Immunoglobulin as a novel ligand for HLA-DM

免疫球蛋白作为 HLA-DM 的新型配体

• 批准号: 8264930
• 负责人: Elizabeth D Mellins
• 金额: $ 19.75万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-05-20 至 2013-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8264930
• 关键词: Address; Animal Model; Antibodies; Antigen Presentation; Antigen Presentation Interaction; Antigen Presentation Pathway; Antigen Receptors; Antigen-Antibody Complex; Antigen-Presenting Cells; Antigens; Attenuated; Autoantigens; Autoimmune Diseases; Autoimmunity; B-Lymphocytes; Binding; Biological Assay; CD4 Positive T Lymphocytes; Cell Count; Cell Line; Cells; Clinical Trials; Complex; Conjugate Vaccines; Data; Dendritic Cells; Detection; Development; Dose; Effector Cell; Engineering; Epitopes; Event; Fc Receptor; Fluorescence Microscopy; Health; Histocompatibility Antigens Class II; Human; Immune response; Immune system; Immunoglobulins; Infection; Insulin-Dependent Diabetes Mellitus; Length; Ligands; Ligation; Link; Mediating; Membrane; Microscopy; Modeling; Molecular; Pathway interactions; Peptides; Pharmaceutical Preparations; Play; Precipitation; Process; Proteins; Rheumatoid Arthritis; Role; Shapes; Site; Surface; Surface Immunoglobulins; System; T-Cell Proliferation; T-Lymphocyte; Testing; antigen binding; antigen processing; base; cell type; functional outcomes; macrophage; mutant; novel; public health relevance; receptor; research study; response; uptake

DESCRIPTION (provided by applicant): Antigen presenting cells are key players in the immune response. They are involved in priming naove and effector cells and are critical for orchestrating a response to infection as well as responses to self- antigens (autoimmunity). Among antigen presenting cells, B cells are uniquely capable of presenting small amounts of antigen, which they capture and take up through surface immunoglobulin (Ig). Based on our preliminary findings, we hypothesize that HLA-DM is a key player in enhancing presentation of antigen taken up through Ig on the surface of the B cell by bringing Ig in close proximity to MHC II and facilitating antigen release from Ig. Here, we propose to assess the functional outcome of the DM/Ig interaction in cells. We will engineer a B cell line to express a GAD65 specific immunoglobulin as well as a mutant DM that does not interact with Ig but does interact with MHC II. Mutant and wild type DM will be compared for their ability to enhance presentation of GAD65 in T cell proliferation assays, across a range of B cell numbers and antigen doses. We also propose to localize the site of the HLA-DM/Ig interaction in cells by using proximity ligation assays and fluorescence microscopy. Although we focus here on surface immunoglobulin as an antigen receptor in B cells, our results will have implications for the function of other antigen presenting cell types, such as macrophages and dendritic cells, that take up immune complexes via surface Fc receptors (FcR). These antigen/antibody complexes are also targeted to the endosomal pathway, where they encounter HLA-DM. PUBLIC HEALTH RELEVANCE: In health, the immune system responds to foreign antigens and mounts a response to infection. In autoimmune disease, the immune system mounts a response against the body's own (self) antigens. Antigen presenting cells mediate a critical initiating role in the development of an effective immune response by presenting self and foreign antigens to responder cells of the immune system. This project investigates a newly discovered interaction between molecules involved in antigen processing and presentation, a process that is key in shaping the immune response against foreign and self antigens with consequences for infectious as well as autoimmune diseases. The experimental system employed uses proteins of relevance to type 1 diabetes in humans.

描述（由申请人提供）：抗原呈递细胞是免疫反应的关键参与者。它们参与启动幼稚细胞和效应细胞，对于协调对感染的反应以及对自身抗原（自身免疫）的反应至关重要。在抗原呈递细胞中，B 细胞具有独特的呈递少量抗原的能力，它们通过表面免疫球蛋白 (Ig) 捕获并摄取抗原。根据我们的初步研究结果，我们假设 HLA-DM 通过使 Ig 靠近 MHC II 并促进 Ig 释放抗原，在增强 B 细胞表面 Ig 摄取抗原的呈递过程中发挥着关键作用。在这里，我们建议评估细胞中 DM/Ig 相互作用的功能结果。我们将设计一个 B 细胞系来表达 GAD65 特异性免疫球蛋白以及不与 Ig 相互作用但与 MHC II 相互作用的突变 DM。将比较突变型和野生型 DM 在 T 细胞增殖测定中在一系列 B 细胞数量和抗原剂量下增强 GAD65 呈递的能力。我们还建议通过使用邻近连接测定和荧光显微镜来定位细胞中 HLA-DM/Ig 相互作用的位点。尽管我们在这里关注的是 B 细胞中作为抗原受体的表面免疫球蛋白，但我们的结果将对其他抗原呈递细胞类型（例如巨噬细胞和树突细胞）的功能产生影响，这些细胞通过表面 Fc 受体 (FcR) 摄取免疫复合物。这些抗原/抗体复合物还靶向内体途径，在那里它们遇到 HLA-DM。 公共卫生相关性：在健康方面，免疫系统对外来抗原做出反应并对感染做出反应。在自身免疫性疾病中，免疫系统会对人体自身抗原做出反应。抗原呈递细胞通过向免疫系统的应答细胞呈递自身和外来抗原，在有效免疫反应的发展中发挥关键的起始作用。该项目研究了新发现的参与抗原加工和呈递的分子之间的相互作用，这一过程是形成针对外来和自身抗原的免疫反应的关键，从而对传染病和自身免疫性疾病产生影响。所采用的实验系统使用与人类 1 型糖尿病相关的蛋白质。

项目成果

Tuning DO:DM Ratios Modulates MHC Class II Immunopeptidomes.

• DOI: 10.1016/j.mcpro.2022.100204
• 发表时间: 2022-03
• 期刊: MOLECULAR & CELLULAR PROTEOMICS
• 影响因子: 7
• 作者: Olsson, Niclas;Jiang, Wei;Adler, Lital N.;Mellins, Elizabeth D.;Elias, Joshua E.
• 通讯作者: Elias, Joshua E.