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.

项目总结/摘要 特应性皮炎（AD）是一种高度过敏性的慢性发作性炎症性皮肤病， 3至6个月大，但也可能出现在儿童后期或成年期。在美国，AD 影响了所有种族和民族的大约10-20%的儿童。AD的患病率呈上升趋势 这是一个全球性的问题，也是一个重大的公共卫生负担。大多数AD儿童也会发生哮喘， 季节性过敏根据最近的全球疾病负担研究，AD是前50名最严重的疾病之一。 它是世界范围内的流行病，在所有非恶性皮肤病中残疾排名第二 疾病许多基因与AD的发病有关。这些基因大多与 皮肤屏障变化（例如FLG）或免疫失调。 已知抗原呈递细胞（APC）参与皮肤免疫应答的启动。 APC将抗原呈递给免疫系统由人白细胞抗原（HLA）分子引导， 其在位于染色体6上的主要组织相容性复合体（MHC）内编码。六家大型 已经发表了AD儿童的群体遗传学研究，其中三项研究表明， 6p21.3细胞带（即MHC）区域与AD之间的关联。在初步研究中，我们有 首次显示，HLA II DRB 1等位基因的特异性变异导致了 位置9（囊袋4）、位置26（囊袋4）和位置78（囊袋4），这些位置与 AD的患病率与AD的持续性显著相关。重要的是，与许多其他 HLA等位基因与疾病之间的关联（例如，糖尿病），已知AD的发病机制是 与皮肤炎症相关，已知HLA II在APC上表达， 炎症级联反应 我们计划使用新技术将重点放在基因组的HLA区域上，以更好地了解 AD的遗传学以及皮肤屏障功能障碍和免疫失调之间的相互作用。这项建议 有两个目标第一个目标是确定与AD发病和持续相关的HLA变异。 第二个目标是证明HLA变异与免疫失调有关， 与AD