MARKER B LYMPHOCYTES IN INFLAMMATORY BOWEL DISEASE PATHOGENESIS

标志性抗体已在炎症性肠病中被识别， 最值得注意的是Panca与溃疡病的免疫遗传关系 结肠炎。由于抗体反映B细胞对活性抗原的反应 挑战，驱动这些标记B细胞反应的抗原很可能 包括那些对潜在的致病粘膜负责的人 发炎。因此，无论抗体本身是不是 致病性，鉴定这些标志性抗体是一种潜在的 在这些细胞中寻找候选靶抗原的强大策略 疾病。 该续期申请侧重于上一批款期间的进展情况， 提示克罗恩病和空肠弯曲菌小肠结肠炎 与其定义的独特和高滴度的抗体反应有关 克隆性限制(VH3-15基因)，以及对一组离散的 人红细胞和空肠弯曲菌表达的抗原。 这一发现表明，一种常见的免疫致病途径，表现为 通过这种B细胞群的抗原性激活，由这些 疾病。至少，抗原(S)及其同源反应可能 提供疾病的一个离散的和分析有用的组成部分- 相关的免疫反应。此外，鉴于幽门螺杆菌在 消化性溃疡疾病，一个简单但具有挑衅性的假设是，这 共同途径是对弯曲杆菌的免疫反应或与之相关 细菌。 更新申请的目的是隔离和单克隆化 利用噬菌体展示技术表达这些标志性抗体(目标1)。 然后将使用常规和重组抗体来识别 同源弯曲菌与红细胞抗原的生化和免疫组化研究 重组方法(目标2和3)。这些目标将在#年完成。 与Targan博士合作，并提供结构信息和 需要分析工具来评估关于以下三种预测 这些抗原在疾病相关的免疫反应中。第一，相关性 应在受影响的粘膜中存在抗原(在AIMS 2和3中进行了测试)。 其次，在这些细胞中应该存在抗原特异性T细胞反应 粘膜部位。在Kronenberg博士和Targan的合作下，抗原- 因此，反应性B和T细胞群体将被表征为 它们的局部丰度、分化状态和效应器的模式 活动(目标4)。第三，与Dr。 罗特将测试这些反应是否与免疫遗传特征有关 对疾病的易感性。

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.