MARKER B LYMPHOCYTES IN INFLAMMATORY BOWEL DISEASE PATHOGENESIS

标记抗体已经在炎症性肠病中被认识到， 最显著的是pANCA与溃疡性结肠炎的免疫遗传学关系， 结肠炎 由于抗体反映了B细胞对活性抗原的反应， 激发后，驱动这些标记B细胞应答的抗原可能是 包括那些负责潜在的致病性粘膜 炎症 因此，无论抗体本身是否 病原性，这些标记抗体的鉴定是一个潜在的 这是一种寻找候选靶抗原的强有力的策略， 疾病 这种更新申请的重点是在过去的赠款期间的进展， 表明克罗恩病和空肠弯曲杆菌小肠结肠炎是 与独特的高滴度抗体反应相关， 克隆限制性（VH 3 -15基因），和特异性的离散集， 在人红细胞和空肠弯曲杆菌上表达的抗原。 这一发现表明，一个共同的免疫致病途径，表现为 通过该B细胞群体的抗原活化， 疾病 至少，抗原及其同源应答可 提供了一个离散的和分析有用的组成部分的疾病- 相关的免疫反应。 此外，鉴于H.幽门 消化性溃疡疾病，一个简单但挑衅性的假设是， 共享途径是对弯曲杆菌或相关的免疫应答 细菌 更新申请的目的是分离和单克隆 通过噬菌体展示技术表达这些标记抗体（Aim 1）。 然后将使用常规和重组抗体来鉴定所述抗体。 同源弯曲杆菌和红细胞抗原通过生化和 重组方法（目的2和3）。 这些目标将在 与Targan博士合作，并提供结构信息和 分析工具需要评估三个预测的作用， 这些抗原在疾病相关的免疫反应。 第一，相关性 抗原应存在于受影响的粘膜中（在目的2和3中测试）。 第二，抗原特异性T细胞应答应该存在于这些细胞中。 粘膜部位。 与Kronenberg博士和Targan合作，抗原- 因此，反应性B和T细胞群将被表征为 它们的局部丰度、分化状态和效应子模式 活动（目标4）。 第三，与Dr. Rotter将测试这些反应是否与免疫遗传特征有关 对疾病易感性的影响

Marker antibodies have been recognized in inflammatory bowel diseases, most notably in the immunogenetic relationship of pANCA to ulcerative colitis. Since antibodies reflect the B cell response to active antigenic challenge, the antigens driving these marker B cell responses are likely to include ones responsible for the underlying pathogenic mucosal inflammation. Thus, whether or not the antibodies are themselves pathogenic, identification of these marker antibodies is a potentially powerful strategy in the search for candidate target antigens in these diseases. This renewal application focuses on progress during the past grant period, indicating that Crohn's disease and Campylobacter jejuni enterocolitis are associated with a distinct and high-titer antibody response defined by its clonal restriction (VH3-15 gene), and specificity for a discrete set of antigens expressed on the human erythrocyte and Campylobacter jejuni. This finding suggests that a common immunopathogenic pathway, manifested by antigenic activation of this B cell population, is shared by these diseases. At the least, the antigen(s) and its cognate response may provide a discrete and analytically useful component of the disease- associated immune response. Moreover, in view of the role of H. pylori in peptic ulcer disease, a simple but provocative hypothesis is that this shared pathway is the immune response to Campylobacter or related bacteria. The aims of the renewal application are to isolate and monoclonally express these marker antibodies by phage display technology (Aim 1). Conventional and recombinant antibodies will then be used to identify the cognate Campylobacter and erythrocyte antigens by biochemical and recombinant approaches (Aims 2 and 3). These aims will be completed in collaboration with Dr. Targan, and provide the structural information and analytic tools needed to evaluate three predictions regarding the role of these antigens in disease-related immune response. First, relevant antigens should be present in affected mucosa (tested in Aims 2 and 3). Second, an antigen-specific T cell response should be present in these mucosal sites. In collaboration with Dr. Kronenberg and Targan, antigen- reactive B and T cell populations will be therefore characterized for their local abundance, differentiative state, and pattern of effector activity (Aim 4). Third, familial studies in collaboration with Dr. Rotter will test whether these responses are immunogenetic traits related to disease susceptibility.