Autoantibodies directed to islet cell surface antigens and their pathologic roles in type-1 diabetes

针对胰岛细胞表面抗原的自身抗体及其在 1 型糖尿病中的病理作用

基本信息

批准号：
10161015
负责人：
Dax Fu
金额：
$ 16.38万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-20 至 2022-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10161015
关键词：
Acute Adsorption Amino Acid Sequence Antigen-Presenting Cells Antigens Appearance Autoantibodies Autoantigens Autoimmune Diseases Autoimmune Process Autoimmune Responses Autoimmunity B-Lymphocytes Beta Cell Binding Biochemical Biological Assay Biological Markers Birth C-terminal Cell Line Cell surface Cells Cellular biology Child Clinical Clinical Research Complement-Dependent Cytotoxicity Coupled Data Detection Detergents Development Diabetes Mellitus Diagnostic Disease Disease Progression Epitopes Estrogen receptor positive Female Future General Population Glucose Histocompatibility Antigens Class I Human Immunization Immunofluorescence Immunologic Inbred NOD Mice Incidence Individual Inflammation Inflammatory Insulin Insulin-Dependent Diabetes Mellitus Islet Cell Knowledge Length Mediating Membrane Metabolic Methods Minor Monoclonal Antibodies N-terminal Natural History Pancreas Pathogenesis Pathogenicity Pathologic Patients Pattern Prediabetes syndrome Prevalence Process Publishing Rattus Research Risk Role Secretory Vesicles Serum Staging Stains Stimulus Structure of beta Cell of islet Surface Surface Antigens T-Lymphocyte Testing Therapeutic Intervention Time Translating Transmembrane Domain Tumor-infiltrating immune cells Work Zinc antibody-dependent cell cytotoxicity antigen binding autoreactivity base chemokine cohort cytokine cytotoxic early detection biomarkers immunogenic improved insulin dependent diabetes mellitus onset insulin secretion islet male miniaturize novel novel diagnostics prognostic proteoliposomes reconstitution response seroconversion tool trafficking

项目摘要

Islet autoantibodies (AAs) are reliable biomarkers of pancreatic autoimmunity. Serum AAs against four major biochemical antigens (insulin, GAD, IA-2, and ZnT8) are routinely used in clinical research as key metrics for diagnostics and prognostics in patients with type-1 diabetes (T1D), and for disease prediction in at-risk individuals before T1D onset. Robust biochemical assays have been developed to detect AAs recognizing soluble antigens or soluble domains of membrane-bound antigens. Detection of AAs to membrane-bound antigens, however, is challenged by technical difficulties in adaption of their insoluble transmembrane domains (TMD) to solution-based assay platforms. At present, we have no knowledge of the prevalence and first appearance of AAs targeting any TMD antigens. Among the four major biochemical antigens, the islet-specific ZnT8 is unique in having a major TMD that encompasses two thirds protein sequence in a full-length ZnT8. Our recent works showed that ZnT8 is trafficked to the surface of pancreatic β-cells following insulin secretion, and the surfaced TMD is highly antigenic, recognized by serum ZnT8 AAs in patients with T1D. These findings suggest that the TMD in ZnT8 is a novel immunogenic domain for surfaced-targeted AAs, and its display on the cell surface may promote antibody-mediated cytotoxicity contributing directly to β-cell autoimmune destruction. To test these hypotheses, we will (i) validate AAs directed to the TMD of ZnT8 (TMDAs) in patients progressing to T1D, and (ii) establish TMDAs as direct-targeting AAs, as such, bind directly to live pancreatic β cells to modulate their functions and survival. The proposed research is expected to validate a completely new class of AAs targeting a recently identified islet cell surface antigen, illuminating the roles of TMDAs in the natural history of T1D (Aim 1) and disease pathogenesis (Aim 2). The knowledge gained will be translated to novel diagnostic tools and potential therapeutic interventions.

胰岛自身抗体 (AA) 是针对四种主要胰腺自身免疫的可靠生物标志物。生化抗原（胰岛素、GAD、IA-2 和 ZnT8）通常在临床研究中用作关键指标 1 型糖尿病 (T1D) 患者的诊断和预后，以及高危人群的疾病预测已开发出在 T1D 发病前检测 AA 的强大生化检测方法。膜结合 AA 的检测然而，抗原在适应其不溶性跨膜结构域方面面临着技术困难的挑战（TMD）到基于解决方案的检测平台目前，我们还不知道其流行程度和第一。出现针对任何 TMD 抗原的 AA，在四种主要生化抗原中，胰岛特异性抗原。 ZnT8 的独特之处在于其主要 TMD 包含全长 ZnT8 中三分之二的蛋白质序列。最近的研究表明，ZnT8 在胰岛素分泌后被运输到胰腺 β 细胞的表面，并且表面的 TMD 具有高度抗原性，可被 T1D 患者血清中的 ZnT8 AA 识别。表明 ZnT8 中的 TMD 是表面靶向 AA 的新型免疫原性结构域，并且其在细胞表面可能促进抗体介导的细胞毒性，直接导致 β 细胞自身免疫破坏。为了检验这些假设，我们将 (i) 在疾病进展的患者中验证针对 ZnT8 TMD (TMDA) 的 AA T1D，以及 (ii) 将 TMDA 建立为直接靶向 AA，因此直接与活胰腺 β 细胞结合，调节它们的功能和生存。拟议的研究有望验证一类全新的细胞。 AA 靶向最近鉴定的胰岛细胞表面抗原，阐明 TMDA 在自然历史中的作用 T1D（目标 1）和疾病发病机制（目标 2）的知识将转化为新的诊断方法。工具和潜在的治疗干预措施。