Effects of Glycation and Carbonylation on MHC II-restricted immunity

糖化和羰基化对 MHC II 限制性免疫的影响

• 批准号: 10335198
• 负责人: LAURA SANTAMBROGIO
• 金额: $ 74万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-02-18 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10335198
• 关键词: Address; Adolescent; Affect; Affinity; Age; Antigen Presentation Pathway; Antigen-Presenting Cells; Antigens; Autoantigens; Binding; Binding Proteins; Biochemical; CD4 Positive T Lymphocytes; Cathepsins; Chronic Childhood Arthritis; Data; Detection; Diabetes Mellitus; Disease; Environment; Epitopes; Goals; Haplotypes; Hot Spot; Human; Hyperglycemia; Immune response; Immune system; Immunity; Immunization; Immunologics; In Vitro; Infection; Insulin; Insulin-Dependent Diabetes Mellitus; Interferons; Malignant Neoplasms; Maps; Mass Spectrum Analysis; Measures; Metabolic stress; Metabolic syndrome; Modification; Multiple Sclerosis; Non-Insulin-Dependent Diabetes Mellitus; Obese Mice; Oxidation-Reduction; Oxidative Stress; Oxides; Pathologic; Pathway interactions; Patients; Pattern; Peptides; Peripheral Blood Mononuclear Cell; Persons; Phenotype; Play; Population; Positioning Attribute; Post-Translational Protein Processing; Prealbumin; Process; Production; Proteins; Proteomics; Role; Salmonella typhimurium; Sampling; Stains; Surface; Surveys; System; T-Lymphocyte; TNF gene; adaptive immune response; analysis pipeline; antigen processing; autoreactive T cell; carbonyl group; chemical group; cytokine; data acquisition; diabetic patient; experimental study; glycation; high throughput analysis; immunogenicity; mouse model; neoantigens; novel; pathogen; protein aminoacid sequence; sex; sugar; tandem mass spectrometry

Approximately 32% of the population in the U.S. have metabolic syndrome, and about 10% have type 2 diabetes (T2D). In these hyperglycemic conditions proteomic modifications associated with glycation and glycoxidation are often observed. In this application we propose to analyze the role played by glycation and carbonylation on the MHC II antigen processing and presentation machinery and its implication for T cell immunity. Prompted by the observation that MHC II proteins, as well as processed peptides, are modified by advanced glycation endpoint (AGE) and carbonyl groups in patients with T2D, we aim to systematically dissect the role played by these moieties on antigen processing, MHC II-peptide binding, DM editing, and T cell presentation. In a step-by-step approach we will address how the antigen processing machinery is affected by glycation/carbonylation post-translational modifications (PTMs) and how this, in turn, affects T cell immunity. In this application we propose to: (i) map glycation and carbonylation on MHC II Molecules in T2D patients, Ob/Ob mice and relevant controls, using state-of- the-art tandem mass spectrometry, (ii) determine the effect of these PTMs on endosomal antigen processing using quantitative MS/MS and hot spot analysis, (iii) analyze the MHC-II immunopeptidomes in T2D patients, Ob/Ob mice and relevant controls to determine how the dysmetabolic environment can affect peptide selection, epitopes copy number and peptides PTM- modifications, (iv) analyze the MHC-II immunopeptidomes in Ob/Ob mice and relevant controls, prior to and after infection with S. Typhimurium, to determine how the dysmetabolic environment can affect MHC II restricted pathogen immunity, (v) characterize immune responses to novel PTM-modified autoantigens by CD4 T cell using tetramer staining following immunization with relevant epitopes, and T cell characterization (surface phenotype, proliferation and cytokine production following antigen stimulation). Ultimately our analysis will provide a mechanistic analysis of how T2D impacts MHC II- restricted immune responses and its consequences on immunity.

在美国，大约32%的人患有代谢综合征，大约10%的人患有2型糖尿病