Differential properties of peripheral versus central nervous system (CNS) antigen-presenting cells: relevance for antigen-presenting cell T cell interactions and implications for the pathogenesis and therapy of CNS inflammation

中枢神经系统中的抗原递呈被认为在神经炎症的启动和持久中起着关键作用。越来越明显的是，小胶质细胞在对炎症刺激的反应和调节免疫反应的能力方面与外周抗原提呈细胞有很大的不同。这项拟议的项目旨在确定外周专业抗原提呈细胞(单核细胞、B细胞、分化成熟的树突状细胞)和小胶质细胞在中枢神经系统炎症中的作用方面存在的相关功能差异。该项目包括研究外周相对于中枢神经系统的抗原提呈细胞如何控制或调节自体和潜在的自身反应性T细胞的激活，以及这些发现如何与多发性硬化症的免疫发病机制和治疗相关。特别考虑到这些差异可能如何影响疾病的起始、传播和慢性化的步骤。具体地说，MHC 11类抗原处理机制、共刺激分子B7家族新成员(B7-H2(ICOS-L)/ICOS、B7-H1(PD-L1)/PD-1非PD-1、B7-DC(PD-L2)/PD1-非PD1、B7-H3/X、B7-H4(B7HS1)/BTLA-4)、免疫球蛋白家族成员和非经典MHC分子在不同抗原提呈细胞亚群上的表达和调控差异将被研究。

Antigen presentation in the CNS is thought to play a critical role in the initiation and perpetuation of neuroinflammation. It is becoming apparent that microglial cells differ considerably from peripheral antigen-presenting cells in terms of their responses to inflammatory stimuli and their abilities to modulate immune responses. The proposed project aims at defining the relevant functional differences that exist between professional antigen-presenting cells in the periphery (monocytes, B cells, differentially matured dendritic cells) versus microglial cells with respect to their contributions to CNS inflammation. The project includes the investigation of how autologous and potentially autoreactive T cell activation is controlled or modulated by peripheral versus CNS antigenpresenting cells and how these findings might be relevant for the immunopathogenesis and the therapy of multiple sclerosis. Special consideration is given to how these differences might impact the steps of disease initiation, propagation and chronicity. Specifically, differences between the expression and regulation of the MHC class 11 antigen-processing machinery, novel members of the B7 family members of costimulatory molecules (B7-H2 (ICOS-L)/ICOS, B7-Hl (PD-L1)/PD-1non-PD-1, B7-DC (PD-L2)/PD1-non-PD1, B7-H3/X, B7-H4 (B7HSl)/BTLA-4), members of the immunoglobulin family and non-classical MHC molecules on distinct antigen-presenting cell subsets will be studied.