Defining the antigenic determinants of the adaptive immune response in IgG4-related disease

定义 IgG4 相关疾病中适应性免疫反应的抗原决定因素

• 批准号: 10284753
• 负责人: Cory Perugino
• 金额: $ 17.5万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10284753
• 关键词: Affect; Alleles; Antigen Receptors; Antigen Targeting; Antigens; Apoptosis; Arthritis; Autoantibodies; Autoantigens; Autoimmune; Automobile Driving; B cell therapy; B-Cell Activation; B-Lymphocytes; Bioinformatics; Biological Assay; Biometry; Blood; CD4 Positive T Lymphocytes; Cell Communication; Cells; Center for Translational Science Activities; Clinical; Clinical Immunology; Clinical Sciences; Clonal Expansion; Clone Cells; Collaborations; Deposition; Development; Disease; Disseminated Malignant Neoplasm; Environment; Epitopes; Extracellular Matrix Proteins; Faculty; Fibrosis; Fostering; Foundations; Funding; Future; Galectin 3; General Hospitals; Genes; Goals; HLA-DR Antigens; Human; Hypersensitivity; IgG4; Immune; Immune response; Immunologic Receptors; Immunologics; Individual; Infiltration; Institutes; Investigation; Journals; Knowledge; Lead; Learning; Lesion; Libraries; Light; Link; Mass Spectrum Analysis; Massachusetts; Mediating; Mentors; Mentorship; Mesenchymal; Molecular; Molecular Biology; Monoclonal Antibodies; Organ; Paper; Parents; Pathogenesis; Pathogenicity; Patients; Peptide/MHC Complex; Peptides; Phenotype; Positioning Attribute; Proteins; Publishing; Recombinants; Reporting; Research; Research Personnel; Rheumatology; Sampling; Scientist; Series; Severity of illness; Specificity; Statistical Data Interpretation; Systemic Scleroderma; T cell receptor repertoire sequencing; T cell response; T-Lymphocyte; T-cell receptor repertoire; Tissues; Training; Training Activity; Transforming Growth Factor beta; Translational Research; Tumor-infiltrating immune cells; United States; United States National Institutes of Health; Universities; Validation; Work; Yeasts; adaptive immune response; base; biobank; career; clinical investigation; clinical phenotype; clinical remission; cohort; cytotoxic; individual patient; member; novel; patient subsets; programs; repository; response; screening; single cell sequencing; single-cell RNA sequencing; skills; tumor

This mentored research program aims to develop Dr. Perugino into an independent investigator studying the immunologic mechanisms of fibrosis. The research goals entail the identification of specific self-proteins driving adaptive immune responses in the context of IgG4-related disease (IgG4-RD), a recently described immune- mediated fibrotic disease. Candidate: Dr. Perugino is a junior faculty member in the Rheumatology Unit at Massachusetts General Hospital and has been conducting bench-based research since 2015. His short-term career goals are to build a stronger foundation in molecular biology, advance his skills in statistical analysis, develop proficiency in single-cell sequencing, gain expertise in creating and screening peptide-MHC yeast display libraries, and build his professional skills towards independent investigation. These goals will be supported by a series of coursework through Harvard University and the Harvard Clinical and Translational Science Center. He has recently published four first-author papers, the first identifying galectin-3 as a novel B cell self-antigen in IgG4-RD (Journal of Allergy and Clinical Immunology, 2019), the 2nd linking the diversity of auto-antibody responses with disease severity in IgG4-RD (Arthritis & Rheumatology, 2019), a 3rd establishing CD4+ T cells with cytotoxic features as likely disease drivers in systemic sclerosis (Journal of Clinical Investigation, 2020) and a 4th establishing the effector phenotype of cytotoxic CD4+ T cells in IgG4-RD (Journal of Allergy and Clinical Immunology, 2020). This work forms the foundation for this K08 proposal. Mentorship, Training Activities, and Environment: Dr. Perugino has been under the direct mentorship of Dr. Shiv Pillai since 2015 and Dr. John Stone since 2014 acting as mentors in investigation and translational research, respectively. The training plan builds upon the skills learned under this mentorship team. Guided by his advisors and collaborators, Dr. Perugino will gain proficiency in (1) single cell RNA sequencing (Dr. Alex Shalek), (2) Ig/TCR repertoire analyses (Dr. Mark Davis), (3) peptide-MHC yeast display library development (Dr. Michael Birnbaum), immune cell interactions (Dr. Michael Brenner) and biostatistical analysis (Dr. Musie Ghebremichael). Research Program: The overarching hypothesis of this proposal is that the immune response in IgG4-RD is driven by the crosstalk between B and T cells directed at specific epitopes derived from the same protein antigen. Leveraging the identification of clonal expansions of B and T cells in IgG4-RD, the proposal entails the determination of dominant B and T cell clones, which will subsequently be used to single cell clone soluble antigen receptors and use those as probes to pull down their cognate antigens. These complementary approaches, one focused on B cells (Aim 1) and the other on T cells (Aim 2), entail the validation of B and T cell responses among the largest single-center cohort of IgG4-RD bio-samples in the United States. These studies will serve as a foundation for Dr. Perugino's future goals of identifying the HLA and antigenic determinants that distinguish the clinical phenotypes of different immune-mediated fibrotic diseases, such as IgG4-RD, as an independent investigator.

