AIH) is traditionally viewed as rare and of unclear etiology. More than 70 years since its first description, nonspecific immunosuppression with corticosteroids remains the cornerstone of therapy. Like other autoimmune disorders, recent data suggest that AIH may be rising in incidence and prevalence. Our group has shown that AIH not only disproportionately affects women but also people of color, both among San Francisco’s underserved population and nationally in terms of hospitalizations for AIH. In order to understand these disparities, we have developed collaborations to study biologic mechanisms underlying AIH. With funding from the American Association for the Study of Liver Diseases, we performed transcriptomic analysis of whole blood samples from AIH patients and controls at Indiana University. The blood of AIH patients was notable for activation of interferon signaling and the presence of pegivirus in several samples. Molecular mimicry has been proposed as a mechanism of AIH pathogenesis, e.g. exposure to a viral antigen may result in aberrant immune recognition of structurally similar antigens in the liver. While the autoantigen for the rarer Type 2 AIH has been identified, no autoantigen has been identified in the more commonly encountered Type 1 AIH. Our collaborators have developed a system for identifying human and viral antigens called Phage Immunoprecipitation-Sequencing (PhIP-Seq). In an ongoing study Prospective Observational Study to Understand Liver Diseases (POSULD), we have been collecting clinical data and biospecimens from AIH patients and controls at UCSF. Preliminary analysis of a small number of POSULD samples by PhIP-Seq identified six potential autoantigens for AIH. These data suggest that analysis of more samples from racially and ethnically diverse patients with AIH and controls could lead to the identification of an autoantigen or autoantigens and clarify the etiopathogenesis of this enigmatic disease. Given these findings, we hypothesize that there is a heretofore unidentified hepatic autoantigen in Type 1 AIH, which may be structurally similar to a viral antigen. This hypothesis will be addressed in the following Specific Aims: (1) To determine human autoantigens in patients with Type 1 AIH; and (2) To investigate viral antigens in patients with Type 1 AIH and, if any are found, assess their similarity to any human autoantigens found in Aim 1. Should this exploratory study improve our understanding of AIH pathogenesis, the findings may provide insight into the health disparities observed by our group and others. Furthermore, therapies aimed at treating or preventing viral infection or modifying the immune response to said antigens may open new avenues of therapy for AIH.