Timing of Gluten Intake In Infant Nutrition and Risk of Celiac Disease Autoimmuni

描述（由申请人提供）：乳糜泻（CD）是一种自身免疫性肠病，由摄入含谷蛋白的谷物（即;小麦、大麦和黑麦）。鉴于麦醇溶蛋白在引起炎症和自身免疫中的无可争议的作用，CD代表了自身免疫性疾病的独特模型，与大多数其他自身免疫性疾病相比，其触发环境因素（麦醇溶蛋白）、与HLA基因（DQ 2或DQ 8）的密切遗传关联以及高度特异性的体液自身免疫应答（组织转氨酶的自身抗体）是已知的。然而，尽管在理解CD发病机制的适应性免疫学方面取得了重大进展，肠粘膜暴露于麦醇溶蛋白后导致耐受性丧失和自身免疫过程发展的早期步骤仍在很大程度上未知。文献中越来越多的证据似乎表明先天免疫和适应性免疫之间的功能失调的串扰是疾病的自身免疫过程中的关键致病因素。最近的回顾性研究还表明，这种功能失调的串扰受到遗传易感CD受试者饮食中麸质引入时间的影响。因此，我们建议调查这方面的CD发病机制的基础和应用研究的混合，这将产生根本的见解面筋引入的早期步骤中所涉及的疾病的发病时间的作用。我们的总体假设是，将含谷蛋白的谷物引入具有CD遗传风险的婴儿的饮食中的时间可能会影响对蛋白质的耐受性的丧失以及随后的适应性免疫系统的激活，从而引起该疾病典型的肠道和肠外炎症。我们将充分利用一个非常有利的环境（包括马里兰州大学的粘液生物学研究中心和腹腔研究中心），主题与本提案相关。我们的长期目标是利用CD作为自身免疫性疾病的独特特征，以深入了解麸质暴露的时间在决定肠对蛋白质和可能导致CD和其他与CD相关的自身免疫性疾病的其他非自身抗原的耐受性丧失中的作用。公共卫生相关性文献中越来越多的证据似乎表明先天免疫和适应性免疫之间的功能失调性串扰是乳糜泻（CD）自身免疫过程中的关键致病因素。几项回顾性研究表明，在有CD风险的婴儿饮食中引入麸质的时间可能会影响疾病的发病率。然而，支持这一假设的数据是间接的，受其回顾性设计的限制，并且经常受到其他解释的批评，这些解释表明，麸质暴露的延迟只是推迟了症状的发作，而不是预防疾病。为了以更严格的方式解决这个问题，我们提出了一项前瞻性、随机、双盲的饮食干预研究，以确定麸质引入年龄与高危婴儿CD自身免疫性发展之间的关系。通过调查婴儿营养的作用（早期与晚期暴露于膳食麸质），该项目将有助于澄清可能导致CD发展的早期病理生理变化。因此，在一般儿科人群中实施CD一级预防策略可以显着降低与诊断和治疗这种终身疾病相关的成本。

DESCRIPTION (provided by applicant): Celiac disease (CD) is an autoimmune enteropathy triggered by the ingestion of gluten containing grains (i.e.; wheat, barley, and rye) in genetically susceptible individuals. Given the undisputable role of gliadin in causing inflammation and autoimmunity, CD represents a unique model of autoimmune disorder for which, in contrast to most other autoimmune diseases, the triggering environmental factor (gliadin), a close genetic association with HLA genes (DQ2 or DQ8), and a highly specific humoral autoimmune response (auto-antibodies to tissue transglutaminase) are known. However, despite the significant progress made in understanding the adaptive immunological aspects of CD pathogenesis, the early steps following intestinal mucosal exposure to gliadin leading to the loss of tolerance and the development of the autoimmune process are still largely unknown. Increasing evidence in literature seem to suggest a dysfunctional cross talk between innate and adaptive immunity as the key pathogenic element in the autoimmune process of the disease. Recent retrospective studies also suggest that this dysfunctional cross talk is influenced by the timing of gluten introduction in the diet of subjects genetically susceptible to CD. Therefore, we propose to investigate this aspect of CD pathogenesis in a blend of basic and applied studies, which will yield fundamental insights into the role of timing of gluten introduction in early steps involved in the onset of the disease. Our overall hypothesis is that the timing of introduction of gluten-containing cereals into the diet of infants genetically at risk for CD may influence the loss of tolerance to the protein and subsequent activation of the adaptive immune system causing the intestinal and extra-intestinal inflammation typical of the disease. We will take full advantage of a very conducive environment (that includes the Mucosal Biology Research Center and the Center for Celiac Research at the University of Maryland) thematically relevant to this proposal. Our long-term objective is to capitalize on the unique features of CD as an autoimmune disorder to gain insights on the role of the timing of gluten exposure in dictating loss of intestinal tolerance to the protein and possibly to other non-self antigens leading to CD and other autoimmune disorders associated with CD. PUBLIC HEALTH RELEVANCE Increasing evidence in literature seems to suggest a dysfunctional cross talk between innate and adaptive immunity as the key pathogenic element in the autoimmune process of celiac disease (CD). Several retrospective studies have suggested that the time of gluten introduction in the diet of infants at risk for CD may affect the incidence of the disease. However, the data supporting this hypothesis are circumstantial, limited by their retrospective design, and often criticized by alternative interpretations suggesting that the delay in gluten exposure merely postpones the onset of symptoms rather than preventing the disease. In order to address this issue in a more rigorous manner, with this application we propose to perform a prospective, randomised, double-blind dietary intervention study to establish the relationship between age of gluten introduction and development of CD autoimmunity in at-risk infants. By investigating the role of infant nutrition (early vs late exposure to dietary gluten) this project will contribute to clarify the early pathophysiological changes that may lead to CD development. The consequent implementation of strategies of primary prevention of CD in the general pediatric population could significantly reduce the costs associated with the diagnosis and treatment of this life-long disorder.