Developing Novel Serological Biomarkers for Autoimmune Liver Diseases

自身免疫性肝病（AILDs），包括自身免疫性肝炎（AIH）、原发性胆汁性肝硬化（PBC）和原发性硬化性胆管炎（PSC），是一种慢性且无法治愈的肝脏免疫疾病。AILDs会导致明显的痛苦和严重的后果，导致肝功能衰竭和肝胆恶性肿瘤。临床问题和挑战：由于显著的临床异质性和AIH与PBC/PSC共存的“重叠综合征”，以及aid与炎症性肠病（IBD）重叠，特异性AILD亚型的诊断在临床上一直具有挑战性。另一个主要挑战是缺乏可靠的生物标志物来评估疾病进展和治疗反应，特别是在PSC中。疾病的诊断/预后在很大程度上依赖于临床表现以及侵入性和消耗资源的基于活检的组织病理学。因此，本研究的长期目标是识别和开发可靠、微创、廉价的血清生物标志物，以帮助医生做出准确的诊断/预后和治疗决策，从而有效地管理AILDs，提高患者的生活质量。基本原理和假设：基于血液的生物标志物检测通常是最简单、侵入性最小、最广泛用于疾病诊断/预后的方法。目前大多数aid生物标志物是自身抗体，如用于1型AIH的ANA/SMA；AMA检测PBC（无特异性PSC标志物），提示血清自身抗体是AILD生物标志物的重要来源。已知在AILD发病机制中起重要作用的细胞因子/趋化因子是AILD生物标志物的另一个潜在来源。然而，由于缺乏高通量技术，广泛筛选旨在确定疾病特异性自身抗体和细胞因子作为血清AILD生物标志物一直很困难。最近，通过对血清细胞因子（通过多重ELISA）和自身抗体（通过人蛋白芯片技术）的高通量分析，我们有初步的数据表明，在AIH、PBC和PSC中存在高度区分的血清细胞因子和自身抗体谱。具体目标：我们建议将最先进的高通量多重ELISA和蛋白质芯片技术与先进的生物信息学分析相结合，以鉴定血清细胞因子和自身抗体的独特特征，作为新的无创生物标志物，用于1)更好地诊断AIH， PBC和PSC，以及2)区分两种PSC亚型：仅PSC与与IBD重叠的PSC。意义：该项目的成功开发出新的、可靠的、无创的生物标志物，用于准确、早期/及时的诊断/预后，从而实现更及时有效的治疗干预，预防或延缓不可逆转的晚期/终末期疾病，如肝衰竭。此外，在AILD中识别疾病特异性细胞因子和自身抗体，不仅可以为疾病发病机制提供新的见解，而且还可能为未来开发新的AILD治疗方法提供新的分子靶点。

DESCRIPTION (provided by applicant): Autoimmune liver diseases (AILDs), including autoimmune hepatitis (AIH), primary biliary cirrhosis (PBC), and primary sclerosing cholangitis (PSC), are chronic and incurable immune disorders of the liver. AILDs result in marked suffering and serious consequences of AILDs lead to liver failure and hepatobiliary malignancy. Clinical problems and challenges: Diagnosis of specific AILD subtypes has been clinically challenging, due to significant clinical heterogeneity and the "overlap syndrome" where AIH coexists with PBC/PSC, and AILDs overlap with inflammatory bowel disease (IBD). Another major challenge is the lack of reliable biomarkers for evaluating disease progression and treatment response, particularly in PSC. Disease diagnosis/prognosis relies heavily on clinical presentations as well as invasive and resource-consuming biopsy-based histopathology. Thus, the long-term objective of this study is to identify and develop reliable, less invasive, and less expensive serum biomarkers to assist physicians to make accurate diagnosis/prognosis and treatment decisions, leading to effective management of AILDs and improved patients' quality of life. Rationale and hypothesis: Blood-based biomarker testing is generally the simplest, least invasive, and most widely used for disease diagnosis/prognosis. Most of the current AILD biomarkers are autoantibodies, such as ANA/SMA for type-1 AIH; AMA for PBC (no specific PSC marker), suggesting that serum autoantibodies are important sources for AILD biomarkers. Cytokines/chemokines, known to play essential roles in the pathogenesis of AILDs, are another potential source of AILD biomarkers. However, extensive screening aimed to identify disease-specific autoantibodies and cytokines as serum AILD biomarkers has been difficult due to the lack of high throughput technologies. Recently, through high-throughput profiling of serum cytokines (by multiplex ELISA) and autoantibodies (by human protein chip technology), we have preliminary data demonstrating that highly discriminate profiles of serum cytokines and autoantibodies are present and identifiable in AIH vs PBC vs PSC. Specific aims: We propose to combine the state-of-art high-throughput multiplex ELISA and protein chip technologies with advanced bioinformatic analysis, to identify unique profiles of serum cytokines and autoantibodies as novel non-invasive biomarkers for 1) better diagnosis of AIH, PBC and PSC, and 2) differentiating two PSC subtypes: PSC only vs PSC that overlaps with IBD. Significance: The success of this project could lead to development of new, reliable and non-invasive biomarkers for accurate and early/timely diagnosis/prognosis, and thus enabling more timely and effective therapeutic intervention, and prevent or delay the irreversible late/end-stage of the diseases such as liver failure. Moreover, identifying disease-specific cytokines and autoantibodies in AILDs, may not only provide new mechanistic insights into the disease pathogenesis, but also potentially lead to the identification of novel molecular targets for future development of new AILD therapeutics.