该指导的研究计划旨在将佩鲁吉诺博士发展成研究 纤维化的免疫机制。研究目标需要识别特定的自蛋白驱动 在IgG4相关疾病（IgG4-RD）的背景下，适应性免疫反应，最近描述的免疫 - 介导的纤维化疾病。候选人：Perugino博士是风湿病部门的初级教师 马萨诸塞州综合医院，自2015年以来一直在进行基于基础的研究。他的短期 职业目标是在分子生物学上建立更强大的基础，提高他在统计分析方面的技能， 提高精通单细胞测序，在创建和筛选肽-MHC酵母方面获得专业知识 展示图书馆，并建立他的专业技能，以实现独立调查。这些目标将是 由哈佛大学和哈佛临床和翻译的一系列课程支持 科学中心。他最近发表了四篇第一作者论文，这是第一个将Galectin-3作为新颖的B IgG4-RD中的细胞自我抗原（过敏和临床免疫学杂志，2019年），第二条联系在一起 IgG4-RD中疾病严重程度的自身抗体反应（关节炎和风湿病学，2019年），第三个建立 具有细胞毒性特征的CD4+ T细胞与全身性硬化症中的疾病驱动因素一样可能（临床杂志 研究，2020年）和第四个建立IgG4-RD中细胞毒性CD4+ T细胞的效应表型（杂志） 过敏和临床免疫学，2020年）。这项工作构成了这项K08提案的基础。指导， 培训活动和环境：佩鲁吉诺博士自从Shiv Pillai博士的直接指导下 2015年和John Stone博士自2014年以来担任调查和转化研究的导师。 培训计划基于该指导团队中学到的技能。在他的顾问和 合作者Perugino博士将获得（1）单细胞RNA测序（Alex Shalek博士），（2）IG/TCR 曲目分析（Mark Davis博士），（3）肽-MHC酵母显示图书馆开发（Michael Birnbaum博士）， 免疫细胞相互作用（Michael Brenner博士）和生物统计分析（Musie Ghebremichael博士）。研究 程序：该提案的总体假设是IgG4-RD中的免疫反应由 B和T细胞之间的串扰针对来自同一蛋白抗原的特定表位。利用 IgG4-RD中B和T细胞的克隆膨胀的鉴定，该提案需要确定 主要的B和T细胞克隆，随后将用于单细胞克隆可溶性抗原受体和 将这些用作探针拉下其同源抗原。这些补充方法，专注于B 细胞（AIM 1），另一个在T细胞上（AIM 2），需要验证B和T细胞响应最大的B和T细胞反应 在美国，IgG4-RD生物样本的单中心队列。这些研究将成为 佩鲁吉诺博士的未来目标是确定区分临床的HLA和抗原决定因素 作为独立研究者，不同免疫介导的纤维化疾病（例如IgG4-RD）的表型。