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

描述(申请人提供)：胆道闭锁(BA)是一种进行性、炎症性、硬化性胆管病，在大多数患者中表现为婴儿期，并导致胆管梗阻、胆汁性肝硬变和需要肝移植。BA的病因是 尚不清楚；一种提出的理论认为，胆管损伤是由病毒感染引发的，随后是针对胆管上皮细胞的渐进性、自身免疫介导的反应。我们的实验室和其他实验室已经在轮状病毒诱导的小鼠BA模型和有限的人类研究中确定了T细胞介导的炎症和自身免疫在胆管损伤中的作用。我们实验室的最新数据显示，B细胞缺陷小鼠对BA具有保护作用，这表明B细胞在胆管损伤的发生发展中是必不可少的。在小鼠模型和人类模型上的研究已经证明，B细胞在许多不同的自身免疫性疾病的发生和发展中做出了重要贡献，尽管这些疾病的器官特异性损伤传统上被认为完全是由于T细胞介导的炎症。在这项建议中要检验的具体假设有两个：1.B细胞发挥作用 在小鼠胆管损伤和梗阻的发生和发展中起重要作用；2.BA患者存在循环血清自身抗体，这些自身抗体可能为疾病发病机制提供线索，并作为疾病严重程度的预后生物标志物。具体目的1：利用B细胞基因敲除小鼠和转基因小鼠，探讨B细胞在小鼠胆管损伤中的作用。对基因敲除和转基因小鼠的研究将建立与胆管损伤有关的B细胞机制，特别是B细胞抗原提呈与免疫球蛋白产生的关系。具体目的2：通过给予B细胞清除剂，确定B细胞在小鼠胆管损伤进展中的作用。这一目标对人类BA的潜在新疗法具有直接的翻译意义。具体目标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身抗原微阵列中鉴定出来。还将评估BA中自身抗体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视角，并增加我们对B细胞如何在病毒诱导的自身免疫中发挥作用的理解。BA自身抗体的发现将为自身免疫发病机制提供线索，并作为有用的生物标志物来评估疾病的严重程度或对新疗法的反应。B细胞耗尽剂在减缓疾病进展方面的潜在好处可能会改变医生对BA患者的护理方式。

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.