Role of DM in generation in immunodominant epitope(s)

DM 在免疫显性表位生成中的作用

• 批准号: 6876342
• 负责人: Scheherazade Sadegh-Nasseri
• 金额: $ 32.5万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-03-01 至 2006-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6876342
• 关键词: MHC class II antigen; T lymphocyte; active immunization; aspartic endopeptidases; biohazard detection; bioterrorism /chemical warfare; cathepsin B; cathepsin D; cysteine endopeptidases; epitope mapping; genetically modified animals; high performance liquid chromatography; immunologic assay /test; immunoprecipitation; influenzavirus A; laboratory mouse; leukocyte activation /transformation; mass spectrometry; matrix assisted laser desorption ionization; method development; microorganism hemagglutinin; peptide structure; protein binding; protein protein interaction; protein structure; virus antigen

DESCRIPTION (provided by applicant): The goals of this proposal are to evaluate the role of DM, a non-classical MHC class II heterodimer, in the selection of immunodominant epitopes from a given protein. Our recent data strongly suggested that DM selectively dissociates complexes of peptide-MHC that have floppy conformation and leaves compact peptide/MHC complexes unaffected. We propose that this preferred interaction with a specific conformation of MHC class II, might influence epitope selection from the pool of all other epitopes that can bind to MHC class II. A new assay is designed here to investigate the role of DM in determinant selection by a given MHC class II. Using purified empty HLA-DR1, soluble HLA-DM, and purified Influenza Hemagglutinin (HA) as a model antigen, we will generate antigenic epitopes that remain bound to DR1 in the presence of DM. We would begin with purified influenza hemagglutinin that has a known immunodominant epitope of HA306-318 in. DR1 expressing individuals. Using enzymes with known activity in antigen processing, such as cathepsins, HA protein will be subjected to enzymatic digestion and DR1 binding in the presence of DR1 and DM in Aim I. Mass spectrometric analyzes of the HPLC fractionated peptides eluted from DR1 under the above condition will reveal whether HA306-318 is selected as a predominant peptide. Aim 2 will investigate effects of HLA-DO on regulation of DM and selection of immunodominant epitopes using similar approach to Aim I. Aim 3 will examine interactions of purified DO with DM in vitro and Aim IV will test biological activity of identified epitopes in vivo. Once the feasibility of the method is established, it should be applicable for identification of antigenic epitopes of any complex proteins from pathogenic organisms. The antigenic epitopes might be used in class II tetramer assays for staining of specific activated T cells in vivo and in design of vaccines and as correlates of immunity for immunization efficacy. This research has great impacts on discovering immunodominant epitopes of infectious agents relevant to biodefense.

描述（由申请人提供）：本提案的目标是评估 DM（一种非经典 MHC II 类异二聚体）在从给定蛋​​白质中选择免疫显性表位中的作用。我们最近的数据强烈表明，DM 选择性地解离具有松软构象的肽-MHC 复合物，而紧凑的肽/MHC 复合物不受影响。我们认为，这种与 MHC II 类特定构象的优选相互作用可能会影响可与 MHC II 类结合的所有其他表位库中的表位选择。这里设计了一种新的测定方法来研究 DM 在给定 MHC II 类决定簇选择中的作用。使用纯化的空 HLA-DR1、可溶性 HLA-DM 和纯化的流感血凝素 (HA) 作为模型抗原，我们将生成在 DM 存在的情况下仍与 DR1 结合的抗原表位。我们将从纯化的流感血凝素开始，该流感血凝素在 DR1 表达个体中具有已知的 HA306-318 免疫显性表位。使用具有已知抗原加工活性的酶，例如组织蛋白酶，在 Aim I 中的 DR1 和 DM 存在下，对 HA 蛋白进行酶消化并与 DR1 结合。 在上述条件下对从 DR1 洗脱的 HPLC 分级肽进行质谱分析将揭示 HA306-318 是否被选为主要肽。目标 2 将使用与目标 I 类似的方法研究 HLA-DO 对 DM 调节和免疫显性表位选择的影响。目标 3 将在体外检查纯化的 DO 与 DM 的相互作用，目标 IV 将测试已识别表位的体内生物活性。一旦该方法的可行性得到证实，它应该适用于鉴定来自病原生物的任何复杂蛋白质的抗原表位。抗原表位可用于 II 类四聚体测定中，用于体内特定活化 T 细胞的染色、疫苗设计以及作为免疫功效的免疫相关性。这项研究对于发现与生物防御相关的感染因子的免疫显性表位具有重大影响。

项目成果

Exogenous antigens bind MHC class II first, and are processed by cathepsins later.

• DOI: 10.1016/j.molimm.2015.07.018
• 发表时间: 2015-12
• 期刊: Molecular immunology
• 影响因子: 3.6
• 作者: Sadegh-Nasseri S;Kim A
• 通讯作者: Kim A

A step-by-step overview of the dynamic process of epitope selection by major histocompatibility complex class II for presentation to helper T cells.

• DOI: 10.12688/f1000research.7664.1
• 发表时间: 2016-01-01
• 期刊: F1000Research
• 作者: Sadegh-Nasseri, Scheherazade

Proteolysis by Granzyme B Enhances Presentation of Autoantigenic Peptidylarginine Deiminase 4 Epitopes in Rheumatoid Arthritis.

• DOI: 10.1021/acs.jproteome.6b00617
• 发表时间: 2017-01-06
• 期刊: JOURNAL OF PROTEOME RESEARCH
• 影响因子: 4.4
• 作者: Darrah, Erika;Kim, AeRyon;Zhang, Xi;Boronina, Tatiana;Cole, Robert N.;Fava, Andrea;Giles, Jon T.;Bingham, Clifton O., III;Chalmers, Michael J.;Griffin, Patrick R.;Sadegh-Nasseri, Scheherazade;Rosen, Antony
• 通讯作者: Rosen, Antony

Multiple genetic programs contribute to CD4 T cell memory differentiation and longevity by maintaining T cell quiescence.

• DOI: 10.1016/j.cellimm.2020.104210
• 发表时间: 2020-11
• 期刊: Cellular immunology
• 影响因子: 4.3
• 作者: Song N;Sengupta S;Khoruzhenko S;Welsh RA;Kim A;Kumar MR;Sønder SU;Sidhom JW;Zhang H;Jie C;Siliciano RF;Sadegh-Nasseri S
• 通讯作者: Sadegh-Nasseri S

Mix to validate: a facile, reversible PEGylation for fast screening of potential therapeutic proteins in vivo.

• DOI: 10.1002/anie.201302181
• 发表时间: 2013-07-01
• 期刊: ANGEWANDTE CHEMIE-INTERNATIONAL EDITION
• 影响因子: 16.6
• 作者: Kim, Tae Hyung;Swierczewska, Magdalena;Oh, Yumin;Kim, AeRyon;Jo, Dong Gyu;Park, Jae Hyung;Byun, Youngro;Sadegh-Nasseri, Scheherazade;Pomper, Martin G.;Lee, Kang Choon;Lee, Seulki
• 通讯作者: Lee, Seulki