Developing Novel Serological Biomarkers for Autoimmune Liver Diseases

描述(申请人提供)：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症(PBC)和原发性硬化性胆管炎(PSC)，是肝脏的慢性和不可治愈的免疫疾病。急性酒精性肝病会导致明显的痛苦，严重的后果会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“重叠综合征”，AIH与PBC/PSC共存，AILD与炎症性肠病(IBD)重叠，AILD亚型的诊断在临床上具有挑战性。另一个主要挑战是缺乏可靠的生物标记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袭性和耗费资源的活检组织病理学。因此，这项研究的长期目标是识别和开发可靠、侵入性更小、价格更低的血清生物标志物，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。理论基础和假设：基于血液的生物标记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。目前AILD生物标志物大多为自身抗体，如ANA/SMA用于1型AIH，AMA用于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。细胞因子/趋化因子在AILD的发病机制中起重要作用，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，旨在将疾病特异性自身抗体和细胞因子识别为血清AILD生物标志物的广泛筛选一直是困难的。最近，通过高通量分析血清细胞因子(通过多重ELISA)和自身抗体(通过人蛋白芯片技术)，我们有初步数据表明，AIH、PBC和PSC之间存在高度区分的血清细胞因子和自身抗体。具体目的：我们建议将最先进的高通量多重酶联免疫吸附试验和蛋白质芯片技术与先进的生物信息学分析相结合，以确定独特的血清细胞因子和自身抗体作为新的非侵入性生物标志物，用于1)更好地诊断AIH、PBC和PSC，以及2)区分两种PSC亚型：仅PSC和PSC与IBD重叠。意义：该项目的成功可能导致开发新的、可靠的和非侵入性的生物标志物，用于准确和早期/及时的诊断/预后，从而使更及时和有效的治疗干预成为可能，并防止或推迟诸如肝功能衰竭等疾病的不可逆转的晚期/末期。此外，识别AILD中的疾病特异性细胞因子和自身抗体，不仅可能为AILD的发病机制提供新的机制见解，还可能为未来新的AILD治疗方法的开发提供新的分子靶点。

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.