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

• 批准号: 9068664
• 负责人: CARA LYNN MACK
• 金额: $ 34.02万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 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/9068664
• 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; Health; 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; 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; novel therapeutics; response; targeted treatment; theories; tool

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、炎性、硬化性胆管病，在婴儿期出现，导致胆管梗阻、胆汁性肝硬化，大多数患者需要肝移植。BA的病因是 未知;提出的理论是胆管损伤是由病毒感染引发的，随后是针对胆管上皮的进行性自身免疫介导的应答。我们的实验室和其他实验室已经在轮状病毒诱导的BA小鼠模型和有限的人体研究中确定了T细胞介导的炎症和自身免疫对胆管损伤的贡献。我们实验室的最新数据显示，B细胞缺陷小鼠对BA有保护作用，表明B细胞对胆管损伤的发展至关重要。在小鼠模型和人类中的研究已经证明了B细胞对许多不同自身免疫性疾病的发作和进展的显著贡献，尽管这些疾病中的器官特异性损伤传统上被认为仅仅是由于T细胞介导的炎症。本提案中要检验的具体假设有两个方面：1。B细胞发挥着 在小鼠BA中胆管损伤和梗阻的发展和进展中的关键作用;和2. BA患者的循环血清自身抗体可提供疾病发病机制的线索，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，确定B细胞对小鼠BA中胆管损伤发展的贡献。对基因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细胞抗原呈递与免疫球蛋白产生。具体目标二：通过给予B细胞耗竭剂，确定B细胞对小鼠BA胆管损伤进展的贡献。这一目标对人类BA的潜在新疗法具有直接的转化意义。具体目标3：确定BA患者的血清自身抗体，并确定与疾病严重程度的相关性。将从蛋白质自身抗原微阵列中鉴定血清自身抗体。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。重要性：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中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衡量疾病的严重程度或对新疗法的反应。B细胞耗竭剂在缓解疾病进展方面的潜在益处可能会改变医生如何护理BA患者的模式。