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

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

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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（AAS）是胰腺自身免疫的可靠生物标志物。血清AAS针对四个专业生化抗原（胰岛素，GAD，IA-2和ZNT8）通常在临床研究中用作关键指标 1型糖尿病患者（T1D）的诊断和预后，以及高危疾病预测 T1D发作之前的个人。已经开发出强大的生化测定来检测AAS识别的AA 膜结合抗原的可溶性抗原或可溶性结构域。检测到AAS到膜结合的然而，抗原在适应其不溶性跨膜域的技术困难受到挑战（TMD）到基于解决方案的评估平台。目前，我们对患病率和第一靶向任何TMD抗原的AA的外观。在四种主要的生化抗原中，胰岛特异性 Znt8在具有全长ZNT8中包含三分之二蛋白序列的主要TMD方面是独一无二的。我们的最近的作品表明，在胰岛素分泌后，Znt8被运输到胰腺β细胞的表面，并且表面TMD具有高度抗原性，在T1D患者中被血清ZNT8 AAS识别。这些发现建议Znt8中的TMD是一个新型的免疫原性，用于表面靶向AAS，并且显示在细胞表面可能促进抗体介导的细胞毒性，直接导致β细胞自身免疫性破坏。为了检验这些假设，我们将（i）验证针对Znt8（TMDA）的TMD的AA（TMDA）的患者到T1D，（ii）将TMDA建立为直接靶向的AA，因此，将TMDA直接与活胰腺β细胞结合到调节其功能和生存。拟议的研究预计将验证全新的一类靶向最近确定的胰岛细胞表面抗原的AA，阐明了TMDA在自然史中的作用 T1D（AIM 1）和疾病发病机理（AIM 2）。获得的知识将转化为新颖的诊断工具和潜在的治疗干预措施。