PATHOGENESIS OF CELIAC DISEASE

乳糜泻的特点是小肠粘膜损伤和 大多数营养物质的吸收不良。疾病是由饮食引起的 小麦醇溶蛋白和类似醇溶蛋白在其他食物中的摄取 谷物。疾病易感性与特定的人类白细胞抗原类别有关 由DQA1*0501编码的II分子(即DQw2杂二聚体) DQB1*0201等位基因。T细胞在活化过程中起重要作用。 和疾病的永久存在。在表达水平上的差异 疾病相关DQ分子与其他人类白细胞抗原II类D的关系 区域分子，或其组织特异性模式的差异 个体发育过程中的表达可能是决定 疾病易感性。我们已经在5‘中定义了多态 乳糜泻相关基因DQA1*0501的调控区 相对于其他DQA1等位基因。使用嵌合报告基因构建 和DQA1*0501转基因小鼠，这些研究的第一个目的是测试 这些多态决定表达水平的假设 DQA1*0501相对于其他DQA1等位基因或其组织特异性 个体发育过程中的表达模式。天冬氨酸的特异性多肽(S) 激活疾病的醇溶蛋白还没有被准确地定义。 因此，这些研究的第二个目标是识别内生的 作为人HLADQw2配体的醇溶蛋白加工肽 与乳糜泻相关的异二聚体。这些实验将 分离含有内源性加工醇溶蛋白的DQw2分子 只表达DQw2分子的转基因细胞系， 合作，通过以下方式确定这些多肽的氨基酸序列 高效液相色谱和质谱学分析。这些研究的第三个目的是 乳糜泻患者特异性T细胞亚群的特征 在这种疾病的发病机制中起着重要作用。这些研究 将使用分子方法的组合a)来定义 T细胞受体使用的α/β和伽马/增量V基因 在缓解期和缓解期患者的乳糜泻病变中 活动性疾病患者，并定义曲目和克隆性 B)定义识别这些受体的T细胞受体 目标2中定义的DQw2-醇溶蛋白多肽复合体；以及c)表征 T细胞受体在早期疾病发病机制中的重要作用 体内用醇溶蛋白激发激活疾病后的时间 多肽。从这些研究中获得的新信息将有助于确定 特定的人类白细胞抗原基因、醇溶蛋白多肽和 T细胞参与了乳糜泻的发病机制，并指向 预防和治疗这种疾病的新战略。

Celiac disease is characterized by small intestinal mucosal injury and the malabsorption of most nutrients. Disease is activated by the dietary ingestion of wheat gliadin and similar alcohol soluble proteins in other grains. Disease susceptibility is associated with a specific HLA class II molecule (i.e., a DQw2 heterodimer) that is encoded by the DQA1*0501 and DQB1*0201 alleles. T cells play an important role in the activation nd perpetuation of disease. Differences in the level of expression of the disease associated DQ molecule relative to other HLA class II D region molecules, or differences in its pattern of tissue specific expression during ontogeny may be a critical factor in determining disease susceptibility. We have defined polymorphisms in the 5' regulatory region of the celiac disease associated DQA1*0501 allele relative to other DQA1 alleles. Using chimeric reporter gene constructs and DQA1*0501 transgenic mice, the first Aim of these studies will test the hypothesis that these polymorphisms determine the level of expression of DQA1*0501 relative to other DQA1 alleles or its tissue specific pattern of expression during ontogeny. The specific peptide(s) of gliadin that activate disease have not been precisely defined. Therefore, a second Aim of these studies is to identify the endogenously processed peptides of gliadin that are ligands for the human HLA DQw2 heterodimer associated with celiac disease. These experiments will isolate DQw2 molecules that contain endogenously processed gliadin from transfected cell lines that express only the DQw2 molecule and, in collaboration, determine the amino acid sequence of those peptides by HPLC and mass spectroscopy. The third Aim of these studies is to characterize the specific T cell populations in celiac disease patients that are important in the pathogenesis of this disease. These studies will use a combination of molecular approaches a) to define the alpha/beta and gamma/delta V genes used by T cell receptors that are present in the celiac disease lesion of patients in remission and patients with active disease, and to define the repertoire and clonality of these receptors; b) to define the T cell receptors that recognize the DQw2-gliadin peptide complex defined in Aim 2; and c) to characterize the T cell receptors that are important in disease pathogenesis in the early period after the activation of disease by in vivo challenge with gliadin peptides. New information derived from these studies will help to define the specific mechanisms by which specific HLA genes, gliadin peptides and T cells contribute to the pathogenesis of celiac disease, and point to new strategies for the prevention and treatment of this disease.