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

婴儿营养中麸质摄入的时机和乳糜泻自身免疫性疾病的风险

基本信息

批准号：
7612761
负责人：
Alessio Fasano
金额：
$ 18.75万
依托单位：
UNIVERSITY OF MARYLAND BALTIMORE
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-04-15 至 2011-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7612761
关键词：
Address Affect Age Age-Months Antibodies Autoantigens Autoimmune Diseases Autoimmune Process Autoimmune Responses Autoimmunity Barley Binding Biology Biometry CXCR3 gene Celiac Disease Cell physiology Cereals Child Childhood Consensus Coupled Data Development Diagnosis Diet Dietary Intervention Disease Double-Blind Method Enrollment Environment Environmental Risk Factor Epidemiology Epithelial Event Exposure to Feasibility Studies Feeding Patterns First Degree Relative Functional disorder Gastroenterology Genetic Gliadin Gluten Goals Human Genetics Immune Immune response Immune system Immunity Immunology In Vitro Incidence Indium Individual Infant Inflammation Inflammatory disease of the intestine Ingestion Intake Intervention Studies Intestines Lead Life Literature Maryland Modeling Molecular Molecular and Cellular Biology Natural Immunity Nutritional Onset of illness Outcome Study Pathogenesis Patients Peripheral Blood Mononuclear Cell Permeability Population Prevention Research Primary Prevention Proteins Randomized Recommendation Research Resources Retrospective Studies Risk Role Rye cereal Serum Symptoms Time Tissues Transglutaminases United States National Institutes of Health Universities Up-Regulation Wheat Work base chemokine receptor cost design evidence base genetic association human leukocyte antigen gene infant nutrition innovation insight medical schools prevent prospective public health relevance response symposium zonulin

项目摘要

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.

描述（由申请人提供）：乳糜泻（CD）是一种自身免疫性肠病，由遗传易感个体摄入含麸质谷物（即小麦、大麦和黑麦）引发。鉴于麦醇溶蛋白在引起炎症和自身免疫方面无可争议的作用，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相比，CD 的触发环境因素（麦醇溶蛋白）与 HLA 基因（DQ2 或 DQ8）有密切的遗传关联。）和高度特异性的体液自身免疫反应（组织转谷氨酰胺酶的自身抗体）是已知的。然而，尽管在了解 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然很大程度上未知。文献中越来越多的证据似乎表明先天性免疫和适应性免疫之间功能失调的相互影响是该疾病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上易患 CD 的受试者饮食中添加麸质的时间的影响。因此，我们建议结合基础研究和应用研究来研究 CD 发病机制的这一方面，这将为了解麸质引入时机在疾病发病早期步骤中的作用提供基本见解。我们的总体假设是，将含麸质谷物引入患有 CD 遗传风险的婴儿的饮食中的时机可能会影响对该蛋白质的耐受性丧失以及随后适应性免疫系统的激活，从而导致典型的肠道和肠外炎症。的疾病。我们将充分利用与该提案主题相关的非常有利的环境（包括马里兰大学粘膜生物学研究中心和乳糜泻研究中心）。我们的长期目标是利用克罗恩病作为一种自身免疫性疾病的独特特征，深入了解接触麸质的时间在决定肠道对蛋白质以及可能对其他非自身抗原的耐受性丧失中所起的作用，从而导致克罗恩病以及与 CD 相关的其他自身免疫性疾病。公共卫生相关性越来越多的文献证据似乎表明，先天性免疫和适应性免疫之间功能失调的相互影响是乳糜泻 (CD) 自身免疫过程中的关键致病因素。几项回顾性研究表明，在有克罗恩病风险的婴儿的饮食中添加麸质的时间可能会影响该疾病的发病率。然而，支持这一假设的数据是间接的，受到回顾性设计的限制，并且经常受到其他解释的批评，这些解释表明延迟接触麸质只会推迟症状的出现，而不是预防疾病。为了以更严格的方式解决这个问题，通过本申请，我们建议进行一项前瞻性、随机、双盲饮食干预研究，以确定高危婴儿摄入麸质的年龄与 CD 自身免疫发展之间的关系。通过研究婴儿营养的作用（早期与晚期接触膳食麸质），该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克罗恩病一级预防策略可以显着降低与这种终生疾病的诊断和治疗相关的成本。

项目成果

期刊论文数量（3）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Divergence of gut permeability and mucosal immune gene expression in two gluten-associated conditions: celiac disease and gluten sensitivity.

DOI：
10.1186/1741-7015-9-23
发表时间：
2011-03-09
期刊：
BMC medicine
影响因子：
9.3
作者：
Sapone A;Lammers KM;Casolaro V;Cammarota M;Giuliano MT;De Rosa M;Stefanile R;Mazzarella G;Tolone C;Russo MI;Esposito P;Ferraraccio F;Cartenì M;Riegler G;de Magistris L;Fasano A
通讯作者：
Fasano A