Human Population Diversity in Leukocyte Receptors

人类白细胞受体的多样性

• 批准号: 8817130
• 负责人: PETER R PARHAM
• 金额: $ 41.76万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1981
• 资助国家: 美国
• 起止时间: 1981-05-01 至 2019-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8817130
• 关键词: Activated Natural Killer Cell; Admixture; Affect; Africa; African; Alleles; Allergic; Amino Acids; Area; Autoimmune Process; Automobile Driving; Back; Binding; Bioinformatics; Biological Assay; Biomedical Research; Birth; Blood Vessels; Cell Communication; Cessation of life; Characteristics; Clinical; Complement; Complex; Data; Development; Discrimination; Disease; Education; Equilibrium; Event; Evolution; Exposure to; Fetus; Frequencies; Gene Cluster; Genes; Genetic Recombination; Genetic Variation; Genotype; Goals; HLA Class I Genes; HLA-A gene; Haplotypes; Histocompatibility Antigens Class I; Human; Human Genome; Immune; Immune system; Immunoglobulins; Indium; Individual; Infection; Inflammatory; Iran; KLRD1 gene; Killer Cells; Lead; Left; Leukocytes; Life; Ligands; Lymphocyte; Mediating; Methods; Molecular; Mothers; Mutation; Natural Immunity; Natural Killer Cells; Nucleotides; Outcome; Peptides; Plastics; Population; Population Group; Process; Proteins; Receptor Gene; Recording of previous events; Reproduction; Research; Resolution; Sequence Analysis; Shapes; Specific qualifier value; System; Technology; Testing; Transplantation; Variant; adaptive immunity; combat; experience; functional group; high throughput screening; immune function; next generation sequencing; p140-KIR3DL2 inhibitory receptor; pathogen; pressure; protein aminoacid sequence; public health relevance; receptor; receptor binding; reproductive success; research study; response; scale up; tool

DESCRIPTION (provided by applicant): Natural killer (NK) cells are a distinctive population of lymphocytes that serve critical functionsin innate immunity, adaptive immunity and reproduction. Key molecular elements in the development, education and effector responses of human NK cells are the interactions between HLA class I molecules and both inhibitory and activating NK cell receptors. The conserved interactions of HLA-E with CD94:NKG2 are complemented by the extraordinarily variable interactions of HLA-A, -B and -C with the killer-cell immunoglobulin-like receptors (KIR), polymorphic ligands and receptors that segregate independently. The combination of HLA class I and KIR genotype uniquely diversifies human immune systems and as a consequence is strongly associated with infectious, allergic, autoimmune and inflammatory diseases as well as with reproductive success and the outcome of clinical transplantation. Many of these associations are with the functionally and genetically distinctive A and B groups of KIR haplotypes that are unique to the human species. Because of the manner by which humans migrated out-of-Africa to colonize the other continents of the world, the genetic diversity of present-day human populations varies over a wide range and involves different subsets of KIR and HLA class I variants. Equally varied is their history of exposure to pathogens. Through the development of new methods for the acquisition of sequence data and its automated analysis, the research proposed in Aim 1 will lead to a complete description of the KIR and HLA class I genes and alleles in human populations worldwide. These data will be analysed to determine how the KIR receptors and HLA ligands have co-evolved in each population and how this differs from one population to another. Aim 2 will investigate a uniquely human KIR gene that emerged early in human evolution, was important in the development of both the KIR A and B haplotypes, but was abruptly inactivated through a single nucleotide insertion. The functionality of this gene will be brought back to life and studied. Aim 3 will develop new high throughput methods that will investigate how the sequences of the peptides bound by HLA class I modulate the interactions with KIR. The initial focus for the application of these methods will be KIR3DL2 recognition of HLA-A*03 and HLA-A*11.

描述（由申请人提供）： 天然杀伤（NK）细胞是在具有天生免疫力，适应性免疫和繁殖的关键功能的淋巴细胞中独特的群体。人NK细胞的开发，教育和效应子反应中的关键分子元素是HLA I类分子与抑制性和激活NK细胞受体之间的相互作用。 HLA-E与CD94：NKG2的保守相互作用得到了HLA-A，-b和-c与杀手型细胞免疫球蛋白样受体（KIR）的异常可变相互作用，多态性的配体和受体独立种植的多态性配体和受体。 HLA I类和KIR基因型的结合使人类免疫系统具有独特的多样化，因此与感染性，过敏性，自身免疫性和炎症性疾病以及生殖成功和临床移植结果密切相关。这些关联中的许多与人类独有的功能和遗传独特的A和B组的KIR单倍型相关。由于人类迁移到世界其他大洲的迁移方式，当今人类种群的遗传多样性在广泛的范围内变化，涉及KIR和HLA I类变体的不同子集。同样不同的是他们暴露于病原体的历史。通过开发获取序列数据及其自动分析的新方法，AIM 1中提出的研究将导致对全球人口中的KIR和HLA I类基因和等位基因的完整描述。将对这些数据进行分析，以确定KIR受体和HLA配体如何在每个人群中共同发展，以及这与一个人群之间的差异如何。 AIM 2将研究一个独特的人类KIR基因，该基因在人类进化早期出现，在KIR A和B单倍型的发展中很重要，但通过单个核苷酸插入而突然失活。该基因的功能将重新栩栩如生并研究。 AIM 3将开发新的高吞吐量方法，该方法将研究HLA I类约束的肽序列如何调节与KIR的相互作用。应用这些方法的最初重点是HLA-A*03和HLA-A*11的Kir3DL2识别。