Atopic Dermatitis and High Resolution HLA

特应性皮炎和高分辨率 HLA

• 批准号: 9729537
• 负责人: DIMITRI S MONOS
• 金额: $ 54.5万
• 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/9729537
• 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; Chromosome 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; I-antigen; IgE; Immune; Immune response; Immune system; Immunologics; Immunosuppressive Agents; Individual; 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; diabetes pathogenesis; disability; early childhood; environmental allergen; immune activation; infection risk; new technology; next generation sequencing; psychological distress; response; seasonal allergies; 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病，常表现为 在3至6个月大，但也可能出现在儿童后期或成年。在美国，公元 影响所有种族和民族的所有儿童的大约10%-20%。阿尔茨海默病的患病率正在上升 在世界范围内，它是一个主要的公共卫生负担。大多数患有阿尔茨海默病的儿童也会患上哮喘和 季节性过敏症。根据最近的全球疾病负担研究，AD是排名前50位的 它是全世界流行的疾病，在所有非恶性皮肤中具有第二高的残疾等级 疾病。许多基因与阿尔茨海默病的发病有关。这些基因主要与 皮肤屏障改变(例如，FLG)或免疫失调。 抗原提呈细胞(APC)参与了皮肤免疫反应的启动。 APC将抗原呈递给免疫系统是由人类白细胞抗原(HLA)分子引导的， 它们编码在位于6号染色体上的主要组织相容性复合体(MHC)内。 阿尔茨海默病儿童的群体遗传学研究已经发表，其中三项研究证明 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 首次表明，人类白细胞抗原II DRB1等位基因的特定变异会导致氨基酸的变异 位置9(凹槽4)、位置26(凹槽4)和位置78(凹槽4) 阿尔茨海默病的患病率与AD的持续性显著相关。重要的是，与其他许多不同的是 人类白细胞抗原等位基因与疾病(如糖尿病)的相关性，阿尔茨海默病的发病机制已知为 与皮肤炎症有关，已知的是人类白细胞抗原II在APC上表达，对 炎症性瀑布。 我们计划利用新技术将重点放在基因组的人类白细胞抗原区域，以更好地理解 阿尔茨海默病的遗传学以及皮肤屏障功能障碍和免疫功能失调之间的相互作用。这项建议 有两个目标。第一个目标是定义与AD的发生和持续有关的人类白细胞抗原变异。 第二个目标是证明人类白细胞抗原的变异与这些患者的免疫失调有关。 使用AD。