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

描述(申请人提供)：乳糜泻(CD)是一种自身免疫性肠病，由基因易感个体摄入含面筋的谷物(即小麦、大麦和黑麦)引发。鉴于醇溶蛋白在引起炎症和自身免疫中的无可争辩的作用，CD代表了一种独特的自身免疫性疾病模型，与大多数其他自身免疫性疾病不同，其触发环境因素(醇溶蛋白)、与人类白细胞抗原基因(DQ2或DQ8)的密切遗传关联以及高度特异性的体液自身免疫反应(组织转谷氨酰胺酶自身抗体)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，但肠粘膜接触醇溶蛋白导致耐受性丧失和自身免疫过程的发展的早期步骤仍然很不清楚。越来越多的文献证据似乎表明，先天性免疫和获得性免疫之间的功能失调是该病自身免疫过程中的关键致病因素。最近的回顾研究还表明，这种功能失调的串音受到饮食中面筋引入的时机的影响，这些人对CD有遗传易感性。因此，我们建议在基础研究和应用研究的结合中研究CD发病的这一方面，这将产生对面筋引入时机在疾病发生的早期步骤中的作用的基本见解。我们的总体假设是，将含面筋的谷物引入具有CD遗传风险的婴儿的饮食中的时机可能会影响对蛋白质的耐受性丧失，以及随后适应性免疫系统的激活，导致典型的肠道和肠外炎症。我们将充分利用与这项提案主题相关的非常有利的环境(包括马里兰大学的粘膜生物学研究中心和腹腔研究中心)。我们的长期目标是利用CD作为一种自身免疫性疾病的独特特征，以深入了解面筋暴露的时机在决定肠道对该蛋白质和可能导致CD的其他非自身抗原以及与CD相关的其他自身免疫性疾病的耐受性丧失中所起的作用。公共卫生相关性越来越多的文献证据似乎表明，先天性免疫和获得性免疫之间的功能失调是乳糜泻(CD)自身免疫过程中的关键致病因素。一些回溯性研究表明，在有CD风险的婴儿的饮食中引入面筋的时间可能会影响疾病的发生率。然而，支持这一假说的数据是间接的，受到回溯性设计的限制，而且经常受到另一种解释的批评，这些解释表明，面筋暴露的延迟只是推迟了症状的出现，而不是预防疾病。为了以更严格的方式解决这个问题，我们建议通过这项应用进行前瞻性、随机、双盲饮食干预研究，以建立面筋引入年龄和高危婴儿CD自身免疫发展之间的关系。通过研究婴儿营养的作用(早期和晚期饮食面筋暴露)，这个项目将有助于阐明可能导致CD发展的早期病理生理变化。随后在普通儿科人群中实施CD初级预防战略可大大减少与诊断和治疗这一终生疾病相关的费用。

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.