Peptide Repertoires of HLA class I molecules

HLA I 类分子的肽库

• 批准号: 9316821
• 负责人: MALINI RAGHAVAN
• 金额: $ 19.38万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-26 至 2019-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9316821
• 关键词: Address; Affinity; Antigen Presentation; Antigen Presentation Pathway; Antigens; Binding; Binding Sites; Bypass; CD8-Positive T-Lymphocytes; Cell Line; Cell surface; Cells; Communicable Diseases; Complex; Data Set; Detection; Disease; Disease Outcome; Endoplasmic Reticulum; Epitopes; Genes; Genetic Polymorphism; Genetic Variation; Genotype; HLA Antigens; Histocompatibility Antigens Class I; Human; Human Genetics; Immune response; Immunity; Infection; Infectious Agent; Inflammatory; Lead; MHC Class I Genes; Major Histocompatibility Complex; Malignant Neoplasms; Mediating; Methods; Outcome; Pathway interactions; Peptides; Predictive Factor; Process; Production; Proteins; Structure; Suggestion; T-Cell Receptor; Vaccine Design; Variant; Virus; antigen processing; antigenic peptide transporter; base; cancer cell; cytokine; liquid chromatography mass spectrometry; method development; novel; pathogen; peptide I; peptide structure; protein aminoacid sequence; tapasin

Major histocompatibility complex (MHC) class I molecules bind to peptide antigens and present these antigens to CD8 T cells. Human MHC class I variants are encoded by the HLA-A, HLA-B and HLA-C genes. These genes are highly polymorphic. The polymorphisms influence outcomes in a number of infectious diseases, cancers and inflammatory diseases. Among the three HLA class I loci, HLA-B molecules are shown have dominant influences upon outcomes in multiple diseases. A given HLA class I allotype can bind to a large number of cellular and pathogen-derived peptides, collectively called the peptidome. The diversity of HLA-B peptidomes could be one factor underlying their different effects upon disease outcomes. A number of factors are predicted to influence peptidome diversity among HLA class I allotypes, including the structure of the peptide-binding site, the intracellular assembly mechanism and the intrinsic stability of the peptide-deficient form. Several HLA-B molecules are assembled via unconventional intracellular pathways that are suggestive of the presence of novel unconventional epitopes within their peptidomes. We propose to use liquid chromatography mass spectrometry (LC-MS) methods to quantify, characterize and understand the full breadth of the peptidomes of selected HLA-B variants. Based on existing MS datasets, we will also develop globally normalized methods to quantify and compare peptidome diversities of different HLA-B variants. The findings of this study will be significant towards epitope and HLA selection during vaccine design against cancers and infectious diseases. The studies will also establish methods to identify novel disease-relevant epitopes, and allow a better understanding of the relationships between HLA class I genotypes and disease outcomes.

主要组织相容性复合体(MHC)I类分子与多肽抗原结合，并 将这些抗原呈递给CD8T细胞。人类MHC I类变体由 人类白细胞抗原A、B、C基因。这些基因具有高度的多态。这个 基因多态会影响许多传染病、癌症和 炎症性疾病。在三个人类白细胞抗原I类基因座中，显示了人类白细胞抗原B分子 对多种疾病的结局有决定性的影响。A给定的人类白细胞抗原I类 同种异型可以与大量的细胞和病原体衍生的多肽结合， 统称为多肽穹顶。人类白细胞抗原-B多肽的多样性可能是一个因素 它们对疾病结果的不同影响。有许多因素是 预测会影响人类白细胞抗原I类同种异型间的多肽组多样性，包括 多肽结合部位的结构、细胞内组装机制和 多肽缺陷型的内在稳定性。组装了几个人类白细胞抗原-B分子 通过非传统的细胞内途径暗示了新的 它们的多肽体内有非传统的表位。我们建议使用液体 色质联用(LC-MS)方法定量、表征和 了解选定的人类白细胞抗原B变异体的全部多肽。基于 对于现有的MS数据集，我们还将开发全局标准化的方法来量化和 比较不同人类白细胞抗原B变异体的多肽多样性。这项研究的结果将 在抗癌疫苗设计中对表位和人类白细胞抗原的选择具有重要意义 和传染病。这些研究还将建立识别小说的方法 与疾病相关的表位，并允许更好地理解 人类白细胞抗原I类基因分型与疾病转归。