Developing Novel Serological Biomarkers for Autoimmune Liver Diseases

描述（由申请人提供）：自身免疫性肝病（AILD），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），是肝脏的慢性和不可治愈的免疫疾病。AILD导致显著的痛苦，并且AILD的严重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AILD与炎症性肠病（IBD）重叠，特定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志物来评估疾病进展和治疗反应，特别是在PSC中。疾病诊断/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鉴定和开发可靠的、侵入性较小的、且较便宜的血清生物标志物，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AILD并改善患者的生活质量。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，并且最广泛用于疾病诊断/预后。目前AILD的生物标志物多为自身抗体，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/趋化因子是AILD生物标志物的另一个潜在来源，已知在AILD的发病机制中起重要作用。然而，由于缺乏高通量技术，旨在鉴定疾病特异性自身抗体和细胞因子作为血清AILD生物标志物的广泛筛选一直很困难。最近，通过血清细胞因子（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与PBC与PSC中存在和可识别的血清细胞因子和自身抗体的高度区分谱。具体目标：我们建议将最先进的高通量多重ELISA和蛋白芯片技术与先进的生物信息学分析结合联合收割机，以鉴定血清细胞因子和自身抗体的独特谱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，和2）区分两种PSC亚型：仅PSC与重叠IBD的PSC。重要性：该项目的成功可能会导致开发新的、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，从而能够更及时和有效地进行治疗干预，并预防或延迟不可逆的晚期/终末期疾病，如肝衰竭。此外，识别疾病特异性细胞因子和自身抗体在AILD中，不仅可以提供新的机制的见解疾病的发病机制，但也可能导致识别新的分子靶点，为未来开发新的AILD治疗。 公共卫生相关性：自身免疫性肝病（Autoimmune liver diseases，AILD）是肝脏中的慢性和不可治愈的疾病，导致巨大的痛苦，并且AILD的严重后果包括肝功能衰竭。到目前为止，还没有足够的和可靠的独立的AILD生物标志物用于诊断/预后，这目前是困难的，并且严重依赖于临床表现以及侵入性和资源消耗的程序。在这项研究中，我们决心通过使用最先进的高通量技术来识别和开发基于血液的生物标志物来解决这个问题，这些生物标志物可以准确诊断患者患有哪种特定亚型的AILD，并可能预测疾病的进展（更好或更糟）以及疾病的管理情况。

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. PUBLIC HEALTH RELEVANCE: Autoimmune liver diseases (AILDs), the chronic and incurable disorders in the liver, result in enormous suffering and a serious consequence of AILDs include liver failure. So far there are no sufficient and reliable stand-alone AILD biomarkers for diagnosis/prognosis, which currently are difficult and rely heavily on clinical presentations as well as invasive and resource-consuming procedures. In this study, we are determined to tackle this problem by using state-of-art high throughput technologies to identify and develop blood-based biomarkers that can accurately diagnose which specific subtype of AILDs a patient has, and potentially predict what course the disease is going (better or worse) and how well the disease is managed.