Antigen processing in the secretory pathway

分泌途径中的抗原加工

• 批准号: 8588887
• 负责人: Nilabh Shastri
• 金额: $ 37.54万
• 依托单位: UNIVERSITY OF CALIFORNIA BERKELEY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-02-15 至 2016-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8588887
• 关键词: Affect; Alleles; Aminopeptidase; Ankylosing spondylitis; Antigen Presentation Pathway; Antigens; Autoimmune Diseases; Autoimmunity; Bacteria; Bacterial Proteins; Biological Assay; Books; CD8-Positive T-Lymphocytes; CD8B1 gene; Cell surface; Cells; Complex; Cytoplasm; Cytosol; Endoplasmic Reticulum; Genetic Polymorphism; Goals; Grant; HLA-B27 Antigen; HLA-C Antigens; Histocompatibility Antigens Class I; Human; Immune response; Immune system; Immunity; Immunologic Surveillance; Knockout Mice; Ligands; Link; MHC Class I Genes; Mass Spectrum Analysis; Modeling; Molecular; Mus; N-terminal; Pathway interactions; Peptide Hydrolases; Peptide/MHC Complex; Peptides; Physiological; Process; Production; Proteins; Proteolysis; Psoriasis; Qa-1 Antigen; Research; Specificity; Structure; Surface; T cell response; T-Cell Receptor; T-Lymphocyte; Testing; Text; Tissues; Viral Proteins; Virus; Wild Type Mouse; antigen processing; base; cell type; chronic autoimmune disease; cytotoxic; genome wide association study; immunogenic; immunogenicity; improved; insight; neoplastic cell; novel; pathogen

DESCRIPTION (provided by applicant): The long term goal of our research is to understand and manipulate immune surveillance pathways. The antigen processing mechanisms yields thousands of peptide/MHC class I complexes (pMHC I) on the cell surface as potential ligands for CD8 T cells. Contrary to text book models which often depict the final antigenic peptide being generated in the cytoplasm itself, recent findings have shown that antigen processing continues in the endoplasmic reticulum (ER). The protease that trims antigenic precursors in the ER is called ERAAP (or ERAP1), for the ER aminopeptidase associated with antigen processing. In ERAAP-deficient mice, lack of peptide trimming in the ER disrupts the normal peptide repertoire presented by the classical (MHC Ia) and surprisingly, non-classical (MHC Ib) as well: many pMHC I go missing and concomitantly many novel, highly immunogenic pMHC I emerge on the surface of ERAAP-deficient cells. The loss and gain of unique peptides results in vigorous reciprocal immune responses in wild-type versus ERAAP-deficient mice. Here we propose to test the hypothesis that the novel peptides presented in ERAAP-deficient cells are structurally distinct because they represent unedited versions of normally trimmed peptides or those that were destroyed by ERAAP. We will determine the structure and origin of the unique immunogenic peptides by mass spectrometry and T-cell based assays. In addition, because polymorphisms in ERAP1 have been associated with autoimmune diseases (ankylosing spondylitis and psoriasis) we will test the hypothesis that the composition of the peptide repertoire is influenced not only by polymorphic MHC molecules themselves, but also by polymorphisms in ERAAP. We anticipate the results of this proposal to provide a deeper understanding of the antigen processing pathway and how the pathway can be manipulated to regulate immunogenicity.

描述（由申请人提供）：我们研究的长期目标是理解和操纵免疫监视途径。抗原加工机制在细胞表面产生数以千计的肽/MHC I类复合物（pMHC I），作为CD8 T细胞的潜在配体。与教科书模型通常描述的最终抗原肽是在细胞质本身产生的相反，最近的研究结果表明抗原加工在内质网（ER）中继续进行。在内质网中修饰抗原前体的蛋白酶被称为ERAAP（或ERAP1），即内质网中与抗原加工相关的氨基肽酶。在eraap缺陷的小鼠中，内质网中缺乏肽修剪会破坏由经典（MHC Ia）和令人惊讶的非经典（MHC Ib）呈现的正常肽库：许多pMHC I缺失，同时许多新的，高度免疫原性的pMHC I出现在eraap缺陷细胞的表面。在野生型小鼠和eraap缺陷小鼠中，独特肽的丧失和获得导致了强有力的互惠免疫反应。在这里，我们提出验证假设，即在ERAAP缺陷细胞中呈现的新肽在结构上是不同的，因为它们代表了正常修剪的未编辑版本或被ERAAP破坏的肽。我们将通过质谱法和基于t细胞的测定来确定独特的免疫原性肽的结构和来源。此外，由于ERAP1的多态性与自身免疫性疾病（强直性脊柱炎和牛皮癣）有关，我们将验证肽集的组成不仅受多态MHC分子本身的影响，还受ERAAP多态性的影响。我们期望这一建议的结果能够提供对抗原加工途径以及如何操纵该途径来调节免疫原性的更深层次的理解。