Atopic Dermatitis and High Resolution HLA

特应性皮炎和高分辨率 HLA

• 批准号: 9550908
• 负责人: DIMITRI S MONOS
• 金额: $ 48.02万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-01 至 2022-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9550908
• 关键词: 6p21; Adult; Affect; Age-Months; Alleles; Allergic; Amino Acids; Antigen Presentation; Antigen-Presenting Cells; Antigenic Variation; Antigens; Asthma; Atopic Dermatitis; Cell Communication; Cells; Cellular Immunity; Child; Childhood; Chromosomes, Human, Pair 6; Chronic; Chronic Disease; Complex; Cutaneous; Data; Diabetes Mellitus; Disease; Environment; Ethnic group; Etiology; Event; Functional disorder; Genes; Genetic; Genetic Population Study; Genetic Variation; Genome; Goals; HLA Antigens; Humoral Immunities; Hypersensitivity; I-antigen; IgE; Immune; Immune response; Immune system; Immunologics; Immunosuppressive Agents; Individual; Infection; Inflammation; Inflammatory; Lupus; Major Histocompatibility Complex; Mental Depression; Mental disorders; Modeling; Non-Malignant; Other Genetics; Pathogenesis; Pathway interactions; Phenotype; Positioning Attribute; Predisposition; Prevalence; Process; Productivity; Pruritus; Public Health; Publishing; Quality of life; Race; Recurrence; Relapse; Reporting; Resolution; Risk; Schools; Skin; Sleep disturbances; T-Lymphocyte; TCR Activation; TSLP gene; Technology; Th2 Cells; Time; Variant; Work; allergic response; base; burden of illness; cost; cytokine; disability; early childhood; environmental allergen; immune activation; new technology; next generation sequencing; psychological distress; response; skin barrier; skin disorder; social

Project Summary/Abstract Atopic dermatitis (AD) is a highly pruritic chronic episodic inflammatory skin disease that often presents between 3 and 6 months of age but may also present during later childhood or in adulthood. In the US, AD affects roughly 10-20% of all children of all races and ethnic groups. The prevalence of AD is increasing worldwide and it is a major public health burden. The majority of children with AD will also develop asthma and seasonal allergies. From the recent Global Burden of Disease study, AD was among the top 50 most prevalent diseases worldwide and it had the second highest disability rank of all non -malignant skin diseases. Many genes have been associated with the onset of AD. These genes are mostly associated with skin barrier changes (e.g. FLG) or immune dysregulation. Antigen-presenting cells (APC) are known to be involved in the initiation of the skin immune response. APC presentation of antigen to the immune system is guided by human leukocyte antigen (HLA) molecules, which are encoded within the major histocompatibility complex (MHC) located on chromosome 6. Six large population genetic studies of children with AD have been published and three of these studies demonstrated an association between the 6p21.3 cytoband (i.e. the MHC) region and AD. In a preliminary study, we have shown, for the first time, that specific variation of the HLA II DRB1 allele results in amino acid variations at position 9 (pocket 4), position 26 (pocket 4), and position 78 (pocket 4) that were marginally associated with the prevalence of AD and markedly associated with the persistence of AD. Importantly, unlike many other associations between HLA alleles and diseases (e.g., diabetes), the pathogenesis of AD is known to be associated with cutaneous inflammation and HLA II is known to be expressed on APCs that have an effect on the inflammatory cascade. We plan to focus on the HLA region of the genome using new technology to better understand the genetics of AD and the interplay between skin barrier dysfunction and immune dysregulation. This proposal has two goals. The first goal is to define HLA variation associated with the onset and persistence of AD. The second goal is to demonstrate that HLA variation is associated with immune dysregulation in those with AD.

项目摘要/摘要 特应性皮炎（AD）是一种高度瘙痒的慢性发作性炎症性皮肤疾病，经常出现 在3至6个月大的时候，但在童年后期或成年期间也可能出现。在美国，广告 在所有种族和族裔的所有儿童中，大约有10-20％的影响。广告的普遍性正在增加 在全球范围内，这是一个主要的公共卫生负担。大多数AD儿童也会发育哮喘和 季节性过敏。从最近的全球疾病负担研究中，AD是最多50位 全球流行的疾病，在所有非举止的皮肤中，它具有第二高的残疾等级 疾病。许多基因与AD的发作有关。这些基因主要与 皮肤屏障变化（例如FLG）或免疫失调。 已知抗原呈递细胞（APC）参与皮肤免疫反应的启动。 APC抗原向免疫系统的呈现由人白细胞抗原（HLA）分子指导， 该编码在位于6号染色体上的主要组织相容性复合物（MHC）中。六个大 AD儿童的人群遗传研究已发表，其中三项研究表明 6p21.3细胞（即MHC）区域与AD之间的关联。在一项初步研究中，我们有 首次显示HLA II DRB1等位基因的特定变化导致氨基酸的变化 位置9（口袋4），位置26（口袋4）和位置78（口袋4）与与众不同 AD的普遍性，与AD的持久性明显相关。重要的是，与许多其他 HLA等位基因与疾病（例如糖尿病）之间的关联，已知AD的发病机理为 已知与皮肤炎症和HLA II相关的APC表达 炎症级联。 我们计划使用新技术专注于基因组的HLA区域，以更好地了解 AD的遗传学以及皮肤屏障功能障碍和免疫功能障碍之间的相互作用。这个建议 有两个目标。第一个目标是定义与AD的发作和持久性相关的HLA变异。 第二个目标是证明HLA变异与其中的免疫失调有关 与广告。