Significance of B cells and humoral immunity in the pathogenesis of biliary atres

B细胞和体液免疫在胆道闭锁发病机制中的意义

基本信息

批准号：
8729236
负责人：
CARA LYNN MACK
金额：
$ 34.33万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-06-01 至 2018-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8729236
关键词：
Adoptive Transfer Antibodies Antigen Presentation Antigen Targeting Autoantibodies Autoantigens Autoimmune Diseases Autoimmune Process Autoimmune Responses Autoimmunity B-Cell Development B-Lymphocytes Bile Duct Epithelium Bile fluid Biliary Biliary Atresia Biliary cirrhosis Biological Markers Caring Cell Survival Cell physiology Child Cholestasis Cirrhosis Data Development Disease Disease Outcome Disease Progression Effectiveness Etiology Goals Human Humoral Immunities Immune Immunoglobulin G Immunoglobulin M Immunoglobulins Immunosuppressive Agents Inflammation Inflammatory Injury Intrahepatic bile duct Investigation Knockout Mice Knowledge Laboratories Lead Liver Macaca mulatta Measures Mediating Modeling Monitor Morbidity - disease rate Mus Obstruction Organ Outcome Pathogenesis Patients Physicians Play Production Prognostic Marker Proteins Research Role Rotavirus Sclerosis Serum Severity of illness T-Lymphocyte Testing Transgenic Mice Translating Virus Virus Diseases autoreactive T cell bile duct defined contribution improved infancy inhibitor/antagonist insight liver transplantation mortality mouse model neonate novel public health relevance response theories tool

项目摘要

DESCRIPTION (provided by applicant): Biliary atresia (BA) is a progressive, inflammatory, sclerosing cholangiopathy that presents in infancy and leads to bile duct obstruction, biliary cirrhosis and the need for liver transplantation in the majority of patients. The etiology of BA is not known; a proposed theory is that the bile duct injury is initiated by a viral infection, followd by a progressive, autoimmune-mediated response targeting bile duct epithelia. Our laboratory and others have established the contribution of T cell-mediated inflammation and autoimmunity to bile duct injury in the rotavirus-induced mouse model of BA and in limited human studies. Recent data from our laboratory reveals that B cell-deficient mice are protected from BA, suggesting that B cells are essential to the development of bile duct injury. Research in murine models and humans have demonstrated the significant contribution of B cells to the onset and progression of many different autoimmune diseases, despite the fact that the organ-specific injury in these diseases was traditionally thought to be solely due to T cell-mediated inflammation. The specific hypotheses to be tested in this proposal are two-fold: 1. B cells play a critical role in the development and progression of bile duct injury and obstruction in murine BA; and 2. BA patients have circulating serum autoantibodies that may provide clues to disease pathogenesis and serve as prognostic biomarkers of disease severity. Specific Aim 1: Establish the contribution of B cells to development of bile duct injury in murine BA through use of B cell knockout and transgenic mice. Investigations of knockout and transgenic mice will establish the B cell mechanism involved in bile duct injury, specifically B cell antigen presentation versus immunoglobulin production. Specific Aim 2: Determine the contribution of B cells to progression of bile duct injury in murine BA through administration of B cell-depleting agents. This aim has direct translational implications to potential new therapies for human BA. Specific Aim 3: Define serum autoantibodies in BA patients and determine correlation with disease severity. Serum autoantibodies will be identified from a protein autoantigen microarray. The utility of autoantibodies in BA as serum biomarkers of disease severity will also be assessed. Significance: These investigations will add a unique perspective and increase our understanding of how B cells function in the setting of virus-induced autoimmunity. Discovery of autoantibodies in BA would provide clues to autoimmune mechanisms of pathogenesis and function as useful biomarkers to gauge severity of disease or response to novel therapies. The potential benefit of B cell depleting agents in alleviating progression of disease could change the paradigm of how physicians care for BA patients.

描述（由申请人提供）：胆道闭锁（BA）是一种进行性，炎症性，硬化性的胆管造成病，可在婴儿期出现并导致胆管阻塞，胆汁性肝硬化以及大多数患者的肝脏移植。 BA的病因是不知道；提出的理论是，胆管损伤是由病毒感染引发的，其跟随靶向胆管上皮的进行性自身免疫介导的反应。我们的实验室和其他实验室已经确定了在轮状病毒诱导的BA小鼠模型和有限的人类研究中，T细胞介导的炎症和自身免疫性对胆管损伤的贡献。我们实验室的最新数据表明，B细胞缺陷的小鼠免受BA的保护，这表明B细胞对于胆管损伤的发展至关重要。鼠模型和人类的研究表明，尽管传统上认为这些疾病的器官特异性损伤仅是由于T细胞介导的炎症，但B细胞对许多不同自身免疫性疾病的发作和进展的显着贡献。在此提案中要测试的特定假设是两个倍：1。B细胞播放A 在鼠类BA中，在胆管损伤和阻塞的发展和进展中的关键作用；和2。BA患者具有循环血清自身抗体，可以为疾病发病机理提供线索，并作为疾病严重程度的预后生物标志物。具体目标1：通过使用B细胞敲除和转基因小鼠，建立B细胞对鼠BA中胆管损伤发展的贡献。对敲除和转基因小鼠的研究将建立涉及胆管损伤的B细胞机制，特别是B细胞抗原表现与免疫球蛋白的产生。具体目标2：确定B细胞通过施用B细胞耗尽剂对鼠BA中胆管损伤进展的贡献。该目标对人类BA的潜在新疗法具有直接的翻译意义。特定目标3：定义BA患者的血清自身抗体，并确定与疾病严重程度的相关性。血清自身抗体将从蛋白质自动抗原微阵列中鉴定出来。还将评估自身抗体在BA中作为疾病严重程度的血清生物标志物的效用。意义：这些研究将增加一个独特的观点，并增加我们对B细胞在病毒诱导的自身免疫性设置中的作用的理解。在BA中发现自身抗体将为发病机理的自身免疫机制提供线索，并起到衡量疾病严重程度或对新疗法反应的有用生物标志物。 B细胞耗尽剂在减轻疾病进展方面的潜在益处可能会改变医生如何照顾BA患者的范式。