HLA B27 AND EXPERIMENTAL SPONDYLOARTHROPATHY

人类白细胞抗原-B27是一种人类I类MHC等位基因，它被发现与惊人的 脊柱关节病(SpA)患者患病率增加。 因为微生物也被认为参与了 到目前为止，这些疾病被认为是通过相互作用而产生的。 人们对环境代理人和遗传基因之间的关系知之甚少 易感宿主。阐明B27与B27之间联系的基础 因此，疾病将增强我们对 基因和环境因子都在慢性炎症的产生中起作用 疾病。本申请描述了一个项目，在该项目中，人类白细胞抗原- B27在疾病中的研究将在动物模型中进行，即大鼠转基因 对于发展为自发性疾病的人类白细胞抗原-B27，具有许多临床和 人体温泉的组织学特征。这些转基因动物的疾病 大鼠可以通过骨骼过继转移到正常的非转基因大鼠 骨髓移植。至少有两组细胞似乎是必需的 与疾病的发展有关：一种来源于 B27转基因骨髓和T细胞的来源。在特定的目标I中，在 将使用活体领养转移来表征危重的非 B27转基因骨髓来源的淋巴细胞群。这个 拟议的实验是基于这样一种假设：这是一个种群 抗原提呈细胞。在第二个具体目标中，将进行一系列研究 旨在确定介导疾病的T细胞，包括在 体内用单抗耗尽，T细胞亚群转移到 转基因裸鼠及其细胞因子产生特性的研究 以及与微生物抗原的反应性，这些微生物抗原与人类 水疗中心。在特定目标III中，易患疾病的B27大鼠在无菌条件下饲养 将对环境进行研究以检验微生物制剂的假设 对B27相关疾病的发展至关重要。以特定的目标 IV，突变的B27分子将在转基因大鼠中进行研究，以检查 特异性B27氨基酸在疾病发病机制中的作用总目标 该项目的核心是使用活体实验来定义关键细胞， 环境影响，以及转基因对 诱导大鼠B27相关疾病。这些研究的结果 将构成确定B27分子基础的合理基础- 人类中的相关疾病。

HLA-B27 is a human class I MHC allele that is found with strikingly increased prevalence in patients with the spondyloarthropathies (SpA). Because microbial agents have also been implicated in the pathogenesis of the SpA, these disorders are thought to arise through interactions, as yet poorly understood, between environmental agents and a genetically susceptible host. Elucidation of the basis for the association between B27 and disease would therefore enhance our understanding of the roles that both genes and environmental agents play in producing chronic inflammatory diseases. This application describes a project in which the role of HLA- B27 in disease will be studied in an animal model, namely, rats transgenic for HLA-B27 that develop a spontaneous disease sharing many clinical and histologic features with the human SpA. The disease of these transgenic rats can be adoptively transferred to normal, nontransgenic rats by bone marrow transplantation. At least two populations of cells appear necessary for the development of disease: a non-lymphocyte population derived from B27 transgenic bone marrow, and a source of T cells. In Specific Aim I, in vivo adoptive transfer will be used to characterize the critical non- lymphocyte population derived from B27 transgenic bone marrow. The proposed experiments are based on the hypothesis that this is a population of antigen-presenting cells. In Specific Aim II, a series of studies will be aimed at identifying the T cells mediating the disease, including in vivo depletion with monoclonal antibodies, transfer of T cell subsets to transgenic athymic nude rats, and characterization of cytokine production and reactivity with microbial antigens that have been implicated in human SpA. In Specific Aim III, disease-prone B27 rats raised in a germfree environment will be studied to test the hypothesis that microbial agents are critical to the development of B27-associated disease. In Specific Aim IV, mutant B27 molecules will be studied in transgenic rats to examine the role of specific B27 amino acids in disease pathogenesis. The overall goal of the project is to use in vivo experiments to define the critical cells, environmental influences, and transgenes necessary and sufficient for induction of B27-associated disease in rats. The results of these studies will form the rational basis for identifying the molecular basis for B27- associated disease in humans.