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Role of HLA class II genes in demyelination

HLA II 类基因在脱髓鞘中的作用

基本信息

批准号：
7193400
负责人：
CHELLA S DAVID
金额：
$ 19.4万
依托单位：
MAYO CLINIC ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-04-01 至 2010-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7193400
关键词：
6p21 Accounting Acetone Affect Animal Model Antigens Area Autoimmune Diseases Brain Brain region Breeding CD28 gene CD4 Positive T Lymphocytes CD80 gene CD8B1 gene Cell surface Cells Cerebrospinal Fluid Chromosomes Class Clinical Clonal Expansion Cytokine Signaling Data Demyelinations Development Disease Disease Association Disease Progression Disease model Environment Epitopes Experimental Autoimmune Encephalomyelitis Folch-Pi apoprotein Frozen Sections Generations Genes Genetic Genetic Polymorphism Genetic Predisposition to Disease HLA-DR Antigens HLA-DR2 Antigen HLA-DR3 Antigen Haplotypes Heterogeneity Histocompatibility Antigens Class II Histopathology Human Immune response Immunodominant Epitopes Incidence Individual Inflammation Inflammatory Inflammatory Response Interleukin-2 Intervention Knock-out Knockout Mice Laser Scanning Confocal Microscopy Link Linkage Disequilibrium MHC Class II Genes Mediating Memory Microglia Modeling Molecular Profiling Monitor Multiple Sclerosis Multiple Sclerosis Lesions Mus Myelin Myelin Proteolipid Protein Nature Necrosis Neurologic Neurologic Deficit Neuronal Injury Neurons Onset of illness Paralysed Pathogenesis Pathology Patients Peptide/MHC Complex Peptides Phenotype Play Population Predisposition Process Production Proteins Regulation Reporting Research Personnel Role Scoring Method Severities Shapes Signal Transduction Simulate Spinal Cord Staining method Stains T-Cell Activation T-Cell Proliferation T-Lymphocyte T-Lymphocyte Subsets TCR Activation TNFRSF10A gene Techniques Testing Tissues Transgenes Transgenic Mice Transgenic Organisms base cell type central nervous system demyelinating disorder central nervous system injury computerized cytokine early onset gene complementation gene interaction insight mouse model programs response white matter

项目摘要

DESCRIPTION (provided by applicant): Susceptibility to multiple sclerosis (MS) has been linked to certain HLA class II genes, although analysis of their exact function remains complicated. We have recently generated humanized class II transgenic mice (AEo) in the context of the new complete class II knockout MHCII-/- mice (produced by Benoist and Mathis) lacking all endogenous class II genes. In contrast to our "Abo" transgenic mice, in this new transgenic line "AEo", T cells express class II on their cell surface and can also present antigen. PLP91-110 peptide induced a severe EAE in HLA-DR3.AEo mice characterized by early disease onset and increased disease incidence as compared to DR3.Abo mice. Further mice with EAE showed severe inflammation and demyelination in CMS. Thus our new transgenic line simulates human MS both in form of expression of MHC class II on T cells as well as severe CNS demyelination. We hypothesize that in autoimmune diseases such as MS, auto- reactive CD4+ T cells expressing class II can present additional myelin antigen inside CNS thus propagate the inflammatory response which ultimately leads to CNS injury. Using this disease model, we will first explore role of human class II in the disease process with particular emphasis on neurological deficits and CNS histopathology. In CNS pathology, we will assess extent of demyelination, remyelination and axonal loss in spinal cord as well as the extent of inflammation, neuronal necrosis and white matter demyelination in brain. Next, we will analyze the expression of class II in different regions of brain and spinal cord as well as on CNS infiltrating cells and its role in modulating disease pathogenesis. We will also analyze role of CD4 T cells and CDS T cells both in pathogenesis as well as regulation of EAE as it has been suggested that they can play both pathogenic and protective role in MS/EAE. Next we will also analyze role and contribution of accessory molecules, costimulatory molecules, and cytokines in modulating the disease. Finally using double transgenic mice, we will study that how gene complementation between DR and DQ gene affect the disease initiation and progression in a susceptible HLA class II transgenic mice. The comprehensive studies outlined in this proposal should yield an insight into the role of HLA class II genes in predisposition, onset, progression, severity, modulation, and intervention of human multiple sclerosis. Finally, this new humanized class II model of EAE may provide new insight into the pathogenesis of MS.

描述（由申请人提供）：对多发性硬化症 (MS) 的易感性与某些 HLA II 类基因有关，尽管对其确切功能的分析仍然很复杂。我们最近在缺乏所有内源性 II 类基因的新型完全 II 类敲除 MHCII-/- 小鼠（由 Benoist 和 Mathis 生产）的背景下生成了人源化 II 类转基因小鼠 (AEo)。与我们的“Abo”转基因小鼠相反，在这个新的转基因系“AEo”中，T细胞在其细胞表面表达II类，并且还可以呈递抗原。 PLP91-110 peptide induced a severe EAE in HLA-DR3.AEo mice characterized by early disease onset and increased disease incidence as compared to DR3.Abo mice.其他患有 EAE 的小鼠在 CMS 中表现出严重的炎症和脱髓鞘。因此，我们的新转基因系以 T 细胞上 MHC II 类表达的形式以及严重的中枢神经系统脱髓鞘的形式模拟人类多发性硬化症。我们假设在多发性硬化症等自身免疫性疾病中，表达 II 类的自身反应性 CD4+ T 细胞可以在中枢神经系统内呈递额外的髓磷脂抗原，从而传播炎症反应，最终导致中枢神经系统损伤。使用这种疾病模型，我们将首先探讨人类 II 类在疾病过程中的作用，特别强调神经缺陷和中枢神经系统组织病理学。在中枢神经系统病理学中，我们将评估脊髓脱髓鞘、髓鞘再生和轴突丢失的程度，以及大脑炎症、神经元坏死和白质脱髓鞘的程度。接下来，我们将分析II类在脑和脊髓不同区域以及中枢神经系统浸润细胞中的表达及其在调节疾病发病机制中的作用。我们还将分析 CD4 T 细胞和 CDS T 细胞在 EAE 发病机制和调节中的作用，因为有人认为它们在 MS/EAE 中既可以发挥致病作用，也可以发挥保护作用。接下来我们还将分析辅助分子、共刺激分子和细胞因子在调节疾病中的作用和贡献。最后使用双转基因小鼠，我们将研究DR和DQ基因之间的基因互补如何影响易感HLA II类转基因小鼠的疾病发生和进展。该提案中概述的综合研究应该能够深入了解 HLA II 类基因在人类多发性硬化症的易感性、发病、进展、严重程度、调节和干预中的作用。最后，这种新的 EAE 人源化 II 类模型可能为 MS 的发病机制提供新的见解。