Modulation of Autoimmune Diabetes by N-acetyl-D-glucosamine Specific B cells

N-乙酰基-D-葡萄糖胺特异性 B 细胞对自身免疫性糖尿病的调节

基本信息

批准号：
7658757
负责人：
Brian Leonard Dizon
金额：
$ 3.3万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-08-01 至 2011-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7658757
关键词：
Acetylglucosamine Affect Antibodies Antibody Formation Antigen Presentation Antigens Autoantibodies Autoantigens Autoimmune Diabetes Autoimmune Diseases B cell repertoire B-Lymphocytes Beta Cell Binding Biological Assay Blood Glucose Blood Vessels C57BL/6 Mouse Cell Line Cells Childhood Data Defect Development Diabetes Mellitus Diagnosis Disease Drug or chemical Tissue Distribution Early Diagnosis Enzyme-Linked Immunosorbent Assay Epidemiologic Studies Epitopes Flow Cytometry Frequencies Genetic Goals Gram-Positive Bacteria Heating Heavy-Chain Immunoglobulins Human Immune Immune system Immunization Immunofluorescence Microscopy Immunoglobulin Idiotypes Immunoglobulin M Immunoglobulins Inbred NOD Mice Incidence Individual Infection Infectious Agent Insulin Insulin-Dependent Diabetes Mellitus Islets of Langerhans Lead Link Lymphoid Measurement Measures Modeling Mouse Strains Mus Neonatal Neurologic Non obese Peripheral Phenotype Preparation Prevention Production Proteins Publishing Rattus Resistance Role Serum Streptococcal Infections Streptococcal Preparation OK-432 Streptococcus pyogenes Streptozocin Stress T-Lymphocyte Techniques Testing Transgenic Mice Transgenic Organisms Whole Blood base blood glucose regulation cell type cohort diabetic enzyme linked immunospot assay improved in vivo insight islet killings male mouse model pathogen response

项目摘要

DESCRIPTION (provided by applicant): Type 1 diabetes (T1D) is an autoimmune disease in which insulin-producing beta cells are destroyed by the immune system. The consequence of beta cell destruction is an inability to regulate blood glucose levels, which ultimately lead to neurological and vascular complications. The long-term goal of this project is to identify factors that can influence the progression of T1D in susceptible individuals, which may improve T1D diagnosis and therapy. We will examine a role for Group A Streptococcal (GAS) infection in modulating the function of antigen-specific B lymphocytes in mouse models of autoimmune diabetes. B lymphocytes recognizing beta cell antigens can promote autoimmune diabetes development. In response to GAS challenge, B lymphocytes produce a large proportion of antibodies recognizing O-linked N-acetyl-D- glucosamine, which can bind self-antigens on beta cells. Interestingly, a strong negative correlation between childhood GAS infection and T1D has been demonstrated in human epidemiological studies, while challenge with a heat-killed GAS preparation leads to diabetes resistance in susceptible mouse and rat models. In fact, the diabetes resistance can be transferred by sera from mice immunized with heat-killed GAS to unimmunized mice, suggesting that factors in the sera, such as antibodies, can protect against T1D development. We hypothesize that infection with GAS can protect as well as promote the development of autoimmune diabetes through mechanisms involving GlcNAc-specific B lymphocytes. To test our hypothesis, we propose the following specific aims: 1) to characterize the response of GlcNAc-specific B cells in autoimmune diabetes, 2) to determine how neonatal GAS challenge affects the development of autoimmune diabetes, and 3) to identify mechanisms by which GlcNAc-specific B cells influence the development of autoimmune diabetes. We will measure diabetes incidence in GAS-immunized and unimmunized wild type (WT) NOD mice, streptozotocin (STZ) treated WT C57BL/6 mice, and STZ-treated C57BL/6 mice transgenic for immunoglobulin'heavy chain (IgH Tg) associated with GlcNAc recognition. The absolute numbers, phenotype, and tissue distribution of GlcNAc-specific B cells, as well as GlcNAc-specific IgM titers, will be measured by flow cytometry, ELISA, ELISPOT, and immunofluorescence microscopy utilizing clonal idiotype markers. This study will attempt to determine how a common infectious organism, Group A Streptococcus, can alter an individual's propensity to develop type I diabetes (T1D). Understanding the mechanisms involved in this link may provide insight on new strategies for earlier diagnosis, treatments, and prevention of T1D.

描述（由申请人提供）：1型糖尿病（T1D）是一种自身免疫性疾病，其中产生胰岛素的β细胞被免疫系统破坏。 β细胞破坏的结果是无法调节血糖水平，最终导致神经系统和血管并发症。该项目的长期目标是确定可以影响易感人群T1D进展的因素，从而可以改善T1D诊断和治疗。我们将研究A组链球菌（气体）感染在调节自身免疫性糖尿病小鼠模型中抗原特异性B淋巴细胞功能中的作用。 B淋巴细胞识别β细胞抗原可以促进自身免疫性糖尿病的发育。为了应对气体攻击，B淋巴细胞产生了识别O连锁N-乙酰-D-葡萄糖胺的大量抗体，该抗体可以结合β细胞上的自我抗原。有趣的是，在人类流行病学研究中已经证明了儿童气体感染与T1D之间的强大负相关性，而热杀态气体制备的挑战会导致易感小鼠和大鼠模型的糖尿病耐药性。实际上，糖尿病的耐药性可以由血清从用热才能气体免疫的小鼠转移到无免疫的小鼠中，这表明血清中的因子（例如抗体）可以预防T1D发育。我们假设气体感染可以通过涉及GlcNAC特异性B淋巴细胞的机制来保护并促进自身免疫性糖尿病的发展。 To test our hypothesis, we propose the following specific aims: 1) to characterize the response of GlcNAc-specific B cells in autoimmune diabetes, 2) to determine how neonatal GAS challenge affects the development of autoimmune diabetes, and 3) to identify mechanisms by which GlcNAc-specific B cells influence the development of autoimmune diabetes.我们将测量糖尿病在气体免疫和未免疫的野生型（WT）NOD小鼠，处理过的WT C57BL/6小鼠的链霉菌蛋白（STZ）以及与GLCNAC相关的Immunoglobulobulobulobulobulobulobulobulobulobulobulobulobulobulobulobulobulobloblobloblobloblobloblobloblobloblobloblobloblobloblobloblobloblobloblobloblectnac识别。 GlcNAC特异性B细胞的绝对数量，表型和组织分布以及GlcNAC特异性IGM滴度将通过流式细胞仪，ELISA，ELISPOT和免疫荧光显微镜测量利用克隆惯用型标记物。这项研究将试图确定常见的传染性生物A组如何改变个人发展I型糖尿病（T1D）的倾向。了解此链接所涉及的机制可能会洞悉用于早期诊断，治疗和预防T1D的新策略。