Role of HLA class II genes in demyelination

描述（由申请人提供）：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。我们最近在新的完全II类敲除MHCII-/-小鼠（由Benoist和Mathis生产）缺乏所有内源性II类基因的背景下，产生了人源化II类转基因小鼠（AEo）。与我们的“Abo”转基因小鼠不同，在这个新的转基因系“AEo”中，T细胞在其细胞表面表达II类，并且也可以呈递抗原。PLP91-110肽诱导HLA-DR3发生严重EAE。与DR3相比，AEo小鼠的特点是疾病发病早，疾病发病率高。土著居民的老鼠。进一步的EAE小鼠在CMS中表现出严重的炎症和脱髓鞘。因此，我们的新转基因系在T细胞上表达MHC II类和严重的中枢神经系统脱髓鞘方面模拟了人类MS。我们推测，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鞘抗原，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，我们将首先探索人类II类在疾病过程中的作用，特别强调神经功能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、再髓鞘和轴突丢失的程度，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class II在脑和脊髓不同区域以及CNS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MS/EAE发病机制和调控中的作用，因为它们在MS/EAE中既起致病作用，又起保护作用。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，我们将利用双转基因小鼠，研究DR和DQ基因的基因互补如何影响HLAⅱ类易感转基因小鼠的发病和进展。本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，这种新的人源化ⅱ类EAE模型可能为MS的发病机制提供新的认识。

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.